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Answer the following medical question. | What does research say about Customized Three-Dimensional Printed Splints for Neonates in the Neonatal Intensive Care Unit: Three Case Reports.? | Critically ill neonates can be vulnerable to positional deformities and joint contractures. Early splints, along with dynamic exercise, may lead to long-term functional improvement. Making splints to perfectly contour neonates' small joints and bodies is challenging. An ill-fitted splint can lead to skin ulcers, nerve damage, poor compliance, and discomfort. Three-dimensional (3D) printing has been applied to create customized, cost-effective, and lightweight orthoses that may be promising for neonates. To explore the feasibility of scanning, designing, and printing 3D splints for neonates. A large neonatal intensive care unit (NICU) in a university teaching hospital. Case series of three neonates in a NICU who had deformities or joint contractures that would benefit from early static splints. We created customized splints for neonates using 3D scanning, digital design software, and 3D printing technology. We monitored the neonates' comfort and clinical improvement. One neonate with a congenital neck deformity had a neck splint created from 3D body-scanned images. Another neonate with a hand deformity was measured and had 3D digitally designed hand splints made. The same hand splint design was modified to fit a third neonate's hand with new measurements. All splints were 3D printed using specialized lightweight materials. The neonates tolerated the splints well. 3D printing technology is feasible for and applicable to NICU neonates. Advancing 3D technology should focus on upgrading scanning quality, improving splint design, and speeding up printing. Further research to evaluate the long-term benefits of early splinting is needed. What This Article Adds: This is the first published article to discuss the feasibility of using 3D printing technology to create customized splints for fragile neonates. Neonates, especially critically ill ones with congenital defects, may benefit from early splinting to preserve function and development. Neonates are the most challenging patients to make a perfect-fit splint for, and 3D printing may offer a potential solution. |
Answer the following medical question. | What does research say about Neonatal Resuscitation Practices in Portuguese Delivery Rooms: A Cross-Sectional Study.? | Data from previous studies have demonstrated inconsistency between current evidence and delivery room resuscitation practices in developed countries. The primary aim of this study was to assess the quality of newborn healthcare and resuscitation practices in Portuguese delivery rooms, comparing current practices with the 2021 European Resuscitation Council guidelines. The secondary aim was to compare the consistency of practices between tertiary and non-tertiary centers across Portugal. An 87-question survey concerning neonatal care was sent to all physicians registered with the Portuguese Neonatal Society via email. In order to compare practices between centers, participants were divided into two groups: Group A (level III and level IIb centers) and Group B (level IIa and I centers). A descriptive analysis of variables was performed in order to compare the two groups. In total, 130 physicians responded to the survey. Group A included 91 (70%) and Group B 39 (30%) respondents. More than 80% of participants reported the presence of a healthcare professional with basic newborn resuscitation training in all deliveries, essential equipment in the delivery room, such as a resuscitator with a light and heat source, a pulse oximeter, and an O2 blender, and performing delayed cord clamping for all neonates born without complications. Less than 60% reported performing team briefing before deliveries, the presence of electrocardiogram sensors, end-tidal CO2 detector, and continuous positive airway pressure in the delivery room, and monitoring the neonate's temperature. Major differences between groups were found regarding staff attending deliveries, education, equipment, thermal control, umbilical cord management, vital signs monitoring, prophylactic surfactant administration, and the neonate's transportation out of the delivery room. Overall, adherence to neonatal resuscitation international guidelines was high among Portuguese physicians. However, differences between guidelines and current practices, as well as between centers with different levels of care, were identified. Areas for improvement include team briefing, ethics, education, available equipment in delivery rooms, temperature control, and airway management. The authors emphasize the importance of continuous education to ensure compliance with the most recent guidelines and ultimately improve neonatal health outcomes. |
Answer the following medical question. | What does research say about Pain management in neonates.? | Multiple lines of evidence suggest an increased sensitivity to pain in neonates. Repeated and prolonged pain exposure may affect the subsequent development of pain systems, as well as potentially contribute to alterations in long-term development and behavior. Despite impressive gains in the knowledge of neonatal pain mechanisms and strategies to treat neonatal pain acquired during the last 15 years, a large gap still exists between routine clinical practice and research results. Accurate assessment of pain is crucial for effective pain management in neonates. Neonatal pain management should rely on current scientific evidence more than the attitudes and beliefs of care-givers. Parents should be informed of pain relief strategies and their participation in the health care plan to alleviate pain should be encouraged. The need for systemic analgesia for both moderate and severe pain, in conjunction with behavioral/environmental approaches to pain management, is emphasized. A main sources of pain in the neonate is procedural pain which should always be prevented and treated. Nonpharmacological approaches constitute important treatment options for managing procedural pain. Nonpharmacological interventions (environmental and preventive measures, non-nutritive sucking, sweet solutions, skin-skin contact, and breastfeeding analgesia) can reduce neonatal pain indirectly by reducing the total amount of noxious stimuli to which infants are exposed, and directly, by blocking nociceptive transduction or transmission or by activation of descending inhibitory pathways or by activating attention and arousal systems that modulate pain. Opioids are the mainstay of pharmacological pain treatment but there are other useful medications and techniques that may be used for pain relief. National guidelines are necessary to improve neonatal pain management at the institutional level, individual neonatal intensive care units need to develop specific practice guidelines regarding pain treatment to ensure that all staff are familiar with the effects of the drugs being used and to guarantee access and safe administration of pain treatment to all neonates. |
Answer the following medical question. | What does research say about The Neonatal Neurological Examination: Improving Understanding and Performance.? | The neonatal neurological examination is a cornerstone in the assessment of a neonate's neurological function. Although current neuroimaging and neurophysiology techniques have markedly improved our ability to assess and diagnose neurologic abnormalities, the clinical neurological examination remains highly informative, cost-effective, and time efficient. Early recognition of abnormal findings can prevent delays in diagnosis and implementation of beneficial therapies. The intent of this article is to improve the understanding and performance of the neonatal neurological examination. A standardized approach to neonatal neurological examination is described, including examination techniques and normal and abnormal findings. |
Answer the following medical question. | What does research say about Neonatal poisoning: causes, manifestations, prevention, and management.? | Neonates are exposed to a growing list of potentially toxic environmental and therapeutic agents. Such exposure may be through mishap, misjudgment in both drug dosage and route of administration, inadvertent misuse of medications, or improper baby care. In addition, the newborn infant may show signs of adverse reactions to a variety of drugs that are given to the mother and cross the placenta, thereby affecting the fetus before or during both labor and delivery. Because of the immaturity of the neonate's liver, lungs, kidneys, and central nervous system, the process of metabolizing and eliminating drugs and poisons is delayed. Moreover, the clinical signs and symptoms of poisoning are not always immediately recognized. Through reviewing various drugs and environmental pollutants, this article places emphasis on prevention rather than treatment. |
Answer the following medical question. | What does research say about Adverse drug reactions in neonates.? | Adverse drug reactions (ADR) are uncommon causes of admission of neonates to the neonatal intensive care unit. The neonate, however, is potentially at significant risk for adverse drug reactions because of underdeveloped mechanisms and systems for handling drugs (the Gray Baby Syndrome with chloramphenicol as a classic example), the fact that infants in neonatal intensive care units are often critically ill with multiple organ system dysfunction, that they may be on multiple drugs, and that they may present with an adverse drug reaction as a result of exposure while still a fetus. There is also a history of misadventures in the neonatal intensive care unit and newborn nurseries due to exposure to antibacterial agents that produced systemic effects from percutaneous absorption. In this review, an overview of the mechanisms of adverse drug reactions will be presented, followed by a general review of the experience of adverse drug reactions in neonates and some specific examples of current adverse drug reactions and a suggested approach for the prevention and evaluation of adverse drug reactions in neonates. |
Answer the following medical question. | What does research say about Complications associated with parenteral nutrition in the neonate.? | Parenteral nutrition (PN) is essential to the practice of neonatology. While PN is life-sustaining, it associated with a host of complications including parenteral nutrition-associated liver disease (PNALD) and central line-associated bloodstream infections (CLASBIs), which carry a high morbidity and mortality and pose a burden to the healthcare system. Evidence has emerged that the dose and composition of intravenous lipid products can alter the incidence of PNALD and CLASBIs. However, other patient- and PN-related factors, such as prematurity, birth weight, and gastrointestinal anatomy and function, must not be ignored. In order improve neonatal care, future research is still needed to optimize the content of PN and decrease the incidence PNALD and CLASBIs. Complications Associated with Parenteral Nutrition in the Neonate |
Answer the following medical question. | What does research say about Early Postnatal Outcome and Care after in Utero Exposure to Lithium: A Single Center Analysis of a Belgian Tertiary University Hospital.? | Knowledge of the impact of in utero exposure to lithium during the postnatal period is limited. Besides a possible teratogenic effect during the first trimester, exposure during the second and third trimesters might lead to neonatal effects. Uniform guidelines for postnatal management of these neonates are lacking. The aim was to retrospectively describe all neonates admitted to the University Hospitals Leuven after in utero exposure to lithium (January 2010 to April 2020), and to propose a postnatal care protocol. Descriptive statistics were performed. For continuous parameters with serial measurements, median population values were calculated. In total, 10 mother-neonate pairs were included. The median gestational age was 37 (interquartile range, IQR, 36–39) weeks. Neonatal plasma lithium concentration at birth was 0.65 (IQR 0.56–0.83) mmol/L with a median neonate/mother ratio of 1.02 (IQR 0.87–1.08). Three neonates needed respiratory support, 7/10 started full enteral (formula) feeding on day 1. The median length of neonatal stay was 8.5 (IQR 8–12) days. One neonate developed nephrogenic diabetes insipidus. This study reported in detail the postnatal characteristics and short-term neonatal outcomes. A postnatal care protocol was proposed, to enhance the quality of care for future neonates, and to guide parental counselling. Future prospective protocol evaluation is needed. Bipolar disorder is a severe psychiatric condition occurring with a lifetime prevalence of 1–2.4% [ 1 , 2 ]. The onset of the disease is around the age of 20 years, which means that women are commonly affected during their reproductive period [ 1 , 2 , 3 ]. During pregnancy and the postpartum period, the risk of a symptomatic exacerbation is elevated [ 4 ]. Pharmacotherapy for bipolar disorder (anti-epileptic drugs, lithium) during this period needs to be based on a risk/benefit analysis for both mother and fetus/child, as mentioned in different guidelines [ 5 , 6 , 7 ]. Anti-epileptics like valproate and carbamazepine are often avoided due to teratogenicity. Lithium is the first-choice treatment for bipolar disorder. It reduces manic and depressive relapse, and suicide risk [ 8 , 9 ]. Also during pregnancy and the postpartum period, lithium is proven effective, and is often used (albeit cautiously) as maintenance therapy, or to prevent postpartum psychosis [ 9 , 10 , 11 ]. Mechanisms regulating cell membrane properties, cell membrane transport, neurotransmitter regulation, ion distribution, and intracellular signalling may contribute to the mood-stabilizing action of the drug [ 12 , 13 ]. An important characteristic of lithium is its equilibration across the placenta, reported by Newport et al. with a mean infant-mother lithium ratio at delivery of 1.05 (SD 0.13) [ 14 ]. Of all psychotropic drugs, lithium has the most clearly documented teratogenic effect [ 15 ]. Although the International Register of Lithium Babies [ 16 ] suggested more than 30 years ago a marked increase in cardiac malformations including Ebstein’s anomaly, Patorno et al. later attenuated the magnitude of this effect [ 17 ]. More recently, the likely association of lithium use during pregnancy with cardiac malformation was also reported in a meta-analysis, and a large population-based cohort study, but this risk indeed remains low [ 10 , 18 ]. In contrast, the meta-analysis of Munk-Olsen et al. documented a significantly increased risk for major malformations, but not for cardiac malformations [ 15 ]. Knowledge on the impact of in utero exposure to lithium during the postnatal period is limited and mainly based on case reports or small cohorts [ 19 , 20 , 21 , 22 , 23 ]. In addition to the possible teratogenic effect associated with lithium in the first trimester, exposure during the second and third trimesters might lead to other complications [ 6 ]. Besides the increased risk of respiratory problems during the adaptation phase after birth, electrolyte disturbances, nephrogenic diabetes insipidus (NDI), hypoglycemia and thyroid dysfunctions have also been reported in the neonate [ 19 , 20 , 21 ]. Based on a retrospective analysis, Molenaar et al. recently reported on a neonatal cohort with in utero exposure to lithium, of whom most mothers had lithium levels within the therapeutic window (0.5–1.2 mmol/L) [ 9 , 23 ]. The authors observed no association between neonatal lithium blood levels at delivery and neonatal outcomes [ 23 ]. Today, uniform guidelines for medical postnatal management of the neonates exposed to maternal lithium (e.g., timing and frequency of blood sampling for electrolytes, lithium therapeutic drug monitoring (TDM), …) are lacking. To improve the postnatal care of this specific neonatal population, the aim was to retrospectively review and describe the cases admitted for this indication to the neonatal department of the University Hospitals Leuven over the past 10 years and subsequently propose a medical postnatal care protocol. In this retrospective study, all neonates with in utero exposure to lithium admitted to the neonatal intensive care unit (NICU) or medium care unit of the University Hospitals Leuven, Belgium, from January 2010 until April 2020, were included. The study was approved by the Ethics Committee of the University Hospitals Leuven (study ID S64062, approval date 5 June 2020). Eligible mother-neonate pairs were identified by two routes. First, available maternal and neonatal lithium TDM results determined during the study period were obtained from the hospital laboratory records. Second, medical files of women receiving a lithium prescription at the obstetrics or maternity ward in the study period were reviewed. Neonatal and corresponding maternal cases from whom sufficient data could be retrieved were included as mother-neonate pairs. Duplicates from the 2 searches, were removed. Clinical and laboratory data were extracted from medical records. Collected neonatal data at birth were sex (male, female), gestational age (GA, weeks), birthweight (BW, grams), APGAR scores, umbilical pH at delivery and presence of congenital malformations. Collected hospitalization data were respiratory and feeding evolution, Finnegan scores, need for neonatal abstinence syndrome (NAS) treatment, daily urine output (mL/kg/h), length of hospital stay (days), and specific biochemical data including plasma sodium (mmol/L), plasma potassium (mmol/L), total and direct bilirubinemia (mg/dL), creatininemia (mg/dL), a liver panel consisting of aspartate transaminase (AST, U/L) and alanine transaminase (ALT, U/L), glycemia (mg/dL), lithium TDM (mmol/L) and thyroid function consisting of thyroid stimulating hormone (TSH, mIU/L) and free thyroxine (FT4, pmol/L). The biochemical data were real-world data, collected during routine clinical care. No formal protocol on biochemical assessment after in utero exposure to lithium is present in our unit, except for the fact that a first lithium TDM is usually collected on the day of birth (i.e., cord blood or venous sampling). The day of birth was defined as postnatal age (PNA) day 1. Collected maternal data were medical diagnosis, relevant co-morbidities, lithium dose at delivery, lithium TDM values, concomitant medication and pregnancy complications. Lithium concentrations in serum were determined with a colorimetric endpoint reaction. From 2010–2012, Dimension RxL (Siemens, Siemens Healthcare, München, Germany) was used, from 2012 Cobas 8000 (Roche, Roche Diagnostics, Mannheim, Germany) is used with a current lower limit of quantification of 0.05 mmol/L. Descriptive statistics were performed and data were presented as median (interquartile range, IQR) or incidence. For continuous parameters with serial measurements (e.g., daily diuresis, plasma sodium, …) median values of the study population were calculated and presented graphically over time using boxplots. Analysis was performed using Excel (Microsoft Corporation, Redmond, Washington, DC, USA, Microsoft 365 version 2204) and Medcalc (MedCalc ® Statistical Software version 20.110, MedCalc Software Ltd., Ostend, Belgium). For figures, Medcalc and SPSS (IBM SPSS Statistics, version 25, IBM Corp., Armonk, NY, USA) were used. Based on the lithium TDM search, 14 mothers and 7 neonates were retrieved. The search based on lithium prescriptions led to 15 mothers and their 15 respective neonates. After matching the mother-neonate pairs, and after removing duplicates, cases missing sufficient maternal or neonatal data were excluded. With 19 mother-neonate pairs left, 9 cases in which maternal lithium therapy was interrupted during pregnancy were excluded. Finally, the study cohort consisted of 10 mother-neonate pairs ( Figure 1 ). Maternal characteristics at delivery are presented in Table 1 . The maternal diagnosis for each case was bipolar disorder ( n = 10). Median maternal TDM at delivery was 0.62 mmol/L (IQR 0.54–0.72 mmol/L). Besides hypertension ( n = 1) and intrahepatic cholestasis of pregnancy ( n = 1) as pregnancy complications, 4 cases suffering from gestational diabetes mellitus (2 of them insulin-dependent) were defined. The use of concomitant medication was present in 9/10 cases. The most frequently used medicine was levothyroxine ( n = 7). One mother was co-treated with an anti-epileptic drug (lamotrigine), and 6 mothers with antipsychotic medication (1 conventional antipsychotic: haloperidol ( n = 1), 3 atypical antipsychotics: quetiapine ( n = 3), olanzapine ( n = 2) and aripiprazole ( n = 1)), and 1 mother with the benzodiazepine lorazepam during their pregnancy ( Table 1 ). Neonatal characteristics at birth and during hospital stay are provided in Table 2 and Table 3 , respectively. The neonatal cases consisted of 6 female and 4 male neonates. The majority were born full term ( n = 7). Overall median GA was 37 (IQR 36–39) weeks. Of the 3 preterm cases (GA < 37 weeks), 1 was very preterm (GA < 32 weeks), and 2 were late preterm (GA > 34 weeks). With a median Apgar score of 9 at 5 min, most babies did not need further intervention immediately after birth. Cord blood analysis showed a median arterial umbilical pH of 7.23 (IQR 7.17–7.27). Median BW was 3000 g (IQR 2620–3440), with one neonate large for GA (BW > 90th percentile) and small for GA (BW < 10th percentile). One neonate presented with a congenital malformation, more specifically a congenital diaphragmatic hernia (CDH) ( Table 2 ). This case was also diagnosed with NDI, with a maximum diuresis of 16 mL/kg/h ( Figure 2 ). Further investigation consisted of a renal ultrasound (two normal kidneys), and a desmopressin test to exclude central diabetes insipidus. Besides one observed diuresis of 6.07 mL/kg/h limited to PNA day 2 in one neonate, diuresis of all other neonates remained below a maximum observation of 4.65 mL/kg/h. Concerning the neonatal characteristics during hospital stay ( Table 3 ), 3 neonates needed respiratory support. Two needed continuous positive airway pressure (CPAP) for 1 day, and 1 neonate needed mechanical ventilation during its hospital stay. All neonates ( n = 10) were formula fed, 7 of them started with full enteral feeding on the day of birth. After 7 days, only 1 neonate was not yet on full oral feeding. This was the neonate with the CDH. Surgical repair of the CDH was performed at PNA day 5. At PNA day 37, this neonate was transferred to another hospital, closer to the parents’ home. In Figure 3 , the incidence of cases with in utero exposure to lithium was plotted for each year of the study period. Most cases ( n = 9) presented during the last 5 years. During the first 6 years, only 1 case was included. Most neonates had an elaborated blood panel on day 1, of which the results are summarized in Table 4 . On day 1, plasma sodium, plasma potassium, creatininemia and FT4 for almost every neonate ( n = 9) were available. While glycemia and TSH were also routinely determined ( n = 10), liver panels on day 1 were rather scarce ( n = 3). One neonate was hypoglycemic on day 1, with a lowest glycemia of 20 mg/dL. Concerning available neonatal biochemical data after day 1, the timing of routine blood sampling varied between the included cases (no structured guidance on PNA and on sampling parameters). Available data on total and direct bilirubinemia, creatininemia, plasma potassium, plasma sodium, ALT, AST, FT4, and TSH of the study population during the neonatal period are provided as Supplementary Figures S1–S9 respectively. The clinical neurological short-term outcome of the neonates was assessed. For 6 cases, Finnegan scores were available from the medical files. Values ranged from 0–7, with the highest values measured during the first 3 days. The highest daily scores during the first week of life showed a declining trend in 5 out of 6 cases. Clinical neurological examinations and neonatal/maternal lithium TDM ratio at birth were assessed using nursing and medical files ( Table 5 ). The examination was normal for 5 neonates. Neonatal lithium TDM on day 1 was available for 8/10 cases, with a median value of 0.65 (0.56–0.83) mmol/L ( Figure 4 ). Median lithium TDM showed a declining trend with PNA ( Figure 4 ). Individual TDM data over time are presented in Supplementary Figure S10 . The primary aim of this retrospective study was to assess the early postnatal characteristics and short-term outcomes of neonates with in utero exposure to lithium. In total, 10 mother-neonate pairs were included. A few results caught our attention. First, 3 cases in this study population displayed hypotonia ( Table 5 ), 3 had respiratory symptoms ( Table 3 ) and 1 had hypoglycemia ( Table 4 ). Four neonates displayed a (mild) abnormal clinical neurological evaluation in the early postnatal phase ( Table 5 ). According to the literature, neonates with in utero exposure to lithium during the second and third trimesters could possibly present with lithium (adverse) effects. Neonatal lithium-related complications documented in case reports are, for example, thyroid dysfunction, cardiac arrhythmia, hepatic abnormalities, and hypoglycemia [ 8 , 9 , 14 , 18 ]. Adverse lithium effects can also present as ‘floppy infant syndrome’ [ 24 ]. Lethargy, poor sucking, tachypnea, tachycardia, respiratory distress syndrome, cyanosis and hypotonia are commonly described symptoms in the literature of neonates with in utero exposure to lithium [ 25 ]. Although causality could not be assessed due to the small sample size, these findings illustrate that indeed mild to moderate neonatal symptoms after in utero exposure to lithium have to be anticipated. Second, in this cohort, the Finnegan score was used to evaluate the presence of NAS [ 26 , 27 , 28 , 29 ]. However, the score was not used consistently during the study period, leading to missing data. This stresses the need to train nursing and medical staff to systematically apply this score to neonates at risk for NAS. It has been documented that the most effective interventions impacting the length of hospital stay for infants with NAS are the development of a staff NAS education program and the implementation of a treatment protocol [ 30 ]. Although initially designed to evaluate NAS severity due to opioid withdrawal [ 28 ], the Finnegan score is currently applied to a broader field of in utero drug exposure, due to the absence of compound-specific scoring tools [ 29 ]. Systematic scoring allows us to assess NAS severity and evolution, and to decide on initiating pharmacotherapy [ 29 ]. Third, lithium levels at birth reflect neonatal exposure. The median maternal lithium TDM at delivery in the cohort was 0.62 mmol/L (IQR 0.54–0.72 mmol/L), and the neonatal lithium TDM at birth was 0.65 mmol/L (IQR 0.56–0.83 mmol/L). This illustrates the equilibration of lithium across the placental barrier, with a median neonatal/maternal TDM ratio of 1.02 (IQR 0.87–1.08). Clark et al. reported that a lithium cord level exceeding 0.64 mEq/L has already been associated with several neonatal complications such as respiratory distress and neurological symptoms [ 31 ]. According to these findings, the delivery of a neonate with in utero exposure to lithium should be well-planned, preferably in a centre with a dedicated multidisciplinary perinatal psychosocial team with prenatal counselling, carefully monitored maternal lithium TDM, and experience in neonates with this condition [ 7 , 8 , 9 ]. Some guidelines suggest interrupting lithium therapy at the onset of labour or 24 to 48 h before induction of labour or caesarian section, to lower lithium TDM at birth to prevent neonatal adverse effects [ 6 , 31 , 32 ]. However, a therapy interruption in this period might lead to a higher risk of relapse during the postpartum period [ 33 , 34 ]. Provided that lithium TDM is strictly monitored during the perinatal period, Molenaar et al. do not recommend anymore the interruption of lithium therapy before delivery based on their recent observational study [ 23 ]. Fourth, our study population contained one neonate diagnosed with NDI. Based on the literature, this might be induced by lithium exposure during pregnancy. The underlying pathophysiology of NDI is complex and consists of different mechanisms [ 21 , 35 ]. Lithium enters the principal cells of the collecting duct through the epithelial sodium channel (ENaC, competition with sodium). There, it inhibits the action of antidiuretic hormone (vasopressin) [ 35 ]. Lithium causes a decrease in intracellular cyclic adenylate cyclase in the principal cells of the collecting tubule resulting in an inhibition of the glycogen synthase kinase-3, and subsequent decreased aquaporin 2 (AQP2) expression, leading to reduced reabsorption of water. This results in polyuria and NDI [ 36 , 37 ]. In addition, decreased sensitivity to vasopressin, increased prostaglandin signalling, and other molecular effects of lithium also cause decreased AQP2 expression, polyuria and NDI [ 38 ]. NDI in the neonate after in utero exposure to lithium has previously been described. The most important characteristics of this condition are polyuria, with normal to high serum osmolality and low urinary osmolality [ 20 , 21 , 39 ]. In our case, a maximum diuresis of 16 mL/kg/h was registered on PNA days 1–2, combined with hypernatremia (150 mmol/L), and a low urinary osmolality of 166 mmol/kg. On the same day, a neonatal lithium TDM of 0.1 mmol/L was measured. The presence of natriuresis and the transient character of the disease help to distinguish primary NDI due to mutations in the AQP2 channel and vasopressin-receptor 2 gene from lithium-induced polyuria. The most important reason to treat this condition in time is to avoid dehydration and further lithium intoxication, by replacing fluid deficits [ 39 ]. The same neonate was diagnosed with a CDH, contributing to the need for intensive care treatment, including mechanical ventilation and no full enteral feeding ( Table 3 ). Based on the neonatal characteristics of the study cohort, increased awareness of the need for postnatal monitoring and clinical observation of neonates exposed to maternal lithium is needed. Even with low exposure, neonatal effects may appear. Careful evaluation of diuresis during the first days of life should be an integral part of this follow-up. Fifth, the neonates in the study cohort all received formula feeding as lithium is contra-indicated during breastfeeding in different guidelines [ 6 , 7 , 9 , 32 , 40 ]. The drug has a relative infant dose (RID) of 0.87–30% and is classified as lactation risk category 4, indicating there is significant evidence lithium is excreted into human milk and has possible hazardous properties [ 41 ]. Lithium excretion into human milk combined with neonatal immature renal function (and subsequently increased half-life compared to adults) may lead to a risk of lithium intoxication [ 42 ]. RID values and effects on neonates vary strongly among studies [ 43 ]. Due to this high variability, most guidelines consider maternal lithium therapy during postpartum not compatible with breastfeeding. Therefore, also in our unit, formula feeding is used as a standard of care for these cases. In addition, women diagnosed with bipolar disorder are vulnerable to relapse during the postpartum period and continuation of lithium therapy is often needed. Maternal support by caregivers and relatives is important during this period, e.g., to minimize sleep deprivation [ 42 ]. However, we are aware that the discussion to breastfeed these neonates or not is a topic of interest and debate in recent literature. Imaz et al. summarized that publications not arguing against the use of lithium during breastfeeding are also available [ 44 ]. Based on their systematic review published in 2019 on clinical lactation studies of lithium, 20.5% of breastfed infants with maternal lithium use presented transient short-term adverse effects [ 44 ]. The available information was based on a small and heterogeneous number of case reports or case series, and the quality of the studies included was all less than optimal [ 44 ]. In 2021, it was documented that the median times for lithium serum concentration to reach a limit of quantification of 0.20 mEq/L in full-term neonates of mothers with lithium monotherapy, and receiving formula, mixed (formula/breastfeeding), or exclusive breastfeeding were 6–8, 7–8, and 53–60 days respectively [ 45 ]. Very recently, Heinonen et al. (2022) considered lithium during breastfeeding safe in selected cases, and under strict follow-up [ 46 ]. Although insights into the pharmacokinetics of lithium during lactation are increasing [ 47 ], further research is warranted. Finally, the incidence of cases was not evenly distributed over time. Figure 3 shows that lithium use was relatively more frequent during the last five years. A first explanation might be found in a change of clinical guidelines on antenatal management of women with bipolar disorder. Since 2014, the National Institute for Health and Care Excellence has proposed to consider the continuation of lithium during pregnancy in specific conditions [ 6 ]. Furthermore, as highlighted earlier, recent studies showed that the association between lithium use and congenital malformations is of a smaller magnitude than previously reported [ 15 , 17 ]. The slightly elevated risk of congenital malformations due to lithium use during the first trimester (4.2%), and the risk of neonatal lithium effects due to exposure in the second and third trimester, should be weighed against the high risk of maternal relapse during pregnancy and postpartum (20 to 70% over 12 months) [ 10 ]. Pregnancy is no longer an absolute contraindication to lithium use [ 6 , 32 ]. This may contribute to the higher incidence during the second half of the study period. Second, preconception and prenatal counselling consultations by the perinatal psychiatric team in our hospital started in 2014, resulting in an increase in the number of patients. The secondary aim of this study was to propose a medical postnatal care protocol for neonates with in utero exposure to lithium. Based on the characteristics and short-term outcome of the study cohort, along with literature, a proposal was drafted ( Figure 5 ), which clearly is the subject of further research. Due to the risk of postnatal symptoms, careful observation of clinical evolution, vital signs and (modified) Finnegan scoring is suggested during the first days of life. Depending on the respiratory and general status of the neonate, this can be done at a medium care unit (NICU if respiratory or other NICU support is needed). In literature, rooming-in for infants at risk for NAS from in utero opioid exposure is supported [ 48 , 49 ]. Multidisciplinary assessment of the maternal medical and psychosocial condition is needed for women suffering from bipolar disorder to decide (often case-by-case) if rooming-in is a suitable option. The availability of trained healthcare professionals for scoring, monitoring and supportive management is important. Concerning the duration of observation and supportive treatment, Smirk et al. investigated 210 neonates who received NAS treatment after in utero exposure to various drugs, predominantly opioids [ 50 ]. Within five days, they detected that 95% of the neonates with NAS symptoms required treatment [ 50 ]. Official guidelines on the duration of observation specifically applicable for neonates with in utero exposure to lithium are lacking. Molenaar et al. reported a rather high rate of neonatal complications (48.3%) after in utero exposure to lithium, and also referred to an observation period of 5 days [ 23 ]. For a drug with a high toxicity profile, such as lithium, this period seems indeed requested. During hospital stay clinical observation and the following supportive measures can be suggested: Monitoring cardiorespiratory parameters (heart rate, oxygen saturation, respiration rate) Measurement of diuresis to detect polyuria Evaluation of (risk for) NAS using the (modified) Finnegan score, every 3 to 4 h. Non-pharmacological supportive management (as part of the general NAS approach) [ 51 ]: Environmental control (swaddling, low-stimulus environment, …) Formula feeding on demand Parental education Monitoring cardiorespiratory parameters (heart rate, oxygen saturation, respiration rate) Measurement of diuresis to detect polyuria Evaluation of (risk for) NAS using the (modified) Finnegan score, every 3 to 4 h. Non-pharmacological supportive management (as part of the general NAS approach) [ 51 ]: Environmental control (swaddling, low-stimulus environment, …) Formula feeding on demand Parental education Environmental control (swaddling, low-stimulus environment, …) Formula feeding on demand Parental education Besides supportive treatment, biochemical parameters need to be evaluated ( Figure 5 ). Most relevant are lithium TDM, plasma sodium and potassium, glycemia, TSH, FT4, AST, ALT, creatininemia and bilirubinemia (total and direct). Lithium TDM sampling on day 1 can be collected from umbilical blood at birth. As derived from Figure 4 , sampling after day 1 mainly occurred on days 3–4. Imaz et al. recommend sampling at birth, after 2 days (i.e., 48 h) and 1 week postpartum for all neonatal feeding trajectories, and additionally at 1 and 2 months in case of exclusive breastfeeding during maternal lithium use [ 44 , 45 ]. In addition, if neonatal lithemia is <0.2 mmol/L, an additional measurement is only recommended in case of symptoms [ 45 ]. Since our median neonatal lithium TDM only fell below 0.20 mmol/L from day 5 ( Figure 4 ), we suggest follow-up at least until this moment, coinciding with the clinical observation period of 5 days. In summary, TDM sampling at birth, day 2–3, and day 5 is advised in our proposal. More frequent (i.e., daily) and longer (i.e., beyond day 5) monitoring of lithium TDM is relevant in case of observed or suspected (based on clinical symptoms) lithium toxicity. The need for other biochemical investigations (e.g., sepsis screening), technical investigations, as well as pharmacological NAS treatment, is based on an individual, case-by-case assessment. The local hospital protocol during the study recommended pharmacotherapy in case of a persistently elevated (modified) Finnegan score (3 times > 8), a strongly elevated score (>12), convulsions or severe dehydration. The topic of pharmacological NAS treatment will not be further discussed here but can be found in relevant reviews [ 51 , 52 ]. In the future, the proposed postnatal care protocol could be further modified according to local practices and preferences and updated considering new insights based on larger cohorts. The availability of a protocol may enhance uniformity and quality of care for future neonates with in utero exposure to lithium and can be used as a guide for parental counselling. Since in utero exposure to lithium is still relatively rare, clinical care recommendations for neonates are currently limited. Therefore, a broad range of parameters was examined providing a detailed overview of the early postnatal outcome and care of neonates in utero exposed to lithium. This evidence was supplemented with information from literature and used to develop a care proposal as a next step. However, the study approach has some limitations. First, and in spite of a study period covering 10 years in the largest Belgian University Hospital, the number of included cases still remained small. Second, no assessment was provided about long-term neonatal outcomes after in utero exposure to lithium, despite being at least as important as short-term outcomes. At present, only a few studies report on developmental outcomes. Forsberg et al. showed no significant association between mothers’ prenatal exposure to lithium or mood disorders and their offspring’s intelligence quotient [ 53 ]. Likewise, van der Lugt et al. reported no adverse effects on the growth, neurological, cognitive and behavioural development of children (3–15 years) with continuing lithium exposure during pregnancy [ 24 ]. However, both studies had a retrospective design and a small cohort [ 24 , 53 ]. The prospective studies of Schou (1976) and Jacobson et al. (1992) reported no differences in development between exposed children and controls [ 9 , 54 , 55 ], and very recently Poels et al. (2022) found no evidence for significantly altered neuropsychological functioning of children (6–14 years) with previously in utero exposure to lithium [ 56 ]. Third, the data were retrospectively collected, which means they were dependent on the quality of the registration of data in medical records. This study retrospectively reports in detail the postnatal characteristics and short-term neonatal outcomes after in utero exposure to lithium. Since one case was diagnosed with NDI, we want to raise awareness of the occurrence of this rare adverse effect in this population. Due to the low incidence of in utero exposure to lithium, multicenter data pooling and structured long-term follow-up of these neonates are needed to further increase knowledge. To support clinical practice, a clinical postnatal care protocol for neonates with in utero exposure to lithium was provided. The median neonatal lithium TDM fell below 0.20 mmol/L (i.e., the level below which TDM is only recommended if symptomatic) from PNA day 5, which coincides with the suggested clinical observation period. Although this protocol may enhance the quality of care for future neonates with this condition and can be used as a guide in parental counselling, future research, including prospective protocol evaluation, is needed. The authors thank Femke Vanwetswinkel for her input on pharmacotherapy for bipolar disorder, and Nele Van den Eede for her input on the lithium quantification method. The research activities of AS and TH are supported by the Clinical Research and Education Council of the University Hospitals Leuven. The research activities of MC are supported by the Faculty of Pharmaceutical Sciences and the Department of Pharmaceutical and Pharmacological Sciences of KU Leuven. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijerph191610111/s1 : Figure S1: Available total bilirubinemia (mg/dL) data of the study population during the neonatal period (postnatal age day 1–28) are presented as boxplots. The dots represent all individual measurements. The x -axis indicates each postnatal day on which total bilirubinemia observations are available. From day 10 to 28, all data originated from 1 patient. Figure S2: Available direct bilirubinemia (mg/dL) data of the study population during the neonatal period (postnatal age day 1–28) are presented as boxplots. The dots represent all individual measurements. The x -axis indicates each postnatal day on which direct bilirubinemia observations are available. From day 10 to 28, all data originated from 1 patient. Figure S3: Available creatininemia (mg/dL) data of the study population during the neonatal period (postnatal age day 1–28) are presented as boxplots. The dots represent all individual measurements. The x -axis indicates each postnatal day on which creatininemia observations are available. From day 9 to 28, all data originated from 1 patient. Figure S4: Available plasma potassium data of the study population during the neonatal period (postnatal age day 1–28) are presented as boxplots. The dots represent all individual measurements. The x -axis indicates each postnatal day on which potassium observations are available. From day 9 to 28, all data originated from 1 patient. Figure S5: Available plasma sodium data of the study population during the neonatal period (postnatal age day 1–28) are presented as boxplots. The dots represent all individual measurements. The x -axis indicates each postnatal day on which sodium observations are available. From day 9 to 28, all data originated from 1 patient. Figure S6: Available plasma alanine transaminase (ALT, U/L) data of the study population during the neonatal period (postnatal age day 1–28) are presented as boxplots. The dots represent all individual measurements. The x -axis indicates each postnatal day on which ALT observations are available. From day 7, all data originated from 1 patient. 3 ALT values were reported as below the limit of quantification (LOQ) of 5 and were replaced by LOQ/2 = 2.5. Figure S7: Available plasma aspartate transaminase (AST, U/L) data of the study population during the neonatal period (postnatal age day 1–28) are presented as boxplots. The dots represent all individual measurements. The x -axis indicates each postnatal day on which AST observations are available. From day 8, all data originated from 1 patient. Figure S8: Available plasma-free thyroxine (FT4, pmol/L) data of the study population during the neonatal period (postnatal age day 1–28) are presented. Due to the limited number of observations for each neonate, and the variable sampling dates, data are presented by a unique symbol for each individual. The x -axis indicates each postnatal day on which FT4 observations are available. For one neonate FT4 was reported in ng/dL (2011). Conversion to pmol/L was performed as ng/dL × 12.86. Figure S9: Available plasma thyroid stimulating hormone (TSH, mIU/L) data of the study population during the neonatal period (postnatal age day 1–28) are presented. Due to the limited number of observations for each neonate, and the variable sampling dates, data are presented by a unique symbol for each individual. The x -axis indicates each postnatal day on which TSH observations are available. Figure S10: Available neonatal lithium serum concentrations (lithium TDM, mmol/L) are presented. Due to the limited number of observations for each neonate, and the variable sampling dates, data are presented by a unique symbol for each individual. TDM observations are available until postnatal age day 8. Click here for additional data file. Conceptualization, M.T. and A.S.; Data curation, M.T. and A.S.; Formal analysis, M.T. and A.S.; Methodology, M.T., T.H., K.V.C. and A.S.; Supervision, A.S.; Writing—original draft, M.T. and A.S.; Writing—review & editing, M.T., T.H., M.C., K.V.C., C.V. and A.S. All authors have read and agreed to the published version of the manuscript. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee Research of the University Hospitals Leuven (internal study ID S64062, date of approval 5 June 2020). Patient consent was waived according to Ethics Committee Research of the University Hospitals Leuven’s approval (This project does not fall within the scope of the Law of 7/5/2004). The data presented in this study are available on request from the corresponding author. The authors declare no conflict of interest. Flowchart presenting the recruitment of the mother-neonate pairs. Detailed diuresis, expressed in mL/kg/h and assessed 12-hourly, during the neonatal period (i.e., first 28 days of life), of 1 neonate of the study cohort presenting with nephrogenic diabetes insipidus. Details on this case can be found in the text. Incidence of neonates with in utero exposure to lithium, born at the University Hospitals Leuven, during the study period. Available lithium therapeutic drug monitoring (TDM) data (mmol/L) of the included neonates are presented as daily boxplots covering postnatal age day 1 to day 8. One value reported as below the limit of quantification (LOQ), <0.05 mmol/L, was replaced by LOQ/2 = 0.025. Proposal of postnatal care management of neonates with in utero exposure to lithium. NAS: Neonatal Abstinence Syndrome, TDM: therapeutic drug monitoring, AST: aspartate transaminase, ALT: alanine transaminase, FT4: free thyroxine, TSH thyroid stimulating hormone. * In case of observed/clinically suspected lithium toxicity more frequent (daily) and longer (beyond day 5) TDM is suggested. If TDM < 0.2 mmol/L, further sampling is only recommended in case of symptoms. Characteristics of the included mothers. TDM: therapeutic drug monitoring, IQR: interquartile range, PPROM: preterm pre-labor rupture of membranes, -: not applicable. Characteristics of the included neonates at birth. F: female, M: male, GA: gestational age (only full weeks are reported), BW: birthweight; * arterial umbilical pH, ** CDH: congenital diaphragmatic hernia. Characteristics of the included neonates during their hospital stay. CPAP: Continuous Positive Airway Pressure, IMV = Invasive mechanical ventilation, -: no data available, TDM: therapeutic drug monitoring. Biochemical (blood) data on postnatal age day 1, of the included neonates. * AST: aspartate transaminase; ** ALT: alanine transaminase; *** FT4: free thyroxine; **** TSH: thyroid stimulating hormone, -: no data available. All values are provided with 2 decimal numbers. For the ALT value below the lower limit (<5.0), the lower limit/2 (=2.5) is used to calculate median and IQR. # For one neonate FT4 was reported in ng/dL (2011). Conversion to pmol/L was performed as ng/dL × 12.86. Neurological assessment and lithium neonate/mother therapeutic drug monitoring (TDM) ratio. IQR: interquartile range, TDM: therapeutic drug monitoring. Early Postnatal Outcome and Care after in Utero Exposure to Lithium: A Single Center Analysis of a Belgian Tertiary University Hospital Pregnancy outcome following in utero exposure to lithium: A prospective, comparative, observational study Bipolar Disorder Depression in Adults: Recognition and Management. Clinical Guideline [CG90] Management of bipolar disorder during pregnancy and the postpartum period The Expert Working Group Mental Health Care in the Perinatal Period: Australian Clinical Practice Guideline Antenatal and Postnatal Mental Health: Clinical Management and Service Guidance. Clinical Guideline [CG192] British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017 Lithium dosing strategies during pregnancy and the postpartum period Lithium during pregnancy and after delivery: A review Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes Clinical use of lithium salts: Guide for users and prescribers Lithium in the treatment of bipolar disorder: Pharmacology and pharmacogenetics Lithium as a Neuroprotective Agent for Bipolar Disorder: An Overview Lithium placental passage and obstetrical outcome: Implications for clinical management during late pregnancy Maternal and infant outcomes associated with lithium use in pregnancy: An international collaborative meta-analysis of six cohort studies Lithium and pregnancy. I. Report from the Register of Lithium Babies Lithium Use in Pregnancy and the Risk of Cardiac Malformations Maternal lithium use and the risk of adverse pregnancy and neonatal outcomes: A Swedish population-based cohort study Goiter in a newborn exposed to lithium in utero Case report and review of the perinatal implications of maternal lithium use Maternal lithium therapy and neonatal morbidity Nephrogenic diabetes insipidus in a preterm neonate after in utero exposure to lithium. Abstract BVK/SBP Congress (Abstract ID Neonatology K16) Management of lithium dosing around delivery: An observational study Fetal, neonatal and developmental outcomes of lithium-exposed pregnancies Neonatal toxicity and transient neurodevelopmental deficits following prenatal exposure to lithium: Another clinical report and a review of the literature Neonatal abstinence syndrome: Assessment and pharmacotherapy Neonatal abstinence syndrome Neonatal abstinence syndrome: Assessment and management Neonatal abstinence syndrome A quality improvement project to reduce length of stay for neonatal abstinence syndrome Psychotropic drug use in perinatal women with bipolar disorder Continuation versus discontinuation of lithium during pregnancy: A retrospective case series Lithium prophylaxis during pregnancy and the postpartum period in women with lithium-responsive bipolar I disorder Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus Molecular mechanisms in lithium-associated renal disease: A systematic review Nephrogenic diabetes insipidus in transplacental lithium intoxication Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder Management of antipsychotic and mood stabilizer medication in pregnancy: Recommendations for antenatal care Breastfeeding and lithium: Is breast always best? Clinical Lactation Studies of Lithium: A Systematic Review Neonatal Feeding Trajectories in Mothers with Bipolar Disorder Taking Lithium: Pharmacokinetic Data Lithium use during breastfeeding was safe in healthy full-term infants under strict monitoring Case Report: Clinical and Pharmacokinetic Profile of Lithium Monotherapy in Exclusive Breastfeeding. A Follow-Up Case Series Rooming-in for Infants at Risk of Neonatal Abstinence Syndrome Rooming-in for Infants at Risk for Neonatal Abstinence Syndrome: Outcomes 5 Years following Its Introduction as the Standard of Care at One Hospital How long should infants at risk of drug withdrawal be monitored after birth? Pharmacological and non-pharmacological treatments for the Neonatal Abstinence Syndrome (NAS) Neonatal Abstinence Syndrome: Update on Diagnostic and Therapeutic Strategies Maternal mood disorders and lithium exposure in utero were not associated with poor cognitive development during childhood What happened later to the lithium babies? A follow-up study of children born without malformations Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester The effect of prenatal lithium exposure on the neuropsychological development of the child |
Answer the following medical question. | What does research say about To Bathe or Not to Bathe: The Neonatal Question.? | After delivery, newborns go through a series of physiologic changes in an effort to adapt to extrauterine life, with preterm newborns more likely to experience medical problems following this transition. Neonatal hypothermia, defined as a temperature <36.5 °C, is a major contributor to neonatal mortality and morbidity. Early bathing may be a contributing factor to hypothermia and interfere with the premature neonate's ability to safely adapt to an extrauterine environment. Skin physiology, the physiologic changes that result from bathing, the importance of maintaining vernix for temperature stability, and how policy change and education-based programs for developmentally supportive care will be discussed in an attempt to improve patient care outcomes for neonates in the NICU. |
Answer the following medical question. | What does research say about Indications for intensive care unit treatment among neonates born to mothers with thyroid disease: A population-based cohort study.? | Thyroid diseases in pregnancy are relatively common and are associated with adverse pregnancy and perinatal outcomes, increasing a neonate’s risk of admission to the neonatal intensive care unit (NICU). The aim of this study was to evaluate the indications for increased risk of NICU admission among the neonates of hypothyroid and hyperthyroid mothers. The study data consisted of all singleton deliveries ( n = 734 773) between 2004 and 2016 in Finland collected from the Finnish Medical Birth Register. The odds of NICU admission (with 95% confidence intervals) were compared between the neonates of hypothyroid or hyperthyroid mothers and of mothers without any thyroid diseases by specified neonatal characteristics and morbidities using logistic regression analysis. The studied neonatal characteristics were preterm birth (<37+0 gestational weeks), low birthweight (<2500 g), the rate of small‐ and large‐for‐gestational age infants, and eight disease‐specific neonatal outcomes: asphyxia, respiratory distress syndrome, meconium aspiration syndrome, pneumothorax, cardiovascular problems, infections, jaundice and hypoglycemia. The most common indications for NICU care were principally the same in the neonates of the mothers with and without thyroid disease: respiratory distress syndrome, infections, preterm birth, low birthweight and neonatal hypoglycemia. The preterm neonates, neonates with low birthweight, and large‐for‐gestational‐age infants had increased odds of NICU admission if their mother had hypothyroidism. Also neonates with cardiovascular problems, jaundice or hypoglycemia associated with maternal diabetes had increased odds of NICU admissions if their mother had hypothyroidism. Further, the preterm neonates, large‐for‐gestational‐age infants, and term infants with jaundice had increased odds of NICU admission if their mother had hyperthyroidism. The most common indications for NICU care were similar for the neonates of the mothers with and without thyroid disease. However, the neonates of the mothers with thyroid diseases were more likely to need NICU care. The neonates of the mothers with thyroid diseases had higher odds of NICU treatment in cases of preterm birth, large for gestational age, and hypoglycemia. Maternal thyroid disease is associated with an increased need for neonatal intensive care. However, the reasons for neonatal intensive care unit treatment are similar for the infants of mothers with and without thyroid disease. , Turunen S , Vääräsmäki M , et al.. Marttila R Indications for intensive care unit treatment among neonates born to mothers with thyroid disease: a population‐based cohort study . Acta Obstet Gynecol Scand . 2022 ; 101 : 1093 ‐ 1101 . doi: 10.1111/aogs.14413 35778835 PMC9812201 confidence interval gestational diabetes International Statistical Classification of Diseases and Related Health Problems large for gestational age levothyroxine the Finnish Medical Birth Register neonatal intensive care unit odds ratio small for gestational age Key message Maternal thyroid disease is associated with an increased need for neonatal intensive care. However, the reasons for neonatal intensive care unit treatment are similar for the infants of mothers with and those without thyroid disease. Maternal thyroid disease is associated with an increased need for neonatal intensive care. However, the reasons for neonatal intensive care unit treatment are similar for the infants of mothers with and those without thyroid disease. Thyroid dysfunction in pregnancy is relatively common, affecting 3%–5% of pregnancies. The prevalence of hypothyroidism in pregnancy is 2%–3%, and hyperthyroidism occurs in 0.4%–1.7% of all pregnancies. 1 , 2 Both overt hypothyroidism and hyperthyroidism have been associated with an increased risk of adverse obstetrical and neonatal events, such as fetal loss, gestational hypertensive disorders and preterm births. 3 , 1 , 2 In addition, thyroid autoimmunity and subclinical hypothyroidism have been associated with pregnancy and perinatal complications. 4 , 4 , 5 , 6 Since the fetus is dependent on maternal thyroid hormones, especially in the first trimester of pregnancy, maternal thyroid disease may also adversely affect neonatal health. 7 Thyroid hormones have a significant effect on fetal brain development, as they regulate many neurobiological processes, such as neurogenesis, the grave example of this being congenital cretinism due to lack of thyroid hormones during fetal development. 8 9 In our previous studies, maternal hypothyroidism and maternal hyperthyroidism 10 were found to be associated with an increased need for neonatal intensive care unit (NICU) treatment—an association also observed in previous studies. 11 , 12 Preterm birth and low birthweight, which are both associated with maternal thyroid disease, 13 , 14 may partly explain this increased need. A recent study also reported increased odds of several specific neonatal morbidities among infants of women with thyroid diseases, including respiratory distress syndrome (RDS), sepsis and neonatal anemia. 15 However, the indications for NICU treatment among neonates of mothers with thyroid disease have not been examined previously. 12 The aim of this study was to evaluate the indications for increased admission to the NICU among neonates of hypothyroid and hyperthyroid mothers. The data in this population‐based study were collected from Finnish nationwide registers and included all singleton live births ( n = 734 773) between 2004 and 2016. The study period was chosen based on data consistency and availability. The data were obtained from the Finnish Medical Birth Register (MBR) and the Care Register for Health Care (HILMO), maintained by the Finnish Institute for Health and Welfare (THL) and the Special Refund Entitlement Register and the Prescription Register maintained by the Social Insurance Institution of Finland (Kela). Personnel at the delivery hospitals complete a structured form for the MBR that includes maternal and neonate data for all live births and stillbirths with a gestational age at birth of >22 weeks or birthweight of >500 g. The HILMO includes diagnosis information from all hospital wards at discharge and for specialized outpatient visits to public hospitals. The Special Refund Entitlement Register and the Prescription Register include information on chronic diseases, medication and reimbursement of medical expenses. The data linkage from the MBR to the other registers was performed using the unique personal identification codes assigned to all Finnish citizens and permanent residents, and these codes were encrypted before analysis. The Finnish registers used in this study are of good quality , 16 and combining them increases their usefulness and validity. 17 18 We obtained information about hypothyroidism and hyperthyroidism diagnoses before and during pregnancy from the MBR, the HILMO and the Special Refund Entitlement Register using the International Statistical Classification of Diseases and Related Health Problems (ICD) codes. In addition to inpatient data, our study contained diagnoses from outpatient hospital clinics for specialized care, diagnoses from primary care in the MBR, information on women entitled for special reimbursement due to hypothyroidism, and information on drug purchases during pregnancy. The ICD‐8 or ICD‐9 code 244 or the ICD‐10 code E03 (with all digits) and the special reimbursement code 104, denoted hypothyroidism, and the ICD‐8 or ICD‐9 code 242 or the ICD‐10 code E05 (with all digits) denoted hyperthyroidism in our study. We obtained data on thyroid medication purchases 3 months prior to and during pregnancy from the Prescription Register, which contains information on all prescription‐only medication purchases and information related to the medication (the International Anatomic Therapeutic Chemical classification code and the time and number of purchases), which is collected from all Finnish pharmacies. Use of thyroid medication was defined as purchase of levothyroxine (H03AA01), propylthiouracil (H03BA02) or carbimazole (H03BB01). Our data did not include information on treatment duration or dosage. Women were classified as hypothyroid if they had a diagnosis of hypothyroidism according to any of the registers or if they had purchased levothyroxine. They were classified as hyperthyroid if they had a recorded diagnosis of hyperthyroidism or antithyroid drug medication. The registers were also used to determine whether maternal diabetes was present. The ICD‐10 codes O24.4 or O24.9 or pathological results according to the oral glucose tolerance test were considered to denote gestational diabetes (GDM). The ICD‐8 or ICD‐9 codes 250 or 6480 or the ICD‐10 codes E10, E11, O24.0 and O24.1 and the special reimbursement codes 103, 171, 177, 215, 285 or 346 were considered to denote pre‐pregnancy diabetes. The HILMO data covered the years 1987–2016, and the Kela data for our cohort the years 2003–2016. The main outcome in our study was neonatal admission to an intensive care unit, as recorded in the MBR data. Background information on maternal demographics included age at delivery, smoking status, parity, body mass index, socioeconomic status, place of residence, diagnoses, hospitalization during pregnancy and mode of delivery. The newborn data included gestational age at birth, birthweight, diagnoses, treatment and hospitalization during the neonatal period until the age of 7 days. Gestational age at birth was primarily based on ultrasound and, when not available, on the date of the last menstrual period as registered in the MBR. If none of this information was available, the beginning of pregnancy was calculated by subtracting 280 days from the date of birth. The neonatal characteristics in this study included preterm birth <37 gestational weeks, low birthweight <2500 g, small‐for‐gestational‐age (SGA) infants (defined as birthweight less than two standard deviations of the gestational age‐adjusted mean), and large‐for‐gestational‐age (LGA) infants (defined as birthweight more than 2 SD of the gestational age‐adjusted mean). The specific neonatal morbidities investigated in this study were asphyxia, RDS, meconium aspiration syndrome, pneumothorax, cardiovascular problems, infections, jaundice and hypoglycemia. Information on preterm birth, low birthweight, SGA and LGA, as well as information on specific neonatal morbidities was extracted from the MBR. We used the ICD‐10 codes P21 for asphyxia, P22 for RDS, P24.0 for meconium aspiration syndrome, P25.1 for pneumothorax, P29 for cardiovascular problems, P36 and P39.9 for infections, P59 for jaundice, and P70 for hypoglycemia. Neonatal jaundice was further classified as jaundice in preterm (<37 gestational weeks) newborns and jaundice in term newborns (≥37+0 gestational weeks). In this study, jaundice denotes non‐hemolytic jaundice leading to phototherapy or other medical treatment. Neonatal hypoglycemia was further classified as hypoglycemia related to GDM, pre‐pregnancy diabetes or unspecified causes. The categorization of the neonates is presented in Figure 19 1 . Flow chart of the study population. The prevalence of perinatal problems and the proportion of admission to NICU care among neonates of women with or without thyroid diseases were counted by cross‐tabulation. The odds of NICU treatment (with 95% confidence intervals [CI]) were compared between the neonates of the hypothyroid or hyperthyroid mothers (exposure groups) and those of the mothers without any thyroid diseases (the reference group) for each specific neonatal feature using logistic regression analysis. The regression analyses therefore estimated, for instance, the total effect of hypothyroidism on NICU admissions on infants born preterm or on infants born with RDS. The analyses were adjusted for the following confounders: maternal age at delivery, pre‐pregnancy body mass index, smoking during pregnancy, parity, socioeconomic status based on maternal occupation during pregnancy and the catchment area of five tertiary hospitals in Finland. The missing data for explanatory categorical covariates were included as a separate category in the regression models. The children with missing data for birthweight, SGA and LGA outcomes were excluded from the analyses. We performed a sensitivity analysis to compare the neonates of the mothers who had purchased levothyroxine (LT4) medication without a recorded diagnosis of hypothyroidism with the neonates of mothers who had purchased LT4 medication and a recorded diagnosis of hypothyroidism. This supplementary analysis was performed because these groups may differ substantially; that is, women with a recorded diagnosis of hypothyroidism and LT4 medication are more likely to have overt hypothyroidism, and those who had purchased LT4 medication but had no recorded diagnosis of hypothyroidism may have subclinical hypothyroidism or a diagnosis of hypothyroidism according to pregnancy thresholds. Likewise, we also performed a sensitivity analysis on the neonates of the hyperthyroid mothers with and without antithyroid drug purchases, assuming that hyperthyroid women on antithyroid drug medication are more likely to have active hyperthyroidism than those with a hyperthyroidism diagnosis but no antithyroid drug medication. Analyses were performed using SAS Enterprise Guide 7.1 (SAS Institute Inc.). The ethical board of the Northern Ostrobothnia Hospital District approved this study on October 13, 2014 (EETTMK: 80/2014). The Finnish Institute for Health and Welfare (THL/928/5.05.00/2014 and THL/408/5.05.00/2019) and Social Insurance Institution (Kela 75/522/2014 and Kela 25/522/2019) gave permissions to access the data from the aforementioned national health registers. This is a register‐based study where study subjects were not contacted. In this study, 3.5% ( n = 25 782) of the neonates were born to mothers with hypothyroidism and 0.4% ( n = 2802) to mothers with hyperthyroidism. The mothers with thyroid disease were older and more often overweight or obese than mothers without any thyroid disease. The hypothyroid mothers smoked less and the hyperthyroid mothers were more often multiparous than the mothers without any thyroid disease (Table 1 ). The most common indications for NICU treatment both in study groups and in the reference group were RDS, infections, preterm birth, low birthweight and neonatal hypoglycemia. However, neonatal hypoglycemia associating with maternal diabetes was more common among the neonates born to mothers with hypothyroidism. In addition, infections were less common among the neonates born to mothers with thyroid diseases (Table 2 ). Demographic characteristics of the mothers with singleton pregnancies with and without thyroid diseases in Finland between 2004 and 2016 Note : The data are reported as number of mothers (%) unless stated otherwise. Neonates with or without maternal thyroid disease admitted to NICU in Finland between 2004 and 2016 Note : The data are reported as number of neonates (%) unless stated otherwise. GDM, gestational diabetes; LGA, large for gestational age; NICU, neonatal intensive care unit; SGA, small for gestational age. Altogether, 14.4% of the neonates of the women classified as hypothyroid needed NICU treatment compared with 10.2% of the neonates of the women without any thyroid disease (Table 2 ). Among the preterm neonates (OR [odds ratio] 1.35, 95% CI 1.20–1.52), the low‐birthweight neonates (OR 1.18, 95% CI 1.02–1.36) and the LGA infants (OR 1.92, 95% CI 1.67–2.20), the odds of NICU admission were increased if their mother had hypothyroidism, compared with the newborns of the women without any thyroid disease (Table 3 ). Infants with cardiovascular problems (OR 1.55, 95% CI 1.12–2.15), jaundice (preterm neonates: OR 1.36, 95% CI 1.06–1.73; term neonates: OR 1.34, 95% CI 1.16–1.54), hypoglycemia associated with GDM (OR 1.21, 95% CI 1.06–1.39) or hypoglycemia associated with pre‐pregnancy diabetes (OR 1.32, 95% CI 1.10–1.58) also had increased odds of NICU admissions if their mother had hypothyroidism (Table 3 ). Proportion and odds of neonates with or without maternal hypothyroidism admitted to NICU care in Finland between 2004 and 2016 by neonatal features Note : The odds of NICU admission with 95% confidence intervals were estimated among mothers with hypothyroidism compared to mothers without thyroid disease. GDM, gestational diabetes; LGA, large for gestational age; NICU, neonatal intensive care unit; SGA, small for gestational age. 622 children omitted from the analysis due to missing data. 623 children omitted from the analysis due to missing data. Also, the neonates of the women with hyperthyroidism were admitted to the NICU more often than the neonates of the mothers without any thyroid disease (16.5% vs 10.2%, respectively) (Table 4 ). Among the preterm neonates (OR 1.45, 95% CI 1.04–2.02) and the LGA infants (OR 3.29, 95% CI 2.12–5.13), the odds of NICU admission were increased if their mothers had hyperthyroidism. Also among the term‐born neonates with jaundice, the odds of NICU care were increased if their mother had hyperthyroidism (OR 1.97, 95% CI 1.29–3.00). The number of neonates of hyperthyroid mothers was low in our study and the results did not reach statistical significance with regard to other specific neonatal morbidities (Table 4 ). Proportion and odds of neonates with or without maternal hyperthyroidism admitted to NICU care in Finland between 2004 and 2016 by neonatal features Note : The odds of NICU admission with 95% confidence intervals were estimated among mothers with hyperthyroidism compared to mothers without thyroid disease. GDM, gestational diabetes; LGA, large for gestational age; NICU, neonatal intensive care unit; SGA, small for gestational age. 613 children omitted from the analysis due to missing data. 614 children omitted from the analysis due to missing data. The neonates of the women with both a recorded diagnosis of hypothyroidism and levothyroxine purchases had increased odds of NICU treatment because of the same indications as described in the main analysis (Tabel S1 ). Additionally, they had increased odds of NICU care if they had asphyxia (OR 1.71, 95% CI 1.19–2.46). In contrast, only the preterm neonates and the term neonates with jaundice had increased odds of NICU admission when their mother had purchased LT4 medication without a recorded hypothyroidism diagnosis (Table S1 ). Maternal hyperthyroidism without antithyroid drug medication was associated with increased odds of NICU care among the LGA infants (OR 3.78, 95% CI 2.29–6.24), the neonates with respiratory distress syndrome (OR 2.11, 95% CI 1.01–4.39) and the term neonates with jaundice (OR 1.98, 95% CI 1.21–3.24) but these associations were not observed in the hyperthyroid mothers on antithyroid medication. This was probably because only a few hyperthyroid mothers were on antithyroid medication. Maternal hyperthyroidism was associated with an increased risk of NICU admission in the preterm infants (OR 2.42, 95% CI 1.18–4.95) of the hyperthyroid mothers on antithyroid medication. Overall, the number of neonates included in the sensitivity analyses was small and our study was underpowered to investigate rare specific neonatal morbidities (Table S2 ). In our previous studies, we found that the need for NICU care was higher in the neonates of mothers with thyroid diseases than in the neonates of mothers without thyroid disease. , 10 Therefore, in this large, register‐based nationwide study, we wanted to evaluate the reasons for this difference. The main finding was that the most common indications for NICU care were principally the same in the neonates of the mothers with and without thyroid disease: preterm birth, low birthweight, respiratory distress syndrome and infections. Nevertheless, the neonates of the mothers with thyroid diseases were more likely to need NICU care. 11 Both maternal hypothyroidism and hyperthyroidism have been associated with somewhat increased risk of preterm births. , 15 , 20 In our previous work, maternal hypothyroidism was associated especially with early preterm birth (<34 gestational weeks). 21 This may explain the observed association with the increased risk of NICU care among the preterm neonates with maternal hypothyroidism. Preterm birth is globally the second most common cause of death in children under 5 years of age, 10 and preterm birth is one of the main indications for NICU treatment. In the present study, the most common indications for NICU care were preterm birth and various neonatal problems associated with prematurity, such as RDS, low birthweight and hypoglycemia. In addition, our study found an association between increased NICU admission rates and maternal hypothyroidism among the neonates with cardiovascular problems. Cardiovascular problems, such as transitional hypotension, septic or cardiogenic shock and pulmonary hypertension, are reported to be more common in preterm neonates than in term neonates. 22 Preterm birth may partly explain this observed association, but we could not study it in detail due to the small number of cases. 23 Maternal hypothyroidism has been associated with an increased risk of GDM and LGA in many previous studies. , 10 , 24 In addition, women with type 1 diabetes have a higher prevalence of thyroid diseases, as both are autoimmune diseases. 25 Increased risk of pre‐pregnancy diabetes or GDM also explains the association between maternal hypothyroidism and neonatal hypoglycemia. In this study, maternal hypothyroidism and hyperthyroidism were also associated with increased risk of an LGA infant’s admission to the NICU. LGA infants are often born to mothers with GDM or pre‐pregnancy diabetes and, accordingly, they have an increased risk of hypoglycemia, which is one of the main indications for NICU treatment. In addition, maternal hypothyroidism was associated with increased odds of NICU admission in both the term and the preterm neonates with jaundice. Jaundice is associated with hypoglycemia, preterm birth and macrosomia, 26 which are also the most probable explanations for jaundice in neonates born to mothers with thyroid disorders. 27 When the analysis was restricted to the mothers with a recorded diagnosis of hypothyroidism and purchase of levothyroxine medication, maternal hypothyroidism was found to increase the risk of a neonate with asphyxia requiring NICU admission. This risk was not observed in the mothers on levothyroxine medication with no recorded diagnosis of hypothyroidism, as determined by the recorded disease codes. Mothers with a recorded diagnosis of hypothyroidism and levothyroxine use can be considered to have more active or more severe forms of hypothyroidism than those without a recorded diagnosis of hypothyroidism. Pregnant women with levothyroxine use with no recorded diagnosis of hypothyroidism may have subclinical hypothyroidism, which is often treated during pregnancy. This difference between these two sensitivity analysis groups may explain the observed difference concerning asphyxia. To our knowledge, this is the first study to assess the risk of NICU admission for specific morbidities among neonates of mothers with thyroid dysfunction. This study is based on high‐quality data from large, nationwide health registers collected and maintained by law, so recall bias is unlikely. The MBR covers all births in Finland, since almost all mothers give birth in hospital. Information on planned home births and unplanned out‐of‐hospital births is collected separately, and information on missing cases is collected by other registers (the Central Population Register for live births and the Cause of Death Register for stillbirths and infant deaths). Combining the MBR data with the other registers increased our study’s reliability. Additionally, the large sample size enabled us to assess less frequently occurring outcomes. However, in the sensitivity analyses, the study was underpowered to investigate very rare neonatal morbidities such as meconium aspiration syndrome and pneumothorax. This study has limitations, as it contains only information available on the registers. Despite the excellent quality of Finnish registers, there were some missing data. Another limitation of the present study was the absence of laboratory tests for the mothers’ thyroid hormone or antibody status. However, this might not be a major concern, as medical treatment is typically initiated after abnormal laboratory measurements. Additionally, we were unable to collect data concerning the exact dates on which the thyroid disease diagnoses were made. A neonate may have had multiple diagnoses, but comorbidity was not studied in detail. Finally, the etiology of prematurity (spontaneous/iatrogenic) could not be studied. Our logistic regression analyses were based on NICU admissions among children having each specific perinatal problem. However, there are multifactorial reasons for NICU admission and we could not determine the kind of role that each state played. In addition, we cannot fully exclude collider‐stratification bias within our analyses, particularly on outcomes such as RDS, which is related to prematurity. 28 The neonates of the mothers with thyroid diseases were more likely to need NICU care, but the indications for NICU treatment were similar compared with the neonates of the mothers without any thyroid disease: preterm birth, low birthweight, RDS, hypoglycemia and infections. The neonates of the mothers with thyroid diseases had higher odds of NICU treatment in cases of prematurity, large for gestational age and hypoglycemia. All authors contributed to the research conception and design and to data acquisition, analysis and interpretation. ST drafted the initial version of the manuscript. The other authors revised it critically for important intellectual content and approved the final version to be published. All authors agree to be accountable for all aspects of the work and to insure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This work was supported in part by the Northern Ostrobothnia Hospital District (Dr. Turunen), the Finnish Medical Society Duodecim (Dr. Turunen), the Drugs and Pregnancy project of the Finnish Institute for Health and Welfare (THL), the Finnish Medicines Agency (FIMEA) and the Social Insurance Institution of Finland (Kela) (Prof. Gissler and Dr. Leinonen). MG and MKL report grants from the Innovative Medicines Initiative (Building an ecosystem for better monitoring and communicating the safety of medicines’ use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimized evidence generation, IMI ConcePTION, grant agreement number 821520) while conducting the study. The other authors have stated explicitly that there are no conflicts of interest in connection with this article. Table S1 Click here for additional data file. Table S2 Click here for additional data file. Indications for intensive care unit treatment among neonates born to mothers with thyroid disease: A population‐based cohort study Indications for intensive care unit treatment among neonates born to mothers with thyroid disease: a population‐based cohort study Differences in diagnostic criteria mask the true prevalence of thyroid disease in pregnancy: a systematic review and meta‐analysis Clinical aspects of hyperthyroidism, hypothyroidism, and thyroid screening in pregnancy Hyperthyroidism in pregnancy 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta‐analysis The impact of thyroid disorders on clinical pregnancy outcomes in a real‐world study setting Associations between maternal thyroid function in pregnancy and obstetric and perinatal outcomes Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child Cretinism revised best practice & research Pregnancy and perinatal outcome among hypothyroid mothers: a population‐based cohort study Maternal hyperthyroidism and pregnancy outcomes: a population‐based cohort study Neonatal outcomes and birth weight in pregnancies complicated by maternal thyroid disease Gestational thyrotoxicosis, antithyroid drug use and neonatal outcomes within an integrated healthcare delivery system Outcomes of pregnancy complicated with hyperthyroidism: a cohort study Maternal thyroid disease and preterm birth: systematic review and meta‐analysis Multi method approach to the assessment of data quality in the Finnish medical birth registry Quality of the Finnish hospital discharge register: a systematic review Nordic medical birth registers in epidemiological research New population based references for birth weight, length, and head circumference in singletons and twins from 23 to 43 gestational weeks Pregnancy complications associated with maternal hypothyroidism: a systematic review Low birth weight in children born to mothers with hyperthyroidism and high birth weight in hypothyroidism, whereas preterm birth is common in both conditions: a Danish national hospital register study Child health epidemiology reference group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000 Noradrenaline in preterm infants with cardiovascular compromise Maternal use of thyroid hormones in pregnancy and neonatal outcome The impact of maternal hypothyroidism during pregnancy on neonatal outcomes: a systematic review and meta‐analysis Hashimoto’s thyroiditis and insulin dependent diabetes mellitus: differences among individuals with and without abnormal thyroid function Characteristics of infants admitted with hypoglycemia to a neonatal unit The birth weight “paradox” uncovered? |
Answer the following medical question. | What does research say about Development, implementation, and evaluation of neonatal thermoregulation decision support web application.? | Thermoregulation is important for all age groups, and in neonates, it is considered a crucial event to adapt to extrauterine life. Therefore, using systems that provide frequent reminders in different ways in the field of thermoregulation can help thermal stability in neonates. The present study aimed to develop, implement, and evaluate a neonatal thermoregulation decision support system (DSS) as a web application. The present research was a multi-method study because it included the three phases of development, implementation, and evaluation of the neonatal thermoregulation decision support web application. In the system designing phase, the waterfall model is used. The second and third phases of the study, implementation, and evaluation, were conducted as a quasi-experimental study. The results of this study were presented in two parts: the developed web application, and the results of the evaluation of the web application. The results of the statistical tests revealed that the use of the web application had a positive and significant effect on both the adjustment of the temperature of the incubator (maintaining the neutral temperature) and the maintenance of the temperature of the neonate’s body (p = 0.000). These results indicate that a nurse’s sensitization and guidance with a neonatal thermoregulation decision support system can help to effectively neonate thermoregulation and the nurse has brought the temperature care close to the standard care based on the conditions of each neonate. The online version contains supplementary material available at 10.1186/s12911-023-02302-4. Thermoregulation is important for all age groups, and in neonates, it is considered an important event to adapt to extrauterine life [ 1 ]. It is one of the most important biological adjustments of the body [ 2 ]. Regulation of the thermal environment of neonates has long been considered one of the vital aspects of care [ 3 ]. The reasons for the increased sensitivity to thermoregulation problems in the neonate include a higher proportion of body surface to weight, more evaporation due to the immaturity of the skin, lack of subcutaneous fat tissue that acts as a temperature insulator, muscular weakness, and insufficiency of the regulation of dermal blood circulation [ 1 ]. Both hypothermia and hyperthermia exert many short-term and long-term negative effects on neonates [ 4 ] and can cause many problems, including weakness and lethargy, failure to weight gain, apnea, and even death of the neonate [ 5 ]. Despite the great advances in knowledge and equipment and supportive methods of thermoregulation, the issue of thermoregulation in neonates, especially in premature neonates, is still very challenging. In high-risk environments such as neonatal intensive care units, maintaining a neutral thermal environment is a serious challenge that can affect mortality and complications in neonates at all gestational ages [ 6 ]. The purpose of neonatal care in an incubator is to maintain a neutral temperature. A neutral temperature is a temperature that does not increase oxygen consumption and the metabolic needs of the neonate’s body [ 5 ]. Thermoregulation is a complex physiological function that is influenced by many factors. Controlling the environmental temperature is one of the main factors in regulating the body temperature of neonates [ 7 ]. Therefore, the purpose of caring for a neonate in an incubator is to help maintain a neutral temperature by controlling the environmental temperature [ 6 ]. Neonatal nurses should have the ability to recognize neonates at risk for thermal instability to prevent, quick and early diagnosis, and management of hypothermia and hyperthermia [ 5 ]; in addition, accurate monitoring of the body temperature of neonates is very important due to its relationship with the mortality and morbidity of neonates [ 8 ]. Research has shown that providing continuous training to neonate nurses and using systems that provide frequent reminders in different ways in the field of thermoregulation can help thermal stability in neonates [ 9 ]. Also using guidelines is one of the useful ways to maintain the neutral temperature of every neonate [ 6 ]. Yet, the complexity of the guidelines for neonatal thermoregulation is one of the most important challenges for nurses, because to maintain a neutral temperature, the environmental temperature of each neonate should be determined based on the daily neonatal weight and age (based on an hour or day), and then adjusted regularly based on changes in daily weight and age. In so doing, nurses must either regularly refer to the temperature adjustment guideline and adjust the temperature of their neonate’s incubator based on the guide table, which is very time-consuming, or they must memorize the adjustment temperatures for each birth weight and age, which is practically impossible. Nowadays to help in clinical decision-making based on guidelines and reduce patient safety challenges, the use of clinical decision support systems has been considered. Clinical decision support systems are a type of electronic system in clinical care [ 10 ] that are designed to support the care team members in the process of reviewing and updating new clinical evidence [ 11 ]. The need for clinical decision support systems is undeniable because most activities in the field of health care require decision-making processes [ 12 ]. In recent years, clinical decision-support systems have been increasingly considered to ensure patient safety and support all stages of clinical decision-making [ 13 ]. The studies conducted on the effectiveness of the clinical decision support systems report results such as improving process outputs like increasing the acceptance of relevant rules and principles, improving teamwork and communication, as well as saving money [ 14 ]. Moreover, the use of clinical decision support systems can improve the knowledge of health caregivers [ 15 ] and affect the quality of nursing documentation and patient safety [ 16 ]. Hence, to improve the quality of patient care and compliance with regulatory standards, it is recommended to use clinical decision support systems [ 17 ]. The noteworthy point in this context is that, despite the development of many clinical decision support systems in the field of nursing care improvement, no system has yet been designed that can help nurses in the field of neonatal thermoregulation; consequently, the present study was conducted to design, implement and evaluating the electronic decision support system for neonatal thermoregulation. The present research was a multi-method study because it included the three phases of designing, implementing, and evaluating the decision support system with each phase having its own methodology. In the system development phase, the waterfall model is used, which is one of the most famous methods of development of information technology products. The waterfall model was chosen in this study because of its special advantages: 1- It has specific steps, 2- The stages of the project can proceed in parallel, 3- From the beginning of the development of the system, the end of the work is clear, 4- It is easy to evaluate the project step by step. The waterfall model includes six interrelated stages, including 1- Requirement analysis, 2- System design, 3- Integration and testing, 4- Implementation, 5- Establishment or deployment, and 6- Maintenance [ 18 ] (Fig. 1 ). The second and third phases of the study, implementation, and evaluation, were conducted as a quasi-experimental study. Fig. 1 Thermoregulation decision support system web application development steps based on the waterfall model Thermoregulation decision support system web application development steps based on the waterfall model In this study, after approving the proposal and obtaining the code of ethics no.: IR.TUMS.MEDICINE.REC.1400.1525, the guideline about neonatal thermoregulation was derived from the latest edition of the CORE CURRICULUM FOR NEONATAL INTENSIVE CARE NURSING textbook [ 5 ], which is the main reference for neonatal nursing care. In this book, a detailed table is provided for setting the temperature of the incubator for neonates based on the neonate’s weight and age (Supplementary file# 1). Considering that the neonatal thermoregulation guideline is a 36-item table that it is not possible to memorize the nurse who wants to adjust the neonate’s temperature, and this is one of the main reasons for the inappropriate temperature management of neonates Requirement analysis: First step of waterfall model). In the next step, System design: The second step of the waterfall model؛ the content supposed to be converted into a web application was drawn on paper with full details in the form of a program (such as program pages, information on each page, how to link pages, program output, etc.); then, the paper program was converted into a web application with the cooperation of an expert computer engineer. In the next step, Implementation: the third step of the waterfall model, each of the different parts of the web application was used individually by three expert nurses for a week, and based on their opinions, fixed some little problems and entered the fourth stage of web application development: Integration and testing. In this step, the whole web application was used as a pilot study by three volunteer nurses again for a week, and using the opinions of nurses, the web application was modified and the final version of the web application was developed. In the last stage of the system development, the web application was delivered to all the nurses of the neonatal intensive care unit in a maternal and neonatal hospital, and the researchers assumed the responsibility of supporting the web application. The output of this research is a clinical decision support system as a thermoregulation web application that not only allows the nurse to set the appropriate temperature based on the specific conditions of each neonate by providing standard guidelines but also, records how to regulate the temperature of neonates, and provides the possibility of evaluating the nurse’s performance. The present research was conducted in Mahdieh Hospital in Tehran, which is a referral center for maternal and neonatal care and has two neonatal intensive care units. The researchers explained the objectives of the project to the nursing colleagues and identified the eight nurses who volunteered to cooperate, in the study. The 100 neonates were calculated as the sample size that was determined with the G Power software, considering a test power of 90% and using the study by Wang (2018) [ 19 ]. The validity of this software has been emphasized in numerous studies. After obtaining informed consent from the parents of the neonates with consideration of inclusion criteria, they were randomly divided into two control and intervention groups (Fig. 2 ). Fig. 2 CONSORT flow diagram CONSORT flow diagram The inclusion criteria for neonates in the study were: incubator care with the ability to adjust the temperature, the neonate’s not having any acute surgical condition, no phototherapy of the neonate (because the phototherapy device probably affects the thermoregulation of the neonate), no sepsis or infectious diseases, and the neonate not being in the end stages of life. The exclusion criteria were: discharge of the neonate or transferring the neonate out of the incubator before at least three temperature records for the neonate, the neonate suffering from sepsis or infectious disease during the implementation of the study. Neonates in the control group received thermoregulation care based on the hospital routine care, and the intervention group received thermoregulation routine care, and the daily neonatal temperature incubator adjustment was done based on the guidelines recommended by the web application. To minimize human error and achieve more detailed results, each neonate was assessed three times at an interval of at least 6 and most 24 h. Finally, 158 temperature records were done in the control group and 221 temperatures were recorded in the intervention group. All neonates of the control and intervention groups were cared for by the same eight volunteer nurses, and each nurse cared for at least 4 and at most 5 neonates from each of the control and intervention groups. Also, the parents were assured that if they were not satisfied, they could withdraw from participating in the study at any time or stage. 15 neonates were excluded during the study due to the exclusion criteria. The developed web application was evaluated from two aspects. First, by determining the effect of using the web application in maintaining the neutral temperature (incubator of the neonate), and maintaining the skin temperature of the neonate in the normal range, and second, by the satisfaction of the nurse users with the neonatal thermoregulation web application. It is worth noting that maintaining the neutral temperature of the neonate’s environment was one of the important points of attention in this research because this issue is usually overlooked. In fact, in many cases, the neonate maintains the body temperature in the normal range by consuming oxygen and increasing the metabolism; this shows the lack of attention to maintaining the neutral temperature of the neonate’s incubator. To evaluate the effect of the web application on the thermoregulation of neonates, a neonatal information registration checklist including gestational age, neonatal weight at the time of temperature recording, postnatal age in hours at the time of temperature recording, incubation temperature, and skin temperature of the neonate was prepared. Furthermore, the Mobile Application Rating Scale was used to evaluate the thermoregulation web application. This scale can be used to evaluate the general level of user satisfaction with all applications that are installed on mobile phones. This scale includes 5 parts and 23 items. Part A, entitled ‘Engagement’, assesses the accurate directing of users by asking 5 questions. Part B, entitled ‘Functionality’, assesses the performance of the program, easy learning, the logic of different parts of the program, and the general appearance of the software using 4 items. Part C, entitled ‘Aesthetics’, assesses the design and graphics of the program, the overall visual appeal of the program, the color scheme, and coordination and integration of the program using 3 items. Part D, entitled ‘Information’ assesses information and quality (including texts, feedback, measurements, and referrals) from reliable sources using 7 items. Part E, entitled ‘App subjective quality’ assesses issues like the possibility of recommending the program to others and buying the program, etc., using 4 items. The scoring of the scale is done using a 5-point Likert scale. Of course, each option is specified in the item. Finally, all data was entered into the SPSS version 16, and the chi-square test was used to compare the temperatures in the two control and intervention groups and to explain the nurses’ satisfaction with the neonatal thermoregulation web application the report of the overall Mean ± SD score and subscales scores of the MARS scale was used. The results of this study were presented in two parts: the developed neonatal thermoregulation web application, and the results of the evaluation of the neonatal thermoregulation web application. In the developed web application, the neonatal nurse (user) entered the system with the user’s name and password defined for her in advance. Each nurse enters the patient’s information (date and time of birth) into the system once, and then every time the patient’s name is searched, the system automatically calculates and displays the neonate’s age. The demographic characteristics of the 8 nurses participating in the study are presented in Table 1 . Table 1 Demographic characteristics of participating nurses (n = 8) Demographic characteristics Category n % Sex Female 8 100 Male 0 0 Age 22 to 27 y 4 50 27 to 32 y 2 25 32 to 37 y 2 25 Educational degree Bachelor’s degree 7 87.5 Master’s degree 1 12.5 Nursing experience 1 to 5 y 5 62.5 5 to 10 y 3 37.5 Neonatal nursing experience 1 to 5 y 4 50 1 to 5 y 4 50 Demographic characteristics of participating nurses (n = 8) Nonetheless, the daily weight of the neonate should be entered by the nurse due to the changing weight of the neonate every day. After choosing the neonate’s name and entering the daily weight, the system will show the nurse the minimum and maximum temperature that the incubator should be set to, according to the neonate’s age and weight (Fig. 3 ). Fig. 3 Calculation of the minimum and maximum temperature of the incubator based on the neonatal age and weight (Web application page) Calculation of the minimum and maximum temperature of the incubator based on the neonatal age and weight (Web application page) The nurse sets the temperature of the incubator to the suggested temperature by the system takes the skin temperature of the neonate 15 to 20 min later and records it in the system. According to the brochure of the available incubators, it takes about 5 to 10 min to reach the air incubator temperature to set the temperature incubator and also about 5 to 10 min for the skin neonate’s temperature to adjust to the air temperature, and therefore the axillary skin temperature of neonates was recorded by a digital thermometer about 20 min after setting the air temperature of the incubator. At this time, the system displays the normal range of body temperature, the chart recorded based on the previously recorded temperatures, and the necessary warnings to the nurse. For example, one downward arrow next to the recorded body temperature indicates mild hypothermia, two downward arrows indicate moderate hypothermia, and similarly, three downward arrows next to the neonate’s body temperature value indicate severe hypothermia. Similarly, hyperthermia was immediately displayed to the nurse with an upward arrow based on the recorded value (Fig. 4 ). Fig. 4 Temperature recording table with downward or arrows (Web application page) Temperature recording table with downward or arrows (Web application page) Besides, the system draws the neonate’s body temperature chart automatically and indicates the cases where the chart is higher or lower than the normal range by color (Fig. 5 ). Finally, the report of the whole process of temperature management of the neonate is displayed in the form of a PDF page with the ability to print (Fig. 6 ). Fig. 5 Neonate’s body temperature chart (Web application page) Neonate’s body temperature chart (Web application page) Fig. 6 Report of the whole process of temperature management (Web application page) Report of the whole process of temperature management (Web application page) The second part of the results was the statistical outputs, which were divided into three parts: 1- The effect of using the web application on maintaining the neutral temperature of the environment (incubator), 2- The effect of using the application on maintaining the temperature of the neonate’s body, 3- The result based on the satisfaction of the nurse users. The results of the statistical tests revealed that the use of the web application had a positive and significant effect on both the adjustment of the temperature of the incubator (maintaining the neutral temperature) and the maintenance of the temperature of the neonate’s body. In this way, no cases of hypothermia were recorded in the intervention group, and the number of cases of hyperthermia in the intervention group was less than that of the control group. Also, the use of the web application was 100% successful in maintaining the neutral temperature of the environment (Table 2 ). Table 2 Frequency distribution and percentage of body temperature and incubator (neutral temperature) in two intervention and control groups Variable Temperature classification Control group N(%) Intervention group N(%) P Value Infant temperature Hyperthermia 40(25.3) 14(6.3) 0.000** Normal 107(67.8) 207(93.7) Hypothermia 11(6.9) 0(0) Incubator temperature (Natural temperature) Hyperthermia 23(14.5) 0(0) 0.000** Normal 106(67.2) 221(100) Hypothermia 29(18.3) 0(0) ** Chi-squared test Frequency distribution and percentage of body temperature and incubator (neutral temperature) in two intervention and control groups Incubator temperature (Natural temperature) ** Chi-squared test It is worth noting that an axillary temperature less than 35.5 is defined as neonatal hypothermia and more than 37.5 degrees as neonatal hyperthermia [ 20 ]. Moreover, considering that the guidelines for adjusting the body temperature of neonates are based on the two criteria of weight and age after birth at the time of temperature adjustment, these two variables were recorded in both groups; in this regard, the control and intervention groups were not statistically significantly different (Table 3 ). Table 3 Frequency and percentage of weight and age after the birth of neonates in two control and intervention groups Variable Classification Intervention group N(%) Control group N(%) P value Neonatal age 0–96 h 35 (15.8) 26(16.5) 0.200 *** 4–14 days 71 (32.1) 74(46.8) 2–6 weeks 115 (52.1) 58(36.7) Neonatal weight Less than 1200 69 (31.2) 43(27.2) 0.257 *** 1200 to 1500 7 (3.2) 10(6.3) 1501 to 2500 108 (48.9) 78(49.4) More than 2500 37 (16.7) 27(17.1) ***Mann-Whitney U Test Frequency and percentage of weight and age after the birth of neonates in two control and intervention groups ***Mann-Whitney U Test The result was based on the satisfaction of the nurse users with the “Mobile Application Rating Scale (MARS)” Among the dimensions of the scale, the” Information” dimension had the highest mean score (29.12 ± 5.38) and the “Aesthetics” dimension had the lowest score mean score (12.25 ± 2.12). Among the subjects of the MARS scale " Target group”, “Ease of use” and “Quantity of information “, had the highest score of 36 and the lowest score was about the “Would you pay for this app?” question with a score of 18 (Table 4 ). Table 4 Satisfaction of the participating nurses with the temperature adjustment decision support system Dimensions Items Scores N(%) Total score of each item Final scores for each dimension 1 2 3 4 5 Mean ± SD Min Max Engagement Entertainment 0 (0) 0(0) 5(62/5) 1(12.5) 2(25) 29 19.63 ± 4.30 14 25 Interest 0 (0) 1(12.5) 2(25) 2(25) 3(37.5) 31 Customization 0 (0) 1(12.5) 2(25) 2(25) 3(37.5) 31 Interactivity 0 (0) 0 (0) 5(62.5) 0(0) 3(37.5) 30 Target group 0 (0) 0(0) 1(12.5) 2(25) 5(62.5) 36 Functionality Performance 0 (0) 0(0) 1(12.5) 5(62/5) 2(25) 33 17.25 ± 3.10 12 20 Ease of use 0 (0) 0(0) 2(25) 0(0) 6(75) 36 Navigation 0 (0) 0(0) 2(25) 2(25) 4(50) 34 Gestural design 0 (0) 0(0) 2(25) 1(12.5) 5(62.5) 35 Aesthetics Layout 0 (0) 0(0) 0(0%) 5(62.5) 3(37.5) 35 12.25 ± 2.12 10 15 Graphics 0 (0) 0(0) 3(37.5) 2(25) 3(37.5) 32 Visual appeal 0 (0) 0(0) 3(37.5) 3(37.5) 2(25) 31 Information Accuracy of app description 0 (0) 0(0( 1(12.5) 4 (50) 3(37.5) 34 29.12 ± 5.38 21 35 Goals 0 (0) 0(0( 3(37.5) 1(12.5) 4(50) 33 Quality of information 0 (0) 0(0( 4(50) 2(25) 2(25) 30 Quantity of information 0 (0) 0(0) 0(0) 4 (50) 4(50) 36 Visual information 0 (0) 1(12.5) 3(37.5) 1(12.5) 3(37.5) 30 Credibility 0 (0) 0(0 2(25) 1(12.5) 5(62.5) 25 Evidence base 0 (0) 0(0) 2(25) 1(12.5) 5(62.5) 25 App subjective quality Would you recommend this app to people who might benefit from it? 0 (0) 0(0) 2(25) 1(12/5) 5(62/5) 25 14.5 ± 2.97 10 17 How many times do you think you would use this app in the next 12 months if it was relevant to you? 0 (0) 0(0) 3(37.5) 5(62.5) 0(0) 29 What is your overall star rating of the app? 0 (0) 0(0) 2(25) 2(25) 4(50) 34 Would you pay for this app? 1 3 5 18 3(37.5) 0(0) 5(62.5) Total Mean ± SD Max Min 92.75 ± 14.82 112 76 Satisfaction of the participating nurses with the temperature adjustment decision support system Scores N(%) Also, to investigate the results of nurses’ satisfaction with the electronic decision support system, nurse colleagues were asked to record at least three temperature records for each neonate; yet, the results showed that in the intervention group, the number of recorded cases by the nurse was more than the predicted minimum. This suggests the attractiveness and user-friendliness of the temperature adjustment decision support system, which made the nurses check and register more than the required number for each neonate. For this reason, the number of registered cases in the intervention group was reported to be more than the number in the control group and the predicted sample size. In analyzing the results of this study, several points should be mentioned. First, in most of the studies conducted in the field of neonatal thermoregulation, attention has been paid to the prevention and treatment of hypothermia, but less attention has been paid to neonatal hyperthermia [ 21 – 23 ]. Second, more importantly, despite the existence of guidelines and frequent recommendations of references and texts, in the reviewed studies, attention to maintaining the neutral temperature of the environment for the neonate has been a missing point and in most of the conducted research, if the neonate’s body temperature is reported in the normal range, the situation is considered desirable. Thus, it has been ignored that the neonate may have maintained the body temperature in the normal range by consuming energy and oxygen due to the lack of adjustment of the neutral temperature of the environment. This problem will lead to long-term complications such as insufficient neonatal weight gain, increased length of hospital stays due to insufficient weight gain, and other similar issues [ 5 ]. Third, the temperature of the incubator is not the only factor affecting the maintenance of the body temperature of the neonate and the neutral temperature in neonates admitted to the neonatal intensive care unit; rather, other factors such as the type of incubator, the humidity of the environment, whether the incubator is close or far from heating or cooling systems, the number of times it is opened and closed, the medical and clinical status of the neonate, and the amount of skin-to-skin contact between the neonate and the mother have also been effective in this regard [ 5 ]. The fourth point is that the use of thermoregulation decision-making systems has not been considered in any of the previous studies. The results of the present study demonstrated that the use of the web application for adjusting the neonate’s temperature was effective both in maintaining the neonate’s body temperature and in maintaining the neutral temperature. This point is important because in the present study, there is not any intervention such as Kangaroo mother care or covering the neonate, etc., and only by using the application, the nurse was able to adjust the temperature of the neonate’s incubator based on the guidelines. Besides, when recording the neonate’s body temperature, abnormal temperatures were reminded to the nurses immediately and other steps of temperature adjustment were left to the clinical judgment of the nurse. These results indicate that only a nurse’s sensitization and guidance can help to effectively thermoregulate the neonate and the nurse has brought the temperature care close to the standard care based on the conditions of each neonate and the available facilities and conditions. Additionally, the results of the present study showed that the use of the web application led to the fact that the body temperature of the neonates in the intervention group was significantly better than the control group. Also, in terms of setting the temperature of the incubator (neutral temperature), in the control group, despite setting the temperature based on the initial temperature of the skin, only 67% of the incubator temperature was in the correct range based on gestational age and daily weight; but this rate was 100% in the intervention group. It is worth noting that the incidence and prevalence of neonatal hyperthermia and hypothermia have been reported very differently in the reviewed studies. For example, in the study by Yangthara et al., which was a longitudinal study performed during 2011–2015, the rate of hypothermia was 5.3 and hyperthermia was 21.4 at the time of admission of high-risk neonates [ 24 ]. In this regard, it should be pointed out that usually at the beginning of admission, neonates are not yet in a stable temperature condition. In addition, in a study conducted during 2016–2019 in the form of a longitudinal study for premature (under 37 gestational weeks) and low weight (under 2.5 kg) to determine the neonatal temperature at the time of transfer, the results showed that only 60% of the neonatal body temperature were in the normal range [ 25 ]. This amount was higher in both the control and intervention groups in the present study than in the study by Glen et al. Of course, in the present study, the neonates were all in the neonatal intensive care unit and were in all gestational age and weight groups. This, per se, can justify the difference between the results of the present study and the results of Glen’s study. In another research, all the neonates under study were healthy neonates weighing 2.5 to 3.5 kg and all were full-term, and 78.3% of the neonates were hypothermic, albeit in a mild form [ 26 ]; this result shows the importance of temperature management and monitoring even in healthy, full term, and normal weight neonates. Perez et al. in their study found that the thermoregulation of VLBW (Very Low Birth Weight) neonates is done as routine care for all neonates regardless of other factors such as weight and gestational age [ 4 ]. This was an important point that was carefully considered in the present study using the web application for neonatal thermoregulation. In addition, in most of the studies conducted in the field of thermoregulation of neonates, the focus has been on the cases of hyperthermia or hypothermia. For example, in the field of neonatal hyperthermia, Amadi et al.‘s study showed that 35% of neonates had hyperthermia, and the results of this study also showed that neonatal hyperthermia is related to infant mortality [ 27 ]. In another study conducted in 2022, 3.3% of neonates in the neonatal intensive care unit suffered from hyperthermia [ 28 ]. The difference in the prevalence and occurrence of hyperthermia can indicate the effect of monitoring, controlling, and appropriate nursing interventions on reducing neonatal temperature instability regardless of any demographic factors such as gestational age, the condition of the neonate, weight, etc. Additionally, in a study conducted to implement a quality improvement project in the neonatal intensive care unit, about 90% of neonates had some degree of hypothermia before the intervention, which significantly decreased after the implementation of the quality improvement program [ 29 ]. In the same line, in another study (2017), also conducted on quality improvement, 50% of neonates had hypothermia before the implementation of the project, and after 4 periods of implementing the quality improvement process, 100% of neonates were within the normal temperature range [ 30 ]. Thus, it appears that the use of electronic decision support systems similar to the temperature adjustment decision support system used in the present study also can be used in all care fields as a quality improvement project. These results indicate that a nurse’s sensitization and guidance with a neonatal thermoregulation decision support system can help to effectively neonate thermoregulation and the nurse has brought the temperature care close to the standard care based on the conditions of each neonate. Also, the results of this study have demonstrated that the use of clinical guidelines, especially in cases where critical care is involved, yields very favorable outcomes in improving the quality of care. On the other hand, electronic and web-based clinical decision support systems can serve as reliable assistants, contributing to both the enhancement of patient care quality and the satisfaction of users(personnel), particularly in clinical settings with severe human resource constraints and limited time for continuous staff training. In the present study, the quasi-experimental method of conducting the research and the small number of nurses who volunteered to participate in the research were the limitations of the study, which can make it difficult to generalize the results. Below is the link to the electronic supplementary material. Supplementary File 1 . Neutral Thermal Environmental Temperatures guideline Supplementary File 1 . Neutral Thermal Environmental Temperatures guideline Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We would like to thank all participants who participated in the study, the authorities of the study setting who provided permission for conducting the study, and all the people who helped us throughout the study. RB, MV, and RN were involved in the conception and design of this study. ERM and MV collected information, and MMS performed the analysis. MV, RB, RN and MH interpreted the results. RB, MV and MH drafted the manuscript, and all authors contributed to writing the final draft and approved the final manuscript. This study was approved by the Nursing and Midwifery Care Research Center of Tehran University of Medical Sciences, Tehran, Iran (code: 55200) and was financially supported by the Tehran University of Medical Sciences. The authors state that the funding body did not play any role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The designed web application can be accessed at the https://thermo.ehms.ir address in any type of browser. The admin’s web application username and password will be sent to you to view different parts of the application. User name: Maryam/Password: 13,441,357. When you enter the web application by clicking on the flag icon, the language of the web application will be changed to English. You can view all parts of the web application based on what is explained in the article. Of course, because this web application was designed and implemented in Iran, the information about the patients is included in the Persian part of the web application. The statistical data was sent to you as part of the research data. The Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran, approved the study (code: IR.TUMS.MEDICINE.REC.1400.1525). The authors declare that the study’s aim and methods were explained to all nurses who participated in the study. All authors declare that all methods were carried out by relevant guidelines and regulations. The authors declare the ethical approval and statement on informed consent. Informed consent was obtained from all the study participants and informed consent was obtained from the parents of neonates for the study. Not applicable. The authors declare no competing interests. Development, implementation, and evaluation of neonatal thermoregulation decision support web application Surface body temperature of full-term healthy newborns immediately after Birth—Pilot study Mothers’ knowledge and practices on thermoregulation of neonates in SriLanka Core concepts: thermoregulation in the newborn, part II: prevention of aberrant body temperature Target body temperature in very low birth weight infants: clinical consensus in place of scientific evidence NANN’s Thermoregulation in the care of Infants Guideline for Practice Executive Summary A study to assess the knowledge and practice of staff nurses regarding Thermoregulation of Neonates selected hospital at Mysuru Role of effective thermoregulation in premature neonates Use of academic electronic medical records in nurse education: a scoping review CDSS-RM: a clinical decision support system reference model Decision support and patient safety Effects of a skill demonstration video delivered by smartphone on facilitating nursing students’ skill competencies and self-confidence: a randomized controlled trial study A systematic review of the implementation of electronic nursing documentation toward patient safety Electronic health records and use of clinical decision support A design science research methodology for information systems research Using polyethylene plastic bag to prevent moderate hypothermia during transport in very low birth weight infants: a randomized trial The global burden of neonatal hypothermia: systematic review of a major challenge for newborn survival Prevalence of pneumonia and its associated factors among under-five children in East Africa: a systematic review and meta-analysis Delivery room interventions for hypothermia in preterm neonates: a systematic review and network meta-analysis Improving thermoregulation in transported preterm infants: a quality improvement initiative Assessment of Hypothermia and the Thermoregulation measures received by neonates of a selected Medical College and Hospital, West Bengal Neonatal hyperthermia and thermal stress in low-and middle-income countries: a hidden cause of death in extremely low-birthweight neonates Association between admission temperature and mortality and major morbidity in very low birth weight neonates–single center prospective observational study The impact of a quality improvement project to reduce admission hypothermia on mortality and morbidity in very low birth weight infants Use of Plan-Do-Study-Act cycles to decrease incidence of neonatal hypothermia in the labor room |
Answer the following medical question. | What does research say about Interpretation of clotting tests in the neonate.? | There are significant differences between the coagulation system in neonates compared with children and adults. Abnormalities of standard coagulation tests are common within the neonatal population. The laboratory tests of activated partial thromboplastin time (aPTT) and prothrombin time (PT) were developed to investigate coagulation factor deficiencies in patients with a known bleeding history, and their significance and applied clinical value in predicting bleeding (or thrombotic) risk in critically ill patients is weak. Routine screening of coagulation on admission to the neonatal intensive care unit leads to increased use of plasma for transfusion. Fresh frozen plasma (FFP) is a human donor plasma frozen within a short specified time period after collection (often 8 h) and then stored at -30°C. FFP has little effect on correcting abnormal coagulation tests when mild and moderate abnormalities of PT are documented in neonates. There is little evidence of effectiveness of FFP in neonates. A large trial by the Northern Neonatal Nursing Initiative assessed the use of prophylactic FFP in preterm infants and reported no improvement in clinical outcomes in terms of mortality or severe disability. An appropriate FFP transfusion strategy in neonates should be one that emphasises the therapeutic use in the face of bleeding rather than prophylactic use in association with abnormalities of standard coagulation tests that have very limited predictive value for bleeding. |
Answer the following medical question. | What does research say about Congenital chylothorax: associations and neonatal outcomes.? | Congenital chylothorax is a rare but significant neonatal entity with major morbidity and mortality. The study aims to describe the related associations, management and outcomes of this condition in neonates. This is a retrospective case series of all cases of congenital chylothorax admitted to a tertiary neonatal centre in the last 15 years. Ten cases of congenital chylothorax were identified. Eight infants were diagnosed antenatally and three infants had antenatal pleural drainage. Most infants were ventilated at birth and required immediate pleurocentesis. Post-natal management included drainage of fluid, ventilation, albumin replacement, octreotide and dietary modification with medium-chain triglyceride-enriched formula. Five infants had chromosomal aberrations identified, while a further two had dysmorphic features not substantiated with routine genetic testing. Noonan's syndrome was the single most common underlying genetic diagnosis. Associated anomalies and malformations were present in 80% of the cohort. There were two deaths in the series, both in infants with multiple co-morbidities. Congenital chylothorax is a rare condition with overall prevalence of less than a case per year in our experience. Majority of infants had associated chromosomal anomalies and significant co-morbidities needing prolonged intensive care. |
Answer the following medical question. | What does research say about Pharmacokinetics of cephalosporins in the neonate: a review.? | The aim of this work was to review the published data on the pharmacokinetics of cephalosporins in neonates to provide a critical analysis of the literature as a useful tool for physicians. The bibliographic search was performed for articles published up to December 3, 2010, using PubMed. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum was consulted. The cephalosporins are mainly eliminated by the kidneys, and their elimination rates are reduced at birth. As a consequence, clearance is reduced and t 1/2 is more prolonged in the neonate than in more mature infants. The neonate's substantial body water content creates a large volume of distribution (Vd) of cephalosporins, as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, the clearance of cephalosporins increases. The maturation of the kidney governs the pharmacokinetics of cephalosporins in the infant. Clearance and t 1/2 are influenced by development, and this must be taken into consideration when planning a cephalosporin dosage regimen for the neonate. Cephalosporins are the most common class of antibiotics used to treat bacterial infection. These drugs have proven to be safe, clinically effective, and easy to use. 1 , 2 The expanded-spectrum cephalosporins (e.g., cefotaxime, ceftriaxone, and ceftazidime), either alone or in combination with other antibiotics, are the most common antibiotics used as initial empiric therapy for treating serious infections. 3 The first generation of cephalosporins has good activity against Gram-positive bacteria and relatively modest activity against Gram-negative bacteria. The second generation of cephalosporins has increased activity against Gram-negative microorganisms but tends to be much less active than the third-generation agents. The fourth generation of cephalosporins is particularly useful for the empirical treatment of serious infections in hospitalized patients when Enterobacteriaceae and pseudomonas are potential etiologies. 4 Cephalosporins are minimally toxic, with the exception of ceftriaxone, which displaces bilirubin from albumin 5 , 6 and precipitates calcium, resulting in serious adverse effects. 7 , 8 The aim of this paper was to review the literature on the kinetics of cephalosporins in the neonate and provide a critical analysis of the literature as a useful tool for physicians. The bibliographic search was performed electronically, using PubMed to find articles published up to December 3, 2010. First, a Medline search was performed with the key words “pharmacokinetics of cephalosporins in neonates," with the limit of “human”. Other Medline searches were performed with the key words “pharmacokinetics of ……… in neonates,” followed by the names of single cephalosporins. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum 9 was consulted. The bibliographic search produced 37 original articles, four review articles and two book chapters. The publication years of this material ranged from 1977 to 2010. The demographic data for the neonates and the pharmacokinetic parameters of different cephalosporins are presented in four tables. Information relative to the first-generation cephalosporin, cefazolin, and the second-generation cephalosporins, cefoxitin, and cefuroxime, is provided in Table 1 . Table 2 summarizes the results relative to the third-generation cephalosporins. Table 3 shows the results relative to cefepime, a fourth-generation cephalosporin, and Table 4 shows the concentrations of various cephalosporins in the cerebrospinal fluid (CSF) and serum. Clearance (Cl) is expressed in different units by different authors. This makes comparisons between studies difficult. To overcome this difficulty, Cl was converted into ml/min/kg. SD cannot be converted; therefore, Cl values are reported without SDs. The pharmacokinetics of cefazolin ( Table 1 ) in 11 neonates were studied by Deguchi et al. 10 There was marked interindividual variability in the distribution volume (Vd). This parameter ranged from 0.21 to 0.37 L/kg. The unbound fraction of cefazolin in neonatal plasma ranged from 0.22 to 0.83. The Vd of cefazolin highly correlated (r = 0.936; p <0.001) with the unbound fraction of this drug. Young and Mangum 9 suggested administering 25 mg/kg cefazolin every 8 to 12 h according to the neonate's postmenstrual age and postnatal age. When the postmenstrual age is >45 weeks, the interval between doses should be six hours. Regazzi et al 11 studied the pharmacokinetics of cefoxitin in 15 neonates. Their reported kinetic parameters are summarized in Table 1 . The half-life (t 1/2 ) negatively correlated with postnatal age (r = -0.58; p <0.05). Young and Mangum 9 suggested administering 25 to 33 mg/kg cefoxitin every 8 to 12 h according to the neonate's postmenstrual age and postnatal age. When the post-menstrual age is >45 weeks, the interval between doses should be six hours. Renlund and Pettay 12 studied the pharmacokinetics of cefuroxime in 104 neonates, and their reported kinetic parameters are summarized in Table 1 . The serum concentration of cefuroxime decreased with body weight from 25.6±9.9 µg/ml (<1 kg body weight) to 19.5±6.8 µg/ml (>4 kg body weight) because of the increase in GFR with neonatal maturation. t 1/2 showed similar behavior, decreasing from 5.6 h (2.83 kg body weight) to 4.0 h (3.83 kg body weight). Cefuroxime did not accumulate over a period of 8 days and was excreted in the urine by more than 70%. The kinetic parameters of cefotaxime are summarized in Table 2 . Kafetzis et al 13 described treating infections with cefotaxime in 32 neonates. The pathogens that sustained the infection were Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia marcescens Staphylococcus aureus, Staphylococcus epidermidis, and β-hemolytic streptococcus. All of the isolated pathogens were susceptible to cefotaxime. These authors clustered the pharmacokinetic parameters of cefotaxime into four groups according to the neonates' gestational age and postnatal age. With neonatal maturation, t 1/2 decreased and Cl increased. For brevity, Table 2 shows the two extremes of the cohort. In five patients with meningitis who received 50 mg/kg cefotaxime twice daily, the concentration of the drug was simultaneously measured in the CSF and serum 1 to 2 h after cefotaxime administration. The CSF and serum concentrations (mean±SD) were 18.2±7.4 and 38.6±10.3µg/ml, respectively. The CSF-to-serum ratio was 45±0.12%. McCracken et al 14 compared the kinetic parameters of cefotaxime in two groups of neonates; the first had an average body weight of 1,103 g, and the second had an average body weight of 2,561 g ( p <0.0001). Vd and t 1/2 were greater in the former than the latter group, whereas Cl was greater in the latter group and AUC was not different in the two groups. Cefotaxime is converted into desacetyl cefotaxime in the neonate, and the peak concentration of desacetyl cefotaxime is about one-tenth of that of cefotaxime. 15 - 17 The t 1/2 of desacetyl cefotaxime is 9.4 h in very low-body-weight neonates. 18 After 50 mg/kg cefotaxime, 50 to 60% of the dose is excreted unchanged in the urine, and approximately 20% is excreted as desacetyl cefotaxime. 18 The renal Cl of cefotaxime is quantitatively more important than its metabolic Cl. Gouyon et al 15 observed that the t 1/2 of cefotaxime was negatively correlated with gestational age (r = -0.8954; p <0.01) and body weight (r = -0.8500; p <0.01). In contrast, Cl was positively correlated with gestational age (r = 0.7280; p <0.02) and body weight (r = 0.8667; p <0.02). The AUC of cefotaxime was negatively correlated with gestational age (r = -0.7950; p <0.01), but it did not correlate with body weight. One recent study examined cefotaxime in neonates undergoing extracorporeal membrane oxygenation (ECMO). 19 Doses of 50 mg/kg of body weight twice a day (postnatal age <1 week), 50 mg/kg three times a day (postnatal age 1 to 4 weeks) or 37.5 mg/kg four times a day (postnatal age >4 weeks) were found to provide sufficient periods of supra-MIC concentrations to give adequate treatment of infants on ECMO. Young and Mangum 9 suggested intravenously administering 25 to 33 mg/kg of cefotaxime every 8 or 12 h according to the postmenstrual age. When the postmenstrual age is >45 weeks, the interval between doses should be six hours. The pharmacokinetic parameters of ceftazidime are summarized in Table 2 . The ceftazidime concentration was measured after intravenous administration to seven neonates and after intramuscular administration to 9 infants. 20 Ceftazidime concentrations after intravenous injection declined biexponentially, and the postdistributive phase occurred 30 to 60 min after administration. The peak ceftazidime concentration was 109±19.9 (intravenously) and 53.0±22.4 (intramuscularly; p <0.05). The t 1/2 of ceftazidime was 4.7±1.5 (intravenously) and 3.8±1.1 (intramuscularly; NS). McCracken et al 21 described the pharmacokinetics of ceftazidime in three groups of neonates with gestational ages of ≤32, 33-37, and ≥38 weeks. Cl increased with gestational age, whereas t 1/2 , AUC and the trough concentrations decreased with gestational age. Blumer et al 22 described ceftazidime's pharmacokinetics and penetration into CSF in ten children aged 12 to 540 days. Ceftazidime at 50 mg/kg was intravenously administered once per day. The t 1/2 of ceftazidime was 1.8±0.8 h, which was 2- to 4-fold lower than that reported in neonates during the first week of life (see Table 2 ). The two youngest children, aged 12 and 23 days, had a t 1/2 of 3.6 and 2.18 h, respectively. The Cl of ceftazidime varied by more than 300%; such a large variation makes it inappropriate to report the average Cl, so the data from Blumer et al 22 are not shown in Table 2 . In contrast, Vd showed little variation and ranged from 0.27 to 0.38 L/kg, with a mean±SD of 0.34±0.07 L/kg. The ceftazidime concentrations in the CSF and serum were 4.7±2.5 and 145±30.4 µg/ml, respectively. The CSF-to-serum concentration of ceftazidime was 3.5±1.8%. The ratio of CSF to serum ceftazidime concentration showed a time-dependent increase, suggesting that ceftazidime was eliminated more slowly from the CSF than from the vascular compartment. The MIC of the isolated pathogens ranged from 0.0156 µg/ml (Neisseria meningitidis) to 0.125 µg/ml (Haemophilus influenzae, Type B). Prenatal exposure to indomethacin resulted in significantly lower GFR and ceftazidime Cl values. 23 The Cl of ceftazidime was 0.46 ml/min/kg (n = 23) in neonates who were prenatally exposed to indomethacin and 0.68 ml/min/mg (No = 84) in infants who were not exposed to indomethacin ( p <0.05). The Cl of ceftazidime increased with gestational age (r = 0.83; p <0.001), whereas t 1/2 showed an opposite trend (r = -0.54; p <0.001). 23 The positive relationship between the Cl of ceftazidime and the Cl of inulin (r = 0.73; p <0.001) indicated that glomular filtration had an important effect on the Cl of ceftazidime. The Cl of ceftazidime correlated with the reciprocal of the serum concentration of creatinine (r = 0.72; p <0.001), suggesting that this compound may interfere with the renal Cl of ceftazidime. The ceftazidime Cl increased from days 3 to 10 of life 24 ( Table 2 ). Such increases are due to an increase in GFR. The inulin Cl was 0.72 (day 3) and 0.91 ml/min (day 10; p <0.05). The Cl of ceftazidime correlated with GFR (r = 0.81; p <0.001). This correlation indicates the important role of GFR in the clearance of ceftazidime. The Vd of ceftazidime decreased between days 3 and 10 of life. During the first week of life, there was a significant decrease in extracellular water. Ceftazidime is mainly distributed in the extracellular water component, and a decrease of extracellular water may cause a decrease in the Vd during this period. Postnatal exposure to indomethacin prevented the pharmacokinetic modification seen from days three to ten of life. This may be explained by renal function's dependence on postnatal changes in extracellular water 24 and the GFR impairment associated with indomethacin use. Once-daily versus twice-daily administration of ceftazidime was studied by van den Anker et al. 25 After 25 mg/kg twice daily, the trough concentration of ceftazidime was 42.0±13.4 µg/ml, which was higher than the target value of 10 µg/ml. After once-daily dosing, the trough concentration was 13.1±4.7 µg/ml, higher than the target value of 10 µg/ml and higher than major neonatal pathogen MIC 99 values such as those for Streptococcus agalactiae and Escherichia coli 26 , 27 (MIC 99 <0.25 µg/ml). Therefore, these authors suggested that once-daily 25 mg/kg ceftazidime is the appropriate therapeutic schedule for ceftazidime in the neonate. This administration schedule conflicts with the one suggested by Young and Mangum. 9 They suggested administering 30 mg/kg of ceftazidime every 8 or 12 h according to the postmenstrual and postnatal age. When the postmenstrual age is ≥45 weeks, ceftazidime should be administered every eight hours. Ceftriaxone is contraindicated in neonates because it displaces bilirubin from albumin binding sites, resulting in a higher free bilirubin serum concentration with subsequent accumulation of bilirubin in the tissues. 5 , 6 Even more dangerous is ceftriaxone's interaction with calcium. This interaction precipitates calcium, which results in serious adverse effects. 7 , 8 Nonetheless, the literature on ceftriaxone was reviewed to provide a comprehensive study of cephalosporin use. The kinetic parameters of ceftriaxone are summarized in Table 2 . The MIC 90 of ceftriaxone ranged between 0.06 and 2 µg/ml for Escherichia coli, Klebsiella species, Proteus species, Enterobacter species, and Staphylococcus aureus, whereas Enterococci and Listeria monocytogenes are resistant. 28 Ceftriaxone reached CSF concentrations of 5.4 and 6.4 µg/ml after intravenous doses of 50 and 75 mg/kg, respectively, and the CSF-to-peak serum concentration was 2.2-2.3%. 29 Sixty percent of ceftriaxone is eliminated by the kidneys, and Mulhall et al 30 have described the pharmacokinetics of this drug in the neonate ( Table 2 ). McCracken et al 31 stratified the kinetic parameters of ceftriaxone based on neonatal body weight. The longest t 1/2 , 7.7 to 8.4 h, was found in neonates weighing ≤1,500 g, compared with 5.2 to 7.4 h in those weighing >1,500 g. The shortest t 1/2 (3.5 and 4.8 h) was found in two neonates aged 45 to 33 days, respectively. Vd ranged between 0.50 and 0.61 l/kg; the smaller value was found in larger and older infants. Of nine neonates who received multiple ceftriaxone doses of 50 mg/kg every 12 h, five showed evidence of drug accumulation in the plasma. The concentrations of ceftriazone increased from 20 to 208% (mean 82%) at 0.5 h and from 15 to 165% (mean 53%) at 6 h after dosing. The ceftriaxone concentration in randomly collected urine ranged from 113 to 3,350 µg/ml (median 618 µg/ml). Young and Mangum 9 suggested administering 50 mg/kg every 24 h. To treat meningitis, they suggested a 100-mg/kg loading dose and then 80 mg/kg once daily. The kinetic parameters of cefoperazone are summarized in Table 2 . Gestational age correlated with Cl (r = 0.67; p = 0.01) and with a constant rate of elimination 32 (Ke; r = 0.57; p = 0.05), while t 1/2 decreased with advancing gestational age 33 (r = -0.81; p <0.001). Rosenfeld et al 34 studied the pharmacokinetics of cefoperazone (50 mg/kg) in 25 infants with a postnatal age of 1 to 2 days. The neonates were divided into three groups according to their gestational age. These authors repeated the cefoperazone treatment in 14 neonates aged 5 to 7 days, and the kinetic parameters were similar to those obtained at a postnatal age of 1 to 2 days. The percentage of the cefoperazone dose excreted in the urine on days 1 and 2 after birth was highest in the most premature patients (55%) but was not statistically different from that of full-term infants (37%). In infants 5 to 7 days old, cefoperazone excretion decreased in the full-term neonates (27%) and was 55% in the most premature infants ( p <0.03). These data suggest that cefoperazone is partially metabolized and that its rate of metabolism depends on neonatal maturation. In adults, 69% of cefoperazone administered orally is eliminated by hepatic routes. 35 A study based on seven neonates with body weights ranging from 1,540 to 3,600 g determined that cefoperazone penetrates the CSF. 34 The cefoperazone concentration (µg/ml) in the CSF and serum was 5.3±3.6 and 89±58, respectively. The CSF-to-serum ratio was 10.9±9.6% and ranged from 1.4 to 31.7%. The kinetic parameters of ceftizoxime are summarized in Table 2 . The pharmacokinetics of ceftizoxime were studied in 52 infants whose postnatal age ranged from 0.1 to 189 days. 36 t 1/2 diminished steadily as the postnatal aged increased, whereas Cl showed the opposite trend. In this study, Vd remained relatively constant 37 , and ceftizoxime was excreted essentially unchanged via the kidney. 36 The kinetic parameters of cefepime are summarized in Table 3 . The serum creatinine concentration was negatively correlated (r = -0.79) with cefepime Cl in neonates. 38 The serum concentration of creatinine was a strong predictor of cefepim Cl. 38 The relationship between cefepime Cl and gestational age was not significant. The maturation of the renal excretory function is an important dosing determinant for cephalosporins, including cefepime. In premature infants, renal function is impaired. Because cefepime is mainly excreted unchanged, the premature and term neonates clear cefepime more slowly than more mature infants. In neonates, the cefepime Cl value was approximately 40% of that of more mature infants, which results in a longer t 1/2 and a higher trough concentration. Vd was greater in infants with less than 30 weeks of postconceptional life. 38 This is consistent with the greater total body water content in the extremely premature neonate. Reed et al 39 described the pharmacokinetics of cefepime in 37 infants and children aged between 2 months and 16 years. The data were grouped by age; the youngest patients ranged between two and six months of age, and the pharmacokinetic parameters of cefepime in these patients are reported in Table 3 . Ninety percent of cefepime was recovered in the urine during 24-h urine collection; thus, the elimination of cefepime is in large part via the kidneys. The data for cefepime reveal disposition parameters similar to those of third-generation cephalosporins, including linearity over a broad dose range (250-2,000 mg), limited disposition and Cl mainly by the kidneys. Lima-Rogel et al 40 compared their own results on the pharmacokinetics of cefepime in neonates with those of Capparelli et al 38 and Reed et al. 39 The kinetic parameters of cefepime measured by Lima-Rogel et al 40 and those of Capparelli et al 38 were obtained in infants with similar demographic data, and t 1/2 and Cl were comparable in these two studies. Reed et al 39 described the pharmacokinetics of cefepime in older infants and children. In this last study, t 1/2 was one-half and Cl was double the values in the neonates. Information on the penetration of cephalosporins in the CSF is limited. Table 4 summarizes the concentrations of cefotaxime, ceftazidime, ceftriaxone, cefoperazone, and cefepime in the CSF and serum and the CSF-to-serum ratio. Information on the penetration in the CSF is available only for these cephalosporins. A relevant CSF-to-serum ratio was observed for cefotaxime 13 and it was 45±12%. Another relevant penetration rate in the CSF was observed for cefoperazone, 34 which was 10.9±9.6%. This figure seems to be overestimated, as it ranged from 1.4% to 37.1%. The rate of penetration of cefepime in the CSF was variable. In two preterm infants, the CSF-to-serum ratio was 30% and 87%, whereas in 7 term infants, it ranged from 3.6% to 59%, with a mean±SD of 16.7±21.4%. Table 4 shows the data for all nine neonates. A common feature in the reviewed literature is the remarkable interindividual variability of the kinetic parameters of cephalosporins in the neonate. Such variability is due to renal maturation, as cephalosporins are fairly water soluble and are mainly eliminated with the urine. The pharmacokinetic parameters of cephalosporins are development dependent; the t 1/2 of cefotaxime, 13 , 14 ceftazidime 24 - 26 and ceftizoxime 37 decrease with increasing gestational and postnatal age, whereas Cl shows an opposite trend. With prenatal and postnatal maturation, GFR increases, and consequently, the Cl of drugs that are mainly eliminated by kidneys increases. 41 , 42 Vd is only slightly influenced by neonatal maturation, although it tends to decrease with the maturation of the neonate. This has been observed for cefotaxime. 20 , 24 Preterm infants have a higher water content than term infants, 40 and because cephalosporins are fairly water soluble, they are distributed at a larger volume in preterm infants than in term infants. The hypersensitivity, resistance and toxicology of cephalosporins have been studied in adults, but little is known about these characteristics in the neonate. Cephalosporin resistance may be related to the drug's inability to reach its sites of action, alterations in the penicillin-binding proteins that are the targets of cephalosporins or hydrolysis of the β-lactam ring by β-lactamase. 4 The most common side effects of cephalosporins are hypersensitivity reactions. The reactions appear to be identical to those caused by penicillins and may be related to the shared β-lactam structure of both groups of antibiotics. Immediate reactions, such as anaphylaxis, bronchospasm, and urticaria, are typically observed. 4 The cephalosporins have been implicated as potentially nephrotoxic agents, although they are not nearly as toxic to the kidneys as the aminoglycosides or polymyxins. In adults, renal tubular necrosis has followed the administration of cephaloridine in doses greater than 4 g/day. 4 With the exception of cefotaxime 15 , 16 and cefoperazone, 34 which are partially metabolized, cephalosporins are mostly eliminated by the renal route, and maturation of the excretory renal function increases with development. Cl correlates with gestational age for cefotaxime, 15 cefoperazone, 32 and ceftazidime. 23 The Cl of cefotaxime is 2- to 3-fold higher in term than preterm infants. 13 , 14 With increasing Cl, t 1/2 clearly decreases. The Cl of ceftazidime negatively correlates with the reciprocal of serum concentration of creatinine; thus, the serum creatinine concentration negatively influences the Cl of ceftazidime. 23 Little is known about the AUC, although this parameter for cefotaxime is similar in preterm and term infants. 14 In contrast, the AUC for ceftazidime is greater in neonates with a gestational age ≤32 weeks than in term infants. 21 This finding is due to the reduced renal excretory function in preterm infants compared with term infants. In premature subjects, the Cl of ceftazidime is reduced; therefore, the ceftazidime serum concentration slowly decreases, and AUC tends to increase. Most of the available information about the kinetics of cephalosporins deals with the third generation of these antibiotics. A considerable body of information is available on cefotaxime, ceftazidime, and ceftriaxone. The Cl of ceftazidime increases between days 3 and 10 of life. 24 This increase is due to the increase in GFR. The Cl of ceftazidime is also correlated with GFR (r = 0.81; p <0.001). This correlation indicates the important effect of GFR on ceftazidime Cl. Intravenous administration of ceftazidime yields double the peak concentration of intramuscular administration. 20 Ceftriaxone is active against Escherichia coli, Klebsiella species, Proteus species, Enterobacter species, and Staphylococcus aureus. 28 Cefepime is a fourth-generation cephalosporin and little is known about this drug, as it is the latest cephalosporin to enter clinical use. Creatinine negatively influences the Cl of cefepime. 39 Cefepime is primarily excreted unchanged. Preterm infants clear cefepime more slowly than full-term infants, as the renal excretory function rate is reduced in preterm subjects. Consequently, cefepime has a longer t 1/2 and a higher trough concentration in the preterm infant than the term infant. 38 Meningitis can be treated with cephalosporins, so the penetration of these drugs in the CSF is important. Information on the concentration of cephalosporins in CSF is available for cefotaxime, ceftazidime, ceftriaxone, cefoperazone, and cefepime. Cefotaxime reaches a considerable CSF concentration, and the CSF-to-serum concentration ratio is relevant. 13 Only one study is available on the penetration of cefepime in CSF. 43 The concentration of this drug varies considerably in serum and CSF, and consequently, the CSF-to-serum ratio ranges widely. The penetration of other cephalosporins into the CSF should be studied, and we feel that further research is required to ensure that the doses recommended for treating sepsis in neonates are entirely evidence-based. This work was supported by the Ministry of University and Scientific and Technological Research (Rome, Italy). Demographic data of the studied neonates and pharmacokinetic parameters of first- and second-generation cephalosporins. Figures are the mean±SD. na = not available. Data obtained in 10 neonates. Data obtained in 5 neonates. Demographic data of the studied neonates and pharmacokinetic parameters of the third-generation cephalosporins. Figures are the mean±SD unless otherwise stated. na = not available. NS = not significant. IM = intramuscular. Mean; the SD was not available; range. Note A: The cefotaxime dose was 25 mg/kg and 50 mg/kg in patients with meningitis. Doses were administered every 12 h in neonates younger than one week of age and every 8 h in patients 1 to 4 weeks of postnatal age. Note B: The ceftazidime dose was 50 mg/kg every 12 h for neonates in the first week of life and every 8 h for older infants. Note C: Twenty-five patients received 25 mg/kg, and 27 patients received 50 mg/kg. Demographic data of the neonates and pharmacokinetic parameters of the fourth-generation cephalosporin cefepime. Figures are the mean±SD unless otherwise stated. na = not available. Cephalosporin concentration in the cerebrospinal fluid (CSF) and serum in neonates. Figures are the mean±SD, unless otherwise stated. *Infants with meningitis. The infants' ages ranged from 12 to 540 days. Mean; SD was not available. Plasma. The CSF-to-serum ratio ranged from 1.4 to 31.7%. Pharmacokinetics of cephalosporins in the neonate: a review Classification of cephalosporins Third-generation cephalosporins Penicillins, cephalosporins, and other β-lactam antibiotics Ceftriaxone—bilirubin-albumin interactions in the neonate: an in vivo study Bilirubin displacement by ceftriaxone in neonates: evaluation by determination of ‘free' bilirubin and erythrocyte-bound bilirubin Evaluation of a potential clinical interaction between ceftriaxone and calcium Ceftriaxone-associated gallbladder sludge. Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate Antimicrobials pp 1-99. Neofax: A Manual of Drugs used in neonatal care. Edition 23 Interindividual changes in volume of distribution of cefazolin in ewborn infants and its prediction based on physiological pharmacokinetic concepts Cefoxitin in newborns. A clinical and pharmacokinetics study Pharmacokinetics and clinical efficacy of cefuroxime in the newborn period Treatment of severe neonatal infections with cefotaxime. Efficacy and pharmacokinetics Pharmacokinetics of cefotaxime in newborn infants Pharmacokinetics of cefotaxime in preterm infants Pharmacokinetics of cefotaxime and desacetyl-cefotaxime in neonates Pharmacokinetics of cefotaxime and desacetylcefotaxime in the newborn Cefotaxime and desacetylcefotaxime pharmacokinetics in very low birth weight neonates Pharmacokinetics of cefotaxime and desacetylcefotaxime in infants during extracorporeal membrane oxygenation Comparison of the concentrations of ceftazidime in the serum of newborns infants after intravenous and intramuscular administration Pharmacokinetics of ceftazidime in newborn infants Pharmacokinetics and cerebrospinal fluid penetration of ceftazidime in children with meningitis Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age Ceftazidime pharmacokinetics in preterm infants: effect of postnatal age and postnatal exposure to indomethacin Once-daily versus twice-daily administration of ceftazidime in the preterm infant Antimicrobial activity, pharmacokinetics, therapeutic indications and adverse reactions of ceftazidime Pathophysiologic basis for the use of third-generation cephalosporins The in vitro activity of ceftazidime compared with that of the other cephalosporins Pharmacokinetics of ceftriaxone in pediatric patients with meningitis Pharmacokinetics and safety of ceftriaxone in the neonate Ceftriaxone pharmacokinetics in newborn infants Cefoperazone pharmacokinetics in preterm infants Pharmacokinetics of cefoperazone in newborn infants Pharmacokinetics of cefoperazone in full-term and premature neonates Cefoperazone: A review of its in vitro antimicrobial activity, pharmacological properties and therapeutic efficacy Ceftizoxime disposition in neonates and infants during the first six months of life Pharmacokinetics of ceftizoxime Population pharmacokinetics of cefepime in the neonate Pharmacokinetics of intravenously and intramuscularly administered cefepime in infants and children Population pharmacokinetics of cefepime in neonates with severe nosocomial infection Clinical pharmacokinetics of antibacterial drugs in neonates Vancomycin. Pharmacokinetics and administration regimen in neonates Cefepime cerebrospinal fluid concentrations in neonatal bacterial meningitis |
Answer the following medical question. | What does research say about Fetal growth and gestational age improve outcome predictions in neonatal heart surgery.? | Current risk adjustment models for congenital heart surgery do not fully incorporate multiple factors unique to neonates such as granular gestational age (GA) and birth weight (BW) z score data. This study sought to develop a Neonatal Risk Adjustment Model for congenital heart surgery to address these deficiencies. Cohort study of neonates undergoing cardiothoracic surgery during the neonatal period captured in the Pediatric Cardiac Critical Care Consortium database between 2014 and 2020. Candidate predictors were included in the model if they were associated with mortality in the univariate analyses. GA and BW z score were both added as multicategory variables. Mortality probabilities were predicted for different GA and BW z scores while keeping all other variables at their mean value. The C statistic for the mortality model was 0.8097 (95% confidence interval, 0.7942-0.8255) with excellent calibration. Mortality prediction for a neonate at 40 weeks GA and a BW z score 0 to 1 was 3.5% versus 9.8% for the same neonate at 37 weeks GA and a BW z score -2 to -1. For preterm infants the mortality prediction at 34 to 36 weeks with a BW z score 0 to 1 was 10.6%, whereas it was 36.1% for the same infant at <32 weeks with a BW z score of -2 to -1. This Neonatal Risk Adjustment Model incorporates more granular data on GA and adds the novel risk factor BW z score. These 2 factors refine mortality predictions compared with traditional risk models. It may be used to compare outcomes across centers for the neonatal population. |
Answer the following medical question. | What does research say about Major determinants of survival and length of stay in the neonatal intensive care unit of newborns from women with premature preterm rupture of membranes.? | To assess the predictors of outcome in terms of length of stay in the neonatal intensive care unit (NICU) and survival of neonates from women with preterm premature rupture of membranes (PPROM). A population-based retrospective study including 331 singleton pregnant women with PPROM at 24-34 gestational weeks between January 2013 and December 2015 was conducted. Gestational age at delivery, birth weight, route of delivery, newborn gender, maternal age, oligohydramnios, premature retinopathy (ROP), necrotising enterocolitis (NEC), sepsis, fetal growth retardation (FGR), intracranial hemorrhagia (ICH), bronchopulmonary dysplasia (BPD), respiratory distress syndrome (RDS), primary pulmonary hypertension (PPH), congenital cardiac disease (CCD), patent ductus arteriosus (PDA), use of cortisol (betamethasone) and maternal complications including gestational diabetes, preeclampsia and chorioamnionitis were used to predict neonatal outcomes in terms of length of stay in the NICU and survival. In linear regression analyses, birth weight, ROP, CCD, BPD, PDA, NEC and preeclampsia were significant confounders for length of stay in the NICU. Among them, birth weight was the most powerful confounder for prolongation of the NICU stay (t: -6.43; p < 0.001). In multivariate logistic regression analyses, birth weight, PDA, ROP and PPH were significantly correlated with neonatal survival. PPH was the most powerful confounder in neonatal survival (β: 7.22; p = 0.005). Prematurity-related complications are the most important problems for which precautions should be taken. Therefore, premature deliveries should be avoided to prevent infection and to prolong the latent period in cases of PPROM in order to decrease prematurity-related outcomes. |
Answer the following medical question. | What does research say about Neonatal doses from X ray examinations by birth weight in a neonatal intensive care unit.? | The aim of this study was to investigate the frequency and type of X ray examinations performed on neonates classified according to their birth weight in a neonatal intensive care unit (NICU). In this study, the radiology records of 2408 neonates who were admitted to the NICU of Oita Prefectural Hospital between January 1994 and September 1999 were investigated. This study revealed that the neonates with earlier gestational ages and lower birth weights required longer NICU stays and more frequent X ray examinations made using a mobile X ray unit. The average number of X ray examinations performed on neonates of less than 750 g birth weight was 26 films per neonate. In regard to computed tomography and fluoroscopy, no significant relationship was found between the birth weight and number of X rays. This study revealed that the entrance-surface dose per neonate was dependent upon the birth weight, while the maximum dose was not dependent upon the birth weight. The average neonatal dose in the NICU was predominantly from computed tomography and fluoroscopy. The individual dose varied widely among neonates. |
Answer the following medical question. | What does research say about Complications of central lines in neonates admitted to a level III Neonatal Intensive Care Unit.? | To investigate the incidence and risk factors for central line related complications in neonates. A retrospective cohort study of infants who underwent central line (CL) placement, from 1 July 2014 to 31 June 2016, was conducted in Neonatal Intensive Care Unit of Centro Hospitalar de São João. Infants hospitalized more than 2 d and CLs placed for more than 24 h were included. Patients' demographic characteristics, hospital data, and information on CLs were collected. Indwelling complications were compared between infant groups and types of CL inserted. A total of 400 CLs were inserted in 240 infants with a CL utilization ratio of 0.64. Overall CL complication rate was 29.6 per 1000 catheter days. Of all complications, central line-associated bloodstream infection had the highest incidence (12.4 per 1000 catheter days). Infiltration was the most reported mechanical complication. Non-umbilical catheters showed a significantly higher incidence of complications than umbilical ones. Low gestational age, low birth weight, prolonged catheter stay, long duration of total parenteral nutrition, and peripherally inserted central catheter placement were associated with a higher risk of indwelling complication. The implementation of measures to prevent catheter-related complications must be a priority in care of vulnerable neonates. |
Answer the following medical question. | What does research say about Automated Medical Care: Bradycardia Detection and Cardiac Monitoring of Preterm Infants.? | Background and Objectives : Prematurity of birth occurs before the 37th week of gestation and affects up to 10% of births worldwide. It is correlated with critical outcomes; therefore, constant monitoring in neonatal intensive care units or home environments is required. The aim of this work was to develop solutions for remote neonatal intensive supervision systems, which should assist medical diagnosis of premature infants and raise alarm at cardiac abnormalities, such as bradycardia. Additionally, the COVID-19 pandemic has put a worldwide stress upon the medical staff and the management of healthcare units. Materials and Methods : A traditional medical diagnosing scheme was set up, implemented with the aid of powerful mathematical operators. The algorithm was tailored to the infants’ personal ECG characteristics and was tested on real ECG data from the publicly available PhysioNet database “Preterm Infant Cardio-Respiratory Signals Database”. Different processing problems were solved: noise filtering, baseline drift removal, event detection and compression of medical data using the à trous wavelet transform. Results : In all 10 available clinical cases, the bradycardia events annotated by the physicians were correctly detected using the RR intervals. Compressing the ECG signals for remote transmission, we obtained compression ratios (CR) varying from 1.72 to 7.42, with the median CR value around 3. Conclusions : We noticed that a significant amount of noise can be added to a signal while monitoring using standard clinical sensors. We tried to offer solutions for these technical problems. Recent studies have shown that persons infected with the COVID-19 disease are frequently reported to develop cardiovascular symptoms and cardiac arrhythmias. An automatic surveillance system (both for neonates and adults) has a practical medical application. The proposed algorithm is personalized, no fixed reference value being applied, and the algorithm follows the neonate’s cardiac rhythm changes. The performance depends on the characteristics of the input ECG. The signal-to-noise ratio of the processed ECG was improved, with a value of up to 10 dB. Prematurity of birth occurs before the 37th week of gestation, affecting up to 10% of births worldwide [ 1 , 2 ]. The European average of preterm birth rate is 7.3%, and the percentage of babies with low birth weight (lower than 2500 g) varies between 4.5% and 8% of all births [ 3 ]. Prematurely born infants and neonates with low birth weight are associated with an immature cardio-respiratory system and an immature immune system, being at greater risk of developing severe infections [ 4 , 5 , 6 ]. Additionally, the COVID-19 pandemic with the associated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) puts some stress on both mother and child, with many questions still being left about the future development of the newborn. The psychological stress upon the mother should not be neglected [ 7 , 8 ], as several studies have associated SARS infections during pregnancy with preterm delivery and intrauterine growth restrictions [ 9 , 10 , 11 ]. The pandemic is also reported to affect the work of neonatal intensive care unit (NICUs) [ 12 ]. The latest developments in the SarsCoV-2 virus affects many children (according to CNN, “Hospitalizations were highest among kids aged up to 4, and teens aged 12–17. One in four of the children who were hospitalized needed intensive care.” [ 13 ]): lately (19 October 2021), Romania has also reported a record number of COVID infections of 18,863 cases [ 14 ], with 486 infected minors. Long-term monitoring of newborns is recommended to establish better the implications of the novel coronavirus [ 7 , 10 ]: remote supervision and automatic diagnosis algorithms aim to provide access to medical assistance in times when hospitals worldwide are under stress and lack sufficient medical personnel. Remote monitoring of neonates is not an easy task, as the newborns are usually moving and various interferences add noise to the useful ECG signal. Technical solutions have been developed to aid medical diagnosis [ 15 , 16 , 17 ] and enable a fast clinical reaction. Another management solution consists in the transfer of some of responsibility for medical care to children’s parents through remote home monitoring [ 18 , 19 , 20 ]. Additionally, infants are able to be infected with the coronavirus at a later date: their immune system is less developed, and therefore neonates need careful supervision [ 21 ]. The preterm state is a vulnerable state, highly related to sudden infant death syndrome (SIDS), due in part to apnea and sleep disorders, calling for special sleep practice to ensure an infant’s safety [ 22 , 23 , 24 , 25 ]. Sleep-related cardio-respiratory instabilities are particularly important to infants, as preterm newborns spend up to 70–90% of the day sleeping. The risk of cardiovascular instabilities is marked during sleeping phases [ 22 ]. Respiratory pauses (called apnea-bradycardia episodes), associated with heart rhythm disorders, are stated as being common to preterm infants [ 26 , 27 , 28 ]. Bradycardia is defined as a cardiac event, where the heart rate slows to less than 100 bpm for at least two beats in duration [ 29 ] (in terms of RR-peaks, the time interval between the consecutive R-peaks must be >0.6 s). Fetal distress is reflected in physiological changes that can be outlined by changes in heart rate variability (HRV) [ 30 ]. Real-time monitoring of HRV metrics are linked [ 31 , 32 , 33 ] to information about the neurological development of the infant: newborns with higher root mean square of successive RR-interval differences (RMSSD), standard deviation of normal RR-intervals (SDNN) and standard deviation of the average normal RR-intervals (SDANN) showed a better neurological development [ 31 , 33 ]. The relation of RMSSD to the infant’s vagal activity could help clinicians in interpreting RMSSD changes: the lower the RMSSD, the lower the modulation by the vagal activity, worsening the infant’s condition [ 31 ]. Still, a sudden rise of RMSSD value can be an indicator of other pathological conditions, such as an intrapartum hypoxia-ischemia (reduced oxygen supply) leading to brain injury [ 31 , 34 , 35 ] (in adults, low HRV is associated with an increased risk of coronary heart disease and a predisposition to premature heart attacks [ 36 , 37 ]). As a study conclusion, the more altered the HRV metrics are, the worse the clinical outcome is (leading to brain injury or even SIDS) [ 38 ]. Personalized and automated diagnostic algorithms should relieve medical stress and assist clinical diagnosis. Some studies associate cardiac arrhythmias (such as bradycardia) with clinical post-symptoms of COVID: bradycardia and COVID-19 have been brought together in recent studies [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ], with an increased incidence of cardiovascular symptoms in patients (both adults and children) being reported. Thus, an automatic surveillance system (for NICU or home monitoring) has a practical medical application. There are also future plans to implement the software algorithms on a hardware device and to build a prototype for a portable monitoring system for neonates, based on Arduino, enabling additional clinical studies on the occurrence and effects of cardiac arrhythmias in infants. The authors tested the signal processing algorithms on the recordings provided by PhysioNet [ 28 , 52 , 53 ], managed by members of the MIT Laboratory for Computational Physiology. The Research Resource for Complex Physiologic Signals was established in 1999 under the auspices of the National Institutes of Health (NIH). The ECG database for preterm infants (added in 2017) can be downloaded as “Preterm Infant Cardio-Respiratory Signals Database” from the physionet.org website [ 52 , 53 ]. The ECGs were recorded at 250 Hz ( infant1_ecgm and infant 5_ecgm ) and at 500 Hz, respectively, and were recorded for 10 subjects in the NICU at University of Massachusetts Memorial Healthcare [ 28 ]: infant1 presented a post-conceptional age (PCA) of 29 weeks, with a birth weight of 1200 g. During 45.6 h of recording, 77 bradycardia episodes were reported. Infant2 and infant3 presented a PCA of 30 weeks and 5 days, birth weights of 1760 g and 1710 g, respectively, and during the 43 h of recording, a number of 72 and 80 bradycardias were reported. Infant4 presented a PCA of 30 weeks and a low birth weight (840 g). During 46.8 h of recordings 66 bradycardias were reported. Infant5 presented a PCA of 32 weeks, a birth weight of 1670 g, and 72 bradycardia episodes during 48.8 h of recording. Infant6, infant7 and infant9 reported a PCA of 30 weeks and similar birth weights: 1140 g, 1110 g and 1230 g, with 56, 34 and 97 respective bradycardia episodes being detected during recording. The high number of bradycardias detected in infant9 can also be correlated with the increased recording time (70.3 h of recording). Infant8 and infant10 presented the highest PCA (32 weeks and 34 weeks, respectively) and the highest birth weights (2100 g and 1900 g, respectively). A number of 28 and 40 bradycardias, respectively, were reported during recording. The infants were breathing room air and did not show perinatal or congenital infection of the CNS or hypoxic-ischemic encephalopathy [ 28 , 53 ]. We aimed to develop a portable device for remote monitoring of newborn infants that would ease the work of overcrowded hospitals in times of the pandemic. For non-invasive monitoring, we proposed a scenario ( Figure 1 ) intended to alert both NICU clinicians and parents of the infant to an intervention necessity. The cardiac activity of the infant could be monitored through a wearable ECG device [ 54 , 55 ] and the signals would be transmitted via Bluetooth to either a NICU computer or a mobile device of the parent. Mobile devices and computers would perform elementary tasks such as data collection, data management and filtering, compression and primary interpretation of ECG rhythm (normal sinus rhythm or arrhythmia). The data would be transmitted via Internet of Things (IoT, used to create a home network to connect and exchange data with a remote monitoring device, for example) or Cloud to a central medical data record unit for final interpretation. The working scheme of the proposed algorithm was constructed using the same wavelet transform for all processing steps ( Figure 2 ), to exploit the properties of time-frequency analysis with minimal resources. No fixed threshold was defined; thus, the algorithm was personalized for each newborn. A geometric measure was defined—the relative RR intervals (RR k ) [ 56 ]. This interval defines the relative variation of two neighboring R-peaks in time, where k is the number of RR-interval terms. Medical engineering applications need a quantification of physical quantities, which would allow us to model and predict a clinical development. For example, the RR k value should differ only to a small amount (approximately between −20% and +20% [ 56 ]), as a higher value would indicate a high irregularity of the RR-intervals (a first symptom of a cardiac abnormality). We also tried to avoid standardized values, as gestational age of preterm infants is usually different, and we consider that each medical interpretation should be related to the infants’ characteristics. The study focused on designing signal processing algorithms for a preliminary diagnosis and arrhythmia alarm—especially if remote monitoring of the newborn would be realized at home due to a lack of hospital space (because of the outbreak of the COVID-19 pandemic). RR K should also enable us to detect a preterm infant’s cardiac status, such as apnea-induced bradycardia (1): RR k = 2(RR k − RR k−1 )/(RR k + RR k−1 ) (1) { RR k > 0.6 s BRADYCARDIA ALERT RR k < 0.6 s Normal Sin us Rhythm Daily life signals reside in the time domain, still sometimes full information about the signal is not always visible. Thus there is a necessity to transform the signal from the time domain to other domains (such as the frequency domain [ 30 ]) to enable computer-assisted solutions. ECGs trace the variation of a voltage over time, with no information about the frequencies that might appear during the signal acquisition (a non-visible information). Wavelets check the frequency content of the signal at multiple resolutions of the analyzed signal. Wavelets are mathematical tools that allow us to assess the intervention on several frequencies: we can transform a signal in the frequency domain and check if there are frequencies that should not appear in cardiac signals (ECG frequencies are usually between 0.6 and 40 Hz). Other frequencies indicate external interference/noise (for example, 50–60 Hz interference is due to a nearby power line) and should be rejected to obtain a neat signal. The useful information can thus be extracted (Equation (2)) and the signals can be returned to the time domain after processing. Wavelets analyze the desired content of the ECG using multiple resolutions of the signal so as to adjust the level of detail needed [ 57 , 58 , 59 ]. Wavelets go from a larger scale to a smaller one (but with more details) through the shifting and dilating of a basic function called the mother wavelet ψ a , (MW). MW is selected in accordance with the analyzed signal (we are actually zooming on the studied signal), Equation (2): b where the wavelet transform (WT) of the analyzed signal (2) W ψ s ( a , b ) = 〈 s ( t ) , ψ a , b ( t ) 〉 = ∫ − ∞ ∞ s ( t ) ⋅ 1 a ψ * ( t − b a ) d t , a ∈ R , b > 0 s ( t ) is obtained through scaling and translating the function called the mother wavelet ψ a , , using dilation ( b ( t ) a ) and translation ( b ) parameters. The asterisk * denotes the complex conjugate of the function. Baseline drift reduction (due to infant movements), noise filtering and ECG compression might use wavelets’ property of sparsity [ 60 , 61 ]: the signal’s energy will be focused into a small amount of non-zero wavelet coefficients. The frequency domain augments the knowledge about the analyzed signal ( Figure 3 ). We noticed an even distribution of all signal samples and a concentration of the wavelet coefficients’ energy on the higher scales, corresponding to low frequencies (up to 20 Hz, with a peak at 15.62 Hz). Thus, we adapted the WT on the lower frequencies so as to concentrate the signal and to reduce as many zero wavelet coefficients as possible. This resulted in a neater and more compressed signal. Suited to our necessities was a translation invariant transform, such as the stationary wavelet transform (SWT), implemented with an algorithm known as “algorithme à trous” [ 62 ]. SWT passes the signal successively through a series of low-pass filters (computing the approximation wavelet coefficients cA) and high-pass filters (computing the detail wavelet coefficients cD). Using these coefficients, several signal processing tasks were performed: To reduce the baseline drift, we approximated the general tendency of the ECG signal using only the wavelet approximation coefficients, on 5 iteration levels. The signal was filtered using an adaptive algorithm in the wavelet domain and a simple soft-thresholding filter. The filter was applied on the detail wavelet coefficients (they corresponded to the high frequency components of the ECG signal). The threshold was related to the small values of the detail wavelet coefficients, which contained the artifacts. Detail coefficients were different for each patient, but were always low in value. We can not reconstruct the ECG eliminating all detail wavelet coefficients, but we eliminated the lower values between them to obtain a neater signal. Therefore, any wavelet coefficient lower than the established threshold was rejected as noise. The method was personalized on the ECG characteristics of each supervised infant (3) and could thus diagnose HRV changes of each infant. where (3) for i = 1 to k T ECG infant = 1 n − 1 ⋅ ∑ k ( cD i − mean ( cD i ) ) 2 i is the number of the WT decomposition level, k the total number of WT iterations, cD the wavelet detail coefficient and n is the ECG sample length. To personalize the algorithm so as to suit the need of each monitored infant, the R-peak value was also adaptively set: the maximal value of the ECG recording (the R-peak), was computed after a delay of 2 s, to cover at least one heartbeat. Values lower than 70% of the infants’ reference peak were rejected and only the peak values were retained. We needed to define a tolerance, as no medical parameter has the same value at all measurement times, still there were no major clinical drawbacks. Thus, we established a threshold of 70% of the reference value to account for a slight baseline drift of the newborn, as newborns are moving and electrodes might slip slightly. After the detection of two heartbeats, the RR-interval was computed and stored. An alarm was set if the time delay between two neighboring RR-peaks > 0.6 s, and the time interval was stored to enable further investigations. Compression ratio (CR) is a performance estimator for the compression of a signal (we want the ECG signal to occupy less computer memory, to have a longer cardiac monitoring over time). Continuous monitoring resulted in a large quantity of data; therefore, engineering solutions that achieved a minimal loss of clinical information were searched for.CR refers to the ratio between the number of input bits related to the number of output bits. Signal compression can be realized using a number of fewer bits for each iteration level, rejecting the zero-valued wavelet coefficients. The final signal was reconstructed on a minimal number of bits, achieving a compression ratio that depended on the number of iterations used [ 61 ]. A noisy segment of the recording named infant6_ecgm (time of recording 1 h 31 min 30 s:1 h 32 min 30 s) was taken to check two clinical aspects ( Figure 4 ): whether the baseline drift removal algorithm is efficient on segments with pronounced drift and whether the mentioned algorithm was influencing the detection of bradycardia segments which occurred on noisy ECG segments. The baseline drift removal ( Figure 5 , blue color) and the denoising procedure ( Figure 5 , green color) improved the SNR, and we also noticed the correction of the baseline drift. We obtained a high SNR improvement of 10.18 dB. For the analyzed preterm infants’ database, the SNR improvement varied between 1.34 and 10.18 dB. Accurate alarm on bradycardia episodes was realized by detecting the R-peaks of the ECG segments and computing the RR-intervals ( Figure 6 and Figure 7 ). To keep the processing time delay as minimal as possible and to allow a continuous monitoring and a timely detection of cardiac anomalies, we operated on blocks of 1000 samples: 1000 samples were processed, while the next 1000 samples were stored. The authors applied the algorithm to the different ECGs of infant recordings available on PhysioNet and the results are synthesized in Table 1 . Thus, for the analyzed ECGs, we achieved varied compression ratios (CR): between 1.72 ( infant5_ecgm ) and 7.42 ( infant6_ecgm ), using an 8-bit resolution. The performance (CR, SNR improvement) depended on the characteristics of the input ECG. The SNR of the processed ECG was improved with a median value of 4 dB: the higher the value of the dB, the stronger the useful signal and the weaker the noise. The CR reflected the characteristics of the ECG recording and can be further enhanced through lossy compression procedures. The proposed compression procedure was personalized, with the CR depending on the regularity of the preterm ECG signal: ECGs with higher baseline drift achieved higher CRs (as an example, for ECG named infant6_ecgm , we reached a high CR of 7.42). A total of 1000 samples segments for all studied cases are displayed in Figure 8 . The bradycardia alarm given through the proposed method coincided with the annotated bradycardia episodes on the PhysioNet database [ 52 ]. The processing time for a sample length of 2 s (1000 samples) was less than 1 s for a standard Intel Core2 computer, on 1.86 GHz and 4.00 GB RAM memory. The samples were digitized on a reduced number of bits and transmitted via Bluetooth connection or IoT to a central NICU or smart device for storage and further processing. The SarsCoV-2 virus affects both adults and children. The medical crisis due to the COVID-19 pandemic determined us to find solutions for remote monitoring of vital signs. Remote monitoring of neonates is not an easy task, as newborns are usually moving, and various interferences add noise to the useful ECG signal. The algorithm aimed to relieve the stress put on a NICU, where prematurely born infants need constant supervision, developing a method to automatically supervise the cardiac monitoring of newborns. The algorithm relies on the traditional diagnostic scheme, but it is implemented with the aid of powerful mathematical operators. The solutions should be implemented on portable devices and should also enable data acquisition and intervention in home environments. The algorithm is tailored to an infant’s personal ECG characteristics. To avoid errors due to infant movements, which are reflected in drifts of the ECG baseline and higher R-peak values, we applied a baseline drift correction method after a minimal delay of 2 s from acquisition start. There is a necessity to correct the baseline drift for accurate automated peak identification. As can be noticed analyzing Figure 5 , Figure 6 and Figure 7 , the baseline drift was completely suppressed. The sample was filtered and a thresholding algorithm was applied in the time domain, detecting the R-peaks. Considering the filtering procedure, in [ 63 ] and [ 64 ] are proposed denoising methods based on the discrete wavelet transform (DWT). The DWT is a non-redundant, shift variant transformation, which has poor denoising performance, although a smaller redundancy than the SWT. DWT is a translation variant transform (contrary to SWT): the signal is passed through a series of low-pass (allowing low frequency components) and high-pass filters (allowing high frequency components). At the output of each filter, DWT eliminates every second coefficient, resulting in fewer and fewer coefficients if the signal analysis is done in more steps. The results will be then constructed through interpolation (approximations of the signal), and some information might be thus lost. This procedure was not applied in case of the SWT (there was no downsampling by a factor of 2 realized), and thus SWT allowed a much more accurate signal reconstruction. Using a denoising procedure in three steps, with the DWT and a fixed threshold value searching method, the authors of [ 63 ] also conducted experiments using only a set of simulated noisy ECG signals. The MW used for DWT computation was not specified. The authors of [ 63 ] did not take into account important aspects of real ECGs, as, for example, the baseline drift, making difficult an objective comparison with our results shown on the fourth column of Table 1 . In [ 64 ], the same denoising method as in [ 63 ] was studied, but different MWs and different filtering procedures in the wavelet domain were considered. The authors of [ 64 ] compared the soft-thresholding filter (selected by us as well) with the hard-thresholding filter and took into account four strategies for the selection of a fixed threshold value: universal, rigorous SURE, heuristic SURE and the minimax criterion. They prove the superiority of soft-thresholding filter versus the hard-thresholding filter from the SNR improvement point of view. The authors of [ 64 ] found that the best MWs for the filtering of the DWT wavelet coefficients with the soft-thresholding filter were sym4 and coif8. The fact that for baseline correction and for noise filtering there are different MWs is a drawback of the DWT. We estimated, based on Figure 8 in [ 64 ], the SNR enhancement of the DWT-based denoising method. The best value of 5 dB was obtained for an input SNR of 0 dB. The worst value of the SNR enhancement obtained, using DWT of 1.4 dB, was obtained for an input SNR of 8 dB. The mean value of the SNR enhancement, obtained for input SNRs between 0 dB and 8 dB, equaled 3.6 dB. Our mean value of the SNR improvement (displayed in Table 1 ) was of 4.2 dB. Therefore, the use of SWT computed with the MW db8 and the adaptive selection of the threshold following equation (3) made our denoising method better. For R-peaks detection, [ 65 ] proposed a different method. First the SWT using the quadratic spline MW is computed, and next the wavelet modulus maximum algorithm is applied. To detect R-peaks, this method requires the intervention of experts. Hence, contrary to the proposed R-peaks detection, the method in [ 65 ] is not automated. In our study, the-RR interval between two neighboring samples was computed: if the interval was >0.6 s, an alarm was raised, calling for the necessity of further investigations. Additionally, a sudden rise of RMSSD could be an indicator of pathological conditions, such as a reduced oxygen supply (which might lead to brain injury). We propose the computing of HRV metrics (for example, the RMSSD) for every 2 s or 5 s to check the personal cardiac variation of neonates. The COVID-19 pandemic has placed an additional stress on intensive care units, as preterm children are prone to infections due to their immature immune system. Remote monitoring enables a timely intervention, when there is lack of medical personnel and restricted or no healthcare access of the infants’ relatives because of the pandemic. We tried to offer a solution for long-term unsupervised monitoring, which should be able to alert medical personnel in the event of cardiac rhythm changes, such as bradycardia. Analyzing the preterm ECG database available on PhysioNet, we noticed that a significant amount of noise could be added to a signal while monitoring using standard clinical sensors. Additionally, recent studies have shown that persons infected with the COVID-19 disease are reported to develop cardiovascular symptoms and cardiac arrhythmias. An automatic surveillance system (both for neonates and adults) has thus a practical medical application. The displayed figures ( Figure 5 , Figure 6 , Figure 7 and Figure 8 ) state that the algorithm detected time durations >0.6 s, which were correlated with bradycardia episodes. The authors tested whether the same wavelet transform could be used and adapted to perform several processing steps (baseline drift removal, denoising, compression, data transmission). We arrived at the conclusion: (1) that we need a translation invariant transform and (2) compression performance is related to the noise contained in the original signal (the greater the removed noise, the higher the compression ratio). A novel mother wavelet tailored to ECG characteristics can be a future interesting research direction. Several signal processing steps were performed with the same mathematical operator (SWT) to keep the operations to a reduced level of complexity. We aimed to allow further development and implementation of the algorithm on a standard smartphone device. The algorithm can be personalized, following the neonate’s cardiac rhythm changes. The bradycardia events annotated by physicians were correctly detected, as can be noticed in Figure 6 , Figure 7 and Figure 8 . Additionally, as we take into consideration the distance between RR-peaks, alarms can also be easily triggered for tachycardia: we must set the system to alert medical personnel if the RR-interval is too great for children (>140 beats per minute, or two detected beats >0.43 s). We tested the ECG algorithms to ensure that we have a working basis for the future development of a remote monitoring system for neonates. Future aims are to test the algorithm on neonates from Timisoara, to provide more clinical characteristics of the studied population. There are still open possibilities of exploring the information contained by a signal: an investigation to be undertaken is to verify whether respiration samples of the preterm infant can be influenced by viruses such as SARS-CoV-2, and whether these changes can be highlighted while analyzing the signals with wavelets. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Conceptualization, B.A. and A.I.; methodology, B.A.; software, B.A. and A.I.; validation, B.A., E.R.I. and A.I.; investigation, B.A., E.R.I. and M.C.; writing—original draft preparation, B.A. and E.R.I.; writing—review and editing, B.A., E.R.I., A.I., D.I. and M.C.; visualization, D.I. and M.C.; supervision, E.R.I., A.I., D.I. and M.C. All authors have read and agreed to the published version of the manuscript. This work was supported by the project “Enhacing the Politehnica University of Timisoara institutional capacity in the research field, 3C-UPT, CNFIS-FDI-2021-0573”. Ethical review and approval were waived for this study, due to the use of anonymized data from a publicly available database ( https://archive.physionet.org/cgi-bin/atm/ATM , accessed on 31 October 2021), placed for the use of researchers anywhere in the world ( https://archive.physionet.org/faq.shtml#who-can-use , Last accessed on 31 October 2021). Patient consent was waived due to the use of anonymized data from a publicly available database ( https://archive.physionet.org/cgi-bin/atm/ATM , Last accessed on 31 October 2021). The anonymized preterm infants’ ECG datasets have been takenfrom PhysioNet ( https://archive.physionet.org/ accessed on 31 October 2021), which offers free web access to collections of recorded physiological signals. The “Preterm Infant Cardio-Respiratory Signals Database (picsdb)” can be accessed at the link: https://archive.physionet.org/cgi-bin/atm/ATM (accessed on 31 October 2021). Additional information and DOI for the “Preterm Infant Cardio-Respiratory Signals Database”: doi:10.13026/C2QQ2M ( https://archive.physionet.org/physiobank/database/picsdb/ accessed on 31 October 2021). The authors declare no conflict of interest. Monitoring architecture. Structure of the automated monitoring system. Energy percentage for the wavelet coefficients, using db8 mother wavelet. Analyzed signal waveform (first panel) and its scalogram (second panel). Original ECG named infant6_ecgm , after 1 h, 31 min and 30 s of standard recording ( https://archive.physionet.org/cgi-bin/atm/ATM (accessed on 29 August 2021). Superposition of original ECG (red color), ECG with reduced baseline drift (blue color) and denoised ECG (green color), for infant6_ecgm . infant6_ecgm (hour 1.31.36–1.31.38 of recording). ( a ) Zoom on bradycardia event for infant1_ecgm , db8 MW, 1000 samples (minute 32–33 of recording). ( b ) Zoom on the detected RR-intervals for infant1_ecgm , db8 MW, 1000 samples (minute 32–33 of recording). Zoom on the detected R-peak values on bradycardia events for preterm infants of the PhysioNet database, db8 MW, 1000 samples. Performance of RR peak detection wavelet algorithm for the preterm infants ECGs. Automated Medical Care: Bradycardia Detection and Cardiac Monitoring of Preterm Infants Bradycardia Assessment in Preterm Infants The worldwide incidence of preterm birth: A systematic review of maternal mortality and morbidity European Perinatal Health Report Preterm birth as a risk factor for metabolic syndrome and cardiovascular disease in adult life: A systematic review and meta-analysis COVID-19 During Development: A Matter of Concern Association of low birth weight and premature birth with the risk of metabolic syndrome: A meta-analysis Maternal Coronavirus Infections and Neonates Born to Mothers with SARS-CoV-2: A Systematic Review Infant Outcomes Following Maternal Infection with SARS-CoV-2: First Report from the PRIORITY Study Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome Potential Maternal and Infant Outcomes from Coronavirus 2019-nCoV (SARS-CoV-2) Infecting Pregnant Women: Lessons from SARS, MERS, and Other Human Coronavirus Infections Impact of COVID-19 infection on pregnancy outcomes and the risk of maternal-to-neonatal intrapartum transmission of COVID-19 during natural birth Managing a tertiary-level NICU in the time of COVID-19: Lessons learned from a high-risk zone Automatic detection of complete and measurable cardiac cycles in antenatal pulsed-wave Doppler signals Automatic Premature Ventricular Contraction Detection Using Deep Metric Learning and KNN Prediction of short-term health outcomes in preterm neonates from heart-rate variability and blood pressure using boosted decision trees Integrating Telehealth Care-Generated Data with the Family Practice Electronic Medical Record: Qualitative Exploration of the Views of Primary Care Staff The impact of direct-to-consumer wearables in pediatric electrophysiology telehealth clinics: A real-world case series Heart Rate Monitoring in Newborn Babies: A Systematic Review First neonates with severe acute respiratory syndrome coronavirus 2 infection in Romania: Three case reports Cardiovascular Consequences of Preterm Birth in the First Year of Life Blood and urine biomarkers associated with long-term respiratory dysfunction following neonatal hyperoxia exposure: Implications for prematurity and risk of SIDS Comparison of Sleep Problems Between Term and Preterm Born Preschool Children Quiet Sleep Organization of Very Preterm Infants Is Correlated with Postnatal Maturation Comparative efficacy of pulmonary surfactant in respiratory distress syndrome in preterm infants: A Bayesian network meta-analysis On-line apnea-bradycardia detection using hidden semi-Markov models Predictors of early synchronized non-invasive ventilation failure for infants < 32 weeks of gestational age with respiratory distress syndrome Predicting Bradycardia in Preterm Infants Using Point Process Analysis of Heart Rate Spectral analysis of fetal heart rate variability associated with fetal acidosis and base deficit values Heart Rate Variability in the Perinatal Period: A Critical and Conceptual Review Altered autonomic control in preterm newborns with impaired neurological outcomes Assessment of general movements and heart rate variability in prediction of neurodevelopmental outcome in preterm infants Saving the brain one heartbeat at a time Evolving changes in fetal heart rate variability and brain injury after hypoxia-ischemia in preterm fetal sheep Heart Rate Variability for Risk Assessment of Myocardial Ischemia in Patients Without Known Coronary Artery Disease: The HRV-DETECT (Heart Rate Variability for the Detection of Myocardial Ischemia) Study Heart Rate Variability and Incident Stroke: The Atherosclerosis Risk in Communities Study Heart Rate Variability: Measurement and Clinical Utility Neonatal manifestations in COVID-19 patients at a Brazilian tertiary center Children’s heart and COVID-19: [3] Up-to-date evidence in the form of a systematic review Bradycardia in Patients with COVID-19: A Calm before the Storm? Sinus Bradycardia Associated with Remdesivir Treatment in COVID-19: A Case Report and Literature Review Cardiovascular sequalae in uncomplicated COVID-19 survivors Bradyarrhythmias in patients with COVID-19: Marker of poor prognosis? Relative bradycardia in patients with coronavirus disease 2019 (COVID-19) COVID-19 Induced Bradyarrhythmia and Relative Bradycardia: An Overview MPH Implementation of a Practice Plan for the Out-patient Cardiac Evaluation of Children after Acute SARS-CoV-2 Infection and a Report of Outcomes A case of bradycardia during SARS CoV-2 infection in a 14-year-old child COVID-19 associated multisystem inflammatory syndrome in children presenting uniquely with sinus node dysfunction in the setting of shock Relative Bradycardia in Patients with Mild-to-Moderate Coronavirus Disease, Japan Sinus bradycardia in a toddler with multisystem inflammatory syndrome in children (MIS-C) related to COVID-19 PhysioBank, PhysioToolkit, and PhysioNet: Components of a New Research Resource for Complex Physiologic Signals Wearable sensor systems for infants Pre-discharge Cardiorespiratory Monitoring in Preterm Infants. The CORE Study Robust, Simple and Reliable Measure of Heart Rate Variability using Relative RR Intervals An Introduction to Wavelets Adaptive Thresholding Algorithm for Noisy Electrocardiograms using Reverse Biorthogonal Mother Wavelets Unitary Systems and wavelet sets ECG signal compression using wavelets. Preliminary results A real-time algorithm for signal analysis with the help of the wavelet transform Hardware Design and Implementation of a Wavelet De-Noising Procedure for Medical Signal Preprocessing ECG Signal Denoising by Discrete Wavelet Transform A Hybrid Wavelet-Based Method for the Peak Detection of Photoplethysmography Signals |
Answer the following medical question. | What does research say about [Number of painful procedures and pain management in a neonatal intensive care unit].? | Összefoglaló. Bevezetés: A neonatalis intenzív centrumokban kezelt betegek naponta számos fájdalmas beavatkozáson eshetnek át. A kezeletlen fájdalom következményeinek ismerete ellenére, fájdalmuk csillapítása még messze nem ideális. Célkitűzés: Obszervációs tanulmányunk célja az osztályunkon kezelt koraszülötteket és beteg újszülötteket ért fájdalmas beavatkozások gyakoriságának és természetének meghatározása volt. Vizsgáltuk a procedurális fájdalom esetén alkalmazott gyógyszeres és nonfarmakológiai fájdalomcsillapítók használatát, valamint a beavatkozások számát és a fájdalomcsillapítás alkalmazását befolyásoló tényezőket. Módszerek: A vizsgálatba az osztályunkon 2019. 09. 01. és 2019. 12. 31. között kezelt betegeket vontuk be. Prospektív adatgyűjtést végeztünk a hospitalizáció első 14 napján, egy erre a célra kialakított kérdőíven, amelyet az egészségügyi személyzet valós időben töltött ki. Eredmények: Kutatásunkba 143 gyermeket tudtunk bevonni. A vizsgálati időszak alatt 43-féle fájdalmas beavatkozás történt, összesen 13 314 alkalommal, amiből 12 953 első, 361 többszöri kísérlet volt. Gyermekenként átlagosan 93,1 beavatkozást végeztünk a hospitalizáció első 2 hetében, ami átlagosan 8,2 fájdalmas procedúrát jelentett naponta és gyermekenként. Fájdalomcsillapítás összesen 4190 alkalommal, a beavatkozások 31,5%-ában történt. Ennek 55,5%-a folyamatos gyógyszeres, 40,7%-a nem gyógyszeres, 2,5%-a alkalmi gyógyszeres, 1,3%-a kombinált terápia volt. A legkisebb születési súlyú, legrövidebb gestatiós időre született és a lélegeztetett koraszülöttek szenvedték el a legtöbb fájdalmas beavatkozást. Következtetés: Betegeink nagyszámú fájdalmas beavatkozáson esnek át, és ezek nagyobb részénél nem történik fájdalomcsillapítás. A beavatkozások tervezésével, összehangolásával, a gyógyszeres és nem gyógyszeres fájdalomcsillapítás kiterjedtebb alkalmazásával jobb fájdalommenedzsment lenne elérhető. Orv Hetil. 2021; 162(48): 1931-1939. Preterm infants and sick neonates treated in neonatal intensive care units may undergo numerous painful interventions. Despite rapidly growing knowledge about consequences of untreated pain, pain management of neonates is far from ideal. To determine the frequency and nature of painful procedures and corresponding analgesic therapies in neonates treated in a neonatal intensive care unit of a university teaching hospital in Hungary. A prospective observational study was performed between September and December 2019. We collected data of all painful procedures, pharmacological and non-pharmacological analgesic therapy performed on neonates during the first 14 days of hospitalization. For data collection, we used a questionnaire designed for this purpose, which was completed in real time by the medical staff. 143 children were enrolled. 43 types of painful interventions were performed, a total of 13,314 times, of which 12,953 were the first, 361 multiple attempts. Each neonate was subjected to a mean of 93.1 interventions in the first 2 weeks of hospitalization, representing an average of 8.2 painful procedures per day per child. Pain relief was performed a total of 4190 times, in 31.5% of the interventions. Of this, 55.5% were continuous pharmacological, 40.7% non-pharmacological, 2.5% occasional drug, and 1.3% combination therapy. Ventilated neonates and preterm infants with shorter gestational age and lower birth weight had the most painful procedures. Patients treated in our unit undergo a large number of painful interventions, most of which are not accompanied by analgesia. Increased efforts are needed to promote our better pain management. Orv Hetil. 2021; 162(48): 1931-1939. |
Answer the following medical question. | What does research say about NeoVault: empowering neonatal research through a neonate data hub.? | Stability during early postnatal life in preterm infants is related to better outcomes. Although vital signs are monitored continuously in Neonatal Intensive Care Unites, this monitoring does not include all physiological parameters nor data such as movement patterns. Although there are scattered sources of data, there is no centralized data hub for neonates information. We have created the first neonate data hub for easy and interactive access to upload or download postural, physiological, and medical data of neonates: NeoVault . NeoVault is a platform that provides access to information through two interfaces: 1) via a Web interface (designed for medical personnel, data scientists, researchers); and 2) via a RESTful API (Application Programming Interfaces) -designed for developers-, aiming to integrate access to information into third-party applications. The web access allows searching and filtering according to specific parameters, visualization of data through graphs and images, and generation of datasets in CSV format. Access through the RESTful API is described in OpenAPI, enabling access to information from any device, facilitating it in an interoperable format. Currently, it contains nearly 800,000 postural records and 3.000 physiological data entries. The physiological and postural data stored for each neonate in NeoVault are collected through the NRP ( Neonates Recording Platform ) tool, which allows for the automatic and reliable collection of data. NeoVault is an open platform for simple access to postural, physiological, and medical data of neonates that can be utilized by researchers, data scientists, medical personnel, and programmers. It enables integration into third-party applications and the generation of customized datasets. Funding for open access publishing: Universidad de Cádiz/CBUA Preterm infants are babies born before the 37 th week of gestation. Due to their immature development they can face an increased risk of experiencing respiratory problems (e.g bronchopulmonary dysplasia), cardiac issues, infections, and neurodevelopmental disorders [ 1 – 4 ]. Due to their physical conditions, they are admitted to the Neonatal Intensive Care Unit ( NICU ), where the clinical evaluation of the baby’s health and constant monitoring of vital signs are carried out. This health assessment is most often conducted through visual observation of the infants’ behavioral traits (movements, facial expressions, crying), neuroimaging exploration, and cardio-respiratory and ECG monitoring by neonatologists [ 5 , 6 ]. The medical information collected from the clinical analysis of preterm infants is often documented in notes or reports crafted by specialists. Additionally, in certain instances, is stored in private platforms or storage systems (such as in the case of medical images) accessible only to designated healthcare professionals, ensuring privacy of the patient´s information. In recent times, there has been a rising interest in exploring the collection and subsequent analysis of video and audio data as non-invasive methods for information gathering. This data, upon thorough examination, has the potential to improve the clinical monitoring of a neonate’s health and the assessments conducted in a NICU [ 5 , 7 – 11 ]. The integration of this medical information into databases (gathered by collection tools or generated in hospitals) significantly streamlines the process for medical staff when reviewing records. This technological advancement not only enhances efficiency but also serves as a valuable tool in gaining insights into the effectiveness of various treatments. By centralizing and organizing the data, the database provides medical staff with a comprehensive and accessible platform for thorough record analysis. This, in turn, contributes to a more informed understanding of the efficacy of different treatment modalities, fostering continuous improvement in patient care and outcomes [ 12 – 14 ]. Public medical databases that house information about preterm infants play an essential role in scientific research, healthcare enhancement, early detection of health issues, and the innovation of new therapies and medications. Beyond that, these databases serve as invaluable assets for the education of healthcare professionals, students, and scientists. They actively promote collaboration among researchers and healthcare professionals, propelling technological advancement by creating a conducive environment for the testing and development of cutting-edge data analysis tools and information technologies in the realm of healthcare [ 15 ]. To the best of the authors’ knowledge, there is a lack of publicly accessible databases specifically designed for the study of neonates. This scarcity is primarily attributed to privacy and security considerations that place constraints on obtaining ethical approval [ 5 ]. Nevertheless, it is noteworthy to mention some data-sets and database that could be found: BabyPose : it is a data-set, encompassing data on 12 limb-joint locations and depth images related to the movement of neonates [ 15 , 16 ]. MIAdataset : it consists in the states vector, along with the corresponding timestamp, derived from depth measurements of a preterm infant. It contains a timeline of 16 different states in which the infant under examination was in. To obtain this dataset, you have to complete, sign and return a form that you can find in the web page where is located the information of the dataset. After that, you will receive the credentials to download it. Note that the data-set is available only for research purposes [ 17 ]. Preterm Clinical Network (PCN) : a web-based systematic method for collecting data concerning the care of women at risk of preterm birth. Notably, it incorporates a registry of children born to women at risk, who have undergone specialized preterm surveillance and and may have received preterm interventions, whether born prematurely or not. However, it is essential to note that it is not specifically a database providing neonatal-specific information, and direct access to the data is not feasible; interested parties can obtain it by making a request to the corresponding author [ 12 ]. MMSdataset : the Multi-Modal Stimulations data-set contains preterm infants data including: gestational age, chronological age, corrected gestational age, sex, birth weight, birth length, birth occipitofrontal circumference (OFC), APGAR at 1-min, and APGAR at 5-min, pre-post intervention (5 days) changes of weight, length, INFANIB (Infant Neurological International Battery) and NIPS (Neonatal Infant Pain Scale) [ 18 , 19 ]. BabyPose : it is a data-set, encompassing data on 12 limb-joint locations and depth images related to the movement of neonates [ 15 , 16 ]. MIAdataset : it consists in the states vector, along with the corresponding timestamp, derived from depth measurements of a preterm infant. It contains a timeline of 16 different states in which the infant under examination was in. To obtain this dataset, you have to complete, sign and return a form that you can find in the web page where is located the information of the dataset. After that, you will receive the credentials to download it. Note that the data-set is available only for research purposes [ 17 ]. Preterm Clinical Network (PCN) : a web-based systematic method for collecting data concerning the care of women at risk of preterm birth. Notably, it incorporates a registry of children born to women at risk, who have undergone specialized preterm surveillance and and may have received preterm interventions, whether born prematurely or not. However, it is essential to note that it is not specifically a database providing neonatal-specific information, and direct access to the data is not feasible; interested parties can obtain it by making a request to the corresponding author [ 12 ]. MMSdataset : the Multi-Modal Stimulations data-set contains preterm infants data including: gestational age, chronological age, corrected gestational age, sex, birth weight, birth length, birth occipitofrontal circumference (OFC), APGAR at 1-min, and APGAR at 5-min, pre-post intervention (5 days) changes of weight, length, INFANIB (Infant Neurological International Battery) and NIPS (Neonatal Infant Pain Scale) [ 18 , 19 ]. The aforementioned databases and datasets exhibit certain constraints that merit consideration: 1) the issue of direct access arises, as some databases demand the initiation of a formal access request process. This can introduce delays and procedural hurdles in obtaining the required data; 2) the absence of a user-friendly website interface is notable. A streamlined and intuitive interface can significantly enhance the user experience, particularly in terms of exporting data, reformatting information, or seamlessly integrating new data into the existing system. This aspect becomes important in ensuring efficient utilization and accessibility for diverse users; 3) a noteworthy limitation pertains to the scope of information within these databases, particularly concerning body pose reference points. The available data-sets offer insights into a limited set of reference points, potentially constraining comprehensive analyses or applications requiring a more extensive array of pose-related data. Moreover, a crucial observation is the absence of databases containing detailed information on the physiological parameters of neonates. This gap in the available resources underscores a potential limitation in comprehensive research and analysis focused on understanding and addressing the unique healthcare needs of preterm infants. As such, tackling these constraints could significantly contribute to the advancement of a research and medical care in the neonatal domain. To overcome these limitations, we have developed NeoVault the first neonate data hub. NeoVault provides public access to a comprehensive collection of perinatal and neonatal data. Besides it goes beyond traditional databases by encompassing vital physiological parameters and data of 33 reference points (landmarks), which are crucial for understanding preterm infant body pose. The different data sources currently considered in this first version of NeoVault are shown in Table 1 . Table 1 Data sources collected and available in NeoVault Parameter Description Expected values Justification for inclusion in NeoVault (medical relevance) Sex Biological sex at birth Boy, Girl, Both It is essential for improving the accuracy in risk assessment, personalizing treatments, and enhancing short and long-term outcomes, considering the biological differences that may influence the health and development of newborns [ 20 , 21 ] Gestational Age Age of a baby during pregnancy [25,36] Weeks It is essential for assessing risk, planning interventions, predicting long-term development, and improving neonatal care protocols [ 22 , 23 ] Birth Size Baby size, measuring from head to toe [20,50] Centimeters It is fundamental for assessing the health of the newborn and predicting short- and long-term risks. This variable allows for the identification of at-risk neonates, personalization of medical care, improved monitoring of development, and ultimately, optimization of both immediate and future health outcomes [ 24 ] Birth Head Circumference Head circumference of the baby [15,45] Centimeters This variable not only provides critical information about fetal growth but also helps predict short- and long-term risks, allowing for timely and appropriate interventions to improve the health outcomes of the newborn [ 25 , 26 ] Birth Weight Newborn weight [0- ] Grams \documentclass[12pt]{minimal}
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\begin{document}$$\infty$$\end{document} ∞ It is a key indicator for assessing the health of the newborn and predicting short- and long-term risks [ 22 ] APGAR1 and APGAR5 Quick assessment performed on a newborn at 1 minute and 5 minutes [0,10] The APGAR score is useful for the assessment and initial management of the newborn’s health. Its use not only provides critical information about the newborn’s condition at birth but also allows for monitoring their development and health over time, thereby contributing to improved outcomes in neonatal care [ 27 – 29 ] CRIB Clinical Risk Index for Babies [0,23] The CRIB score helps identify newborns at risk and provides valuable information to optimize care and improve long-term health outcomes [ 30 , 31 ] Brain Damage Brain damage or neurological damage Yes/No Recording neonatal brain damage in a database is essential for tracking development, guiding personalized care, and improving long-term outcomes. It helps link brain injury with clinical factors, enabling better treatment and research into neurological development [ 32 ] Vital Signs SP02 (Oxygen Saturation) and Heart Rate (Times of heart beats per minute - BPM-) [0,100] for SP02 and [,220] for Heart Rate The monitoring of vital signs is essential for the continuous assessment and proper care of newborns. This data not only facilitates the early detection of health issues but is also crucial for personalizing treatment, improving clinical outcomes, and contributing to the development of best practices in neonatal care [ 33 , 34 ] Pose Estimation A total of 33 body points, each with x, y, and z values (spatial position) [0,1] for x and y [−1,1] for z (normalized values) The study of neonatal movement patterns (pose tracking), along with other clinical data (weight, gestational age, physiological parameters), can be used to assess motor development and facilitate the early identification of neurological or motor anomalies [ 32 , 35 ] Data sources collected and available in NeoVault At the forefront of artificial intelligence, NeoVault functions as a platform for training cutting-edge AI models, facilitating the automating early detection of health problems (such as neurological and motor [ 35 – 38 ]) and holding the potential to revolutionize the efficiency and accuracy of neonatal care. Noteworthy is NeoVault ’s user-friendly interface, enabling seamless navigation through complex queries, data mining, and visualization, positioning it as an indispensable tool in the realm of preterm infants’ healthcare and research. Furthermore, NeoVault includes a high-level API ( Application Programming Interface ) implemented through a RESTful style [ 39 ] to provide a set of web services than can be used by developers/programmers to access data automatically or integrate data access in third-party applications. In summary, NeoVault is a proposal for promoting open science by the collection of large and rich standardized datasets in the field of neonatal care. The primary focus of NeoVault is to provide a web for compiling neonatal information of clinical interest, accessible for reading and writing by both medical personnel and researchers. A data hub like NeoVault can be useful not only for easily visualizing and searching for information but also for providing a compilation of different measurands of clinical interest that often are found scattered in different data-bases, that are rarely stored in clinical settings, or that until recently have not been recorded as they depend on the subjective observations done by medical staff. Numerous studies have shown that combining data from various sources can be beneficial for evaluating the physical condition of neonates [ 40 ], predicting risks [ 41 ], or associating movement patterns with motor development or the early identification of neurological or motor anomalies [ 32 ]. NeoVault not only provides all this information, but its access is also interactive and user-friendly, allowing users to obtain organized and structured data ready for analysis, without the need to worry about data cleaning or curation. NeoVault is a platform for interactive, real-time access, from any device, to physiological, medical, and postural information of neonates. NeoVault is hosted on https://conversational.ugr.es/neovault/ . NeoVault follows a client-server architecture implemented through a Service-Oriented Architecture (SOA) philosophy [ 42 ]. In the server-side (also known as backend ) of NeoVault , a set of web services are implemented to provide functionality: registering new neonates, searching by filters, listing all neonates, obtaining physiological parameters, generating datasets, etc. These services are implemented in Python using the Flask framework 1 . Additionally, other libraries are used for data processing and other functionalities such as Pandas 2 , Numpy 3 , os, zipfile, and shutil. MySQL is used as the database management system, and its interaction with the services is done through the SQLAlchemy library 4 . One of the functionalities implemented in the backend, in addition to information management, is the ability to generate an animated image (GIF) from a set of postural data. This is done for each package of postural data uploaded for the neonate, to visualize it illustratively later on. This functionality is implemented using the MediaPipe 5 , Matplotlib, and ImageMagick libraries. On the other hand, NeoVault’s front-end utilizes native HTML5, CSS, and Javascript technologies. Additional libraries are used for design (CSS), such as Bootstrap 6 and Fontawesome, and for functionality (Javascript), such as JQuery 7 and Highcharts 8 . All the information in NeoVault is accessible through two different interfaces: Web Interface . Through the options on the website, users can list available data, filter the information according to medical parameters as well as by date, and generate custom datasets. These datasets are stored in CSV files, so they can be easily exploited by doctors and data scientists through data processing software such as Excel, Jupyter, etc. API (Application Programming Interface). A RESTfull API is provided for programmers to access information automatically, aiming to integrate medical data in real-time into other types of systems. The API specification is described in OpenAPI, accessible from the same website through a dedicated webpage. All information returned by the services is represented in JSON format to ensure operability and enable access to the information from any device and platform. Web Interface . Through the options on the website, users can list available data, filter the information according to medical parameters as well as by date, and generate custom datasets. These datasets are stored in CSV files, so they can be easily exploited by doctors and data scientists through data processing software such as Excel, Jupyter, etc. API (Application Programming Interface). A RESTfull API is provided for programmers to access information automatically, aiming to integrate medical data in real-time into other types of systems. The API specification is described in OpenAPI, accessible from the same website through a dedicated webpage. All information returned by the services is represented in JSON format to ensure operability and enable access to the information from any device and platform. NeoVault is a platform that has been created from scratch, aiming to expand its dataset over time. Currently, there are data registered for 11 neonates (8 boys and 3 girls) including the following medical indicators: sex, gestational age, birth size, head circumference at birth, birth weight, Apgar 1 and Apgar 5 tests, CRIB ( Clinical Risk Index for Babies ), and whether the neonate has brain injury or not assessed by clinicians through brain ultrasonography. For each neonate, there are records at different time points regarding their physiological parameters (heart rate and oxygen saturation) and postural data. In total, as of March 2024, NeoVault has approximately 3000 physiological records (each containing heart rate and oxygen saturation) and close to 800.000 postural records, where each record stores information for 33 body points (nose, left elbow, various parts of the eyes, etc.) in three spatial coordinates ( x, y, z ). The Fig. 1 shows the architecture and data flow of NeoVault . Fig. 1 NeoVault architecture and workflow NeoVault architecture and workflow The data have been collected using the Neonate Recording Platform (NRP) [ 8 ], which was deployed at Puerta del Mar University Hospital (Cádiz, Spain) throughout the year 2023 (1). NRP allows for the scheduling of automatic clinical trials for data collection, creating a folder structure for each trial where study metadata (study identifier, neonate ID, start time, end time, etc.) are stored, along with physiological data captured in real-time through an artificial vision system, positional data captured in real-time through an AI camera system, labeling data, and audio capture-related data (2). NRP has two main cameras. The first camera is a regular camera (similar to a webcam) that focuses on the medical monitor connected to the neonate, where all vital signs (heart rate, SpO2, respiratory rate) are displayed. Through NRP, frames of the medical monitor’s front are captured, and using an algorithm called CardMed , which is based on computer vision (e.g., deep learning classification, image cropping, Optical Character Recognition, OCR ...), these physiological parameters are extracted from each frame along with a timestamp. This algorithm is extensively described in [ 8 ], where it was shown to have a reliability of 91% for heart rate and 90% for SpO2. On the other hand, the second camera is a three-lens depth and AI camera (Luxonis OAK-D model 9 ), which loads the pre-trained Google Mediapipe®model 10 and allows the extraction of 33 body landmarks from the neonate in real time (>20 frames per second, fps). For each frame, all 33 landmarks are recorded in three dimensional spatial coordinates, that is, consisting of x, y, and z components (see Fig. 2 ). Additionally, when nurses or doctors access the incubator to handle the neonate, NRP only detects and stores the body of the neonate. On the other hand, if an arm, hand, or object obscures the body, the software does not store partial body data—only complete data—to ensure its quality. For this reason, all data recorded in NeoVault correspond to full-body captures of the neonate. Fig. 2 Pose landmarker model - Image obtained from ( https://ai.google.dev/edge/mediapipe/solutions/vision/pose_landmarker ) (Property of Google) Pose landmarker model - Image obtained from ( https://ai.google.dev/edge/mediapipe/solutions/vision/pose_landmarker ) (Property of Google) To this folder structure, a CSV file containing medical data known only to medical staff (for privacy reasons) is added (so far this process is done manually) (3). This entire information is compressed into a single file (4) that is used by NeoVault as input data. Currently, this information is uploaded through the RESTful API with security constraints (5), which is then transformed into database records via a parser implemented in Python. Once the information is registered, it is easily and conveniently accessible through the web interface for both medical personnel or data scientists (6), as well as for programmers or developers using the API (7), aiming to integrate this information in real-time and automatically into other systems or solutions. The Web interface is structured around four blocks: (a) filtering and searching for neonates; (b) list of available neonates along with medical information; defining a time frame for (c) postural information, where you can filter to indicate which parts of the body you want to include in the dataset; and finally, (d) physiological parameters (heart rate and oxygen saturation). The search block (a) allows obtaining all available neonates (without filters) or applying a filter according to the following parameters: 1) gender (boy, girl, both); 2) gestational age (value between 25 and 36 weeks); 3) birth size (value between 20 and 50 centimeters); 4) birth head circumference (value between 15 and 45 centimeters); 5) minimum and maximum birth weight (in grams); 6) APGAR 1 and APGAR 5 scores (values between 0 and 10); 7) CRIB (Clinical Risk Index for Babies) score (value between 0 and 23); and finally, whether the neonate has 8) brain damage or not. Additionally, in this block, each parameter can be enabled or disabled to consider it in the search or not. Once the search criteria are applied (b) , the available neonates are listed, displaying for each of them the gender (using blue color for male and pink for female, along with an illustrative icon), the neonate identifier (integer number), and the last data update date. Additionally, when hovering over each neonate, the values associated with the medical parameters indicated in the search block ( a ) are displayed in a pop-up. Figure 3 shows an illustrative example of these two blocks. Fig. 3 Search by medical parameters and neonate list in web interface Search by medical parameters and neonate list in web interface From a selected neonate, it is possible to search for postural parameters data within a date range ( c ). NeoVault provides data for 33 landmarks (see footnote 5), and the platform allows selecting the upper body, lower body, entire body, or a customized selection. As an illustrative example, the user can view a 2D representation showing a few seconds of movement of the selected neonate. The same search request also returns existing physiological parameters (heart rate, oxygen saturation) ( d ). In NeoVault , each data record has, and will continue to have, an associated timestamp (in milliseconds), regardless of the type of data. This allows for the chronological recording of all data and its subsequent exploitation, as well as the ability to observe evolution over time. For this reason. Additionally, instead of specifying a date range, the web interface allows returning all existing data for the selected neonate. Figure 4 illustrates these two blocks. Fig. 4 Postural and physiological data Postural and physiological data In order to enable automatic, real-time data access and integration into third-party systems, NeoVault provides an API for programmers/developers. This API follows a RESTful philosophy, and its usage description can be found on the page accessible from the web interface or from its specification through OpenAPI. All information for interacting with the services is described using JSON to ensure access by any platform or software. The services offered by the API include 1) listing neonates according to medical parameters; 2) obtaining postural data; and 3) obtaining physiological data for a neonate within a time range. The specification of these RESTful API endpoints can be found clicking in the green button located in the top-right corner with the text “API for Developers”. Although the most common way to access information is through one of these two channels (Web interface or RESTful API), the database can be found in NeoVault data repository 11 , which will be periodically updated to provide the same information as both access interfaces. In contrast to other databases dedicated to preterm infants, as highlighted in “ Background ” section), NeoVault stands out by offering a multitude of advantages. These differentiating factors contribute to its uniqueness and enhanced utility in the domain of neonatal care and research. A summary of the comparison between NeoVault and other databases is included in Table 2 . Table 2 Comparison of preterm infants data-base Features BabyPose MIAdataset Preterm Clinical Network (PCN) MMSdataset NeoVault Intuitive Navigation Yes Yes No Yes Yes Responsive Design Yes Yes Yes Yes Yes 3D visualization tool No No No No Yes Data Type 12 limb-joint locations and depth images related to the movement of neonates A timeline of 16 different states vector of a preterm infant Data concerning the care of women at risk of preterm birth and registry of children born to women at risk(born prematurely or not) Perinatal data-neonatal data Perinatal data-neonatal data; physiological parameters and 33 reference points of the preterm body User-friendly interface No No Yes No Yes Accessibility Public Restricted Restricted Public Public Support for Complex Queries No No Yes No Yes Collaborative environment No No Yes No Yes Cost Free Free Free Free Free Ease Import/Export Yes No No Yes Yes Comparison of preterm infants data-base One of the main contributions of NeoVault is its operation as a publicly accessible database, that houses perinatal and neonatal data, encompassing crucial physiological parameters such as oxygen saturation and heart rate. Additionally, it meticulously provides spatial data of 33 landmarks defining the body pose of preterm infants, offering an understanding of their intricate neuromotor development. The platform goes beyond mere data storage by providing an useful 2D visualization tool of neonates body movements. Moreover, NeoVault emerges as an invaluable resource for healthcare professionals, researchers, and AI scientists. In the realm of neonatal care, NeoVault could play a pivotal role in early diagnosis thanks to the data that can be found in the database, empowering healthcare practitioners to identify developmental deficits in the preterm infant’s stages. This early detection is crucial for the initiation of therapeutic interventions, fostering optimal outcomes for the neonates. Although, in the AI era, NeoVault stands at the forefront, offering a robust foundation for training AI models. The data housed within the database becomes a training ground for cutting-edge AI, enabling the automation of early detection processes for neonatal medical issues. This intersection of healthcare and AI holds the promise of revolutionizing the efficiency and accuracy of neonatal care. Beyond its substantive data holdings, NeoVault distinguishes itself with a user-friendly interface. This interface is not merely a gateway for data retrieval, also provides seamless data visualization, integration, and formatting, enhancing the overall user experience and making NeoVault a versatile and indispensable database in the landscape of preterm infants healthcare and research. On the other hand, the possibility of accessing NeoVault data through its RESTful API not only enables another way for developers or programmers to access the data, but also the opportunity to access that data in real-time and integrate such access into other applications or systems, such as hospital systems, private software, medical repositories for data scientists, etc. The current version of NeoVault is stable, but it is true that there are several shortcomings which are being considered for future work and will be implemented in the near future. These planned improvements include: User management system . Currently, information is uploaded manually without any record of which users (neonatologists, doctors) contribute that information. The aim is to add a user management system where each medical personnel can manage their neonates through a username/password access method. However, the user/password access method, while necessary, is not sufficient. Additional personnel verification mechanisms will be implemented to ensure that any user wishing to register to upload information is indeed healthcare or research personnel. For example, institutional email will be verified, and professional credentials or those from their institution will be requested, among other methods, to validate their identity and role. Improve the system for adding data . Currently, adding new information is done through the RESTful API using a username and password to prevent unauthorized users from uploading false or unreliable data in the current version. With the user management mentioned in (1), each identified user will be able to upload data more easily and with more credibility. This means opening up the capability for the rest of the community to contribute new data. NeoVault accepts data structured according to the format used by NRP . In future versions, there are plans to publish the specification so that any researcher or medical personnel can adapt their data to the format accepted by NeoVault and upload it easily. Automatic data dump from NRP . Although the option to upload information manually (2) will be available, the NRP software (used as data collector) [ 8 ] will be modified so that the data collected is automatically saved in NeoVault , eliminating the need for manual processing. Adding new data sources . In addition to physiological and postural parameters, NRP records audio and labels made by medical personnel that can be included as data sources in NeoVault. Additionally, external data sources can be added to NeoVault , such as blood analysis results or medical test outcomes (e.g., heel prick test) and clinical data that may be useful from a medical standpoint, such as post-menstrual age, whether the birth was by cesarean section, premature apnea, systolic murmur or even maternal characteristics like genetic factors, age, pre-existing medical conditions like diabetes, hypertension, heart disease, etc.. These data will be added based on medical criteria and the usefulness they may have as fundamental variables for data exploitation. The different improvements will be gradually included in NeoVault . Automatic tagging of events . An improvement of the recording of the data will be that of the implementation of algorithms for the automatic annotation of the videos. For example, an algorithm could be applied to the video source during recording to classify events happening in the field-of-view and to add tags such as if the baby is present or not, if the baby is being manipulated or not by the medical staff, or if the position of the baby is not in supine. Ensuring data quality . Although all information stored in and uploaded to NeoVault is consistent, with no empty values, null values, etc., there remains the possibility—either due to error or ill intent from users in the future—that the data, despite following a correct structure, may not be accurate or reliable. This means that the data could be fabricated, generated (for example, through generative AI), erroneous, or duplicated. Therefore, in the future, work will focus on algorithms or techniques that allow for the analysis of movement patterns before uploading the data to determine if they are coherent and real, thus minimizing the risk of erroneous data contaminating the rest of the reliable dataset. User management system . Currently, information is uploaded manually without any record of which users (neonatologists, doctors) contribute that information. The aim is to add a user management system where each medical personnel can manage their neonates through a username/password access method. However, the user/password access method, while necessary, is not sufficient. Additional personnel verification mechanisms will be implemented to ensure that any user wishing to register to upload information is indeed healthcare or research personnel. For example, institutional email will be verified, and professional credentials or those from their institution will be requested, among other methods, to validate their identity and role. Improve the system for adding data . Currently, adding new information is done through the RESTful API using a username and password to prevent unauthorized users from uploading false or unreliable data in the current version. With the user management mentioned in (1), each identified user will be able to upload data more easily and with more credibility. This means opening up the capability for the rest of the community to contribute new data. NeoVault accepts data structured according to the format used by NRP . In future versions, there are plans to publish the specification so that any researcher or medical personnel can adapt their data to the format accepted by NeoVault and upload it easily. Automatic data dump from NRP . Although the option to upload information manually (2) will be available, the NRP software (used as data collector) [ 8 ] will be modified so that the data collected is automatically saved in NeoVault , eliminating the need for manual processing. Adding new data sources . In addition to physiological and postural parameters, NRP records audio and labels made by medical personnel that can be included as data sources in NeoVault. Additionally, external data sources can be added to NeoVault , such as blood analysis results or medical test outcomes (e.g., heel prick test) and clinical data that may be useful from a medical standpoint, such as post-menstrual age, whether the birth was by cesarean section, premature apnea, systolic murmur or even maternal characteristics like genetic factors, age, pre-existing medical conditions like diabetes, hypertension, heart disease, etc.. These data will be added based on medical criteria and the usefulness they may have as fundamental variables for data exploitation. The different improvements will be gradually included in NeoVault . Automatic tagging of events . An improvement of the recording of the data will be that of the implementation of algorithms for the automatic annotation of the videos. For example, an algorithm could be applied to the video source during recording to classify events happening in the field-of-view and to add tags such as if the baby is present or not, if the baby is being manipulated or not by the medical staff, or if the position of the baby is not in supine. Ensuring data quality . Although all information stored in and uploaded to NeoVault is consistent, with no empty values, null values, etc., there remains the possibility—either due to error or ill intent from users in the future—that the data, despite following a correct structure, may not be accurate or reliable. This means that the data could be fabricated, generated (for example, through generative AI), erroneous, or duplicated. Therefore, in the future, work will focus on algorithms or techniques that allow for the analysis of movement patterns before uploading the data to determine if they are coherent and real, thus minimizing the risk of erroneous data contaminating the rest of the reliable dataset. NeoVault stands as a data hub for contributing to advancement in neonatal healthcare research. It is a platform created to become a key resource, offering researchers, medical professionals, students, and data scientists access to meticulously organized datasets of preterm infants. These datasets would not only facilitate investigations into diagnostic improvements and treatment strategies but also empower studies focused on early disease detection, providing valuable insights for enhancing neonatal care protocols. At its core, NeoVault emerges as a publicly accessible database, offering a comprehensive repository of movement data, physiological parameters, and neonatal and perinatal records for preterm infants who underwent hospitalization in a NICU. Its user-friendly interface allows users to define and filter queries, visualize datasets, and seamlessly export results in various file formats. The platform goes beyond conventional data storage by providing an advanced 3D visualization tool, enabling users to explore and analyze neonatal movements dynamically. Future initiatives involve leveraging the database for cutting-edge studies, particularly in the realm of early detection of neurological issues, such as those managed by the PARENT project 12 . Additionally, NeoVault envisions establishing connections with more extensive datasets encompassing larger populations of preterm infants, promising to broaden its scope and impact in the field of neonatal healthcare research. Artificial Intelligence Appearance - Pulse - Grimace - Activity - Respiration Application Programming Interface Clinical Risk Index For Babies Cascading Style Sheets Comma-separated values Electrocardiogram Graphics Interchange Format Hypertext Markup Language Javascript Object Notation co-founder Michael Widenius’s daughter name Neonatal Intensive Care Unit Neonatal Infant Pain Scale Neonate Recording Platform Occipitofrontal Circumference PrematuRe Newborn Motor and Cognitive Impairments Preterm Clinical Network Representational State Transfer Service-Oriented Architecture Structured Query Language https://flask.palletsprojects.com/en/3.0.x/ https://pandas.pydata.org/ https://numpy.org/ https://www.sqlalchemy.org/ https://developers.google.com/mediapipe/solutions/vision/pose_landmarker https://getbootstrap.com/ https://jquery.com/ https://www.highcharts.com/ https://shop.luxonis.com/products/oak-d https://ai.google.dev/edge/mediapipe/solutions/vision/pose_landmarker https://github.com/bihut/neovault-database https://parenth2020.com/ Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The authors would like to thank all the healthcare staff at Puerta del Mar University Hospital (Cádiz, Spain) for their collaboration during data collection, as well as the parents who granted permission for the collection of data about their baby. JPR conceived the idea of NeoVault, implemented the web interface (front-end), and conducted data collection at the hospital. ARZ designed the architecture of NeoVault and implemented the back-end (services and RESTful API). IBF and SPL planned the studies with neonates at the hospital and processed the documentation with the ethics committee. SAHS and SATS assisted in data cleaning, curation, and management. LCG is the project organizer and, along with JPR, prepared the paper which was then read and approved by all authors. The author(s) read and approved the final manuscript. Funding for open access publishing: Universidad de Cádiz/CBUA This work is part of the “PremAtuRe nEwborn motor and cogNitive impairment: Early diagnosis PARENT project”. The PARENT project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Maria Sklodowska-Curie Innovative Training Network 202, Grant Agreement Nº 956394. In addition, this work also received inputs from the Spanish R&D projects funded by MCIN/AEI/10.13039/501100011033 GOMINOLA (Grant PID2020-118112RB-C21 and Grant PID2020-118112RB-C22). The data used is available through the web interface of the NeoVault platform ( https://conversational.ugr.es/neovault ) as well as through the RESTful API https://conversational.ugr.es/neovault/api/v1 . The raw dataset is available in the repository https://github.com/bihut/neovault-database . The study was approved by the Puerta del Mar University Hospital (Cadiz, Spain) (reference number 125.22) and after obtaining the informed consent of the parents. All research data are de-identified and securely stored. Not applicable. The authors declare no competing interests. NeoVault: empowering neonatal research through a neonate data hub Public health implications of very preterm birth Maturational changes associated with neonatal stress in preterm infants hospitalised in the NICU Do NICU developmental care improve cognitive and motor outcomes for preterm infants? A systematic review and meta-analysis Principles of plasticity in the developing brain Video-Based Automatic Baby Motion Analysis for Early Neurological Disorder Diagnosis: State of the Art and Future Directions Early-life factors associated with neurobehavioral outcomes in preterm infants during NICU hospitalization Automatic Detection of Epileptic Seizures in Neonatal Intensive Care Units Through EEG, ECG and Video Recordings: A Survey NRP: A multi-source, heterogeneous, automatic data collection system for infants in neonatal intensive care units NeoCam: An edge-cloud platform for non-invasive real-time monitoring in neonatal intensive care units The Preterm Clinical Network (PCN) Database: a web-based systematic method of collecting data on the care of women at risk of preterm birth Requirements of health data management systems for biomedical care and research: scoping review Education and Training on Electronic Medical Records (EMRs) for health care professionals and students: A Scoping Review Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers? Predicting the outcomes of preterm neonates beyond the neonatal intensive care unit: what are we missing? Neonatal sepsis and its association with birth weight and gestational age among admitted neonates in Ethiopia: systematic review and meta-analysis Size at birth and neonatal and postneonatal mortality Neonatal mortality and associated factors in the specialized neonatal care unit Asmara Cause and predictors of neonatal mortality among neonates admitted to neonatal intensive care units of public hospitals in eastern Ethiopia: a facility-based prospective follow-up study The relationship between the five minute Apgar score, mode of birth and neonatal outcomes Evaluation of neonatal mortality risk in the crib score application Rgb-d videos-based early prediction of infant cerebral palsy via general movements complexity Vital signs analysis algorithm detects inflammatory response in premature infants with late onset sepsis and necrotizing enterocolitis Vital signs as physiomarkers of neonatal sepsis Deep learning-based quantitative analyses of spontaneous movements and their association with early neurological development in preterm infants The importance of assessing general motor activity in premature infants for predicting neurological outcomes Spontaneous movements as a prognostic tool of neurodevelopmental outcomes in preterm infants: A narrative review Reduction in limb-movement complexity at term-equivalent age is associated with motor developmental delay in very-preterm or very-low-birth-weight infants Risk factors for neonatal mortality in Neonatal Intensive Care Units (NICUs): a systematic literature review and comparison with scoring systems Machine learning models for predicting neonatal mortality: a systematic review Service oriented architecture |
Answer the following medical question. | What does research say about Transitional cardiovascular physiology and comprehensive hemodynamic monitoring in the neonate: relevance to research and clinical care.? | A thorough understanding of developmental cardiovascular physiology is essential for early recognition of cardiovascular compromise, selective screening of at-risk groups of neonates, and individualized management using pathophysiology-targeted interventions. Although we have gained a better understanding of the physiology and pathophysiology of postnatal cardiovascular transition over the past decade with the use of sophisticated methods to study neonatal hemodynamics, most aspects of neonatal hemodynamics remain incompletely understood. In addition, targeted therapeutic interventions of neonatal hemodynamic compromise have not been shown to improve mortality and clinically relevant outcomes. However, the recent development of comprehensive hemodynamic monitoring systems capable of non-invasive, continuous and simultaneous bedside assessment of cardiac output, organ blood flow, microcirculation, and tissue oxygen delivery has made sophisticated analysis of the obtained physiologic data possible and has created new research opportunities with the potential of direct implications to patient care. |
Answer the following medical question. | What does research say about Intelligent neonatal monitoring based on a virtual thermal sensor.? | Temperature measurement is a vital part of daily neonatal care. Accurate measurements are important for detecting deviations from normal values for both optimal incubator and radiant warmer functioning. The purpose of monitoring the temperature is to maintain the infant in a thermoneutral environmental zone. This physiological zone is defined as the narrow range of environmental temperatures in which the infant maintains a normal body temperature without increasing his or her metabolic rate and thus oxygen consumption. Although the temperature measurement gold standard is the skin electrode, infrared thermography (IRT) should be considered as an effortless and reliable tool for measuring and mapping human skin temperature distribution and assist in assessing thermoregulatory reflexes. Body surface temperature was recorded under several clinical conditions using an infrared thermography imaging technique. Temperature distributions were recorded as real-time video, which was analyzed to evaluate mean skin temperatures. Emissivity variations were considered for optimal neonatal IRT correction for which the compensation vector was overlaid on the tracking algorithm to improve the temperature reading. Finally, a tracking algorithm was designed for active follow-up of the defined region of interest over a neonate’s geometry. The outcomes obtained from the thermal virtual sensor demonstrate its ability to accurately track different geometric profiles and shapes over the external anatomy of a neonate. Only a small percentage of the motion detection attempts failed to fit tracking scenarios due to the lack of a properly matching matrix for the ROI profile over neonate’s body surface. This paper presents the design and implementation of a virtual temperature sensing application that can assist neonatologists in interpreting a neonate’s skin temperature patterns. Regarding the surface temperature, the influence of different environmental conditions inside the incubator has been confirming. Recently, the rapid improvement in medical thermography technologies in various clinical fields has promoted the use of thermography imaging as a contactless physiological sensor. In particular, neonatal intensive medicine is a clinical field in which infrared thermography may play a future role in non-invasive monitors. Initially, Clark et al. [ 1 ] performed the first clinical trials using direct thermography measurement in neonates, which was dated back to 1980. To perform non-invasive skin temperature measurements, the setup included a hole in the roof of the incubator and the assistance of a mirror system; these additions [ 1 , 2 ] allowed for real-time measurements of thermal reputation. Adams et al. [ 3 ] achieved successful direct thermography imaging in the earliest minutes of life by using a long-wave infrared (LWIR) system. In that project, continuous thermal monitoring of the neonate was accomplished at intermittent intervals ranging between 20 and 30 minutes at the initial stage. Then, a modified protocol was defined to monitor preterm infants inside a convective incubator, kangaroo mother care, and open radiant warmer. The results were compared with values obtained from multiple weighted measurements of resistance temperature device (RTD) sensors. Pavlidis et al. [ 4 - 6 ] developed a tracking system for infrared thermography as part of an augmented computer vision system. This development was based on a coalitional tracking approach in which a distinct region of interest (ROI) was defined over the neonate’s face and its position was tracked over numerous infant motion planes. Recently, Abbas et al. [ 7 ] developed a concept for non-contact respiration monitoring in infants based on IR thermography (IRT). This technique also tracks the nostrils’ thermal signature to detect the infant’s breathing rate at a distance, and it provides an insightful analysis of possible error sources within the neonatal IRT (NIRT) imaging technique. The need for a robust and intelligent temperature monitoring methodology has increased, which makes NIRT imaging a suitable candidate for contactless temperature measurement and observation inside neonatal intensive care unit (NICU) facilities [ 2 , 8 ]. The NIRT method demonstrates good outcomes for the real-time and continuous quantification of a neonate’s surface and core temperatures; however, it lacks the ability to estimate the real temperature value on a neonate’s body surface accurately. This lack of reliability is mainly due to the unknown emissivity, ε. For reference, the experimenter could utilize an emissivity value ε for a known material surface or could utilize fabric supplies, such as a hand band or head caps, sutured with a material of known emissivity, such as copper, polished steel, or polyvinyle-flouride electrical tape (e.g., scotch-764). However, in such clinical study, it is impossible to use like material due to the hygienic and disinfection concern that roses within the utilization of these material inside infant incubators. Radiation in the long wave infrared (LWIR) bands (8-14 μm) is important because the human body emits most of its thermal radiation, which encodes valuable physiologic information, in this region of electromagnetic spectrum. This vital information, if properly processed and analyzed, may be used in many biomedical applications, such as mean body temperature mapping and arterial pulse measurements [ 6 , 9 , 10 ]. A solid base that includes an understanding of the physics of image formation principles, the choice of imaging IR band, and instrumentation is crucial for successful biometrics signature processing. Such signatures include superficial vessel blood flow [ 11 ], forehead mean temperature, and nostril thermal patterns [ 4 , 12 - 14 ]. Possible IRT tracking and monitoring sites on a neonate’s body are displayed in Figure 1 ; these spatial points will be the reference sites for virtual temperature sensing as the issue is discussed further in this paper. Positions of different possible locations of the virtual temperature sensor developed for NIRT. Directing from (a) initial position of black window (on face) as reference sensor and white windows as ancillary points showing spatial variation over (b, c, d and e) to register different temperature of the neonate and incubator. Thermography imaging offers a high-quality concept for the observation and monitoring of different physiological processes [ 8 , 15 , 16 ]. Recently, we used IR thermal imaging to monitor and map the temperature distribution over the preterm infant’s body [ 12 , 17 , 18 ]. We believe that this technique will become an alternative technique in the future to gold-standard technologies in neonatal temperature monitoring and control [ 19 ]. All measurements were performed using a VarioCAM® hr head (InfraTec GmbH, Germany) IR camera (LWIR, 7 μm to 14 μm). The camera transferred the thermal map to a PC via the IEEE 1394 FireWire interface. The neonate’s thermal images were taken inside a convective infant incubator (Caleo, Draeger AG, Germany) and converted to a 2D array containing temperature information within the LabVIEW software platform. Additionally, these data were used to test the algorithm software’s ability to track the specified virtual temperature sensor points on a neonate’s skin after motion. Figure 2 illustrates a typical setting for NIRT clinical study inside a convective incubator. Experimental setup of the NIRT Clinical study by using thermography imaging technique in association with a clinical temperature measurement (a) 3D schematic for components and elements of the setup (1) patient monitoring system, (2) convective infant incubator unit, (3) analysis workstation, (4) IR camera and (5) infant with two skin electrodes connected. (b) Photograph of typical clinical setting. Only ten newborn infants were selected to participate in the clinical study, five of them were under radiant warmer therapy and the rest are placed inside convective incubator. A referential ground truth measurement was implemented by using skin temperature electrodes as gold standards. The accuracy of these clinical skin electrodes is (± 0.1°C). The NIRT imaging and measurement was performed at the Department of Neonatology (RWTH Aachen University Hospital), and this has been approved by the medical ethics committee of the RWTH Aachen University Hospital, issued on 19 August 2009 with reference code (EK032/09). The acquired thermography datasets used for testing the tracking algorithm. Each dataset contained one measurement scene consisting of a newborn infant undergoing thermography inside a convective incubator or under a radiant warmer. The tracking time was approximately 20 minutes for each subject with a frame rate of 25 fps, and the measurements were conducted as a real-time imaging operation. In principle, a higher frame rate (up to 50 fps) could be achieved; however, a higher frame rate would increase the size of the thermography data to an out-of-memory level in many PCs. Principally, the selected thermography datasets often included involuntary movements of the neonate during the 20 minutes of thermography acquisition time. The thermography data featured out-of-plane rotation of the facial tissue, hands, feet, and main trunk as the neonates rotated their heads left, right, up, down, or in a random motion. For covering all planes and geometry of the neonate, we configure and selected ROI over the neonate’s skin to guarantee effective temperature detection over examination time (Figure 3 ). Virtual geometric profiles utilized in ROI tracking for NIRT images (a) and the corresponding profiles over the neonate’s body (b), which will be tracked throughout all of the video frames (the perspective of the overhead ROI changes). A ring-projection transformation was selected in the tracker hierarchy to be compared against the active ROI tracker. The calibration phase of the IR camera was performed directly throughout the measurement time. The typical NIRT protocol sequence used in this study explained in Figure 4 , in which the NIRT measurement phase indicates different intervals throughout time. NIRT protocol used in the virtual sensor tracking. (a) ROI profiles located over the neonate’s skin (b) and an alternative layout of the neonate prior to NIRT imaging. The calibration process of the thermal camera took place inside the NICU ward in synchronization with the NIRT measurement phases [ 20 ]. This process is called automatic non-uniformity calibration (ANUC), and the procedure compensates for temperature drift during measurements. In addition, the selected field of view (FOV) for the camera assured that there is no influence on thermography resolution during NIRT imaging despite the inclined side angle of the thermal camera within the allocated FOV. This was confirmed during analysis and modeling of heat fluxes dissipated from neonate within NIRT measurement [ 19 ]. Temperature and humidity variations inside the convective incubator are commonly considered the main factors that prevent accurate temperature calibration. Therefore, to avoid any incorrect temperature registration and physical related errors in NIRT imaging, the calibration process was implemented during the clinical measurement using the IRBIS® Professional software of the IR camera. Objects of interest (OOIs) inside the acquired thermogram were selected and the environmental, incubator and object settings were performed through an IR transparent window (with 0.01 mm thickness) made of polyethylene (PE) material [ 3 ]. The transmission of IR radiation through the foil is between 0.92 and 0.94. Therefore, this transparent foil was chosen to block the opened incubator clapper while allowing the baby inside the incubator to be visualized because the Plexiglas® material of the incubator hood is an IR-reflecting material with emissivity values reaching 0.97 [ 1 , 21 ]. A geometric correction was applied to the acquired thermography using selected region of interests (ROI) over the neonate’s skin and setting the physical parameters (e.g., incubator air temperature, outside window temperature, humidity, IR transmission of PE thin-foil and body temperature) for optimal thermography correction. Figure 5 shows the difference in calibration setting between different thermography scenes where in scene (a) the thermography imaging performed through IR-transparent window and in scene (b) thermography imaging performed directly without interfering media [ 19 ]. Two thermograms showing the effect of geometric correction of the neonate, it is noticed that the neonates skin temperature in thermogram (a) with higher value than in thermogram (b) of the same neonate, therefore, correction step prior to NIRT imaging is important for accurate thermography acquisition. Moreover, the data were registered against an emissivity equal to unity (considering neonatal skin as a typical blackbody radiator), although the actual value of emissivity was equal to 0.972 [ 22 , 23 ]. This correction strategy plays a vital role in accurate temperature mapping because any slight difference in the emissivity value will tend to add inaccuracies to the temperature reading from the IR camera. The term “Virtual InfraRed SENSor” (VIRSENS) relates to a sensing method based on augmented visual or physical measurements. In this work, a virtual temperature sensor was developed wherein contactless temperature measurements essentially replace the clinical gold standards. Furthermore, virtual sensor tracking software was developed using LabVIEW® Vision Assistance (National Instruments®) as an integrated toolkit. This software allowed the thermal camera to be connected directly the LabVIEW console by using a native interface file provided by the manufacturer (Figure 6 ). Architecture of thermography imaging acquisition within the LabVIEW platform for the virtual thermal sensor. Thermography acquisitions began after IR camera calibration and were followed by the extraction of the thermal data from the color space of the image; this task formed a crucial step of the VIRSENS concept. Moreover, the selection of the ROI array was initiated afterward to set the tracking coordinates of the neonate’s body regions to be implemented the image-processing loop and architecture (Figure 7 ). (Left): Successive thermography frame-by-frame definition and tracking of selected ROIs from the different body parts of a neonate, (Right): Simplified flow diagram for tracking method in the virtual sensor. The key aspect for robust virtual sensing is the tracking method, which should accurately monitor the motion of the target surface even in the presence of partial occlusion or deformation [ 24 ]. This tracking system is applied to follow the motion of the target’s outline (and not only superficial features) [ 25 - 28 ]. Generally, motion tracking is not a straight forward process; it depends on the proper definition of the tracked anatomical geometry and the ability to follow-up and mark the defined ROI over multiple thermography frames (Figures 7 and 8 ). Fundamental steps of the ROI tracking algorithm for NIRT virtual thermal sensing, illustrating processing flow from thermal acquisition down to the surface temperature presentation. Primarily, the tracking algorithm can be divided into five main stages, as illustrated in Figure 8 : IR thermography acquisition, ROI geometry profile definition, object coordinate tracking, information extraction, and sensor display. The manner in which the active ROI moves through the image frames is illustrated in Figure 9 , where the yellow rectangle moves with the relative motion of the baby inside the camera’s field of view (FOV). Two successive ROI tracking images used in the virtual sensing technique, were the ROI profile moves due to the neonate’s body movements along relative coordinates. When template matching, the ring projection template (RPT) process was used to address rotational variations within the thermography-imaging scene. The RPT reduces a 2D thermogram image into a 1D vector. In general, this task is used as a pre-processing step in the VIRSENS approach. We define the initial template to be T(x,y) of size (M × N). The RPT process begins by deriving a center point on the Template T(x,y) that is denoted as (x c ,y c ) . Subsequently, the Cartesian frame coordinate Template T(x,y) is transformed into polar frame coordinates based on the following relations: x = r cosθ (for horizontal reference) , y = r sinθ (for vertical reference) where (1) r = int x − x c 2 − y − y c 2 , r ∈ 0 , R , R = min M , N Basically, the ring projection in the selected template T(x,y) at radius r is denoted as P T (r) and is defined as follows: (2) P T r = 1 S r ∑ k T r cos θ k , r sin θ k , where S is the total number of pixels falling on the circle of radius r r = 0,1,2,…,R and k denotes the number of correlation iterations in template matching kernel. Note that P T (r) is defined as the mean pixel intensity along a circle whose radius to the center of the template has equal order in the correlation computation. Because the RPT is synthesized along circular rings of increasing radii, the derived 1D RPT on the thermography image is invariant to the rotation of its corresponding 2D image template. To effectively obtain the RPT computation along concentric circles, the method employs a look-up table (LUT) whose diameter is set to the size of the template in the ring projection process. Finally, the RPT is obtained simply by summing up the pixel values along a concentric circle within the template results. For the matching process, the normalized correlation (NC) is adopted in the similarity measurement. Therefore, we consider the following: (3) P → T = Δ P T 0 , P T 1 , … , P T R and (4) P → S = Δ P S 0 , P S 1 , … , P S R Generally, the representations of the reference template ring-projection vectors ( ) and thermography scene subimage ( P → T ) are computed consecutively. The normalization correction (NC) process between the ring projection vectors P → S and P → T , denoted by P → S , is defined as P → T , P → S (5) P → T , P → S = R + 1 ∑ r = 0 R P T r P S r − ∑ r = 0 R P T r ∑ r = 0 R P S r 2 × 100 R + 1 ∑ r = 0 R P T r 2 − ( ∑ r = 0 R P T r ) 2 R + 1 ∑ r = 0 R P S r 2 − ( ∑ r = 0 R P S r ) 2 With this definition, the value is unaffected by rotational and linear changes (at constant gain and contrast offset in the thermal imaging) in the reference template and thermography scene subimage. In addition, the dimensional length of the ring projection vector is only (R + 1). This significantly increases the computational efficiency for the vector P → T , P → S . The method proposed here is inspired by the PT method, which is characterized by a decrease in computational complexity when the thermography image involves a change of scale and rotation. Therefore, it is considered a robust solution for the large-scale image data generated in medical thermography [ 26 , 29 , 30 ]. To obtain rotation/scale invariance in the matching process, a simple approach using a P T vector (template image) and a P S vector (scene subimage) was proposed. In the VIRSENSE approach, a PT vector was constructed from a base-ring projection set ( P → T P ) consisting of the RPTs and including the template image and differently scaled images as follows: P → t 0 , P → t 1 , … , P → t N (6) P → T P = Δ P → t 0 ω 0 + P → t 1 ω 1 + … + P → t N ω N P → t 0 ω 0 + P → t 1 ω 1 + … + P → t N ω N , 0.0 ≤ ω i ≤ 1.0 , ∑ i = 0 N ω i = 1 . The NC between the scene subimage vector and a P → S PT vector becomes P → T P ; then, the problem under consideration can be solved by constrained optimization, that is, P → T , P → S (7) max ω → P → T , P → S , subject to ∑ i = 0 N ω i = 1 . Essentially, the Lagrangian multiplier (LM) method can solve this problem of difference optimization. The solution of is given by ω → (8) ω → = L − 1 F → n → • L − 1 F → , where ω → = Δ ω 0 ⋮ ω N , L = Δ P → t 0 , P → t 0 … P → t 0 , P → t N ⋮ ⋱ ⋮ P → t N , P → t 0 ⋯ P → t N , P → t N , F → = P → S , P → t 0 ⋮ P → S , P → t N and n → = Δ 1 ⋮ 1 The next step of the algorithm is producing the scaling value sq estimation of the scene subimage, which initiates in terms of the following equation (9) sq = ∑ i = 0 N ω i s i , where s for 0 ≤ i ≤ N denotes the different scaling values generated by scaling the template image. The approach enables fast matching in the ROI tracking algorithm. The computational efficiency is significantly increased because the RPT process reduces a 2D thermography image array into a 1D vector. Additionally, the correlation matrix ( i L) can be determined in the training phase while the optimal parameters , the scaling value obtained directly from the correlation vector ω → , and the correlation matrix F → L are determined in the matching phase [ 30 ]. In fact, there is no iteration step involved in this tracking template-matching-based algorithm. Therefore, the computational time is considerably reduced. Generally, this data description is appended to the input template image. During the matching phase, the template descriptor (the ROI descriptor, P ROI (x T , y T ) ) is extracted from the template image and used to search the template in the inspection image [ 31 - 33 ]. The mathematical process of image cross-correlation is simple; the RPT is overlaid on the source thermogram image, and the intensity values for each corresponding pixel are multiplied individually. Additionally, all of the matched templates are summed to produce a single correlation value [ 32 , 33 ]. The correlation value matrix is then scanned for its peak value. This position generally conforms to the position in the source image that most closely matches the template [ 22 , 34 , 35 ]: (10) P → T ≡ P T 0 , P T 1 , … , P T R T . P x , y where P(x,y) is the reference template position on the thermography image. The correlation matrix can include several high values that correspond to several instances (events) of tracked templates in the source thermography image [ 36 - 38 ]. One of the greatest flaws in cross-correlation is its inability to match objects in a source image that are either a different size or rotated compared to the reference template. These two template-matching mechanisms are used in the ROI descriptor tracking (corresponding to the projected template) in the frame matrix. The mathematical approximation of such a template inside a rectangular contour with T k (x k ,y k ) is as follows: (11) P T u = 1 S k ∑ k T x k , y k , To overcome and compensate for this issue throughout the NIRT data frames, the template must be rescanned over the thermography scene image using different rotations and sizes (variances in both the x- and y-axes). This process can be extremely time consuming; consider performing a cross-correlation 360 times just to perform a rotation-invariant match without even sub-degree precision [ 35 , 39 , 40 ]. If the tracked portion always has the similar size and no spatial distortion exists, then the virtual sensor does not scan for size variations [ 4 , 26 , 27 , 41 ]. The identical principle is applicable for rotation variance if the body part will be repeatedly positioned at the same orientation (Figure 10 ). In that case, the source thermography image is rescanned using a range of different angles (cross-correlation can typically detect object rotations of approximately ±5° without rescanning) is not necessary. Imaging-plane layout of ROI tracking over a neonate’s different body regions displaying the out-of-plane rotation coordinates that were used to develop an ROI tracking algorithm for medical IRT. The detection of object rotations can be accomplished at up to ±12°-18° angle of rotation without rescanning and initializing the reference ROI template. However, the inability of cross-correlation to match objects in a source image that are either a different size or rotated compared to the template is still one of the shortcomings in the rotation-and shift (scale)-invariant method for the object detection system [ 26 , 30 , 42 - 44 ]. In summary, the results obtained from the virtual sensor demonstrate its ability to accurately track different geometric profiles over the external anatomy of a neonate. Only a small percentage of the motion detection trials failed to track due to the lack of a properly matching matrix for the ROI descriptor under study (see Table 1 ). Comparison of scoring rate success for VIRSENS in NIRT imaging 1 The table also illustrates the correlation of the tracked ROI descriptor over the measurement scene with respect to a newly chosen position of the ROI descriptor. 1 The table presents the comparison of different success rates for the virtual temperature sensor used within the NIRT imaging for illustrating the scoring percentage of fitted and tracked ROI over the misallocated ones. The main clinical application of the presented virtual sensor approach is the continuous monitoring of patients without loss of the ROI due to unexpected movements or involuntary motions initiated by the patient. The VIRSENS approach offers the flexibility to perform stress-test infrared thermography, e.g., on treadmills, or to monitor unconscious patients (e.g., under intensive or critical care). Furthermore, this non-contact temperature monitor may become a tool in high-risk missions, such as for pilots or submarine staff [ 9 , 12 , 45 ], to provide online monitoring of respiration activity through convective heat-loss during expiration and inspiration [ 7 , 20 , 41 , 46 ]. To further advance the use of VIRSENS in neonatal medicine, we used embedded contactless temperature monitoring and regulation in a neonatal incubator closed-loop control system. This approach can reduce the need for skin temperature electrodes and the problems associated with their use, such as sensor dislocation, motion artifacts, calibration drift, wire crowding, false connections, and the possibility of infection for newborn infants. Moreover, this tracking method requires additional validation tests and clinical trials to provide beside the proof-of-concept (POC) of this technology feasibility in the neonatal monitoring field. In addition, the ability of VIRSENS to perform geometric identification of selected body parts (e.g., face, hands, legs, interscapular, and maxillary region) (see Additional files 1 , 2 and 3 ) adds a crucial role in anatomical posture identification for neurological reflexes and postural control of neonates. Because the VIRSENS has several misallocated ROI over the neonate’s geometry during the tracking process (Figure 11 ), which indicates that this method need further optimization and feasibility studies. This believed to be solved when more stable and precise tracking algorithms used in the VIRSENS architecture to become more stable monitoring technique. Setting of erroneous ROI tracking over neonate's body regions, displaying the desired ROI position set in sub-figure (a) and changing its position as illustrated in sub-figure (b) through sub-figure (d) by misallocation of the coordinate in the tracking software. Table 2 provides some of quantitative analysis for performance measuring in different thermography datasets within NIRT study. This table showing the scoring of matches of tracked ROI per anatomical regions for seven infants participating in the study. As we can see from Table 2 that the higher success rate of this scoring occurs, in the facial, plane where there is a prominent landmark such as nose, orbital, forehead and maxillofacial regions. Therefore, this is highly discriminated from other anatomy such as hand, arms, legs and trunk can be use the facial tracking as referential template for tracking accuracy and validation procedure of virtual thermal sensor. Comparison of different desired ROI locations of virtual temperature sensor 2 2 This table gives the quantitative index for the total numbers of fitted ROIs and missed ROIs over the total number of these selected ROIs for different spatial positions over neonate’s body. In this study, a thermal imaging tracking method was proposed and tested based on a template-matching algorithm. The developed method uses a spatially trained ROI tracker whose interactions are modeled using cross-correlations of the ROI template and a searchable IR image. The method’s output provides pixel-level tracking accuracy even in the presence of multidimensional target transformation. The proposed tracking method was effectively tested in thermal and visual datasets featuring facial regions and other anatomical objects. The thermography tracking system for neonatal monitoring was implemented and tested for clinical monitoring inside NICU unit. The main conclusion from this experiment is that the tracking can be robust over well-calibrated thermography frames and for lesser jerky movements of the neonate. In fact, thermography measurements performed at a distance are beneficial from a psychological viewpoint for both staff and the patient’s relatives but produce challenges from the medical perspective. The tracking problem, which is pivotal in this study, was particularly challenging due to the functional nature of thermal IR imaging and its application in real-time operation. Moreover, NIRT imaging depicts physiological changes; therefore, it is highly dynamic, non-linear, unpredictable in its uncertainties, and difficult to model. In addition, the estimation of the emissivity value at certain tracking points requires further optimization and development before it can be included in prospective NIRT applications, such as the detection of respiration signatures with the IRTR method or evaluation of superficial blood perfusion over active metabolic regions (e.g., liver and brain). Because these applications would appear to be difficult tasks due to the slow hemodynamic activities of the superficial vessels, the method requires further development and improvement for clinical convention in contactless blood perfusion and hemodynamics parameters. Furthermore, this physiological tracking application based on thermography might consider a good candidate for running on smartphones and other mobile communication devices. These applications can be a part of the widespread adoption and use of mobile and computing vision technologies is opening new and innovative ways to improve health care delivery. This in turn can transform a mobile platform into a regulated medical monitoring system. An oral consent was gained from the parents of the patent for publication of optical and thermography images and their related files according to medical ethics approval from Medical Ethics committee of the RWTH Aachen University Hospital, issued on 19 August 2009 (EK032/09). Abbreviation: Explanation; IR: Infrared; VIRSENS: Virtual InfraRed SENSor; FOV: Field of view; RPT: Ring projection template; NICU: Neonatal intensive care unit; ROI: Region of interest; OOI: Object of interest; NIRT: Neonatal infrared thermography; PT: Projection template; IRTR: Infrared thermography respiration signal; fps: Frame per second. The authors declare that there are no competing interests. AK writes the whole article conducting all experimental, technical and analytic works. SL reviews the whole paper and supervises the completely experimental and analytic works. Both authors read and approved the final manuscript. A. K. Abbas was born in Baghdad, Iraq, on Feb. 7 th , 1979. He received M.Sc. degree in Biomedical engineering in 2004 from Nahrain University, Baghdad, Iraq. He is currently working toward Ph.D. degree (Dr.rer.medic) in the Philips Chair of Medical Information Technology at RWTH Aachen University. His research interests include of Neonatal Infrared Thermography (NIRT) Imaging and developing intelligent monitoring solution for neonatal intensive care units. S. Leonhardt was born in Frankfurt, Germany, on Nov. 6 th , 1961. He holds a M.S. in Computer Engineering from SUNY at Buffalo, NY, USA, a Dipl.-Ing. and a Dr.-Ing. degree in Control Engineering from Technical University of Darmstadt, Germany, and a Dr. med. degree from the Medical School of Goethe University, Frankfurt, Germany. He has 5 years of R&D management experience in medical engineering industry and was appointed Head of the Philips Chair of Medical Information Technology at RWTH Aachen University, Aachen, Germany, in 2003. His research interests include physiological measurement techniques, personal health care systems and feedback control systems in medicine. The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2342/14/9/prepub Thermography video file for virtual temperature sensor (VIRSENS) used in NIRT imaging application (respiratory monitoring) for a neonate one cared in open radiant warmer. Click here for file Thermography video file for virtual temperature sensor (VIRSENS) used in NIRT imaging application (respiratory monitoring) for a neonate two cared in open radiant warmer. Click here for file Thermography video file for virtual temperature sensor (VIRSENS) used in NIRT imaging application (respiratory monitoring) for a neonate three cared in open radiant warmer. Click here for file The authors express their thanks to the Department of Neonatology, RWTH Aachen for cooperation and assisting in thermography video acquisition for this research study. Intelligent neonatal monitoring based on a virtual thermal sensor Neonatal skin temperature distribution using infra-red colour thermography Infrared thermography in newborns: the first hour after birth Use of infrared thermographic calorimetry to determine energy expenditure in preterm infants Thermistor at a distance: unobtrusive measurement of breathing Virtual thermistor Periorbital thermal signal extraction and applications Non-contact respiratory monitoring based on real-time IR-thermography A reappraisal of the use of infrared thermal image analysis in medicine Contact-free measurement of cardiac pulse based on the analysis of thermal imagery Analysis of breathing air flow patterns in thermal imaging Harvesting the thermal cardiac pulse signal Abdominal thermography in infantile and childhood liver disease Thermal infrared imaging: a novel method to monitor airflow during polysomnography Thermal vision for sleep apnea monitoring Computerized breast thermography: study of image segmentation and temperature cyclic variations Physiology-based face recognition in the thermal infrared spectrum Infrared thermography: experience from a decade of pediatric imaging Neonatal infrared thermography imaging: analysis of heat flux during different clinical scenarios Neonatal monitoring technologies: Design for integrated solutions Thermal image analysis for polygraph testing Thermal detection of embedded tumors using infrared imaging Efficacy of computerized infrared imaging Limits of event-related potential differences in tracking object processing speed Fast and robust optic disc detection using pyramidal decomposition and Hausdorff-based template matching Tracking motion, deformation, and texture using conditionally gaussian processes Tissue tracking in thermo-physiological imagery through spatio-temporal smoothing Robust observation detection for single object tracking: deterministic and probabilistic patch-based approaches Automated method for tracking vasomotion of intravital microvascular and microlymphatic vessels Template matching using the parametric template vector with translation, rotation and scale invariance Framework for performance evaluation of face, text, and vehicle detection and tracking in video: data, metrics, and protocol Template match using local feature with view invariance Tracking of non-rigid articulatory organs in X-ray image sequences Counting heartbeats at a distance Wavelet networks for face processing Computerized detection of breast cancer with artificial intelligence and thermograms Forehead thermal signature extraction in lie detection Imaging facial signs of neurophysiological responses Tracking of multiple targets using online learning for reference model adaptation Infrared tympanic thermometry for neonatal temperature assessment Three dimensional template matching segmentation method for motile cells in 3D + t video sequences Real-time automatic fiducial marker tracking in low contrast cine-MV images Neonatal non-contact respiratory monitoring based on real-time infrared thermography Rigid shape matching by segmentation averaging Measurement of fever in children–is infrared tympanic thermometry reliable? Seeing through the face of deception |
Answer the following medical question. | What does research say about Golden Hour Education, Standardization, and Team Dynamics: A Literature Review.? | The "golden hour" is the critically important first 60 minutes in an extremely low birth weight neonate's life that can impact both short- and long-term outcomes. The golden hour concept involves several competing stabilization priorities that should be conducted systematically by highly specialized health care providers in both the hospital and transport settings for improvement in patient outcomes. Current literature supports utilizing an experienced team in the golden hour process to improve patient outcomes through standardization, improved efficiency, and positive team dynamics. Although a variety of teaching methods exist to train individuals in the care of extremely low birth weight infants, the literature supports the incorporation of low- or high-fidelity simulation-based training. In addition, initial and ongoing educational requirements of individuals caring for a golden hour-eligible infant in the immediate post-delivery phase, as well as ongoing care in the days and weeks to follow, are justified. Instituting standard golden hour educational requirements on an ongoing basis provides improved efficiency in team function and patient outcomes. The goal of this literature review was to determine whether implementation of golden hour response teams in both the inpatient and transport setting has shown improved outcomes and should be considered for neonatal intensive care units admitting or transporting golden hour eligible infants. |
Answer the following medical question. | What does research say about Evaluation and Nonsurgical Treatment of Neonatal Ear Anomalies: A Case Report.? | Inspection and evaluation of the neonate's ears are important parts of the neonatal examination. Neonates display a wide variety of ear size and configuration. In many cases, ear molding techniques obviate the need for future surgical correction. This article provides a review of the fetal ear development and describes common physical examination findings of the newborn's external ear. A case report reviews a successful nonsurgical treatment of a minor ear deformity. Newborn infant with near absent to very thin bilateral helical rims and otherwise normal bilateral ear shape and structures. Bilateral Stahl's ear deformity. The EarBuddies product was applied to bilateral ears in an outpatient pediatric plastic surgery clinic. This product remained in place for 8 weeks. The family was pleased with the overall progress and shape of their child's ears. At 18 months of age, the family has no desire to pursue surgical correction of their child's ears. Assessment of the newborn's external ear is part of a routine admission examination. Careful attention to abnormal or unusual findings allows for prompt evaluation and nonsurgical intervention. |
Answer the following medical question. | What does research say about Skin microbiome sampling in the preterm neonate.? | Conflicts of Interest The authors have no relevant conflicts of interest to disclose. Despite advances in our understanding of the human microbiome, there exist significant knowledge gaps in our understanding of the skin microbiome of the preterm neonate. Herein we describe skin microbiome sampling of 6 preterm neonates at multiple timepoints, and compare the skin microbiome samples to environmental (crib/isolette swabs) and negative controls. Samples of the same type (skin, crib, control) were more similar than when compared by week or by patient. Skin microbiome sampling in the preterm neonate |
Answer the following medical question. | What does research say about Accuracy of temporal artery thermometry in neonatal intensive care infants.? | To determine the accuracy of temporal artery and axillary temperatures and the discomfort level of stable neonates during temperature measurement. Convenience sample of neonates between the ages of 32 and 40 weeks' gestation cared for in an isolette or crib. A method-comparison design was used to compare different methods for noninvasive temperature monitoring (infra-red temporal artery; axillary electronic) to core body temperatures (indwelling rectal probe). Bias and precision of test temperature devices (temporal artery; axillary). Bias and precision for the temporal artery and axillary devices were 0.30 ± 0.44 and 0.28 ± 0.33, respectively. Analysis of variance found significant differences between both temporal and axillary temperatures compared to rectal temperatures (P < .01). Statistical differences were small and did not represent a clinically important difference. No statistical difference was found between temporal artery and axillary temperatures (P = .81). Increases in neonate discomfort after temperature measurement were significantly greater with axillary than increases after temporal artery temperature measurement (P = .03). This study found that body temperature measured with the temporal artery thermometer was similar to temperatures obtained with an axillary thermometer in stable, afebrile neonates. The use of temporal artery thermometry appears to be an acceptable approach for noninvasive temperature measurement in neonates, which causes less discomfort in neonates. |
Answer the following medical question. | What does research say about Modelling the neonatal system: A joint analysis of length of stay and patient pathways.? | In the United Kingdom, one in seven babies require specialist neonatal care after birth, with a noticeable increase in demand. Coupled with budgeting constraints and lack of investment means that neonatal units are struggling. This will inevitably have an impact on baby's length of stay (LoS) and the performance of the service. Models have previously been developed to capture individual babies' pathways to investigate the longitudinal cycle of care. However, no models have been developed to examine the joint analysis of LoS and babies' pathways. LoS at each stage of care is a critical driver of both the clinical outcomes and economic performance of the neonatal system. Using the generalized linear mixed modelling approach, extended to accommodate multiple outcomes, the association between neonate's pathway to discharge and LoS is examined. Using the data about 1002 neonates, we noticed that there is a high positive association between baby's pathway and total LoS, suggesting that discharge policies needs to be looked at more carefully. A novel statistical approach that examined the association of key outcomes and how it evolved over time is developed. Its applicability can be extended to other types of long-term care or diseases, such as heart failure and stroke. |
Answer the following medical question. | What does research say about Leptospermum Honey for Wound Care in an Extremely Premature Infant.? | Neonatal wound care is challenging due to the fragility and vulnerable skin structure. Neonates are often left susceptible to the forces of their environment, leaving them open to infection when skin injury occurs. Leptospermum honey has been used successfully in adult patients, with evidence lacking in the neonatal population. This case demonstrates the management of a difficult-to-heal wound in a 23-week gestation infant. Selecting the proper treatment and products for wound healing is challenging, with little evidence-based research available for the treatment of neonatal wounds. Leptospermum honey and other adult-driven dressings have been used for neonatal wound care as well as other adult-driven dressings. This case demonstrates the benefits of Leptospermum honey as an option for neonatal wounds. This case presents the treatment and healing of an extensive wound of a 23-week gestation neonate using a hydrogel product initially and then transitioning to a Leptospermum honey dressing due to suboptimal healing. Results of this treatment included quick healing time, little to no scarring, and no loss of movement or function to the affected extremities. The incorporation of Leptospermum honey for wound care has the potential to promote faster wound healing, with less scarring in the neonatal population. Adult wound care principles have been applied in the face of a weak evidence base relating to neonatal-specific cases. There is a need for continued research related to moist wound healing in the neonatal population, with resulting product and practice recommendations. |
Answer the following medical question. | What does research say about Immediate Skin-to-Skin Contact in Very Preterm Neonates and Early Childhood Neurodevelopment: A Randomized Clinical Trial.? | Accepted for Publication: February 12, 2025. Published: April 16, 2025. doi: 10.1001/jamanetworkopen.2025.5467 Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2025 Kristoffersen L et al. JAMA Network Open . Author Contributions: Ms Kristoffersen and Dr Aker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Kristoffersen, Støen, Bergseng, Grunewaldt. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Kristoffersen, Bergseng, Aker. Critical review of the manuscript for important intellectual content: All authors. Statistical analysis: Bergseng, Aker. Obtained funding: Støen. Administrative, technical, or material support: Kristoffersen, Støen, Flottorp, Grunewaldt. Supervision: Støen, Bergseng, Aker. Conflict of Interest Disclosures: None reported. Funding/Support: This study was funded by grant 46056724 from the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (Ms Kristoffersen). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Data Sharing Statement: See Supplement 3 . Additional Contributions: We thank the Norwegian Prematurity Association, chaired by Hege Nordhus, BS, and user representative May Jorunn Barlien, MS; no compensation was given. We also thank the staff at the Department of Neonatology at St Olav’s Hospital, Trondheim University Hospital; the Hospital of Southern Norway, Kristiansand; and Drammen Hospital. This randomized clinical trial evaluates whether direct skin-to-skin contact between very preterm neonates and their mothers immediately after delivery vs standard care in an incubator improves neurodevelopmental outcomes at 2 to 3 years of age. Does skin-to-skin contact (SSC) between very preterm neonates and their mothers immediately after delivery affect neurodevelopmental outcomes in early childhood? In this randomized clinical trial of 108 neonates born at 28 weeks 0 days’ to 31 weeks 6 days’ gestation and randomized to immediate SSC or standard care in an incubator, no difference in neurodevelopmental outcomes at age 2 to 3 years was found. These findings suggest that immediate SSC after delivery for very preterm neonates does not affect neurodevelopment at age 2 to 3 years. Preterm neonates are at risk for neurodevelopmental impairments, and there is a need to identify protective factors that can modify the harmful effects of preterm birth on the immature brain. To evaluate whether immediate skin-to-skin contact (SSC) for preterm neonates improves early childhood neurodevelopmental outcomes. This open-label randomized clinical trial was conducted in 3 Norwegian neonatal units between February 2014 and October 2020. Participants were preterm neonates born at 28 weeks 0 days’ to 31 weeks 6 days’ gestation with birth weight greater than 1000 g and no major congenital malformations or need for intubation or oxygen supplementation of more than 40%. Intention-to-treat analysis was conducted from July 2023 to July 2024. Neonates were randomized 1:1 to immediate SSC between mother and neonate in the delivery room for 2 hours or to standard care with direct transport to the neonatal unit in an incubator. The primary outcome was cognitive development at 2 to 3 years of age, measured by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Secondary outcomes were language and motor neurodevelopment measured by the BSID-III, parental questionnaires at 3 and 12 months and 2 to 3 years, and breastfeeding practices up to 12 months. Of 108 included neonates (68 [63%] male; mean [SD] gestational age, 30 weeks 3 days [1 week 1 day]), 51 received SSC and 57 received standard care. Eighty-six (80%) had follow-up at 2 to 3 years, and 81 (75%) completed the BSID-III and were analyzed for the primary outcome. The mean difference in BSID-III cognitive composite scores was 0.21 (95% CI, −5.26 to 5.68; P = .94). There was no difference between the groups in the proportion at risk of developmental delay at 2 to 3 years: 21 of 41 (51%) and 22 of 45 (49%) in the SSC and standard care groups, respectively (odds ratio, 1.10 [95% CI, 0.47-2.56]; P = .83). More neonates in the SSC group were breastfed at hospital discharge (42 of 50 [84%] vs 36 of 54 [67%]; P = .04). In this randomized clinical trial, 2 hours of mother-neonate SSC in the delivery room did not enhance neurodevelopmental outcomes at 2 to 3 years of age. However, the SSC group demonstrated improved breastfeeding practices up to 12 months compared with standard care, suggesting that the feasible and low-cost SSC intervention should be encouraged in clinical practice. ClinicalTrials.gov Identifier: NCT02024854 Long-term health issues are still a major problem for many individuals born preterm. Compared with full-term neonates, very preterm neonates (28-31 weeks’ gestation) are at increased risk of long-term impairments such as cerebral palsy; motor, cognitive, and language delay; behavioral problems; psychiatric disorders; and visual and hearing impairments. 1 , 2 The mean IQ score in very preterm infants is approximately 1 SD lower than in infants born full-term. 1 , 3 , 4 , 5 , 6 Numerous early intervention programs have been developed to compensate for the negative consequences of preterm birth. 4 One intervention is kangaroo mother care (KMC), 7 , 8 in which skin-to-skin contact (SSC) is the primary component. 9 SSC between a caretaker and a preterm newborn in the neonatal intensive care unit (NICU) is associated with reduced neonatal morbidities and parental stress and with improved parental mental health. 10 11 , 12 , 13 The first hours after birth are considered an early sensitive period that is important for mother-neonate interaction and secure attachment. This has led to an increased focus on a nonseparation approach and immediate SSC following delivery between preterm neonates and their mothers or caregivers. The World Health Organization recently amended its recommendations for the care of preterm infants to advise immediate SSC “as soon as possible after birth.” 14 , 15 , 16 This recommendation is based on a randomized clinical trial (RCT) including more than 3000 low-birth-weight infants in low-resource settings and reporting reduced mortality in infants receiving SSC from birth. 10 Studies from low- and high-resource settings have shown improved thermoregulation and cardiorespiratory stability in preterm neonates receiving immediate SSC. 17 Studies have also reported less maternal depression; reduced feelings of fear, guilt, and frustration; and a higher breastfeeding rate with immediate SSC between mother and newborn. 18 , 19 , 20 , 21 , 22 , 23 The nonseparation approach and immediate SSC following delivery is a paradigm shift in neonatal medicine. Yet, few hospitals facilitate immediate SSC, and no studies to our knowledge have reported an association between delivery room SSC and early childhood outcomes. 24 , 25 , 26 We conducted an RCT comparing 2 hours of delivery room SSC between very preterm neonates and their mothers vs standard care. The primary aim of this study was to investigate whether immediate SSC improves cognitive outcomes at 2 to 3 years. Safety and feasibility have been reported elsewhere. 27 19 This was a prospective, multicenter, open-label RCT comparing 2 hours of early SSC between mothers and very preterm neonates with standard care in an incubator ( NCT02024854 ). The original trial protocol is provided in Supplement 1 . The study was initiated at St Olav’s Hospital, Trondheim University Hospital (Trondheim, Norway) in February 2014. In January 2017, 2 additional Norwegian hospitals (Drammen Hospital, Drammen, and Hospital of Southern Norway, Kristiansand) started recruiting participants. The Regional Committee for Medical and Health Research Ethics in central Norway approved the trial. Written informed consent was obtained from participating mothers and their partners. This study followed the Consolidated Standards of Reporting Trials ( CONSORT ) reporting guideline for RCTs. Between February 2014 and October 2020, a dedicated neonatal nurse or physician approached and informed pregnant patients admitted due to the risk of preterm birth between pregnancy weeks 28 and 31. Neonates were included if born at a gestational age of 28 weeks 0 days to 31 weeks 6 days and with a birth weight of at least 1000 g. Exclusion criteria were the need for more than 40% oxygen to maintain oxygen saturation of greater than 90% at 20 minutes of life, the need for intubation and mechanical ventilation in the delivery room, major congenital malformations, and maternal general anesthesia. Eligible pregnant patients and their partners received information about the study and completed written informed consent before the delivery. Following delivery and cord clamping, baseline assessment and screening were done by the neonatal delivery room team. Included neonates were randomized in a 1:1 ratio to 2 hours of mother-neonate SSC in the delivery room or standard care with transfer to the NICU in an incubator. After the attending physician decided on the neonate’s eligibility, randomization was done by the neonatal nurse in charge using sealed envelopes stratified by center and gestational age (28 weeks 0 days to 29 weeks 6 days or 30 weeks 0 days to 31 weeks 6 days) with variable block sizes. Thereafter, the physician or the nurse allocated the neonate to the designated intervention arm. During SSC, the neonate was placed in an upright position between the mother’s breasts, with arms and legs flexed. The head was slightly elevated to 1 side to secure airways. Blinding was not possible due to the nature of the intervention. A recent publication from the same cohort provides a more detailed description of the study participants and the intervention. 19 Data on the amount of breastfeeding at NICU discharge were extracted from the neonate’s medical record. Information about breastfeeding and breast milk up to 1 year of age was obtained from a parental questionnaire comprising 8 selected questions from a questionnaire by the Norwegian Directorate of Health. Growth was calculated by PediTools Growth Parameters based on the 2013 Fenton growth charts. Small for gestational age is defined as birth weight below the 10th percentile and large for gestational age as birth weight above the 90th percentile. 28 Data were collected prospectively. 29 , 30 After discharge, infants were followed up at 3 months, 12 months, and 2 to 3 years of corrected age (the age calculated from the due date at ultrasonography). When reporting age, we refer to the corrected age unless otherwise specified. An overview of the outcome assessments is presented in the eFigure in Supplement 2 . At 10 to 16 weeks of age, infants were videorecorded for 3 to 5 minutes for the General Movement Assessment (GMA), and motor development was evaluated with the Motor Optimality Score–Revised (MOS-R). The videorecordings were performed and classified according to the Prechtl method. 31 The MOS-R and the presence or absence of fidgety movements are used to identify infants at risk of adverse developmental outcomes. 32 Certified GMA observers were blinded to the intervention. The MOS-R score ranges from 5 to 28, where a score of 25 to 28 is considered optimal; 20 to 24 indicates the child’s motor repertoire is mildly reduced; 9 to 19, moderately reduced; and 5 to 8, severely reduced. 32 31 Two parent-completed questionnaires, the Ages & Stages Questionnaire (ASQ) and the ASQ–Social-Emotional (ASQ-SE), were completed at the following time points: 3 months (only ASQ-SE), 12 months, and 2 to 3 years of age. The ASQ is a questionnaire evaluating the child’s development in 5 domains: communication, problem solving, fine motor, gross motor, and personal-social. A Norwegian version of this screening tool has been validated as an appropriate assessment for evaluating children’s development. 33 The scores are summed to give scores for each subscale and a total sum score. In this study, risk of developmental delay was defined as a score below the cutoff in the Norwegian ASQ manual. 34 There are different age-dependent cutoff scores for all domains. The child’s socioemotional and behavioral difficulties and competencies were assessed using the ASQ-SE 35 The domains assessed are self-regulation, compliance, communication, adaptive functioning, autonomy, affect, and interaction with people. Scores are summed to give a total sum score. This screening instrument is valid in identifying social and emotional difficulties in children. 36 Risk of developmental delay was defined as a score above the age-dependent cutoff score in the Norwegian ASQ-SE manual. 37 38 At 12 months and 2 to 3 years of age, neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). The BSID-III comprises 3 developmental domains: cognitive, language, and motor. Each domain has a normed score (composite score) with a mean score of 100 and an SD of 15. Higher scores indicate development consistent with normative data. 39 We defined risk of developmental delay as a composite score below 90 in any domain. This is the clinical cutoff used in the Swedish neonatal guidelines based on assessments of healthy controls born early-, full-, or late-term in the Extremely Preterm Infants in Sweden Study (EXPRESS). 39 Two licensed practitioners blinded to the intervention conducted the assessments. After 2 years of enrollment, the 12-month BSID-III assessment was replaced with the ASQ and ASQ-SE. This was due to limited staff resources to conduct the testing and to reduce the burden of physical follow-up assessments on the families. The last follow-up was planned at 2 years of age, but due to the COVID-19 pandemic, some participants had their follow-up postponed up to age 3 years. 40 , 41 The primary outcome of this study was BSID-III cognitive composite score at 2 to 3 years. BSID-III language and motor composite scores were secondary outcomes. Other secondary outcomes were ASQ-SE and GMA at 3 months, ASQ-SE and ASQ or BSID-III at 12 months, ASQ and ASQ-SE at 2 to 3 years, and breastfeeding practices up to 12 months. The sample size was calculated to detect a mean (SD) difference of 7.5 (15.0) in BSID-III cognitive composite scores at 2 years (α = .05; β = 0.08). Allowing for 6% loss to follow-up, the total sample size needed was 136 neonates. Based on the number of very preterm births at the 3 collaborating hospitals, the sample size was expected to be achieved by the end of 2018. After 6.5 years, inclusion was stopped after enrollment of 108 neonates on October 1, 2020. 27 Analysis was by intention to treat. Demographic factors and clinical characteristics were summarized with counts (percentages) for categorical variables and means (SDs) or medians (IQRs) for continuous variables. Differences between the SSC and standard care groups for continuous variables were analyzed using 2-sample t tests or Mann-Whitney U tests, as appropriate. Categorical variables were analyzed by the Pearson χ 2 test, Fisher exact test, or linear-by-linear associations. Two-sided P < .05 was considered statistically significant. The primary outcome was presented as an unadjusted mean difference with a comparison between groups using the 2-sample t test. The adjusted mean difference was calculated using linear regression adjusting for the neonate’s sex and maternal educational level of a bachelor’s degree or higher. We summarized children at risk of developmental delay in any of the assessments (ASQ, ASQ-SE, and BSID-III) at 2 to 3 years, with a comparison between the groups using Pearson χ 2 test or Fisher exact test. Results are reported as unadjusted odds ratios (ORs). Adjustments for child’s sex and maternal educational level did not affect the results and are not reported. The statistical analysis was conducted from July 2023 to July 2024 using SPSS, versions 28 and 29 (IBM Corp). A total of 108 neonates (mean [SD] gestational age, 30 weeks 3 days [1 week 1 day]; 40 females [37%] and 68 males [63%]) of 101 mothers were included in the study and randomly assigned to either immediate SSC (n = 51) or standard care (n = 57). Twenty-two neonates (20%) were lost to follow-up; hence, 86 (80%) had any or some follow-up at 2 to 3 years of age (BSID-III, ASQ, ASQ-SE, or any 2 or 3 of these assessments) ( Figure and eFigure in Supplement 2 ). Eighty-six children (80%) met for BSID-III assessment at 2 to 3 years, but assessments for 5 of those children (6%) could not be evaluated due to no BSID-III or the child’s inability to test. Therefore, 81 children (75%) were analyzed for the primary outcome (39 [76%] in the SSC group and 42 [74%] in the standard care group). Maternal and neonatal characteristics at birth are summarized according to the intervention group in Table 1 for all participants and in eTable 1 in Supplement 2 for participants with the primary outcome. ASQ indicates Ages & Stages Questionnaire; ASQ-SE, Ages & Stages Questionnaire–Social-Emotional; BSID-III, Bayley Scales of Infant and Toddler Development, Third Edition. Data are presented as number (percentage) of participants unless otherwise indicated. Completed a bachelor’s degree or higher. Calculated by PediTools growth parameters based on the 2013 Fenton growth charts. Small for gestational age is defined as birth weight below the 10th percentile and large for gestational age as birth weight above the 90th percentile. 29 , 30 The median age at BSID-III was 24 months (IQR, 24-25 months) in the SSC group and 25 months (IQR, 24-26 months) in the standard care group. There was no significant difference between groups in the primary outcome, BSID-III cognitive composite score (mean difference, 0.21; 95% CI, −5.26 to 5.68; P = .94) ( Table 2 ). Abbreviations: AMD, adjusted mean difference; ASQ, Ages & Stages Questionnaire; ASQ-SE, Ages & Stages Questionnaire–Social-Emotional; BSID-III, Bayley Scales of Infant and Toddler Development, Third Edition; MD, mean difference; NA, not applicable. Adjusted for sex and maternal university education (completion of a bachelor’s degree or higher). ASQ and ASQ-SE scores are not normally distributed; thus, data were analyzed using the Mann-Whitney U test, and MDs and AMDs are not reported. Higher ASQ scores indicate better development. P value from Mann-Whitney U test. Lower ASQ-SE scores indicate better development. At 2 to 3 years, 21 of 41 children (51%) in the SSC group and 22 of 45 (49%) in the standard care group were classified as at risk of developmental delay on either the BSID-III, ASQ, or ASQ-SE, with no difference between the groups in the proportion of infants at risk of developmental delay (OR, 1.10; 95% CI, 0.47-2.56; P = .83) ( Table 3 ). Ninety-two infants (85%) returned for follow-up at 3 months and 88 (81%) at 12 months (eFigure and eTable 2 in Supplement 2 ). In the standard care group, 1 infant (2%) with absent fidgety movements was lost to follow-up after 3 months. No infants had severely reduced MOS-R scores, and 3 infants in each group had moderately reduced MOS-R scores. Infants in the SSC group had significantly lower scores in the personal-social domain of the ASQ compared with infants in the standard care group at 12 months (median, 35 [IQR, 30-45] vs 45 [IQR, 40-55]; P = .02) (eTable 1 in Supplement 2 ), but this difference was not present at 2 to 3 years ( Table 2 ). Abbreviations: ASQ, Ages & Stages Questionnaire; ASQ-SE, Ages & Stages Questionnaire–Social-Emotional; BSID-III, Bayley Scales of Infant and Toddler Development, Third Edition; OR, odds ratio. Clinical cutoff was according to the Norwegian ASQ manual. 35 Clinical cutoff was according to the Norwegian ASQ-SE manual. 38 More neonates in the SSC group were breastfed at discharge (42 of 50 [84%], vs 36 of 54 [67%] in standard care; P = .04) ( Table 4 ). The duration of exclusive breastfeeding was longer in the SSC group, and at 12 months, 18 of 41 (44%) in the SSC group and 11 of 42 (26%) in the standard care group were breastfed ( P = .07). In this RCT comparing delivery room SSC with standard care in an incubator for very preterm neonates, we found no significant or clinically relevant differences between groups in neurodevelopmental outcomes at 2 to 3 years of age. There were also no differences in neurodevelopmental outcomes between groups at 3 and 12 months. However, significantly more neonates in the SSC group were breastfed at discharge compared with those in the standard care group. This difference persisted up to 1 year of age. To our knowledge, this is the first RCT reporting early childhood outcomes after delivery room SSC for very preterm neonates. An RCT in Columbia reported long-term outcomes of continuous KMC initiated after a median of 4 days after birth vs traditional care. It found no difference between groups at 6 and 12 months, but in a subset of the study population assessed at 20 years of age, there was a dose-dependent positive association between the duration of KMC and the volume of certain brain structures measured with magnetic resonance imaging. The clinical significance of such a finding is not clear. 42 , 43 Improved bonding and maternal-infant relationship have been demonstrated at 4 and 6 months of age, respectively, in preterm neonates exposed to immediate SSC after delivery. Studies also report that a longer duration of KMC in the NICU improves infant growth, breastfeeding, and neurobehavioral performance. 25 , 44 No early childhood or long-term follow-up is available from these studies. However, results are difficult to compare for all outcomes, as there are various definitions of early or immediate KMC and SSC (from immediately after delivery to several days after birth) as well as differences in gestational age groups included and how data on duration of KMC and SSC are retrieved. 45 , 46 17 , 18 , 19 , 20 , 23 , 25 Our results are similar to those of a recent RCT on music therapy intervention in the NICU for preterm neonates (the LongSTEP trial), reporting no difference between groups in BSID-III composite score at 2 years. It has been difficult to demonstrate improved long-term benefits after both music therapy and SSC despite short-term improvements in physiological stability and reduced maternal stress and anxiety shown in smaller studies. 47 Very preterm infants in high-income settings have high survival rates, and almost 80% do not have motor or cognitive delays. 19 , 20 , 23 , 25 , 47 In our study, the mean BSID-III composite scores at 2 to 3 years were within what is considered the normal range. However, both groups had a lower mean composite score on all BSID-III domains compared with 633 healthy full-term infants who served as a control group in the Swedish EXPRESS. 48 Few infants included in our study had severe complications of prematurity, and there were no differences in complication rates between the groups. 40 Our results suggest that in this high-resource context where most infants experience normal neurodevelopment, single interventions like SSC may not influence hard end points like survival and BSID-III scores at 2 to 3 years. 19 The present study showed that more neonates in the SSC group were breastfed at discharge, and the duration of exclusive breastfeeding was longer than among neonates receiving standard care. These findings are in accordance with another study on immediate SSC for preterm neonates reporting a higher, although nonsignificant, incidence of exclusive breastfeeding at discharge in the SSC group. A recent study reported that close contact between the mother and neonate within 30 minutes after birth and regular SSC between mother and child during the NICU stay were associated with successful breastfeeding in moderate- to late-preterm infants. 25 This finding was supported by a meta-analysis including 1900 preterm and low-birth-weight infants that demonstrated that KMC was associated with reduced breastfeeding initiation time compared with conventional care. 49 Although we did not find an association of immediate SSC with neurodevelopment, a recent Swedish study reported that not receiving breast milk at discharge from the NICU was 1 of the 5 most important features of cognitive delay in very preterm infants. 50 The associations between SSC, breastfeeding, nutritional status, socioeconomic and societal conditions, and cognitive outcomes in preterm infants are impossible to explore in small studies like ours and may be difficult to assess even in larger studies. We do not believe that the lack of association between immediate SSC and neurodevelopmental outcomes should be used as an argument against the positive changes that have occurred in neonatal care over the past decades. On the contrary, focus on family-integrated care, closeness between parents and infant, and empowering of parents in their caretaking role must be considered essential to optimize and promote a nurturing environment for preterm infants and their parents. 51 Our study has important limitations. By protocol, the sickest neonates were excluded since this was our first attempt to provide SSC in the delivery room for very preterm neonates, and safety concerns were important to address. We also did not collect data on the total duration of SSC during the hospital stay. After 6 years of recruitment, the estimated sample size of 136 was not reached, and we found it unethical to continue randomization and consequently hinder immediate mother-neonate SSC. However, with almost 80% of the planned sample size included, there were no trends in any direction, and we find it unlikely that a slightly larger sample size would have changed our conclusions. Another limitation was the follow-up process. We underestimated the challenge of repeated follow-up appointments. The COVID-19 pandemic and the inclusion of more study sites also added to the complexity of follow-up. The lack of a healthy, full-term–born control group was also a limitation, as we do not have Norwegian norms for the BSID-III. However, the control group of 366 healthy full-term infants in EXPRESS was considered suitable. In this study, socioeconomic status was assessed solely based on maternal educational level, as these were the only data available. Additional information on socioeconomic status, educational level, and the home environment would have been beneficial. Additionally, we had limited data on markers of neonatal illness. 40 Since the available data showed no difference between groups, we did not include this in the adjusted outcome analyses. 19 In this RCT, 2 hours of mother-neonate SSC in the delivery room did not improve neurodevelopmental outcomes at 2 to 3 years of age. Significantly more neonates in the SSC group were breastfed at discharge and up to 1 year of age compared with those in the standard care group. Although immediate SSC did not translate into improved neurodevelopment, a nonseparation approach might still have an impact on breastfeeding outcomes. Instead of doing more studies on immediate SSC, resources should be focused on implementing this important, feasible, and low-cost intervention. Trial Protocol eFigure. Overview of Outcome Assessments at 3 and 12 Months and 2 to 3 Years of Corrected Age eTable 1. Maternal and Neonatal Characteristics Among Infants With the Primary Outcome, According to Intervention Group eTable 2. Neurodevelopmental Outcomes at 3 and 12 Months of Corrected Age eReferences. Data Sharing Statement Immediate Skin-to-Skin Contact in Very Preterm Neonates and Early Childhood Neurodevelopment An overview of mortality and sequelae of preterm birth from infancy to adulthood The life course consequences of very preterm birth Cognitive outcomes in children and adolescents born very preterm: a meta-analysis Cognitive outcomes of children born extremely or very preterm since the 1990s and associated risk factors: a meta-analysis and meta-regression Neurocognitive function and associations with mental health in adults born preterm with very low birthweight or small for gestational age at term Association of preterm birth with prescription of psychotropic drugs in adolescence and young adulthood Early environment and long-term outcomes of preterm infants Effectiveness of early intervention programs for parents of preterm infants: a meta-review of systematic reviews Myth of the marsupial mother: home care of very low birth weight babies in Bogota, Colombia The effectiveness of kangaroo mother care in lowering postpartum depression in mothers of preterm and low birth weight babies: a systematic review and meta-analysis Understanding kangaroo care and its benefits to preterm infants “Now she has become my daughter”: parents’ early experiences of skin-to-skin contact with extremely preterm infants Sensitivity and attachment: a meta-analysis on parental antecedents of infant attachment Maternal attachment: importance of the first post-partum days Impact of early bonding during the maternal sensitive period on long-term effects: a systematic review Immediate “kangaroo mother care” and survival of infants with low birth weight Newly born low birthweight infants stabilise better in skin-to-skin contact than when separated from their mothers: a randomised controlled trial Skin-to-skin contact in the delivery room for very preterm infants: a randomised clinical trial Immediate skin-to-skin contact may have beneficial effects on the cardiorespiratory stabilisation in very preterm infants Immediate skin-to-skin contact after birth ensures stable thermoregulation in very preterm infants in high-resource settings Skin-to-skin care after birth for moderately preterm infants Randomized controlled trial of skin-to-skin contact from birth versus conventional incubator for physiological stabilization in 1200- to 2199-gram newborns Postpartum experiences of early skin-to-skin contact and the traditional separation approach after a very preterm birth: a qualitative study among mothers Delivery room skin-to-skin contact for preterm infants—a randomized clinical trial Parents’ experiences of immediate skin-to-skin contact after the birth of their very preterm neonates Early skin-to-skin contact or incubator for very preterm infants: study protocol for a randomized controlled trial PediTools electronic growth chart calculators: applications in clinical care, research, and quality improvement A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants Cerebral palsy: early markers of clinical phenotype and functional outcome A validation study of the Norwegian version of the Ages and Stages Questionnaires Måleegenskaper ved den norske versjonen av Ages and Stages Questionnaires (ASQ) Social-emotional screening for infants and toddlers in primary care Måleegenskaper ved den norske versjonen av Ages & Stages Questionnaire: Social and Emotional, ASQ:SE. Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden Kangaroo mother care had a protective effect on the volume of brain structures in young adults born preterm A randomized, controlled trial of kangaroo mother care: results of follow-up at 1 year of corrected age Skin-to-skin contact at birth for very preterm infants and mother-infant interaction quality at 4 months: a secondary analysis of the IPISTOSS randomized clinical trial Systematic review and meta-analysis suggest that the duration of kangaroo mother care has a direct impact on neonatal growth Music therapy in infancy and neurodevelopmental outcomes in preterm children: a secondary analysis of the LongSTEP randomized clinical trial Neurodevelopmental outcome in very preterm and very-low-birthweight infants born over the past decade: a meta-analytic review Social predictors of breastfeeding and the impact of interventions on breastfeeding of preterm infants: a longitudinal study The effects of kangaroo mother care on the time to breastfeeding initiation among preterm and LBW infants: a meta-analysis of published studies Prediction of 2-year cognitive outcomes in very preterm infants using machine learning methods |
Answer the following medical question. | What does research say about Palliative care in the fetus and newborn.? | The changing environment in neonatology and perinatology has led to the examination of issues surrounding palliative care. Newborn palliative care should be considered in three general areas: (1) Neonates at the limits of viability. As advances in technology and outcomes become available, it is the responsibility of the health-care community and society to reach a consensus regarding the limits of viability. (2) Neonates with lethal congenital anomalies. When appropriate, and diagnosis and prognosis are certain, why should a family be deprived the opportunity to choose palliative care for the unborn child? (3) Neonates not responsive to aggressive medical management where continuing therapy may prolong suffering and postpone death. The question 'Are you doing for the neonate or to the neonate?' should be asked. These complex issues, along with best interest issues, site, mode and timing of delivery, and the development of palliative care are the subject of this manuscript. |
Answer the following medical question. | What does research say about Near-Infrared Spectroscopy: Clinical Use in High-Risk Neonates.? | In this review, we describe the near-infrared spectroscopy (NIRS) technology and its clinical use in high-risk neonates in critical care settings. We searched databases (e.g., PubMed, Google Scholar, EBSCOhost) to find studies describing the use of NIRS on critically ill and high-risk neonates. Near-infrared spectroscopy provides continuous noninvasive monitoring of venous oxygen saturation. It uses technology similar to pulse oximetry to measure the oxygen saturation of hemoglobin in a tissue bed to describe the relative delivery and extraction of oxygen. Near-infrared spectroscopy can be a valuable bedside tool to provide clinicians indirect evidence of perfusion. It may prompt early interventions that promote oxygen delivery, which can improve high-risk neonatal outcomes. |
Answer the following medical question. | What does research say about Hyperbilirubinemia and Choledocholithiasis in an Extremely Premature Neonate.? | Cholestasis affects 2% of newborns admitted to the neonatal intensive care unit and 20% of premature infants and requires a thoughtful evaluation and diagnostic workup.There may be a single responsible etiology, or its development may be multifactorial. Premature neonates are especially predisposed because of their increased risk of infections and acute illness, need for parenteral nutrition, and exposure to certain medications. Clinically, an infant may present with jaundice, evidence of hepatic injury, or worsening hepatic function. Diagnosis may be made in consultation with various pediatric subspecialists including gastroenterology, genetics, and surgery. Treatment depends on the etiology but may include medications or surgical interventions. Timely recognition and intervention improve outcomes. |
Answer the following medical question. | What does research say about Pharmacokinetic and Pharmacodynamic Approaches to Optimize Antibiotic Use in Neonates.? | Newborn infants (particularly those born preterm) are frequently exposed to empiric antibiotics at birth, and antibiotics are among the most commonly prescribed medications in neonatal intensive care units. Challenges in optimizing neonatal antibiotic dosing include: technical and ethical barriers to neonatal pharmacoanalytic study design and sampling, difficulty in extrapolating adult and pediatric data due to unique neonatal physiology, and a lack of validated pharmacodynamic targets specific to neonatal populations. In this review, we summarize basic concepts in pharmacokinetics (PK) and pharmacodynamics (PD), describe pharmacometric strategies utilized in contemporary PK/PD analyses, and review the evolution of PK/PD data guiding neonatal dosing among 3 commonly used antibiotics. |
Answer the following medical question. | What does research say about An analysis of the kangaroo care intervention using neonatal EEG complexity: a preliminary study.? | Skin-to-skin contact (SSC) promotes physiological stability and interaction between parents and infants. Temporal analyses of predictability in EEG-sleep time series can elucidate functional brain maturation between SSC and non-SSC cohorts at similar post-menstrual ages (PMAs). Sixteen EEG-sleep studies were performed on eight preterm infants who received 8 weeks of SSC, and compared with two non-SSC cohorts at term (N=126) that include a preterm group corrected to term age and a full term group. Two time series measures of predictability were used for comparisons. The SSC premature neonate group had increased complexity when compared to the non-SSC premature neonate group at the same PMA. Discriminant analysis shows that SSC neonates at 40 weeks PMA are closer to the full term neonate non-SSC group than to the premature non-SSC group at the same PMA; suggesting that the KC intervention accelerates neurophysiological maturation of premature neonates. Based on the hypothesis that EEG-derived complexity increases with neurophysiological maturation as supported by previously published research, SSC accelerates brain maturation in healthy preterm infants as quantified by time series measures of predictability when compared to a similar non-SSC group. Times series methods that quantify predictability of EEG sleep in neonates can provide useful information about altered neural development after developmental care interventions such as SSC. Analyses of this type may be helpful in assessing other neuroprotection strategies. |
Answer the following medical question. | What does research say about Procedural pain management for neonates using nonpharmacological strategies: Part 1: sensorial interventions.? | Neonates who are born preterm and are admitted to neonatal intensive care units endure frequent procedures that may be painful. Nonpharmacological interventions that have been studied to relieve their pain may be categorized in 2 main groups according to their nature: interventions that focus on creating a favorable environment and offering pleasant sensorial stimuli and interventions that are centered on maternal care. These interventions may be considered within the philosophy of developmental care, since they are aimed at adjusting the environment to the needs of the neonate and involve family-centered care. In this article, the first of a 2-part series, we will synthesize the evidence from experimental studies of interventions that focus on the environment and on tactile and gustatory stimulation. The mechanisms suggested by researchers as possible explanations for the efficacy of these interventions are pointed, and the implications for procedural pain management in neonatal care are drawn. |
Answer the following medical question. | What does research say about Pneumothorax in the neonate.? | Neonatal critical-care nurses frequently care for neonates experiencing pneumothoraces. The treatment of a pneumothorax varies with the cause. Knowledge of the condition will help the nurse in caring for the neonate at high risk. In this article, types of pneumothoraces will be reviewed, and information will be provided regarding the pathophysiology, diagnosis, treatment, and nursing responsibilities in caring for an infant experiencing a pneumothorax. |
Answer the following medical question. | What does research say about Predictors of time to full enteral feeding in low birth weight neonates admitted to neonatal intensive care unit: a prospective follow up study.? | Survival of LBW infants has increased in recent years because of novel perinatal interventions, but the introduction and advancement of enteral feeds for low birth weight infants is challenging. In Ethiopia the proportion of low birth weight infants is thought to be 17.3%. The purpose of this study was to determine the time to full enteral feeding (FEF) and its predictors in LBW neonates admitted to neonatal intensive care unit in selected hospitals of Addis Ababa, Ethiopia. An institutional based prospective follow up study was conducted from March 15 to June 15, 2022 among 282 LBW neonates admitted to six randomly selected hospitals. Both primary and secondary data was used by interviewing mothers and prospective medical chart review of neonates. The Cox regression model was used and variables having a p -value less than 0.05 with 95% CIs in a multivariable analysis were declared as statistically significant association with time to full enteral feeding. Out of 282 neonates involved in this study, 211 (74.8%) of them reached at FEF. The overall median time to full enteral feeding was 5 days. Predictors significantly associated with time to full enteral feeding were educational level, birth weight, cesarean delivery, hospital acquired infection, being on antibiotics, age at initiation of trophic feeding, routine gastric residual evaluation and NICU location (hospital). This study demonstrated the difficulty of understanding which low birth weight neonate will attain FEF in a timely manner and factors that affect time to FEF. There is a delay in full enteral feeding achievement among low birth weight neonates and there is a great deal of heterogeneity of practice among health care providers regarding feeding of infants as it was evidenced by a variation in feeding practice among hospitals. Nutrition should be considered as part of the management in neonatal intensive care units since low birth weight neonates are developing edematous malnutrition while they are in the NICU. There should be standard feeding protocol to avoid heterogeneity of practice and additional study should be conducted for each categories of GA and BW with long follow up time. Infant and young child feeding (IYCF) is fundamental for infant and child survival, healthy growth and development, a healthy future generation and national development [ 1 ]. The United Nations (UN) Convention on Child Rights declared that every infant and child has the right to good nutrition [ 2 ]. Since LBW (low birth weight) infants had an interrupted growth trajectory, immediate nutrition after birth is important to avoid postnatal delay in nutritional intake and growth restriction over time [ 3 ]. According to a prospective study done in Ethiopia in 2020 majority of the neonates (86.2%) had extra uterine growth restriction (EUGR) at the time of discharge from the hospital, which indicates suboptimal nutrition during their stay in the neonatal intensive care unit [ 4 ]. The problem affects the most vulnerable groups of newborns like LBW (low birth weight) and small for gestational age neonates which aggravates complications associated with their prematurity. In addition to its nutritional benefits human milk have an increasingly central role in immune protection and intestinal maturation of a highly vulnerable population such as severely preterm infants [ 3 ]. LBW and critically ill infants have an increased metabolic needs and minimal macronutrient stores and this increases their energy requirement and evidence supports that early enteral feeding affect important outcomes like enhanced neurodevelopmental outcome and growth and development [ 5 , 6 ]. But in spite of these benefits, late breast feeding initiation, low breastfeeding rates and short breastfeeding duration is common in LBW infants [ 5 ]. Enteral nutrition is preferred over total parenteral nutrition (TPN), because it avoids complications related to vascular catheterization, sepsis and adverse effects of TPN [ 7 ]. Early full enteral feeding also increase nutrient intake and growth rates, accelerate time to achieve full enteral feeding, and prevent late-onset sepsis (LOS) in infants [ 8 ]. Late attainment of full enteral feeding in LBW neonates will prolong hospitalization and healthcare costs and suboptimal nutrition in these groups of neonates will lead to decreased survival, poor childhood growth and it will have a negative effect on healthy future generation and national development [ 1 ]. In recent years, much has been researched on possible short and long-term health consequences related to under nutrition and important results have been achieved with regard to nutrition in neonates [ 6 ]. Parenteral nutrition, enriched preterm formula, and fortification of human milk have been proven to be critically important for LBW infants admitted to neonatal intensive care units [ 9 ]. But these nutrition options are usually not available in low-resource countries, and unfortified human breast milk is the only option available in many low-income countries and varying degrees of protein energy malnutrition are very common [ 10 ]. The only parenteral source of nutrition for infants admitted to our unit, like many units in sub-Saharan Africa, is 10% dextrose solution with or without sodium chloride. This solution is usually reconstituted in the ward with potassium chloride and calcium to provide the infant’s daily recommended requirements until they can tolerate enteral feeds. The use of total parenteral nutrition can be limited by feasibility and affordability and human breast milk is practically feasibly strategy of feeding LBW infants in countries with low socioeconomic status like Ethiopia. Currently, in most settings in resource-limited countries, there is inevitable suboptimal feeding of LBW infants. Unlike the general recommendation to initiate early enteral feeding, a considerable number of the infants were kept NPO (nothing by mouth) in the first few days, receiving only maintenance fluid. This was associated with increased risk of death and development of hypoglycemia [ 11 ]. Therefore, the purpose of this study was to estimate time to full enteral attainment and its predictors among low birth weight neonates admitted to selected public hospitals of Addis Ababa. Institution based multicenter prospective follow up study was conducted in NICU (Neonatal intensive care unit) of six randomly selected public hospitals in Addis Ababa, Ethiopia, from March to June 2022. The city has twelve public hospitals among these, six hospitals (Gandhi Memorial Hospital, Yekatit 12 Hospital Medical College, Zewditu Memorial Hospital, Ras Desta Damtew Memorial Hospital, Menelik II Referral Hospital and Tirunesh Beijing General hospital) are governed by Addis Ababa City Health Bureau and the rest five (St Peter Specialized Hospital, St’ Paul’s Hospital Millennium Medical College, Amanuel Hospital, Alert Hospital and Eka Kotebe Hospital) are governed by federal ministry of health and one university hospital (Tikur Anbessa Specialized Hospital). All hospitals except Amanuel Hospital, have their own neonatal intensive care unit. So, the study was conducted on NICUs located in Gandhi Memorial Hospital, Zewditu Memorial Hospital, Menelik II Referral Hospital, St Peter Specialized Hospital, St’ Paul’s Hospital Millennium Medical College and Tikur Anbessa Specialized Hospital. Each selected low birth weight infants with their indexed mothers were the study units. The source population comprises all low birth weight neonates and the study population includes all randomly selected low birth weight neonates and their respective care takers during the study period. All low birth weight neonates admitted to NICU in selected hospital with in the study period were included and neonates with major congenital cardiac disease, gastro intestinal defect, necrotizing enterocolities, and neonates who died in their immediate postnatal day were excluded. To determine the required sample size, different factors which were significantly associated with the time to full enteral feeding in low birth weight neonates were considered with the following assumption; 95% confidence level, 80% power, margin of error = 5%=0.05 and maximum sample size (278) was taken for the required sample size. Double population proportion formula was used by considering study in Auckland, New Zealand [ 12 ], by taking gestational age as a predictor variable. The sample size was calculated using STATA version 14. Six hospitals were selected by lottery method. To estimate the total source population during the data collection period, monthly average low birth weight admission was estimated based on the data taken from the recent three months HMIS registration of each selected hospital. The estimated source population was 340 and the k value was 1.22. Therefore, by using systematic sampling technique, four from each five consecutive low birth weight admissions that fulfill the inclusion criteria were selected randomly throughout the study period in each hospital (Fig. 1 ). Fig. 1 Schematic representation of sampling procedures of the study, Addis Ababa, Ethiopia, March 2022 G.C. Schematic representation of sampling procedures of the study, Addis Ababa, Ethiopia, March 2022 G.C. Neonate: A neonate is a child under 28 days of age. Low birth weight: Babies who are born weighing less than 2,500 g [ 13 ]. Very low birth weight: Babies who are born weighing less than 1,500 g [ 14 ]. Full enteral feeding: Newborn infants receive all of their nutrition as milk feeds (either human milk or formula) orally [ 15 ] and total enteral intake of 150 ml/kg/day or at least 110 Kcal per kg per day sustained for 24 h sustained for 24 h through tube feeding [ 16 ]. Time to event: Time from birth of a low birth weight infant to full attainment of enteral feeding. Censored: LBW neonates who left the study before reaching at the event of interest (FEF) or does not attain full feeding before the study ends (28 days). Event: Refers to the occurrence of the outcome of interest (attainment of FEF). Follow up time: Time from recruiting up to either the study subjects attains full enteral feeding or censored. Trophic feeding: The volume of feeding considered trophic in most neonatal nurseries is 12 cc/Kg/d or less [ 17 ]. Survival time: the length of time in days followed starting from birth to full enteral feeding. Interviewers administered structured questionnaire was used to collect the data. The data extraction tool was adapted from previous related studies [ 18 – 29 ] and modified to local context. Six data collectors were recruited based on their experience in data collection, qualification and ability of the local language. A one day training was given to data collectors and the supervisor regarding significance of the study and ways of data collection process. Data extraction form was checked before data collection for completeness and consistency using 14 LBW neonates from Ras Desta Hospital and faults found during the process were corrected by the principal investigator. Data was examined for completeness and consistency during data cleaning, storage, and analysis. Time to full enteral feeding attainment was calculated in days using the time interval between the time of birth and the time of full enteral feeding attainment. Data was entered and cleaned by using EPi Data version 4.6 and transported to STATA version 14 for analysis. The Kaplan Meier failure method was used to estimate the cumulative probability of full enteral feeding, and a log-rank test was used to compare the time to event curves of categories of variables. Bi-variable Cox-regression was computed for each predictor variable, and variables with p -value of < 0.25 were entered to multivariable Cox-regression and the significant association was declared with a p -value less than 0.05 in a multivariable Cox regression model. A total of 286 neonates were involved initially but four neonates were diagnosed with the exclusion criteria after they had been recruited to the study. Response was obtained from 282 (response rate of 98.6%) participants (Fig. 2 ). The mean age of indexed mothers was 27.27 ± Std. Dev. of 4.88 years and 242 (85.82%) were married. The maximum and minimum maternal ages found in this study were 17 and 40 respectively. 82(29%) mothers had no formal education and 50(17.73%) have higher educational level. Most 216 (76.6%) mothers were urban residents. Fig. 2 Diagrammatic presentation of the number of neonates initially to the study and numbers of neonates finally included into the study and analysis from each hospitals Diagrammatic presentation of the number of neonates initially to the study and numbers of neonates finally included into the study and analysis from each hospitals 88 (31.2%) of mothers were found to have at least one pregnancy related complications and the major reported complication was premature rupture of membrane (21.6%). Majority, 276 (97.8%) of the mother gives birth at health institution. 146 (51.7%) of mothers were multipara. The minimum and maximum GA at birth was 26 weeks and 41 weeks respectively. The mean GA was 33.58 ± 2.7 SD week and a 95% CI of 33.2–34 weeks respectively. The smallest and largest BW were 900 gram and 2490 gram respectively with a mean birth weight of 1729.7 ± SD 427.7 gram (95% CI of 1679.5–1780 gram) Table 1 . Table 1 Distribution of the neonatal characteristics of LBW neonates admitted in selected governmental hospital of Addis Ababa, Ethiopia 2022. ( N = 282) Variables Categories Total Status Number (%) Reached FEF (%) Censored (%) Sex of neonate Male 151 (53.5%) 114 (54%) 37 (52%) Female 131 (46.45%) 97 (46%) 34 (48%) Gestational age ≤ 28 weeks 6 (2%) 1 (0.47%) 5 (7%) 29–31 weeks 65 (23%) 40 (19%) 26 (36.6%) 32–36 weeks 168 (60%) 134 (63.5%) 32 (45%) ≥ 37 weeks 43 (15.2%) 35 (16.5%) 8 (11%) Birth weight 1500–2499 gm. 192 (68%) 75 (35.5%) 17 (24%) 1000–1499 gm. 81 (28.7%) 79 (37.4%) 21 (29.5%) < 1000 gm. 9 (3.2%) 0 9 (12.6%) Birth Plurality Single 220 (78%) 170 (80.6%) 50 (70.4%) Multiple 62 (22%) 39 (19.4%) 21(29.6%) Weight for gestational age SGA 74 (20.57%) 62 (29.3%) 12 (17%) AGA 206 (73.05%) 147 (69.6%) 59 (83%) LGA 2 (0.71%) 2 (1%) 0 AGA, Appropriate for gestational age; FEF, Full enteral feeding; LGA, large for gestational age; SGA, Small for gestational age Distribution of the neonatal characteristics of LBW neonates admitted in selected governmental hospital of Addis Ababa, Ethiopia 2022. ( N = 282) AGA, Appropriate for gestational age; FEF, Full enteral feeding; LGA, large for gestational age; SGA, Small for gestational age Majority (87.6%) of neonates were on antibiotics and 224 (79.43%) needs respiratory support. 31.21% of indexed mothers reported that they did not receive instructions and counseling about feeding of their child (Table 2 ). Table 2 Treatment related predictors among LBW neonates admitted to neonatal intensive care unit of Addis Ababa public hospitals, Ethiopia, 2022 Variables Categories Total Status Number (%) Reached FEF (%) Censored (%) Respiratory support type CPAP 140 (62.22%) 88 (41.7%) 52 (73%) INO2 85(37.78%) 69 (58.3%) 16 (27%) Kangaroo mother care 91 (32.27%) 88 (41.7%) 3 (4.2%) Trophic feeding initiated 204 (72.3%) 180 (85.3%) 24 (33.8%) Milk type while on trophic feeding Human milk 177 (86.7%) 154 (85.6%) 23 (95.8%) Formula 25 (12.25%) 24 (13.3%) 1 (4.2%) Mixed 2 (1%) 2 (1.1%) 0 TF interval ≤ 3 h 167 (81.8%) 150 (83.3%) 17 (70.8%) 3–6 h0ur 32 (15.6%) 26 (14.4%) 6 (25%) Above 6 h 5 (2.5%) 4 (2.2%) 1 (4.2%) Routine Evaluation of Gastric Residual 71 (34.8%) 59 (32.7%) 12 (50%) Was Using Pacifier 13 (4.6%) 12 (5.6%) 1 (1.4%) CPAP, continuous positive airway pressure; FEF, Full enteral feeding; INO2, Intranasal oxygen Treatment related predictors among LBW neonates admitted to neonatal intensive care unit of Addis Ababa public hospitals, Ethiopia, 2022 CPAP, continuous positive airway pressure; FEF, Full enteral feeding; INO2, Intranasal oxygen Two hundred eighty two LBW neonates have been followed to a total of 2179 neonate-days with a mean follow up days of 7.72 ± 5.97 days SD and a minimum of 1 day to a maximum of 28 days. Finally 211 (74.82%) neonates were attained FEF and the rest were censored with death being the primary cause 64 (90.14%). 46 (72%) of deceased neonates died without any enteral feeding attempts. The earliest time to reach at FEF was at first postnatal day while the latest time was at 28 days of post natal age. The median and mean age at FEF was 5 and 7.18 + 5.3 day (95% CI of 6.4–8 days) respectively. About 64.93% of neonates reached at FEF within 7 days of post natal age and 13.27% of LBW neonates reached FEF after 14 days. Within the first week of postnatal age, the curve has a tendency to decline rapidly, implying that most low birth weight neonates attain full enteral feeding with in this time frame (Fig. 3 ). Fig. 3 The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonates admitted to neonatal intensive care unit of Addis Ababa public hospitals, Ethiopia, 2022 The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonates admitted to neonatal intensive care unit of Addis Ababa public hospitals, Ethiopia, 2022 The median time to attain full enteral feeding (FEF) have a strong variation depending on the GA and BW of the neonates. Time to FEF is inversely related to both gestational age (GA) and birth weight (BW). Neonates whose GA is between 28 and 31 weeks have a median time to FEF of 11.5 days (95% CI: 9–14) and those neonates who born at a GA of between 32 and 37 weeks attains FEF at a median age of 5 days (95% CI: 5–6) while term born LBW neonates attains FEF at a median age of 3 postnatal days (95% CI: 2–3). Neonates whose BW was between 1500 and 2499 gram attains FEF at a median postnatal day of 4 while those whose BW was between 1000 and 1499 gram reached at FEF at their median age of 11 postnatal day (95% CI: 9–12) (Table 3 ). Table 3 Median time to FEF and log-rank test for equality of survivor functions among LBW neonates admitted to NICU of Addis Ababa public hospitals, Ethiopia, 2022 ( n = 282) Variables Category Median time to FEF Point estimate(95%CI) Log-rank x2 value p -value Parity Primipara 6 (5–7) 2.05 0.15 Multipara 5 (4–6) Gestational age in weeks < 28 15 ( only 1 observation) 85 0.00 28–31 12 (9–14) 32–36 5 (5–6) Term 3 (2–3) Birth weight in gram 1500–2499 4 (4–5) 37 0.0000 1000–1499 11 (9–12) < 1000 No any Age at admission in hour Within 1 h 7 (5–8) 12.01 0.007 1–6 h 4.5 (4–5) 6–24 h 7 (5–19) After 24 h 4 (3–6) Onset of labor Spontaneous 5 (4–6) 3.82 0.05 Induced 7 (5–8) Weight for gestational age SGA 4 (3–6) 4.1 0.04 AGA 6 (5–7) Apgar score ≤ 3 12 7.2 0.06 4–6 7 (5–10) ≥ 7 5 (4–6) unknown 6.5 (4–9) Plurality Single 5 (5–6) 1.7 0.19 Multiple 6 (4–11) Hypothermia Yes 6 (5–6) 6.4 0.01 Respiratory distress Yes 6 (5–7) 21 0.0000 New diagnosis during follow up Yes 7 (6–9) 62 0.0000 Hospital acquired infection Yes 11 (7–16) 22.4 0.0000 Necrotizing enterocolitis Yes 16 (3 - ) 10 0.001 Apnea during follow up Yes 12 (10–19) 7.4 0.006 Thrombocytopenia in the follow up Yes 9 (7–11) 17 0.0000 On antibiotics Yes 6 (5–7) 49.8 0.0000 Respiratory support Yes 7 (6–8) 64 0.0000 Type of respiratory Support CPAP 9 (7–11) 17.4 0.000 Intra nasal O2 5 (4–6) Feeding instruction provided Yes 5 (5–6) 2.3 0.13 Trophic feeding Yes 6 (5–7) 25 0.000 Age at trophic feeding initiation in hour Within 24 h 3 (3–4) 31.92 0.0000 24-48 h 5 (5–7) 48-72 h 8 (6–11) After 72 h 13 (10–18) Trophic feeding interval Every 2-3 h 5 (5–7) 1.2 0.55 Every 3-6 h 7 (5–10) Above 6 h 5 (5- ) Routine gastric residual evaluation Yes 9 (7–12) 23.46 0.0000 Milk type at trophic feeding Human milk 6 (5–7) 8.4 0.015 Formula 4 (3–7) Mixed 5 (5- ) AGA, Appropriate for gestational age; CPAP, continuous positive airway pressure; FEF, Full enteral feeding; SGA, Small for gestational age Median time to FEF and log-rank test for equality of survivor functions among LBW neonates admitted to NICU of Addis Ababa public hospitals, Ethiopia, 2022 ( n = 282) AGA, Appropriate for gestational age; CPAP, continuous positive airway pressure; FEF, Full enteral feeding; SGA, Small for gestational age No neonate with a BW of less than 1000 gram attains FEF during the follow up due to their decreased survival rate to reach at full enteral feeding and an earlier death. LBW neonates who were on respiratory support attains FEF at 7 (95% CI: 6–8) and those who didn’t need respiratory support attains at their median age of 3 (3–3) days (Fig. 4 ). Fig. 4 The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonates based respiratory support The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonates based respiratory support Based on this study’s finding there is also a strong variation in time to FEF based on some clinical condition of the neonates which is newly developed after admission like hospital acquired infection during follow up (Fig. 5 ) and pre feed gastric evaluation (Fig. 6 ). Fig. 5 The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonates based HAI during the follow up The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonates based HAI during the follow up Fig. 6 The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonate with pre-feed gastric evaluation The Kaplan-Meier estimate of time to event (full enteral feeding) curve used to estimate the time to full enteral feeding of low birth weight neonate with pre-feed gastric evaluation Maternal Higher educational level (AHR 2.17 and 95% CI 1.012–4.66), birth weight of 1000–1499 gram (AHR 0.31 and 95% CI 0.142–0.67), cesarean delivery (AHR 0.59 and 95% CI 0.36–0.96), hospital acquired infection (AHR 2.25 and 95% CI 1.15–4.41), being on antibiotics (AHR 2.92 and 95% CI 1.31–6.53), age at initiation of trophic feeding, routine gastric residual evaluation (AHR 1.7 and 95% CI 1.1–2.87) and NICU location (SPHMMC) (AHR 4.85 and 95% CI 1.51–15.6) were found to have a statistically significant association with time to attain full enteral feeding in LBW neonates with p -Value < 0.05. Maternal educational level was the only maternal socio-demographic characteristics found to have statistically significant association with the time to FEF and this shows neonates whose indexed mothers were at higher educational level 2.17 times more likely to attain full enteral feeding at a given time frame than those whose indexed mothers have no formal education. Based on the output of multivariate cox regression birth weight of 1000–1499 gram (AHR: 0.31), TF initiation within the first 3 days of postnatal age (AHR: 6, 3.9 and 3.2) respectively were statistically significant predictors with p value < 0.05. This indicates that those whose birth weight was in the very low birth weight range (1000–1499 gram) the hazard to FEF at a given time was reduced by 69% when it was compared to their counterparts (95% CI: 0.13–0.62) and early initiation of trophic feeding in the first 24, 24–48 and 48–72 h of birth are six, four and three times more likely to attain full enteral feeding at a given time frame than those who starts TF then after (Table 4 ). Table 4 Multivariate Cox regression model for predictors of time to attain FEF in LBW neonates admitted to neonatal intensive care unit of Addis Ababa public hospitals, Ethiopia, 202 Covariates Categories FEF (%) Censored (%) CHR AHR P -value 95% CI for AHR Educational level No education 52 (24.64) 30 (42.25) 1 1 Primary 56 (26.54) 15 (21.12) 1.27 0.78 0.541 0.405 1.52 Secondary 44 (20.85) 6 (8.45) 2.2 2.05 0.030* 1.08 4.68 Technical 19 (9.0) 10 (14.08) 1.5 1.22 0.509 0.436 3.45 Higher 40 (18.9) 10 (14.08) 2.22 2.17 0 .047* 1.012 4.6 Gestational age 28–31 40 (19) 26 (36.6) 0.29 0.82 0.718 0.276 2.4 32–37 134 (63.5) 32 (45) 0.636 0.91 0.835 0.38 2.16 ≥ 37 35 (16.5) 8 (11) 1 1 Birth weight in gram 2000–2499 75 (35.5) 17 (24) 1 1 1500–1999 79 (37.4) 21 (29.5) 0.65 0.601 0.150 0.30 1.2 1000–1499 57 (27) 24 (33.8) 0.358 0.31 0.003* 0.142 0.67 Age at admission Within 1 h 98 (46.4) 39 (55) 1 1 1–6 h 76 (36) 20 (28.2) 1.37 0.68 0.156 0.40 1.15 6–24 h 9 (4.3) 2 (3) 0.89 2.38 0.090 0.87 6.5 after 24 h 28 (13.3) 10 (14) 1.05 0.48 0.186 0.16 1.41 Delivery - mode SVD 104 (49) 42 (59) 1 1 Cesarean section 106 (50) 28 (39.4) 1.3 0.59 0.034* 0.36 0.96 Hypothermia Yes 116 (55) 40 (56) 1 1 No 95 (45) 31 (44) 1.18 1.37 0.285 0.789 2.23 Respiratory distress Yes 146 (69.2) 63 (88.7) 1 1 No 65 (30.8) 8 (11.3) 1.92 1.16 0.623 0.637 2.11 New diagnoses During follow up. Yes 135 (64) 63 (88.7) 1 1 No 76 (36) 8 (11.3) 3.91 1.78 0.063 0.933 3.15 HAI during follow up Yes 31 (15) 30 (42) 1 1 No 180 (85) 41 (58) 3.52 2.25 0.017* 1.15 4.41 Antibiotics Yes 177 (84) 70 (98.6) 1 1 No 34 (16) 1 (1.4) 4.35 2.92 0.009* 1.31 6.53 Respiratory support Yes 156 (74) 68 (95.7) 1 1 No 55 (26) 3 (4.3) 4.08 4.49 0.236 0.37 54.13 TF initiation age Within 24 h 53 (23.1) 3 (4.22) 7.12 6.05 0.000* 2.48 14.7 24-48 h 57 (27) 6 (8.45) 3.47 3.94 0.000* 1.84 8.45 48-72 h 43 (20.4) 6 (8.45 2.15 3.21 0.001* 1.591 6.51 After 72 h 27 (13) 9 (12.7) 1 1 Routine Pre-feed gastric residual evaluation Yes 59 (32.7) 12 (50) 1 1 No 121 (67.3) 12 (50) 2 1.70 0.046* 1.1 2.87 Pacifier Yes 12 (5.6) 1 (1.4) 1 1 No 199 (94.3) 70 (98.6) 0.582 0.564 0.376 0.159 2.00 Hospital TASH 31 (14.7) 25 (35.2) 1 1 ZMH 30 (14.22) 11 (15.5) 1.14 2.43 0.142 0.742 7.98 GMH 50 (23.7) 7 (9.8) 1.32 2.55 0.083 0.886 7.3 M II RH 25 (11.8) 13 (18.3) 0.96 1.46 0.589 0.365 5.88 St. Peter hospital 32 (15.16) 5 (7.04) 1.4 1.7 0.351 0.557 5.18 SPHMMC 43 (20.38) 10 (14.1) 2.34 4.85 0.008 1.51 15.6 AHR, Adjusted hazard ratio; CHR, Crud hazard ratio; FEF, Full enteral feeding; SVD, Spontaneous vaginal delivery; TASH, Tikur Anbessa specialized Teaching hospital; ZMH, Zewditu memorial hospital; GMH, Ghandi memorial hospital; M II RH, Menelik II Referral hospital; SPHMMC, St. Paul’s Hospital Millennium Medical College Multivariate Cox regression model for predictors of time to attain FEF in LBW neonates admitted to neonatal intensive care unit of Addis Ababa public hospitals, Ethiopia, 202 Age at admission New diagnoses During follow up. AHR, Adjusted hazard ratio; CHR, Crud hazard ratio; FEF, Full enteral feeding; SVD, Spontaneous vaginal delivery; TASH, Tikur Anbessa specialized Teaching hospital; ZMH, Zewditu memorial hospital; GMH, Ghandi memorial hospital; M II RH, Menelik II Referral hospital; SPHMMC, St. Paul’s Hospital Millennium Medical College This prospective follow up study was aimed to estimate time to full enteral feeding attainment and its predictors among low birth weight neonates admitted to selected public hospitals of Addis Ababa, Ethiopia. Although it has strong variation depending on GA and birth weight the median time to attain full enteral feeding in this study was 5 days. This indicates that they achieve full enteral feeding with in a shorter time when they compared with Hawassa city, Sidama region Ethiopian [ 30 ] with a comparable study subjects. According to this study, 70.1%, 51.8%, 33.4% and 28% of neonates were kept NPO in their 1st, 2nd, 3rd and 4th postnatal day respectively getting only 10% dextrose intravenously. This finding in the first day is almost similar with the results of a hospital-based multicenter prospective study in Ethiopia (76%) [ 11 ] but high in the subsequent days. This variation may be due to a difference in the number of study participant involved and study design. The highest hazard time was the first seven days of life in which majority (64.93%) of LBW were reached at FEF. More than 22% of LBW neonates died before reaching full feeds. Maternal educational level, birth weight, mode of delivery, hospital acquired infection, being on antibiotics, age at initiation of trophic feeding, routine gastric residual evaluation and NICU location were found to have a statistically significant association with time to attain full enteral feeding. Neonates with birth weight of 2000–2499 gram attains FEF at median postnatal day of 3 while neonates with birth weight of 1500–1999 and 1000–1499 gram attains FEF at 6 and 11 days respectively (Table 3 ). This result strongly varies with a study done in 13 NICU worldwide (with only one NICU in Africa) which shows the median time to FEF (TFF; 8–33 days) [ 31 ]. This variation might be due to availability of TPN in these 13 NICU worldwide (administered for a longer time, 13–25 days) and there is no need to rush for enteral feeding. The other possible explanation for this variation is a difference in the mean GA and birth weight of the study subjects (33.6 ± 2.7 weeks and 1700 ± 426 gram in our case). However, the median time to attain FEF for VLBW neonates (11 days) was relatively similar with the finding of a population-based retrospective cohort study conducted among VLBW (< 1500 gram) in Bologna, Italy in 2014 with an estimated median time to FEF was 12.9 days (IQR = 8.0–21.5 days) [ 22 ]. The difference in our case is no infant less than 1000 gram attains FEF in the neonatal period. The time to FEF for VLBW (< 1500 gram) neonates observed in this study is exactly the same with the finding of studies done in India, 11 days [ 19 ]. This might be due to similarity in the study designs and socio-demographic similarity in the study participants. Maternal educational level was an independent socio-demographic factor in this study, and it had a substantial impact on the time to attain FEF. Neonates whose indexed mothers have a higher education level attains FEF faster than those neonates whose indexed mothers have no formal education. This might be due to poor education/counselling regard to feeding and better awareness on early initiation of feeding among mothers with higher educational level as supported by a study in china [ 32 ]. Cesarean delivery delays time to FEF at any time during the follow up by 41% (AHR 0.59 and 95% CI 0.36–0.96) which might be because of CS impairs early breastfeeding activity and a wide range of routine care after CS has become a hindrance to breastfeeding. Neonates without hospital acquired infection (AHR 2.25 and 95% CI 1.15–4.41), are 2.25 times more earlier to attain FEF at any time period during the follow up which was also supported by a study in India in 2018 [ 19 ]. Birth weight and Gestational age of neonates are also a significant predictors of time to reach FEF. Neonates with a birth weight of 100–1499 gram (AHR O.31 and 95% CI 0.142–0.67) were up to 69% less likely to attain FEF at any time during the follow up than those neonates whose birth weight is between 2000 and 2499 gram and this is consistent with studies in India [ 19 ]. Each 1 week increment in GA leads to 17% increase in the hazard of FEF which is nearly similar with the study done in Bologna, Italy [ 22 ]. The timing of initiation of trophic feeding was a significant predictor of time to reach FEF and as the timing of initiation delays, time to FEF also significantly prolonged. Those who start TF in their immediate postnatal day and 2nd were 6 and 3.9 times more faster to reached at FEF than those who starts TF at their 4th day and then after. This is supported by the evidence that starting TF, improves feeding tolerance, significantly fewer days of parenteral nutrition, and oxygen supplementation, and consistently earlier discharge [ 33 ]. Despite lack of clear evidence, the practice of routine pre-feed gastric residue aspiration before the next feed is common. Some units and healthcare providers routinely measures the gastric residue volume of every neonate feeding by tube irrespective of the presence of symptom of feeding intolerance. Routine gastric residual evaluation was done for 25.2% of LBW neonate before their next feeding and those who were not on routine gastric residual evaluation were 1.7 times more likely to reached at FEF earlier (AHR 1.7 and 95% CI 1.1–2.87). This is supported by a systematic review and meta-analysis which concludes as avoiding routine pre-feed aspiration was associated with achieving full enteral feeds earlier and shorter duration of hospitalization [ 34 ]. Those who were not on antibiotics (AHR 2.92 and 95% CI 1.31–6.53) reaches FEF faster which might be due to the reason that sepsis predicts time to FEF. NICU location (SPHMMC, AHR 4.85 and 95% CI 1.51–15.6) were found to have a statistically significant association with time to attain full enteral feeding which might be due to a difference in feeding practice among hospitals and health professionals and lack of consistent and standard feeding protocol. The study was conducted prospectively which can increase quality of data. Data were not missed due to chart incompleteness and it has no conflicts of interest. Study participants were recruited from different health care institution and as a result, the findings can be generalized. As a limitation the study period was short and the health care institution involved in this study were in a similar geographic region where most of the residents are urban. This study demonstrated the difficulty of understanding which low birth weight neonate attain FEF in a timely manner and identifies some predictors of the time to FEF achievement in LBW neonates. For countries like Ethiopia where 10% glucose is the only available parenteral supplementation and total parenteral nutrition is difficult to afford, this median time to attain FEF is thought to be considered as delayed. Maternal Higher educational level, birth weight of 1000–1499 gram, CS delivery, hospital acquired infection, being on antibiotics, age at initiation of trophic feeding, routine gastric residual evaluation, and NICU location, were found to have a statistically significant association with time to attain full enteral feeding in LBW neonates. Health care staffs treating LBW neonates should consider preterm nutrition as part of the management and early initiation of trophic feeding should be practiced and concern should be given for prevention of HAI which delays time to FEF and further research is better to be conducted; by taking long follow up time and in each GA and BW category. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We would like to acknowledge Addis Ababa University for sponsoring this research. Our gratitude and appreciation go to all data collectors, NICU staffs and study participants and indexed mothers for their cooperativeness and for sharing this use full information. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Addis Ababa University funds this study. The data extraction tool and data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request and it is also submitted to Addis Ababa University for repository. We declare and affirm that we have followed all ethical principles of scholarship through ought this study. Ethical clearance was obtained from Research Ethics Review Committee of department of Nursing College of Health Sciences, Addis Ababa University. A formal letter of cooperation from the University was submitted to each hospitals administrative body for data collection and permission was obtained from all concerned bodies in the hospital. A written informed consent was taken from parents of the neonate and care was taken not to disclose patient’s records and confidentiality was maintained by omitting their name and personal identification from the data collection format. All methods were carried out in accordance with the Declaration of Helsinki with respect for individuals, the right to make informed decisions, recognition of vulnerable groups. Not applicable. The authors declare no competing interests. Appropriate For Gestational Age Acute Kidney Injury Birth Weight Continuous Positive Airway Pressure Cesarean Section Early Onset Neonatal Sepsis Full Enteral Feeding Gestational Age Hospital Acquired Infection Intra Nasal Oxygen Extra Uterine Growth Restriction Infant and Young Child Feeding Low Birth Weight Late Onset Sepsis Necrotizing Enterocolitis Neonatal Intensive Care Unit Nothing Per Mouth Pregnancy Induced Hypertension Perinatal Asphyxia Respiratory Distress Spontaneous Vaginal Delivery Trachea Esophageal Fistula Trophic Feeding Time to Full Feeding Total Parenteral Nutrition Very Low Birth Weight Predictors of time to full enteral feeding in low birth weight neonates admitted to neonatal intensive care unit: a prospective follow up study Breastfeeding: a smart investment in people and in economies New insights in Preterm Nutrition Incidence and associated factors of extrauterine growth restriction (EUGR) in preterm infants, a cross-sectional study in selected NICUs in Ethiopia Early attainment of breastfeeding competence in very preterm infants Intake of own Mother’s milk during the First days of Life is Associated with decreased morbidity and mortality in very low Birth Weight infants during the first 60 days of life Guidelines for feeding very low Birth Weight infants Probiotics Prevent Late-Onset Sepsis in Human Milk-Fed, very low Birth Weight Preterm infants: systematic review and Meta-analysis Protein intake and growth in Preterm infants Severe Acute Malnutrition in very low Birth Weight Preterm infants Preterm Nutrition and Clinical outcomes Predictors of the time to attain full oral feeding in late preterm infants 2500-g low Birth Weight Cutoff: history and implications for Future Research and Policy Early total enteral feeding in stable very low Birth Weight infants: a before and after study The effects of kangaroo mother care on the time to breastfeeding initiation among preterm and LBW infants: a meta-analysis of published studies Factors Associated with Time to full feeds in Preterm very low Birth Weight infants Variations in breastfeeding rates for very preterm infants between regions and neonatal units in Europe: results from the MOSAIC cohort The trends in the usage of breast milk in neonatal intensive care setting Predictors of full enteral feeding achievement in very low Birth Weight infants The effect of feeding experience on clinical outcomes in preterm infants Transition Times to oral feeding in premature infants with and without Apnea Early versus late trophic feeding in very low Birth Weight Preterm infants Short versus extended duration of Trophic Feeding to Reduce Time to achieve full enteral feeding in extremely Preterm infants: an observational study Non-nutritive sucking for Preterm infants in Egypt Longer duration of kangaroo care improves neurobehavioral performance and feeding in preterm infants: a randomized controlled trial Time to full enteral feeding for very low-birth-weight infants varies markedly among hospitals Worldwide but May not be Associated with incidence of necrotizing enterocolitis: the NEOMUNE-NeoNutriNet cohort study Association between maternal education and breast feeding practices in China: a population-based cross-sectional study Routine prefeed gastric aspiration in preterm infants: a systematic review and meta-analysis |
Answer the following medical question. | What does research say about What does the evidence tell us? Revisiting optimal cord management at the time of birth.? | Communicated by Daniele De Luca. A newborn who receives a placental transfusion at birth from delayed cord clamping (DCC) obtains about 30% more blood volume than those with immediate cord clamping (ICC). Benefits for term neonates include higher hemoglobin levels, less iron deficiency in infancy, improved myelination out to 12 months, and better motor and social development at 4 years of age especially in boys. For preterm infants, benefits include less intraventricular hemorrhage, fewer gastrointestinal issues, lower transfusion requirements, and less mortality in the neonatal intensive care unit by 30%. Ventilation before clamping the umbilical cord can reduce large swings in cardiovascular function and help to stabilize the neonate. Hypovolemia, often associated with nuchal cord or shoulder dystocia, may lead to an inflammatory cascade and subsequent ischemic injury. A sudden unexpected neonatal asystole at birth may occur from severe hypovolemia. The restoration of blood volume is an important action to protect the hearts and brains of neonates. Currently, protocols for resuscitation call for ICC. However, receiving an adequate blood volume via placental transfusion may be protective for distressed neonates as it prevents hypovolemia and supports optimal perfusion to all organs. Bringing the resuscitation to the mother’s bedside is a novel concept and supports an intact umbilical cord. When one cannot wait, cord milking several times can be done quickly within the resuscitation guidelines. Cord blood gases can be collected with optimal cord management. Conclusion : Adopting a policy for resuscitation with an intact cord in a hospital setting takes a coordinated effort and requires teamwork by obstetrics, pediatrics, midwifery, and nursing. What is Known: • Placental transfusion through optimal cord management benefits morbidity and mortality of newborn infants. • The World Health Organisation has recommended placental transfusion in their guidance. What is New: • Improved understanding of transitioning to extrauterine life has been described. • Resuscitation of newborn infants whilst the umbilical cord remains intact could improve the postpartum adaptation. During pregnancy, fetal blood circulates between the fetus and the placenta providing essential nutrients and oxygen. At delivery, infants undergo rapid changes in Circulation and breathing in order to adapt to extra-uterine life. Optimal cord management (OCM), involving waiting several minutes before clamping and cutting the cord has been shown to increase circulatory stability and reduce in-hospital mortality [ 1 – 3 ]. Or if unable to wait, gently milking the cord towards the infant provides some placental transfusion and is preferable over immediate cord clamping (ICC) [ 3 ]. The different methods of OCM are listed in Table 1 . The World Health Organization (WHO) has recommended delayed cord clamping (DCC) as standard practice at the delivery of all infants but implementation is still variable across health care settings and countries [ 4 , 5 ]. We provide an overview of current knowledge about OCM and future perspectives. Table 1 Methods of optimal cord management Method name Explanation of procedure Delayed (deferred) cord clamping Leaving the cord intact for 30– 60 s in preterm infants, at least 3–5 min in term infants before clamping and cutting the cord Resuscitation with the intact cord Leaving the cord intact and starting resuscitation before clamping and cutting the cord Intact cord milking Repeated compression and stripping of the cord from the placental side, toward the infant while connected to the placenta after birth Cut cord milking Draining the cord by compression and stripping from the cut end toward the infant after clamping and cutting a long segment Methods of optimal cord management The residual placenta blood returns to the newborn warm (body temperature) and oxygenated. It contains about 15–20 mL/kg of red blood cells which provides the term infant with an adequate iron supply for four to 12 months [ 6 , 7 ]. There are several million to a billion stem cells providing an autologous transplant which may reduce the infant’s susceptibility to both neonatal and age-related diseases [ 8 ]. Progesterone is neuroprotective, and levels in the blood of term infants at birth are higher than the mother’s levels. This likely aids vasodilation and enhances the bodily distribution of the large amount of placental transfusion [ 9 , 10 ]. In addition, there are numerous additional components such as cytokines, growth factors, and important messengers in cord blood that most likely support and drive the process of transition but are too numerous to discuss here [ 11 ]. The full placental transfusion offers high pulmonary artery pressure in the first few hours of life to assist with neonatal adaptation [ 12 ]. It is likely that the force of the increased blood volume stimulates multi-organ perfusion for normal organ function, growth, and development. New research reveals that enhanced vascular perfusion causes an organ’s endothelial cells to release angiocrine responses to guide essential functions [ 13 ]. Throughout pregnancy, the fetal blood volume is approximately 110–115 mL/kg of fetal weight [ 14 ]. Only ~ 10% of the fetal cardiac output goes to the systemic circulation in the lungs, while 30 to 50% goes to the placenta where gas exchange takes place. In order to change from placental gas exchange to lung air exchange at birth, 45–50% of the newborn cardiac output must rapidly go into the alveolar capillary network in the lungs. Waiting to clamp the cord results in a net transfer of approximately 30% of the fetal-placental blood volume over the first few minutes after birth from the placenta to the neonate. This provides the blood volume needed to fill the alveolar capillary network for the first time and to fully perfuse organs previously supported by the placenta [ 15 ]. Classic physiologic studies completed over the past 60 years have documented that placental transfusion results in improved perfusion in the neonate’s respiratory, hematologic, urinary, gastrointestinal, and neurological systems [ 16 – 18 ]. We have proposed that the blood volume received from a placental transfusion increases systemic and regional blood flow and vasodilation in the newborn and aids in normal organ development and health. Immediate cord clamping (ICC) reduces the neonate’s blood volume and may contribute to loss of organ-specific vascular competence [ 13 ]. Receiving an adequate blood volume from placental transfusion may be especially protective for the distressed neonate preventing hypovolemia and supporting optimal perfusion to all organs [ 13 , 19 ]. One of the key features of the normal fetal to neonatal transition at birth is a reduction in the pulmonary vascular resistance (PVR) which allows an increase in pulmonary blood flow and redirects the right ventricular output through the lung instead of through the ductus arteriosus [ 20 ]. Credit has been given to lung aeration for decreasing the PVR at birth although the mechanisms causing this has been debated for decades [ 21 ]. A new study demonstrated that vagotomy inhibits the previously observed increase in pulmonary blood flow with partial lung aeration [ 21 ]. Compared to control newborn rabbits, Lang et al. found that animals after vagotomy had little or no increase in pulmonary blood flow when ventilated with air or nitrogen gas. Using 100% oxygen for ventilation only partially mitigated this effect. This information suggests that the initial dramatic fall in PVR likely does not occur with ventilation and breathing alone and that the vagus nerve, likely stimulated by the increased blood volume, plays a significant role. It appears that with the important task of lowering the PVR, there are multiple overlapping mechanisms to ensure that the transition happens [ 21 ]. The volume of the transfusion in the term infant receiving DCC is approximately 85 to 100 g or ~ 30 mL/kg [ 22 – 24 ]. For preterm infants, Aladangady reported increased blood volume with DCC at all births, but a smaller increase when born by cesarean section [ 25 ]. Factors that affect the amount and speed of the placental transfusion include the timing of umbilical cord clamping, gravity, cord pulsations, uterine contractions, and milking the umbilical cord (UCM) which are discussed below, (see Figs. 1 and 2 ). Fig. 1 Factors influencing placental transfusion with DCC. Timing of cord clamping, uterine contractions, spontaneous respirations, and gravity influence the magnitude of transfusion. Reported long-term benefits are shown. (Copyright Satyan Lakshminrusimha — used with permission) Fig. 2 The speed and volume of placental transfusion in relation to time and relative position of the neonate in relation to the placenta (Courtesy of Ola Andersson — used with permission.) Factors influencing placental transfusion with DCC. Timing of cord clamping, uterine contractions, spontaneous respirations, and gravity influence the magnitude of transfusion. Reported long-term benefits are shown. (Copyright Satyan Lakshminrusimha — used with permission) The speed and volume of placental transfusion in relation to time and relative position of the neonate in relation to the placenta (Courtesy of Ola Andersson — used with permission.) It is well known that DCC or a delay before clamping increases the amount of placental transfusion to the infant but the optimal time is still controversial. As one delays clamping longer, the neonatal hematocrit at 24–48 h increases [ 23 , 26 , 27 ]. Term infants with a 5-min delay showed an early hematologic advantage compared to infants receiving ICC, without any increase in hyperbilirubinemia requiring phototherapy or symptomatic polycythemia out to 48 h of age [ 28 ]. New evidence from a recent landmark study in asphyxic and asystolic lambs found that leaving the cord intact over a 10-min period mitigated the rebound hypertension (by 20–30 mmHg) commonly seen after an asphyxial event [ 29 ]. If cord clamping was immediate or only delayed 1 min, the hypertension tended to be worse. This study suggests that the post-asphyxia rebound response may contribute to the brain injury and seizures that often follow severe asphyxia. Prevention of the overshoot may alleviate its contribution to brain injury. Clinical studies (see Table 2 ) underway to address the question of longer delays in cord clamping with normal and distressed neonates are discussed later under “ Ongoing research and future considerations .” Table 2 Current or proposed studies on intact cord resuscitation Study acronym and country Proposed N GA (weeks) Intervention Cord clamping time, control Cord clamping time, intervention Primary outcome Expected end date VentFirst (USA) NCT02742454 [ 75 ] 940 23–28 CPAP 30–120 s 30–60 s 120 s IVH, HR, SpO2, Apgar scores ≤ 10 min 2024 PCI-Trial (Italy) NCT02671305 [76] 202 23–29 Resuscitation as needed Intact UCM × 4 3 min Composite outcome of severe IVH, CLD or death 2022 ABC2 (Netherlands Trial Registry) NTR7194 [77] 660 24–30 Resuscitation if needed ICC Cord clamping when stable* Intact survival — without IVH or NEC 2024 MINVI – Milking in Non-Vigorous Infants (USA) NCT03631940 1200 35–42 Milking the cord × 4 times ICC UCM × 4 before clamping Admission to the NICU 2023 Baby DUCC (Australia) 12,618,000,621,213 [78] 120 32–41 Resuscitation if needed ICC Until 1 min after CO2 detector changes or 5 min Heart rate at 60 and 120 s 2023 SAVE: Effects of DCC during resuscitation (Sweden) NCT04070560 600 35–42 Resuscitation for non-breathing infants 60 s to resuscitaire > 180 s with intact cord near mother Apgar at 5 min 12/2026 CHIC — congenital diaphragmatic hernia intact cord (France) NCT04429750 [ 51 ] 180 > 36 Resuscitation of Infants with Congenital Diaphragmatic Hernia ICC with transfer to Resus room Intact cord resuscitation on dedicated trolley near mother Apgar score at 1 and 5 min No data Current or proposed studies on intact cord resuscitation PCI-Trial (Italy) NCT02671305 [76] ABC2 (Netherlands Trial Registry) NTR7194 [77] MINVI – Milking in Non-Vigorous Infants (USA) NCT03631940 Baby DUCC (Australia) 12,618,000,621,213 [78] SAVE: Effects of DCC during resuscitation (Sweden) NCT04070560 CHIC — congenital diaphragmatic hernia intact cord (France) NCT04429750 [ 51 ] Holding the newborn above the placenta slows transfusion, whereas lowering the newborn hastens transfusion [ 7 , 30 ]. However, cord clamping at 1 min with the infant on the maternal abdomen can reduce the estimated placental transfusion by 50% [ 31 ]. Weight gain (a proxy for amount of placental transfusion) was only 50% of expected amount after two minutes of DCC in a study that weighed infants to compare the effect of gravity. The researchers lowered half the cohort below the perineum and placed the other half on the maternal abdomen [ 32 ]. The influence of gravity is illustrated in Fig. 2 . Pulsations of the intact cord appear to last longer than previously thought according to two recent studies [ 33 , 34 ]. Using a Doppler, Boere found that over 80% of the infants had umbilical artery flow for over 4 min after birth and 43% still had flow when the cord was cut at 6 min [ 33 ]. The flow was pulsatile similar to the infant’s heartbeat and was mainly unidirectional, from the infant to the placenta. DiTommaso, using palpation to examine duration of cord pulsations at vaginal birth, found that the median duration was 3.5 min. They found that infants with a longer duration of cord pulsations had higher birthweights (3530 vs. 3250, p = 0.005) and a longer third stage of labor (12 vs 8 min, p < 0.001), without any increased risk of postpartum hemorrhage [ 34 ]. Both studies suggest that the placenta continues to support the infant longer than previously thought. During the few minutes surrounding birth, uterine contractions squeeze blood from the placenta to the infant. However, as the uterus relaxes in-between contractions, blood can flow through the placenta exchanging nutrients and gases for the fetus/infant [ 35 , 36 ]. This process continues for longer than originally thought and is a valuable asset especially for the infant who is not breathing [ 33 ]. Even after the umbilical arteries close, the strong uterine contractions of third stage force more blood to the infant via the umbilical vein, if the cord is left intact. Although it is not physiologic, milking the umbilical cord two to four times towards the baby has been studied as an alternative to waiting for at least 60 s before clamping the cord [ 37 , 38 ]. Meta-analyses of studies using UCM show similar benefits to waiting for 60 s, with increased survival by 27% compared to ICC with no difference in major co-morbidities of prematurity [ 3 , 39 , 40 ]. Based on this evidence, many key perinatal learned societies and stakeholders recommend the use of UCM before clamping the cord but only if DCC is deemed not feasible [ 39 , 40 ]. Benefits for term neonates include higher hemoglobin levels, less iron deficiency in infancy, improved brain myelin volume out to 12 months, and better motor and social development at 4 years of age especially in boys [ 41 – 43 ]. For preterm infants, benefits include less intraventricular hemorrhage, fewer gastrointestinal issues, lower transufusion requirements, and decreased mortality by 30% in the NICU and out to two years of age [ 1 , 44 , 45 ]. Perhaps the benefit most familiar with clinicians is the prevention of iron deficiency and anemia in infancy. Both iron deficiency and anemia have a high prevalence in low- and middle-income countries and are associated with perinatal mortality, delayed child mental and physical development, and reduced visual and auditory function [ 43 , 46 ]. Anemia in infancy contributes to the global burden of morbidity and mortality during the first year of life. OCM can contribute to preventing anemia in the newborn and increased better iron storage up to 12 months of age in term infants [ 7 ]. Providers should consider that OCM is free of charge and an easy preventative measure which can be applied in any health care setting, in any gestational age and is strongly recommended by the WHO [ 4 ]. Fetuses who were small for gestational age at birth also benefit from OCM [ 47 , 48 ]. DCC improves iron stores in SGA infants ≥ 35 weeks at 3 months of age without increasing the risk of symptomatic polycythemia, need for partial exchange transfusions, or morbidities associated with polycythemia. Thus, the WHO recommends providing OCM for them at birth. The same applies to mothers with human immunodeficiency virus infection and low viral load as transmission from mother to fetus is very low [ 49 ]. A study of mother-infant pairs with Rhesus-alloimmunisation demonstrated that infants who received placental transfusion at delivery had reduced need for immediate blood exchange transfusion after birth and were successfully managed with phototherapy and blood transfusions as needed [ 50 ]. The myth about an increase in jaundice requiring phototherapy has been refuted by recent meta-analyses [ 1 , 2 , 23 , 44 ]. Studies on infants with congenital heart disease or diaphragmatic hernia have demonstrated benefits for postnatal adaptation due to their increased need for red blood cells as oxygen carriers. It makes sense to provide them with more of their own blood through placental transfusion at birth [ 51 , 52 ]. Studies of multiple births have demonstrated feasibility of providing OCM to twins and triplets [ 53 , 54 ]. Thus, multiple births should not be routinely excluded. The plan for delivery of fetuses with the conditions mentioned above should be considered on an individual basis with a decision about OCM made by an experienced perinatal team ahead of birth. Maternal contraindications of OCM especially focused on DCC have not been formally studied. There are almost no indications for ICC, nor contraindications to OCM. The need for maternal resuscitation in the face of massive, acute hemorrhage would be a rare, justifiable reason to proceed with ICC but cut UCM may still benefit the newborn. A ruptured vasa praevia, snapped cord, or other trauma to the cord vessels, which will result in hemorrhage from the baby, would also be reasons for ICC. In the case of a complete placental abruption where the placenta is delivered at the same time as the baby, it could be held above the baby, with gentle application of pressure to the placenta, and then clamped before the placenta is lowered. Cord milking could also be considered in this situation. A short cord length might interfere with the management of the mother or baby but can usually be addressed with optimal positioning. It should not be considered as an automatic indication for ICC, nor a contraindication to OCM. When an infant is born, the intrapartum provider must quickly decide how to manage the umbilical cord. At an uncomplicated birth, DCC is a well-supported, evidence-based practice which facilitates placental transfusion. When an infant is in distress, providers in hospital settings will often practice ICC and transfer the infant to the warmer for resuscitation, away from the mother’s bedside. This practice may lead to increased morbidity and mortality and a disruption in neurodevelopment [ 44 , 55 ]. The risks of ICC have been studied indirectly as ICC has been the comparator for many studies on DCC and UCM. A list of potential risks is shown in Table 3 . The practice of stabilization and resuscitation with an intact cord is not a new idea yet it is infrequently used in hospital settings. Midwives, in out-of-hospital settings, frequently maintain an intact cord after birth and regard the umbilical cord as a lifeline to assist in transition to neonatal life [ 7 , 56 ]. Table 3 Potential harmful effects of immediate cord clamping compared to delayed cord clamping or milking of the cord Organ system Effects of immediate cord clamping Hematology ↓ RBC Volume, ↓ Hematocrit, ↓ Hemoglobin ↑ Hypovolemia Body Iron Stores ↓ Ferritin (out to 4–8 months) ↓ Total Body Iron (at 6 months) Cardiovascular ↓ Adaptation ↓ Blood Pressure ↑ Vascular resistance ↓ RBC flow to brain (18%) ↓ RBC flow to gut (15–20%) Birth weight ↓ Lighter by 60–101 g Skin ↓ Cutaneous perfusion ↓ Peripheral temperature Renal function ↓ Renal blood flow ↓ Urine output ↑ Sodium excretion Respiratory circulation ↓ Pulmonary vasodilatation RBC: red blood cells; ↑ increase; ↓ decrease [1–3, 79] Potential harmful effects of immediate cord clamping compared to delayed cord clamping or milking of the cord ↓ RBC Volume, ↓ Hematocrit, ↓ Hemoglobin ↑ Hypovolemia ↓ Ferritin (out to 4–8 months) ↓ Total Body Iron (at 6 months) ↓ Adaptation ↓ Blood Pressure ↑ Vascular resistance ↓ RBC flow to brain (18%) ↓ RBC flow to gut (15–20%) ↓ Cutaneous perfusion ↓ Peripheral temperature ↓ Renal blood flow ↓ Urine output ↑ Sodium excretion RBC: red blood cells; ↑ increase; ↓ decrease [1–3, 79] New evidence suggests a distressed infant should be stabilized and resuscitated with an intact cord. This fosters placental transfusion and allows the placenta to continue its important respiratory role in gas exchange and supports volume repletion. A tight nuchal cord and/or a shoulder dystocia are often associated with slow-to-start infants secondary to hypovolemia. The Somersault Maneuver is recommended to release the tight nuchal cord allowing the cord to remain intact [ 57 ]. For both nuchal cord and shoulder dystocia, the restoration of blood volume and continued oxygen support from the placenta, alongside Neonatal Resuscitation Program (NRP) and International Liaison Committee for Resuscitation (ILCOR) protocols, help to assist the newborn’s transition [ 19 , 55 ]. and are important actions which can help protect the newborn’s heart and brain. Resuscitation tables (trolleys) and the accompanying resuscitation equipment have been developed for this purpose [ 55 ]. These tables can be moved alongside the mother’s bedside, and the resuscitation can be conducted with an intact cord. Andersson and colleagues (2019) demonstrated in distressed infants, ≥ 35 weeks gestation, that resuscitation with an intact cord resulted in better oxygen saturation levels and Apgar scores [ 58 ]. Two birth practices, cord blood banking and cord gas collection, imply ICC and challenge the support of an intact cord at birth. Umbilical cord blood banking is the collection of residual placental blood, per parental request, for the purposes of stem cell collection which is then stored in a private or public blood bank. Placental transfusion, via DCC, is not compatible with cord blood banking. In the USA, the American College of Obstetricians and Gynecologists do not recommend the practice of private blood banking nor the interference of the routine practice of DCC [ 59 ]. Parents should be informed about the entire contents of cord blood and risks associated with ICC before they make a decision about banking their infant’s blood [ 7 ]. The practice of umbilical cord gas collection is routine in some hospital settings or may be used judiciously to assess acid–base balance in complex clinical situations. Most providers double clamp the cord immediately after birth and save a section of the cord to be used for analysis. In light of the benefits of DCC, researchers have examined the accuracy of cord gas results comparing ICC and DCC. In a recently published systematic review, it was found that a delay of 2 min in clamping made little difference on the accuracy of cord gas results [ 60 ]. Also, cord blood gases may be collected from an intact cord [ 61 ]. There has been increasing interest in stabilization of the preterm or term infant, while the cord is still intact. A list of ongoing or planned studies is provided in Table 2 , and Katheria has written an excellent review [ 62 ]. We propose that the totality of a placental transfusion is what is important to the baby. It is not just the components — red blood cells, stem cells, cytokines, growth factors, plasma, blood volume, progesterone, or force of the blood for transduction — that make a difference. Collectively, all these pieces working together create the whole process of a normal transition for the neonate. This is a clear biological case where the “whole is greater than the sum of its parts.” If the whole is not considered, it does not work as well and can leave the infant deficient in a variety of ways. This idea may be part of the reason that the uptake of DCC/placental transfusion into clinical practice is slow as placental transfusion does not fit well into the current scientific paradigm of reductionism. Support of placental transfusion is recommended as the standard of care at the time of birth, across all birth settings, all modes of delivery and for both term and preterm newborns [ 4 , 7 ]. This recommendation helps to decrease iron deficiency anemia in infancy and reduces a negative impact on the developing brain [ 41 , 63 ]. Distressed infants who require resuscitation often have their cords cut immediately and are rapidly transferred to a resuscitaire (warmer), away from the mother’s bedside. [ 64 , 65 ] Leslie and colleagues (2020) found that US midwives often practiced DCC (98%) and waited for cord pulsations to cease. But these same midwives felt they needed to use ICC in situations which required neonatal resuscitation and/or umbilical cord gas collection often because of institutional policies and time pressures [ 66 ]. Emerging evidence suggests that distressed infants require a placental transfusion as much if not more than a healthy newborn[ 7 , 19 ] In complex clinical situations that require neonatal resuscitation, new available research suggests the resuscitation can be conducted with an intact umbilical cord managed at the mother’s bedside [ 55 , 67 ]. This can enhance resuscitation efforts and provide a return of the infant’s own warm, oxygenated blood. When resuscitation with an intact cord is not feasible, milking the cord can be done quickly (several times) within the current NRP and ILCOR standards benefitting infants 28-week gestation or greater [Madar, 2021]. Milking can accelerate the transfer of residual placental blood although not as completely as DCC or an intact cord [ 55 , 68 ]. Establishing a policy for resuscitation with an intact cord within a hospital setting takes a coordinated effort, logistical considerations and requires multidisciplinary support [ 55 , 65 , 69 ]. One large randomized controlled trial, comparing DCC with UCM, found a significant higher rate of intraventricular hemorrhage with UCM, in infants less than 28-week gestation, but recent meta-analyses of comparative studies found no difference for this outcome [ 2 , 70 ]. The question remains as to how UCM in infants less than 28-weeks compare to infants receiving ICC differ on variables of IVH and neurodevelopmental follow-up [ 40 ]. It can take significant time (sometimes 10 years or more) for evidence-based approaches to become accepted into clinical practice [ 71 ]. In fact, many effective interventions fail to be adopted (60–70%) [ 72 ]. This presents significant challenges when trying to translate research findings, such as those from OCM, into practice. Unfortunately, failure to adopt beneficial practices in a timely fashion may lead to unnecessary harm to the newborn [ 71 – 73 ]. Mounting evidence, especially a decrease of mortality in preterm infants, supports the benefits of DCC [ 45 ]. This has led to a greater willingness for hospital settings to adopt DCC. Yet, DCC appears to be more easily adopted by providers caring for preterm infants when compared to term infants [ 74 ]. Implementation of OCM for all infants requires a step wise approach in planning and implementation [ 5 ]. This includes a needs assessment to assess organizational and individual willingness to change. Stakeholders and end users (such as obstetricians, midwives, pediatricians and nurses) must be included in order to reduce reluctance to change and to increase confidence and adherence [ 5 ]. A multidisciplinary approach supports teamwork and enhances adoption to change. At this point in the process, any concerns and potential contradictions should be addressed in multidisciplinary discussions prior to delivery. A clinical guideline or policy which is simple, easy to follow, and based on current evidence should be developed with input from all team members and should be updated regularly as new evidence emerges. An example of new emerging evidence is the improvement of neonatal resuscitation by maintaining an intact umbilical cord. This is a novel clinical practice in most hospital settings although has been practiced at out of hospital settings back to the time of Aristotle [ 75 ]. Once the decision is made to introduce OCM to the hospital setting, a variety of motivational and educational strategies are available. After implementation, an ongoing monitoring plan is needed to watch compliance rates. Reflection, evaluation, and responsiveness (feedback) will enhance sustainability [ 5 ]. Receiving a placental transfusion is beneficial for all term and preterm infants, including those that are distressed. Placental transfusion plays a major role in neonatal transition by preventing hypovolemia and providing better perfusion to all organs. Adopting resuscitation with an intact cord in a hospital setting will take a concerted effort and team works by obstetricians, midwives, pediatricians, and nurses. Delayed cord clamping Immediate cord clamping International Liaison Committee for Resuscitation Intraventricular hemorrhage Neonatal intensive care unit Neonatal Resuscitation Program Optimal cord management Pulmonary vascular resistance Umbilical cord milking World Health Organization The original online version of this article was revised: The arrows of data under second column of the Table 3 has been updated. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Change history 2/14/2022 A Correction to this paper has been published: 10.1007/s00431-022-04414-x All authors conceptualized the composition of the manuscript, updated their literature searches, and wrote parts of the manuscript. All authors coordinated the writing and finalized the manuscript. All authors have read and agreed to the contents of the manuscript. Not applicable. Not applicable. Not applicable. The authors declare no competing interests. What does the evidence tell us? Revisiting optimal cord management at the time of birth Correction to: What does the evidence tell us? Revisiting optimal cord management at the time of birth Association of umbilical cord management strategies with outcomes of preterm infants: a systematic review and network meta-analysis Strategies for implementing placental transfusion at birth: a systematic review Session 4: Mineral metabolism and body composition iron status of breast-fed infants Cord management of the term newborn Enhancing endogenous stem cells in the newborn via delayed umbilical cord clamping Progesterone actions during central nervous system development Variations in umbilical cord hematopoietic and mesenchymal stem cells with bronchopulmonary dysplasia Pulmonary arterial pressures of newborn infants born with early and late clamping of the cord Placental transfusion: may the “force” be with the baby Placental transfusion: determinants and effects Physiology of the fetal circulation Renal function and blood volume in newborn infant related to placental transfusion The circulatory and respiratory adaptation to early and late cord clamping in newborn infants Effect of Leboyer childbirth on cardiac output, cerebral and gastrointestinal blood flow velocities in full-term neonates Is it time to rethink cord management when resuscitation is needed? Fetal and neonatal pulmonary circulation Vagal denervation inhibits the increase in pulmonary blood flow during partial lung aeration at birth Measuring placental transfusion for term births: weighing babies with cord intact: measuring placental transfusion for term births Distribution of blood between infant and placenta after birth Infants’ blood volume in a controlled trial of placental transfusion at preterm delivery Venous and capillary hematocrit in newborn infants and placental transfusion Effect and safety of timing of cord clamping on neonatal hematocrit values and clinical outcomes in term infants: a randomized controlled trial Effects of delayed cord clamping on residual placental blood volume, hemoglobin and bilirubin levels in term infants: a randomized controlled trial Cardiopulmonary resuscitation of asystolic newborn lambs prior to umbilical cord clamping; the timing of cord clamping matters! Effect of gravity on placental transfusion Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial Umbilical blood flow patterns directly after birth before delayed cord clamping The bearing-down efforts and their effects on fetal heart rate, oxygenation and acid base balance Delayed cord clamping in South African neonates with expected low birthweight: a randomised controlled trial Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks’ gestation: a randomised controlled trial Part 5: Neonatal Resuscitation 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Considering an update on umbilical cord milking for the new guidelines for neonatal resuscitation Effects of delayed cord clamping on 4-month ferritin levels, brain myelin content, and neurodevelopment: a randomized controlled trial Effect of delayed cord clamping on neurodevelopment at 4 years of age: a randomized clinical trial Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis Functional significance of early-life iron deficiency: outcomes at 25 years Delayed cord clamping in infants with suspected intrauterine growth restriction Early versus delayed cord clamping in small for gestational age infants and iron stores at 3 months of age — a randomized controlled trial Delayed cord clamping in Rh-alloimmunised infants: a randomised controlled trial Early versus delayed umbilical cord clamping in infants with congenital heart disease: a pilot, randomized, controlled trial Efficacy of intact cord resuscitation compared to immediate cord clamping on cardiorespiratory adaptation at birth in infants with isolated congenital diaphragmatic hernia (CHIC) Neonatal outcomes in preterm multiples receiving delayed cord clamping A randomized controlled trial of immediate versus delayed umbilical cord clamping in multiple-birth infants born preterm How to provide motherside neonatal resuscitation with intact placental circulation? Bedside resuscitation of newborns with an intact umbilical cord: experiences of midwives from British Columbia Nuchal cord management and nurse-midwifery practice Intact cord resuscitation versus early cord clamping in the treatment of depressed newborn infants during the first 10 minutes of birth (Nepcord III) — a randomized clinical trial 771: Umbilical cord blood banking Effect of delayed cord clamping on umbilical blood gas values in term newborns: a systematic review Effects of delayed compared with early umbilical cord clamping on maternal postpartum hemorrhage and cord blood gas sampling: a randomized trial: Delayed vs early clamping effect on PPH and pH Neonatal resuscitation with an intact cord: current and ongoing trials Time to implement delayed cord clamping Acceptability of bedside resuscitation with intact umbilical cord to clinicians and patients’ families in the United States Umbilical cord practices of members of the American College of Nurse-Midwives A review of different resuscitation platforms during delayed cord clamping Placental transfusion for asphyxiated infants Whole blood volumes associated with milking intact and cut umbilical cords in term newborns Association of umbilical cord milking vs delayed umbilical cord clamping with death or severe intraventricular hemorrhage among preterm infants Building capacity for evidence-based public health: reconciling the pulls of practice and the push of research ACOG Committee Opinion, Number 814 Historical perspectives on umbilical cord clamping and neonatal transition |
Answer the following medical question. | What does research say about Randomized Controlled Trial on the Effect of the Neonatal Nurse Navigator Program on Maternal Stress and Neonatal Cortisol Levels.? | To assess the effect of the Neonatal Nurse Navigator Program (NNNP) compared to usual care on maternal stress and neonatal salivary cortisol level (SCL) in the NICU. Randomized control trial. NICU in a tertiary health care hospital in Manipal, Udupi District, Karnataka, India. Neonates between 34 and 36 weeks gestation and their mothers (N = 120 dyads). We used block randomization to assign dyads to the intervention or control group. We measured maternal stress using the Parental Stress Scale: Neonatal Intensive Care Unit, and we estimated neonatal stress by measuring SCLs within 24 hours of NICU admission and before discharge from the unit. We conducted a descriptive analysis on participant characteristics and reported maternal stress levels using means and standard deviations. We used the analysis of covariance change score test to determine the difference in maternal and neonatal stress levels between the intervention and control groups. The NNNP group exhibited significantly lower maternal stress scores before discharge than the control group, and we observed reductions across all three subscales of the Parental Stress Scale: Neonatal Intensive Care Unit. Mean neonatal salivary cortisol levels were significantly lower in the interventional group than in the control group, F(1.117) = 24.03, 95% confidence interval [7.9, 18.6], p < .001. Use of the NNNP reduced maternal stress SCLs in high-risk neonates by actively engaging mothers in the care of their neonates in the NICU. We recommend adoption of the NNNP model as a standard care policy in NICUs throughout India. |
Answer the following medical question. | What does research say about Unplanned extubation and subsequent trial of noninvasive ventilation in the neonatal intensive care unit.? | Unplanned extubation (UE) occurs as an infrequent complication of mechanical ventilation in the neonatal intensive care unit (NICU). Following UE, a trial of noninvasive ventilation (NIV) may be considered if a neonate is showing adequate respiratory effort. This study investigated the success and failure rate of NIV management of neonates experiencing UE. Retrospective single-center study of neonates experiencing UE in the NICU over a 9-year period. Reintubation within 12 hours of a trial of NIV following UE was defined as treatment failure. Short-term respiratory outcomes were analyzed for all infants plus the incidence of bronchopulmonary dysplasia for preterm infants born less than 32 weeks' gestation. A total of 43 patients were included. Of those, 30 infants were trialed on NIV following UE. Baseline demographics were similar between both the groups except for the oxygen requirement before UE. The NIV was successful in 20 and failed in 10 infants. Infants who failed a trial of the NIV were reintubated between 0.45 and 5.25 hours following UE. Respiratory outcomes in very preterm infants did not differ between groups. A trial of NIV may be considered as a treatment option in preterm and term newborns experiencing UE in the NICU. |
Answer the following medical question. | What does research say about Clinical pharmacology of fentanyl in preterm infants. A review.? | Fentanyl is a synthetic opioid that is very important in anesthetic practice because of its relatively short time to peak analgesic effect and the rapid termination of action after small bolus doses. The objective of this survey is to review the clinical pharmacology of fentanyl in preterm infants. The bibliographic search was performed using PubMed and EMBASE databases as search engines. In addition, the books Neofax: A manual of drugs used in neonatal care and Neonatal formulary were consulted. Fentanyl is N-dealkylated by CYP3A4 into the inactive norfentanyl. Fentanyl may be administered as bolus doses or as a continuous infusion. In neonates, there is a remarkable interindividual variability in the kinetic parameters. In neonates, fentanyl half-life ranges from 317 minutes to 1266 minutes and in adults it is 222 minutes. Respiratory depression occurs when fentanyl doses are >5 μg/kg. Chest wall rigidity may occur in neonates and occasionally is associated with laryngospasm. Tolerance to fentanyl may develop after prolonged use of this drug. Significant withdrawal symptoms have been reported in infants treated with continuous infusion for 5 days or longer. Fentanyl is an extremely potent analgesic and is the opioid analgesic most frequently used in the neonatal intensive care unit. |
Answer the following medical question. | What does research say about Fresh Frozen Plasma Administration in the NICU: Evidence-based Guidelines.? | The use of FFP in neonatology should be primarily for neonates with active bleeding and associated coagulopathy. However, since there is limited and poor-quality evidence supporting neonatal FFP transfusion, considerable FFP usage continues to be outside of this recommendation, as documented by neonatal transfusion audits. This review updates the scientific evidence available on FFP use in neonatology and reports the best evidence-practice for the safety of neonates receiving FFP. |
Answer the following medical question. | What does research say about [Iatrogenic burns in neonates].? | Despite the availability of different medical tools to simplify blood withdrawal, an old-fashioned method is still frequently being used in neonatal infants: the use of warm elements such as a warm washcloth or a glove filled with warm water, wrapped around an extremity. Use of these warm elements may easily cause contact burns in neonates. Unfortunately, not seldom we see and treat neonates with these burn injuries. We present the case of a neonate, who was referred to our outpatient clinic with an iatrogenic contact burn. The patient received topical treatment and wound dressings for over a month time. Scars remained. We would like to raise awareness among care givers on this type of injuries. To prevent these iatrogenic burns injuries, we advise to use alternative methods to simplify blood withdrawal. |
Answer the following medical question. | What does research say about Review of sleep-EEG in preterm and term neonates.? | Conflict of interest None Neonatal sleep is a crucial state that involves endogenous driven brain activity, important for neuronal survival and guidance of brain networks. Sequential EEG-sleep analysis in preterm infants provides insights into functional brain integrity and can document deviations of the biologically pre-programmed process of sleep ontogenesis during the neonatal period. Visual assessment of neonatal sleep-EEG, with integration of both cerebral and non-cerebral measures to better define neonatal state, is still considered the gold standard. Electrographic patterns evolve over time and are gradually time locked with behavioural characteristics which allow classification of quiet sleep and active sleep periods during the last 10 weeks of gestation. Near term age, the neonate expresses a short ultradian sleep cycle, with two distinct active and quiet sleep, as well as brief periods of transitional or indeterminate sleep. Qualitative assessment of neonatal sleep is however challenged by biological and environmental variables that influence the expression of EEG-sleep patterns and sleep organization. Developing normative EEG-sleep data with the aid of automated analytic methods, can further improve our understanding of extra-uterine brain development and state organization under stressful or pathological conditions. Based on those developmental biomarkers of normal and abnormal brain function, research can be conducted to support and optimise sleep in the NICU, with the ultimate goal to improve therapeutic interventions and neurodevelopmental outcome. Review of sleep-EEG in preterm and term neonates |
Answer the following medical question. | What does research say about Psychometric Properties of the Turkish Version of the Neonatal Infant Acute Pain Assessment Scale.? | Even the healthiest neonates experience pain during painful interventions (e.g. administration of Vitamin K, heel lance) in their first moments of life. This study aimed to examine the validity and reliability of the Turkish version of the Neonatal Infant Acute Pain Assessment Scale. This methodological study was conducted with 100 newborns receiving treatment and care in a tertiary neonatal intensive care unit. The data were collected using the Neonate Demographic Form, the Neonatal Infant Acute Pain Assessment Scale, and the Premature Infant Pain Profile. The scale was analyzed in terms of validity, internal consistency, and interobserver reliability. The content validity index of the scale was found to be between 0.87 and 1.00, while Cronbach's alpha coefficient was between 0.708 and 0.833. According to the item analysis results, item-total correlation values were high. A strong positive correlation was found between the scores of the two scales that were analyzed for concurrent validity. The Turkish version of the Neonatal Infant Acute Pain Assessment Scale was determined to be valid and reliable. More studies should be done to accurately measure and effectively manage neonatal pain. |
Answer the following medical question. | What does research say about The ventilatory pump: neonatal and developmental issues.? | This review documents the current knowledge with regard to the structure and function of the developing ventilatory pump. We note that while the neonate's compliant rib cage and diaphragmatic configuration may predispose the newborn to pump failure, its diaphragmatic endurance properties and ability to recruit accessory muscles of respiration may protect against such impairment. We also share evidence that central neural failure can lead to an inability to defend minute ventilation during periods of heightened respiratory effort. Nevertheless, our fund of knowledge remains limited and at this juncture it is unclear which factors or interplay of factors contribute to the development of ventilatory failure in the human neonate and infant. The ventilatory pump is a vital component of the respiratory system. As such, our understanding of the pathogenesis and reversal of ventilatory pump impairment is crucial to improving our management of respiratory failure. We are only beginning to develop such an understanding within a neonatal and developmental context. Future research endeavors will enlarge our fund of knowledge regarding the thorax, the respiratory muscles, and the central neural respiratory-related neurons that control them. From such an understanding will emerge clinically relevant information that has therapeutic implications for the care of newborns and infants with respiratory disease. |
Answer the following medical question. | What does research say about Neonatal Organ and Tissue Donation for Research: Options Following Death by Natural Causes.? | The donation of organs and tissues from neonates (birth to 28 days) for transplantation has been a relatively infrequent occurrence. Less common has been the use of neonatal organs and tissues for research. Specific ethical and legal questions beg for rational and transparent guidelines with which to evaluate referrals of potential donors. Donation of organs and tissues from a neonate can play a key role in the care and support provided to families by health care professionals around the time of a neonate’s death. We report on the recovery of neonatal organs and tissues for research. A working group made up of bioethicists, neonatologists, lawyers, obstetric practioners as well as organ procurement and tissue banking professionals evaluated legal, ethical and medical issues. Neonatal donor family members were also consulted. Our primary goals were (a) to ensure that referrals were made in compliance with all applicable federal and state laws, regulations and institutional protocols, and (b) to follow acceptable ethical standards. Algorithms and policies designed to assist in the evaluation of potential neonatal donors were developed. Neonatal donation is proving increasingly valuable for research into areas including diabetes, pulmonary, gastrointestinal, genitourinary and neurological development, rheumatoid arthritis, autism, childhood psychiatric and neurologic disorders, treatment of MRSA infection and pediatric emergency resuscitation. The development of policies and procedures will assist medical professionals who wish to offer the option of donation to family members anticipating the death of a neonate. The developing practice of using neonatal organs and tissues for research raises specific ethical and legal questions that beg for rational and transparent guidelines with which to evaluate referrals. This is especially true because of the rapidly increasing use of neonatal organs for research. To this end, a working group of scholars representing disciplines including bioethics, neonatology, obstetrics, and law, as well as professionals from Organ Procurement Organizations (OPO) and tissue banks including IIAM was formed. Neonatal donor families were also consulted. Its task was to consider the myriad of issues and to develop algorithms and policies for screening potential neonatal donors. Our primary goals were: (a) to ensure that referrals were evaluated in compliance with all applicable federal and state laws, regulations, and institutional protocols; and (b) to follow acceptable ethical standards. The donation of organs and tissues from neonates (birth to 28 days) for transplantation has been a relatively infrequent occurrence for a number of reasons, including a relative scarcity of recipients who are size matched to these small donors (Stiers et al. 2015 ; Boucek et al. 2018 ). Director of Research from the United Network for Organ Sharing Robert Carrico shares that since 2010, annual totals of neonatal organ donors in the United States, both from donation after brain death (DBD) and donation after circulatory death (DCD), have ranged from 3 to 21 donors annually. This represents between 0.03 and 0.21% of organ donors recovered in any given year. The donation of neonatal organs and tissues for research is even less common than for transplantation, primarily because family members who receive a pre-natal diagnosis of a lethal anomaly (LA) or experience the death of a neonate are not routinely offered information about research donation. Moreover, until recently researchers rarely sought neonatal organs and tissues. In the mid-2010s, some families who received a pre-natal diagnosis of a LA such as anencephaly decided to carry their pregnancy to term regardless of the poor prognosis for long-term survival, often wishing to donate after the anticipated natural death of their neonate (Gray 2016a , b , c , d , e , f , g ; Young 2017 ). Social media, blogs, and websites, including www.purposefulgift.org and www.anencephaly.info , have increasingly connected parents who receive a diagnosis of a LA. Some expectant parents began contacting the International Institute for the Advancement of Medicine (IIAM) with requests for assistance. IIAM is among the largest 501c3 non-profit organizations in the U.S. that coordinates the placement of non-transplantable organs and tissues with Organ Procurement Organizations (OPOs) and researchers. IIAM is a division of MTF Biologics, one of the largest non-profit providers of donated human tissues (e.g., musculoskeletal, dermal and placental). Founded in 1986, IIAM annually receives over 15,000 referrals of non-transplantable organs and tissues authorized for research from donors from U.S. OPOs. In the past 20 years, they have placed more than 14,000 research organs. Matching donors and research projects is a challenging process, as researchers have very specific donor criteria and logistics requirements. Research organs provided by IIAM are used by academic researchers as well as by pharmaceutical and medical device companies in the U.S. and abroad. At the same time, academic researchers began requesting neonatal organs through IIAM. Prior to this time, researchers had limited access to such organs and relied either on organs from adult donors or fetal tissue. No national guidelines or standards existed for the coordination of neonatal donation for research so referrals of potential neonatal donors were sporadic and managed on an ad hoc basis. They typically depended on the interest/capabilities of the individual OPO that would manage and coordinate the donation. As requests by expectant parents escalated, it became apparent that guidelines were necessary. The early interactions with expectant parents, OPO staff and researchers prompted the work that has resulted in this paper. A more detailed taxonomy of acceptable and unacceptable donations appears later in this paper. After a brief discussion of ethical and legal issues as well as clinical ramifications of neonatal donation, we will explain how they helped shape our policy recommendations. Lastly, we will present data about the outcomes of more than 224 neonatal referrals. Although neonatal organs and tissues can be used for both transplantation and research, we will mainly focus on donation for research. Neonatal organ and tissue donation represent a desire to make an altruistic gift and can play a key role in the care and support provided to families by hospital staff around the time of a neonate’s death. Indeed, many families who have donated the organs and tissues of their deceased neonate reported that the decision brought them solace and comfort (Gray 2016a , b , c , d , e , f , g ; Rhodes 2014 ; Purposeful Gift). Moreover, neonatal donation is proving increasingly important for research into a variety of areas, including determining the causes of neural tube defects (NTD); treating vision impairment; diabetes; organ system development; rheumatoid arthritis; pancreatic cancer; treatment of MRSA infection; pediatric emergency resuscitation (Gray 2016a , b , c , d , e , f , g ; Aguayo-Mazzucato et al. 2017 ; Gregg et al. 2012 ; Ardini-Poleske et al. 2017 ; Cogger et al. 2017 ). The primary goal of families with whom some of the authors (GDS, JO, MA, SBG) have interacted was to carry a fetus diagnosed with LA to term (or as close to term as possible) in order to achieve a live birth, knowing that aggressive treatment after birth would be futile. The possibility of organ and tissue donation was a secondary goal and provided an opportunity to find something positive in the midst of a tragic situation. Legal and ethical questions that must be addressed require adherence to a variety of laws, regulations, and ethical principles. Various state and federal laws regulate the donation of organs and tissues regardless of the age of a potential donor. Federal law does not contain any restrictions that are uniquely relevant to neonatal organ and tissue donation. The federal National Organ Transplant Act (NOTA) and related regulations prohibit the sale of organs or tissues and creates a framework to facilitate and standardize the donation and recovery process (42 U.S.C. § 273 et seq). At the state level, there are laws that may affect tissue and organ donation for research. For example, every state has an anatomical gift act that adopts some version of the Uniform Anatomical Gift Act (UAGA) (UAGA 2019). All states have adopted the Uniform Determination of Death Act (DDA), which describes the events that trigger the possibility of organ and tissue donation (DDA 1980). Organ and tissue donation must conform to the so-called Dead Donor Rule, which states that no patient’s death may be caused by organ recovery (Robertson 1999 ). Under the policies stipulated by the Organ Procurement and Transplant Network, it is mandatory to separate the medical care of a patient and the determination of death from the recovery of organs or tissues in all cases of donation (Organ Procurement and Transplant Network Policies (pp. 28–29) Available at: https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf ). If life-sustaining treatment is withdrawn, donation may occur if the patient dies and organ and tissue recovery can occur within a time period specified by the intended researcher. Obtaining authorization for donation from parents of neonatal patients can be complex, and has received significant attention in previous studies (Martin et al. 2015 ). Typically, OPO staff conduct the authorization process, but they are not involved in the routine care of the neonate, or in determining or pronouncing the death of the neonate. Family members are given the latitude to determine which organs or tissues they wish to donate, and whether they wish to donate solely for transplantation or transplantation and research. Some families may wish to donate organs in the context of actively terminating a pregnancy with an ultimately lethal outcome. The American College of Obstetricians and Gynecologists (ACOG) has established guidelines regarding medically acceptable indications for pre-term delivery for maternal or newborn benefit, but such a choice raises the legally and ethically fraught issue of abortion (Nicholson 2015 ; Committee Opinion No. 560 2013 ). Many state laws have unique implications for the legality of neonatal organ donation in certain circumstances. In particular, laws forbidding donation of, or research upon, tissue resulting from an abortion may be relevant in cases in which a pre-term delivery technically meets the state-law definition of abortion. Recently, several states and the federal government have passed or considered such laws (Ark. Code § 20-17-802, Ind. Code §§ 16-34-3-4(a); 16-41-16-4(d); 16-41-16-5; 16-41-16-7.6.; 15A N.C. Admin. Code 13B.1301.; 41 Tex. Reg. 9709-41). Although abortion is a legal medical procedure in the United States, for purposes of this project we rejected the possibility of accepting donations that resulted from abortions. Our guidelines do, however, allow acceptance of donations from some neonates who are delivered pre-term–but only if the delivery would not qualify as an abortion under applicable law. Finally, we considered federal and state laws governing the withholding or withdrawing of life-sustaining care from disabled neonates. These laws, most specifically the Baby Doe Regulations (BDR) and the Born Alive Infant Protection Act (BAIPA), apply primarily to clinicians and hospitals that are directly involved in the pre-term delivery and subsequent care of a neonate, and do not constrain organ donation. BDR and BAIPPA are federal laws that apply to pre-term delivery and resuscitation. BDR are federal statutory provisions that impose certain requirements on states as a condition of accepting federal Child Abuse Prevention and Treatment Act (CAPTA) funds (Pub.L. 98-457, 98 Stat. 1749 (codified as amended at 42 U.S.C. §§ 5101–5106i (2006)). States are required to enact procedures for reporting and responding to “medical neglect,” which is defined to include withholding treatment (including appropriate nutrition, hydration, and medication) from neonates with disabilities and life-threatening conditions (42 U.S.C. § 5106a(b)(2)(C)). This requirement imposes a fairly sweeping mandate to provide care for neonates born with potentially lethal conditions. There are, however, three exceptions to the requirement of providing medically indicated treatment. Treatment is not required if, “in the treating physician’s or physicians’ reasonable medical judgment: The neonate is chronically and irreversibly comatose”; Providing treatment would only prolong the death of the neonate, would not be effective in correcting or ameliorating the conditions, or would “otherwise be futile in terms of the survival of the neonate” and, The treatment “would be virtually futile in terms of the survival of the neonate” and “the treatment itself under such circumstances would be inhumane” (42 U.S.C. § 5106 g(a)(5)). The neonate is chronically and irreversibly comatose”; Providing treatment would only prolong the death of the neonate, would not be effective in correcting or ameliorating the conditions, or would “otherwise be futile in terms of the survival of the neonate” and, The treatment “would be virtually futile in terms of the survival of the neonate” and “the treatment itself under such circumstances would be inhumane” (42 U.S.C. § 5106 g(a)(5)). The American Academy of Pediatrics and the Ethics Committee of the American College of Critical Care Medicine have both affirmed that it is ethically and legally justifiable to withhold or withdraw aggressive life-sustaining treatment in neonates when the burdens of such treatment far outweigh its benefits (Ethics Committee 2001 ; Committee on Bioethics 2013 ; Sarnaik 2015 ; AAP policy Statement 2010 ; Kon et al. 2016 ; Gries et al. 2013 ). BAIPA is a second federal law that has an intent similar to that of BDR. BAIPA states that any infant who is “born alive,” at any stage of development, must be treated as a person for purposes of the protections of federal law (1 U.S.C. § 8). This law has long been viewed as symbolic legislation with an anti-abortion message, since it is unclear that it has any actual impact on the application of any federal law. It might, however, mean that the Emergency Medical Treatment and Active Labor Act’s (EMTALA) requirement of stabilizing patients who arrive at the hospital in an emergency condition would apply to very premature infants as well (42 U.S.C.A. § 1395dd) EMTALA, combined with the BAIPA, may therefore be understood to require some treatment of extremely premature infants who are born with a heartbeat or other signs of life. Futile or non-medically-indicated treatment would not likely be required for a very premature infant, since such treatment would not, within reasonable medical probability, prevent the neonate’s condition from deteriorating. Thus, as long as it is appropriate to characterize any care withheld from very premature neonates as being futile (in reasonable medical judgment), there is little danger of running afoul of BDR or BAIPA, as applied to EMTALA. In 2015, there were 15,652 total U.S. neonatal deaths (3.93 per 1000 live births) ( Murphy et al. 2017 ). Congenital malformations, deformations, and chromosomal abnormalities were noted to be primary causes of neonatal death. One such congenital malformation is anencephaly, one of the most common central nervous system disorders. Anencephaly is a neural tube defect that occurs when the cephalic (head) end of the neural tube fails to close, usually between the 23rd and 26th days of pregnancy; this results in the absence of the major portion of the brain, skull, and scalp. Some rudimentary forebrain, a part of the brain consisting mainly of the cerebrum, may exist. A functioning brainstem is usually present. Prenatal diagnosis of anencephalic neonates typically occurs at 12–14 weeks. The majority of anencephalic pregnancies are terminated early in the pregnancy (Brierley 2010 ; Stiers et al. 2015 ). The CDC estimates that anencephaly annually affects approximately 3 pregnancies in every 10,000, or 1206 pregnancies (CDC 2015 ). Most anencephalic neonates die within days or weeks without life-supporting interventions (Shewmon 1989 ). The care of a mother carrying a baby with a LA can be complex, requiring close coordination between the obstetrician, neonatologist, and other healthcare professionals. In some instances, mothers experience a typical pregnancy except for the fact that they have received a diagnosis of a LA; those who receive minimal or no prenatal care are unaware of a LA until the baby is born. In many cases, the syndrome or condition afflicting the fetus may cause concern for maternal, fetal, and/or both maternal and fetal health and may lead to a decision to induce pre-term (iatrogenic) labor. Alternatively, pre-term delivery may occur spontaneously without intervention. The leading causes for pre-term delivery are: Spontaneous labor with intact membranes Pre-term premature rupture of membranes (PPROM) Delivery for maternal or fetal indications ( Thakor et al. 2008 ). Spontaneous labor with intact membranes Pre-term premature rupture of membranes (PPROM) Delivery for maternal or fetal indications ( Thakor et al. 2008 ). Tucker reports that 15–25% of pre-term infants are iatrogenically delivered early because of maternal or fetal pregnancy complications (Tucker and McGuire 2004 ). Complications may include hypertension, preeclampsia or eclampsia, polyhydramnios, oligohydramnios, gestational diabetes, intrauterine growth restrictions, infection, and twin-to-twin transfusion syndrome. Despite the recent widespread use of hypothermia therapy, Hypoxic Ischemic Encephalopathy (HIE) is a major cause of neurologic disabilities in term neonates. The incidence of HIE ranges from 1 to 8 per 1000 live births in developed countries and is as high as 26 per 1000 live births in underdeveloped countries ( Douglas-Escobar and Weiss 2015 ). HIE neonates frequently receive ventilation, hypothermia, or other therapy, until brain death is confirmed or until a decision is made to withdraw treatment and to allow for a natural death, also known as “AND”. Medical literature is scant regarding discussion about neonates with HIE who became organ donors for transplantation or research. There are anecdotal reports of neonatal organ donation from HIE donors, including one author’s center. Jadcherla, et al., reported a case of neonatal organ donation in a full-term neonate with severe HIE complicated by multi-organ dysfunction who underwent therapeutic hypothermia (Bokisa et al. 2015 ). In non-ventilated cases, palliative care is provided to the neonate (hydration, comfort, etc.) allowing for a natural death (AND). It is at that point that criteria for DCD may be applied. Medical challenges include working with hospital staff who may have inadequate information or awareness about the potential of neonates to become donors. Because transplant surgeons normally perform organ recovery only for transplant, OPO staff need to be trained in organ recovery for research. Specific details of the delivery of neonates can have a significant effect on the donation process—i.e., whether delivery occurred at term or prior to term; whether the neonate was delivered by natural delivery or whether labor was induced; the indications for medical intervention if labor was induced. The criteria used for the acceptance of organ donors for research may vary, based on the type of research and individual research protocols. A neonate with LA may be considered as a potential donor for liver, lung, heart, kidney, pancreas, intestine, thymus, or tissue (skin, eyes, bone marrow, musculoskeletal and reproductive tissues). Multiple recipients or research studies can often benefit from a single donation. The researcher (or the protocol) needs to establish requirements such as minimum gestational age of the neonate. Exact time of death and a clear plan for organ recovery surgery have to be determined and documented. Donation must occur in a timely manner because of concern regarding the effect of warm ischemic time (WIT) on organ viability; this concern should be balanced with the family’s need for time with their neonate after the neonate has passed away. Neonatal donors, especially anencephalic donors, provide a unique set of challenges to an OPO. Whether the donation will ultimately result in transplanted organs or tissues, research organs or tissues, or some combination of these outcomes is often unclear until the surgical recovery occurs. The lack of formation of cerebral cortex and exposed brain structure make it impossible to determine brain death in anencephalic neonates. In other circumstances, such as HIE, it may be possible because the cerebral cortex is formed, and the skull structure is intact. In ventilated neonatal donors, including neonates with HIE, the process will often unfold in the same way as in older donors. Thus, coordinating neonatal anencephalic donation requires flexibility and establishment of contingency plans to maximize successful donation. The challenges faced by OPOs in coordinating anencephalic donors fall largely into one of three categories: donor identification and referral; family and staff counseling; donation logistics. A brief discussion of each follows. In the United States, OPOs are to receive referrals on all in-hospital and imminent deaths. Most OPOs have established “clinical triggers” for referral, which include variables such as Glasgow Coma Scale 5 or below, discussion of withdrawal of care, initiation of brain death testing, or cardiac arrest. In the context of ventilated neonatal donors, these clinical triggers may apply; in anencephalic donors, who are typically non-ventilated, they will not. The challenge, therefore, is to establish referral processes for practitioners working with the families of anencephalic neonates, to educate both OPO staff and donor hospital professionals about neonatal donation, and to implement protocols for both OPO and hospital staff to manage these cases. Sample protocols are available upon request to IIAM ( www.iiam.org ). The standard approach for OPOs in terms of counseling donor family and hospital staff regarding donation begins with the initial referral and after an evaluation of the clinical suitability for donation. Because the timing of a referral is quite different in the anencephalic donor, two variables come into play. First, the donor family may be several months short of the actual delivery and will have much more time to consider their options for donation. This is unusual and requires multiple follow-ups with a family over an extended period as their decision-making evolves. Second, the context of the discussions with perinatal and neonatal practitioners regarding the pregnancy and other related decisions is quite different from traditional organ donor situations, in which the discussion centers around brain death, withdrawal of care in a patient who is not brain dead and helping the family come to grips with the finality of the patient’s brain injury. With anencephalic neonates, the family is addressing a far different set of issues, such as whether to carry to term and development of an appropriate birth plan. The process typically proceeds as with any organ/tissue donor referral in scenarios with HIE or LA. In standard DBD or DCD scenarios, regardless of the age of the potential donor, OPOs obtain authorization for donation, evaluate organ function, attempt to maximize organ function, match organs to recipients, and then coordinate the surgical recovery, which may include allowing teams from distant centers to fly to the hospital for the surgical recovery. Surgical recovery is scheduled after organ evaluation and preliminary acceptance by a transplant center or, in the case of research donation, by a researcher. Donor blood type, height, weight, and many other data factor into this process. A ventilated neonatal donor will follow much the same path. Anencephalic donors are not typically intubated. As a result, the OPO will have limited clinical information about the donor. It is vital to underscore that no donation can take place until death has occurred, through the pronouncement of death either by neurological criteria (i.e., brain death) or by circulatory death. OPOs can implement a few key strategies to maximize the benefit of the donation for the neonatal donor family, transplant recipients, and researchers. They include: Proactively identify centers where these potentially complex cases may be referred and transplant centers willing to consider neonatal organs for transplant. Have research outlets for all possible organs and tissues since transplantation rarely occurs with these potential donors. Closely collaborate with the specialists caring for the mother and neonate. It is not uncommon for these cases to unfold over months. Have at least two OPO staff supporting and counseling the family. The prolonged process of neonatal donation and the importance of bonding with the family require a team approach in order to avoid compassion fatigue ( Nicely and Delario 2011 ; Maloney and Wolfelt 2011 ; Larowe 2005 ). Proactively identify centers where these potentially complex cases may be referred and transplant centers willing to consider neonatal organs for transplant. Have research outlets for all possible organs and tissues since transplantation rarely occurs with these potential donors. Closely collaborate with the specialists caring for the mother and neonate. It is not uncommon for these cases to unfold over months. Have at least two OPO staff supporting and counseling the family. The prolonged process of neonatal donation and the importance of bonding with the family require a team approach in order to avoid compassion fatigue ( Nicely and Delario 2011 ; Maloney and Wolfelt 2011 ; Larowe 2005 ). In 2012, Bethany C., who was pregnant with an anencephalic baby, contacted IIAM. She wanted to donate her son’s organs and tissues following his death. Despite contacting her obstetrician, local medical schools and hospitals, and the OPO that serves her hometown, she had been unsuccessful. She found IIAM’s website and contacted IIAM just days before her scheduled C-section. Within 2 h, IIAM found researchers who were willing to accept her baby’s liver and pancreas, and another researcher who was interested in receiving his entire body after organ donation. Their son, Amalya Nathaniel, lived for 80 min, surrounded by his parents, maternal and paternal grandparents, and other extended family members. The OPO performed the organ recovery after his death. As a result of his donation, researchers were able to evaluate pancreatic beta cells in their earliest stages of development, leading them to understand why some people develop Type 1 Diabetes; other researchers studied hepatocytes, which is critical to understanding cell generation. Images generated by his body led to FDA clearance for a medical device used for rapid pediatric resuscitation (Ardini-Poleske et al. 2017 ; Li et al. 2018 ; Gray 2016a , b , c , d , e , f , g ). Between 2012 and 2017, IIAM coordinated the recovery of organs and tissues from 86 donors, placing 281 organs and tissues. Most neonates who became donors were anencephalic (60%), followed by neonates who died because of anoxia or HIE (23%). Other causes of death included Trisomy 18, fatal cardiac and renal anomalies, trauma, and other genetic and neurological conditions. Gestational age (GA) varied, with the majority being delivered at term (which includes early term, full term and late term; 37 0/7 weeks–41 6/7 weeks) ( see Fig. 1 ) (Taylor et al. 2019 ). Pre-term deliveries (20 0/7 weeks–36 6/7 weeks) often occurred for medically indicated reasons (either maternal or fetal health or both); the majority of these deliveries were iatrogenic. Pre-term deliveries for non-medical reasons were not accepted as referrals. One was referred following miscarriage at 16 weeks and was able to donate skin. Fig. 1 Time Elapsed from Birth to Death 2012 to June 2019 Time Elapsed from Birth to Death 2012 to June 2019 All of the families who pursued donation did so with the intent of having a live birth, spending as much time as possible with the neonate, and donating, if possible, after the neonate’s death. The time elapsed from birth to death ranged from minutes to days ( See Fig. 2 ). In most cases, the neonate remained in the Labor and Delivery area; on one occasion, the neonate was taken home, given hospice care, and then her body was returned to the hospital following her death at 5 days. Fig. 2 Gestational Age 2012–June 2019 Gestational Age 2012–June 2019 Considering the legal, medical, ethical and practical issues surrounding these donation opportunities, the working group developed a set of algorithms designed to guide staff from OPOs and IIAM in evaluating potential donors. Three separate algorithms were developed: one for neonates being delivered at term with a LA (See Fig. 3 ); one for neonates being born pre-term with a LA (See Fig. 4 ); one for neonates who die as a result of other conditions, such as HIE or trauma (See Fig. 5 ). Referrals are now evaluated according to these algorithms. Reasons for declining referrals of potential neonatal donors include: Fig. 3 At term delivery with lethal anomaly Fig. 4 Pre-term delivery with lethal anomaly Fig. 5 Post-natal fetal defect At term delivery with lethal anomaly Pre-term delivery with lethal anomaly Post-natal fetal defect Iatrogenic labor planned to terminate a pregnancy, not for maternal and/or fetal health (1%) GA less than 24 weeks (3%) Extended Cold Ischemic Time (CIT) or Warm Ischemic Time (WIT) (11%) Diagnosis/medical condition (12%) Unable to identify available researchers (13%) Family withdrew offer (19%) Family withdrew offer Family did not call OPO back after initial inquiry Family declined donation OPO withdrew offer (41%) OPO did not have an internal policy for neonatal donation OPO did not have the skill set or appropriate procurement setting OPO would not proceed unless an organ would also be recovered for transplant Medical Director refused authorization Iatrogenic labor planned to terminate a pregnancy, not for maternal and/or fetal health (1%) GA less than 24 weeks (3%) Extended Cold Ischemic Time (CIT) or Warm Ischemic Time (WIT) (11%) Diagnosis/medical condition (12%) Unable to identify available researchers (13%) Family withdrew offer (19%) Family withdrew offer Family did not call OPO back after initial inquiry Family declined donation Family withdrew offer Family did not call OPO back after initial inquiry Family declined donation OPO withdrew offer (41%) OPO did not have an internal policy for neonatal donation OPO did not have the skill set or appropriate procurement setting OPO would not proceed unless an organ would also be recovered for transplant Medical Director refused authorization OPO did not have an internal policy for neonatal donation OPO did not have the skill set or appropriate procurement setting OPO would not proceed unless an organ would also be recovered for transplant Medical Director refused authorization Researchers who accepted neonatal organs and tissues through this program study such diverse areas as regenerative medicine, diabetes, chronic kidney disease, cancer, congenital organ malformation, abnormal lung development, and fertility (See Fig. 6 ). Pulmonary research in particular, has been advanced using donated neonatal lungs. Over 75 neonatal donors have been provided to the Biorepository for the Investigation for Diseases of the Lung (BRINDL)/University of Rochester Medical Center (URMC) Human Tissue Core and distributed to more than 10 other academic laboratories. BRINDL and the URMC Human Tissue Core are responsible for all the human data that currently appears on LungMAP.net. Papers and presentations arising from the LungMAP project primarily focus on characterization of neonatal lung cells, and clinical and translational studies in rare lung diseases. This project has also explored why neonates and infants frequently progress to severe lung failure when exposed to Respiratory Syncytial Virus (RSV) versus adults whose systems respond to RSV in a less severe manner. This information is expected to provide new options for treatment and prevention (Taylor et al. 2019 ; Jiang et al. 2019 ; Wang et al. 2019 ; Lal et al. 2018 ; Whitsett 2018 ; Kyle et al. 2018 ; Bandyopadhyay et al. 2018 ; Luo et al. 2018 ; Zhu et al. 2018 ; Zhou et al. 2018 ; Ardini-Poleske et al. 2017 ; Warburton 2017 ; Du et al. 2017 ). Research findings from other projects using neonatal organs have been presented at scientific conferences and published in scientific journals (Gray 2016a , b , c , d , e , f , g ; Ardini-Poleske et al. 2017 ; Gittinger 2015 ). Placements of research organs and tissues range from one organ per donor to over ten organs and tissues per donor. Fig. 6 Neonatal placements 2012–June 2019 Neonatal placements 2012–June 2019 Donation of organs and tissues for research from neonates who die following a live birth has recently become an option some families wish to consider. Pursuing this donation option requires careful attention to legal, ethical, medical, and procedural issues. It is vital to ensure that the integrity of the donation process be safeguarded, and that the desire to support neonatal donor families does not compromise ethical and legal standards. The comfort and solace that donation provides following the death of a neonate can be vital to families’ healing processes and should be supported whenever possible. Given the potential legal and ethical barriers to donation and the fact that not all OPOs are currently equipped to provide this service even if the request falls within acceptable standards, it is important that families have realistic expectations with respect to donation opportunities. Coordinating neonatal referrals requires careful collaboration between hospital administration, health care professionals, OPO staff, staff of the agency interfacing with researchers and OPOs, and the researchers themselves. The uses of neonatal organs and tissues have led to remarkable breakthroughs in science. Family donation of organs and tissues from a neonate represents a desire to make an altruistic gift and can play a key role in the care and support provided to families by hospital staff at the time of a neonate’s pending death. Family members who suffer the tragic loss of a newborn through either congenital abnormalities such as anencephaly, or situations arising from a traumatic birth or HIE, have found “unexplainable peace, joy and healing” in their ability to donate, thereby allowing their child to make an “impact on the world” ( Rhodes 2014 ). Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. MA: conceptualization, research, writing, RDS: conceptualization, research, writing, SGB: research, writing, BJH: conceptualization, research, writing, RRN: research, writing, JPOi: research, writing, SY: conceptualization, research, writing. MTF Biologics provided funding for the development of the project.The authors wish to thank Wee Siang Tay for his assistance with references. Neonatal Organ and Tissue Donation for Research: Options Following Death by Natural Causes β cell aging markers have heterogeneous distribution and are induced by insulin resistance LungMAP Consortium. LungMAP: the molecular atlas of lung development program Dissociation, cellular isolation, and initial molecular characterization of neonatal and pediatric human lung tissues Death by neurologic criteria in a neonate: implications for organ donation Pediatric heart transplantation after declaration of cardiocirculatory death Neonatal organ donation: has the time come? Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors Ethical controversies in organ donation after circulatory death Hypoxic-ischemic encephalopathy: a review for the clinician Lung gene expression analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development American college of critical care medicine, society of critical care medicine: recommendations for non-heartbeating organ donation Formation of a human β-cell population within pancreatic islets is set early in life an official american thoracic society/international society for heart and lung transplantation/society of critical care medicine/association of organ and procurement organizations/united network of organ sharing statement: ethical and policy considerations in organ donation after circulatory determination of death Alteration of cystic airway mesenchyme in congenital pulmonary airway malformation defining futile and potentially inappropriate interventions Cell type-resolved human lung lipidome reveals cellular cooperation in lung function Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia A comparison of adult and neonatal human hepatocytes in drug metabolizing enzyme activities Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development Pediatric deceased donation—a report of the transplantation society meeting in geneva Virginia henderson’s principles and practice of nursing applied to organ donation after brain death The 39-week rule and term stillbirth: beneficence, autonomy, and the ethics of the current restrictions on early-term labor induction in the US The dead donor rule Neonatal and pediatric organ donation: ethical perspectives and implications for policy The use of anencephalic infants as organ sources Potential and actual neonatal organ and tissue donation after circulatory determination of DEath The pediatric cell atlas: defining the growth phase of human development at single-cell resolution Anaemia, weight loss, and round shadows in the lungs Epidemiology of preterm birth A novel in vitro model of primary human pediatric lung epithelial cells Overview of lung development in the newborn human Airway epithelial differentiation and mucociliary clearance Extracellular matrix in lung development, homeostasis and disease Proteomic analysis of single mammalian cells enabled by microfluidic nanodroplet sample preparation and ultrasensitive NanoLC-MS |
Answer the following medical question. | What does research say about Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples.? | Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury. Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples |
Answer the following medical question. | What does research say about Skin antisepsis in the neonate: what should we use?? | Neonates in intensive care are more susceptible to sepsis. Infection is commonly acquired via the transcutaneous portal. It is necessary to identify the most effective yet safest topical antiseptics for use in neonates to reduce nosocomial sepsis. Recent national surveys indicate that a wide range of topical antiseptic preparations are used in the neonatal nursery. There are very few comparative studies in neonates and no robust evidence in favour of any particular antiseptic. There are significant safety and potential toxicity issues for neonates with all the commonly used antiseptics, particularly in very small immature babies. There are no convincing roles for routine application of emollient creams on the skin, topical antiseptics on the umbilical stump, or maternal vaginal washes with chlorhexidine for the prevention of neonatal infection. Large multicentre trials are needed to determine the optimal antiseptic to use for neonates undergoing intensive care, especially for extremely preterm infants. |
Answer the following medical question. | What does research say about Management of the neonate at the limits of viability.? | The active treatment of fetuses or neonates at the limits of viability is an ongoing debate for perinatal physicians. Although initiating intensive care at 26 weeks is generally accepted, the gray zone of gestational ages at which aggressive perinatal care should be offered is less clear and ranges from 22 to 25 weeks. The gray zone has remained rather unchanged over the last decade. Attitudes vary among different countries, centres and individuals. The benefit-burden ratio of neonatal intensive care is balanced differently according to competing moral values. Several factors underlie the difficulty in approaches to management decisions. Neonates lack the capacity to make decisions and most parents ignore the complexity of care during and after hospitalisation. Parents have to be informed about the survival rates and the risks of long term disabilities, but accuracy for each individual baby is very weak. Outcome data are published many years after the intensive care period, and results about the prevalence of severe disabilities over time are conflicting and vary widely (ranging from 10% to 60%). Information about more subtle disabilities which only become apparent around school age is scarce. Data on the impact of the longer term outcomes of new strategies like developmental care approaches (Neonatal Individual Developmental Care Assessment Programme: NIDCAP) are still insufficient but could prove to be an important recent step in improving outcome in extremely immature babies. |
Answer the following medical question. | What does research say about Amplitude-integrated electroencephalography in neonates.? | Conventional electroencephalography (EEG) has been used for decades in the neonatal intensive care unit for formulating neurologic prognoses, demonstrating brain functional state and degree of maturation, revealing cerebral lesions, and identifying the presence and number of electrographic seizures. However, both the immediate availability of conventional EEG and the expertise with which it is interpreted are variable. Amplitude-integrated EEG provides simplified monitoring of cerebral function, and is rapidly gaining popularity among neonatologists, with growing use in bedside decision making and inclusion criteria for randomized clinical studies. Nonetheless, child neurologists and neurophysiologists remain cautious about relying solely on this tool and prefer interpreting conventional EEG. The present review examines the technical aspects of generating, recording, and interpreting amplitude-integrated EEG and contrasts this approach with conventional EEG. Finally, several proposed amplitude-integrated EEG classification schemes are reviewed. A clear understanding of this emerging technology of measuring brain health in the premature or sick neonate is critical in modern care of the newborn infant. |
Answer the following medical question. | What does research say about Providing clarity around ethical discussion: development of a neonatal intervention score.? | To develop a Neonatal Intervention Score (NIS) to describe the clinical trajectory of a neonate throughout their neonatal intensive care unit (NICU) admission. The NIS was developed by modifying the Neonatal Therapeutic Intervention Scoring System (NTISS) to reflect illness severity, dependency on life-sustaining interventions and overall life trajectory on a longitudinal basis, rather than illness burden. Validity for longitudinal use within the NICU was tested by calculating the score for 99 preterm babies born less than 28 weeks at predetermined time points throughout their admission to tertiary level care at two institutions. A total of 1333 NISs were analysed, ranging from 0 to 32.5 (mean 9.77, SD 5.4). Internal consistency (Cronbach alpha) reached 0.8. NIS moderately correlated to both SNAPPE-II and SNAP-II (Spearman's rho = 0.47, p =< 0.001) within the first 24 hours. The NIS is a useful and reliable descriptive tool of relative illness severity and degree of medical interventions throughout a baby's admission. Integrating a longitudinal description of medical dependency of a patient may assist both clinical and ethical decision-making and empirical research by providing an objective account of a baby's clinical trajectory. Establishment of validity within individual institutions is required. |
Answer the following medical question. | What does research say about Early neonatal drug utilization in preterm newborns in neonatal intensive care units. Italian Collaborative Group on Preterm Delivery.? | The pattern of drug use in preterm newborns admitted to neonatal intensive care units (NICU) was monitored as part of a large multicenter study including a representative sample of Italian NICUs. All prescriptions from the admission of the mother through the 1st week of the neonate's life were carefully documented on standardized ad hoc forms, with particular attention to the timing and duration of each prescribed drug. The 706 babies included in the surveillance program received an average of 1.7 drugs during the early neonatal period, and were exposed to an average of 3.4 drugs over the whole perinatal period. The most commonly used drugs postnatally were vitamins, antibiotics (ampicillin, gentamicin and tobramycin), methylxanthines (aminophylline and caffeine), phenobarbital and furosemide. The frequency and intensity of the use of these drugs appears to be directly related to the severity of the clinical status, and inversely related to birth weight and gestational age. |
Answer the following medical question. | What does research say about A Setup for Camera-Based Detection of Simulated Pathological States Using a Neonatal Phantom.? | These authors contributed equally to this work. Premature infants are among the most vulnerable patients in a hospital. Due to numerous complications associated with immaturity, a continuous monitoring of vital signs with a high sensitivity and accuracy is required. Today, wired sensors are attached to the patient’s skin. However, adhesive electrodes can be potentially harmful as they can damage the very thin immature skin. Although unobtrusive monitoring systems using cameras show the potential to replace cable-based techniques, advanced image processing algorithms are data-driven and, therefore, need much data to be trained. Due to the low availability of public neonatal image data, a patient phantom could help to implement algorithms for the robust extraction of vital signs from video recordings. In this work, a camera-based system is presented and validated using a neonatal phantom, which enabled a simulation of common neonatal pathologies such as hypo-/hyperthermia and brady-/tachycardia. The implemented algorithm was able to continuously measure and analyze the heart rate via photoplethysmography imaging with a mean absolute error of 0.91 bpm, as well as the distribution of a neonate’s skin temperature with a mean absolute error of less than 0.55 °C. For accurate measurements, a temperature gain offset correction on the registered image from two infrared thermography cameras was performed. A deep learning-based keypoint detector was applied for temperature mapping and guidance for the feature extraction. The presented setup successfully detected several levels of hypo- and hyperthermia, an increased central-peripheral temperature difference, tachycardia and bradycardia. Worldwide, about 10% of all children are born prematurely, which results in 15 million premature infants each year. Even though advanced medical treatment in combination with technical development have already led to a 50% reduction in child mortality from 1990 to 2019 [ 1 , 2 ], the World Health Organisation (WHO) estimated 2.4 million deaths in 2019, which means on average about 6700 neonates per day worldwide [ 3 ]. About one million of these infants die due to complications related to preterm birth, making prematurity the second-leading cause of death in children under 5 years in 2012 [ 4 ]. Despite the high mortality, only data of 2.5% of global neonatal deaths are based on reliable vital registration systems, while the rest originates from estimations and surveys [ 5 ]. Prematurity is an often occurring phenomenon with rising rates. In 2012, the WHO reported that 5–18% of all infants were born preterm. The mortality of these patients strongly decreases with higher gestational age, higher birth weight, and more expensive care. In a neonatal intensive care unit (NICU), the special care especially focuses on keeping the newborns’ body core temperature within a range, which maximizes their chances of survival and is beneficial regarding morbidity and growth [ 5 ]. This support is vital, because the thermoregulation of a preterm neonate cannot yet handle large deviations of body temperature, which could lead to a deterioration of the health state due to hypothermia or even death from associated severe infections [ 6 ]. Regardless of the core temperature, changes in the central-peripheral temperature difference can indicate abnormal clinical states, such as an unspecific sign of a sepsis [ 7 ]. Preterm infants receive medical care inside an incubator in a NICU where several vital signs such as heart rate (HR), respiration rate, oxygen saturation and temperature are monitored. The continuous surveillance of the cardio-respiratory system enables the determination of a patient’s health status and an early detection of a deterioration of this state. Furthermore, monitoring a newborn’s thermal condition can also help to detect signs of abnormal clinical states such as cold or heat stress as well as infections by closely tracking not only the central but also the peripheral temperature [ 6 , 8 ]. While adhesive electrodes are used for the measurement of cardio-respiratory activities, the thermoregulation monitoring is usually conducted using adhering thermistors, whose resistance varies with temperature. Despite benefits such as low price and easy handling, the removal of the probes can cause skin irritations to the still immature skin and induce wounds, which can lead to an infection [ 9 ]. Additionally, wired probes require cables, which not only complicate transport and interaction like kangaroo-care, but also cause psychological stress for the parents [ 10 ]. To overcome the disadvantages of wired patient-monitoring for neonates, contact-free camera surveillance may be a promising technology and is welcomed by clinical staff [ 11 ]. The research interest in the field of camera-based vital signs measurement has continuously increased in recent years. While RGB cameras can be used for Region-of-Interest (ROI) detection and monitoring of vital signs such as HR using photoplethysmography imaging (PPGI) and respiration activity, infrared thermography (IRT) devices can measure the surface temperature of objects and, therefore, are able to derive the thermal state of a patient [ 12 ]. Since continuous vital sign monitoring requires real-time data processing, classical approaches from the field of medical imaging may not be applicable due to the high computing power required. In contrast to this, deep learning (DL)-based approaches have shown to enable real-time image processing for clinical surveillance [ 13 , 14 ]. To determine the HR or skin temperature distribution of the neonatal body, segmentation or keypoint detection algorithms can be used, featuring contact-less supervision of all desired and visually accessible body parts [ 12 , 15 ]. These algorithms could further facilitate contactless alarm systems by classifying the extracted vital signs for pathology detection. However, for the training and validation steps of such DL-based algorithms, large datasets with various disease progressions are required, which are not publicly available at this moment. Therefore, the literature in this field is still in an early stage. So far, there have been several studies about neonatal pathology detection which used vital signs recorded from cable-based sensors in combination with DL or machine learning (ML). In 2019, Ansari et al. [ 16 ] published a study about neonatal seizure detection from electroencephalography (EEG) data using deep convolutional neural networks (CNNs). In the same year, Ihlen et al. [ 17 ] applied ML on neonatal movement data for the early prediction of cerebral palsy. One year later, Turova et al. [ 18 ] applied ML models for the prediction of cerebral hemorrhage in infants from clinical data. In addition, in recent studies DL was used to support vital signs monitoring and pathology classification from images [ 19 ]. In 2019, Villarroel et al. [ 20 ] implemented a multitask DL algorithm to segment skin areas and estimate vital signs in a NICU. In 2021, Huang et al. [ 14 ] trained spatio-temporal neural networks for non-contact neonatal HR monitoring. Furthermore, Nagy et al. and Khanam et al. [ 19 , 21 ] both proposed an algorithm for the measurement of pulse and breathing rate. Simultaneously, Ervural et al. [ 22 ] classified neonatal diseases using thermographic data in combination with CNNs. Although these DL-based approaches showed promising results, the models were trained on relatively small neonatal image datasets. Thus, any statement on generalization of the models is difficult. To overcome the issue of missing large neonatal image datasets, one solution could be the generation of artificial data using a neonatal phantom which can simulate vital signs such as cardiac activity and thermoregulatory processes and enables the configuration of pathological states. In a previous work, we introduced a neonatal phantom, which is able to simulate a PPG signal and thermoregulatory processes on the skin surface in individually controllable areas [ 23 ]. In this work, we present a low-cost, camera-based monitoring approach which is able to measure vital signs simulated by such a neonatal phantom inside an incubator in order to detect pathology patterns. A pre-trained DL-based keypoint detector was used to extract ROIs on the skin surface of the phantom and monitor vital signs such as HR and thermoregulation in real-time. During live monitoring, pathological vital signs patterns were set for cardiac activity and temperature distribution, which were independently measured and classified with the camera-based system. A simultaneous simulation of vital signs using the neonatal phantom and the camera-based measurement of the signals with a deep learning-supported detection of pathological patterns have so far not been reported in the literature, and are considered a novel contribution. As presented in [ 23 ], a 3D-printed scaffold was covered with different layers of silicone to resemble the shape and outer appearance of a premature neonate. It was manufactured using rigid acrylonitrile butadiene styrene (ABS) and equipped with hardware components such as carbon-based heating elements to simulate a temperature distribution on the body surface and LEDs for PPG emulation. Temperature sensors were placed next to the thermal components to enable feedback control. Since these sensors were located in different positions for each region, the measured skin temperature deviated from the corresponding temperature sensor. Thus, an individual offset was added to the set temperature for each region, enabling a stable control of the skin temperature. The neonatal phantom and all individually controllable heating regions can be seen in Figure 1 . While the head and the limbs are divided into two regions, the torso can be heated with three individual areas. An LED-driven PPG emulation enabled the simulation of pulsatile blood flow through the body, distributed over all body parts. In total, 48 red and 60 infrared LEDs were integrated into the scaffold for HR simulation. The wiring of all hardware components was guided to the back of the phantom, where it was connected to the main board holding the ultra-low-power STM32L4R7VIT (STMicroelectronics, Switzerland) and the required peripherals to control the simulation [ 23 ]. The phantom was connected to a host computer running MATLAB R2020a (MathWorks, USA) to adjust user-defined temperature and HR settings. The operation of the phantom was implemented using profiles for the temperature process and HR behavior. A temperature profile for a certain pathology consisted of a target temperature for every body part, a temperature step width and the current set temperature. Every 30 s, one temperature step width was added to the set temperature, until the body part had reached its target temperature. After that, the set temperature was not updated any further, until the time given for the execution was over, as illustrated in Figure 2 . The temperature steps were implemented to ensure heat-up speeds of less than /min, resembling typical temperature dynamics. The value was based on the temperature difference between the first step and the target temperature. A decrease in temperature did not need to be limited by software, because the sufficiently small temperature differences did not lead to unusually fast temperature drops. Hence, the set temperature was directly set to the target temperature without further updates. 1 ∘ C The temperature-related pathologies, along with their detection thresholds simulated in this work, can be found in Table 1 . In general, varying temperature boundaries are provided in the literature, leading to a persistent disagreement on what is considered as a normal body temperature in newborns. However, most studies and guides follow the WHO guidelines [ 24 , 25 , 26 ]. The physiological temperature ranges for pathology detection in this work were specified according to the WHO, with the normal range of body temperature being 36.5– [ 37.5 ∘ C 27 ]. While all temperatures above are referred to as hyperthermia, the hypothermia is subdivided into three different stages. The range 36– 37.5 ∘ C indicates a mild hypothermia which should trigger cause for concern. If the body temperature drops below 36.4 ∘ C , it is defined as moderate hypothermia, which should prompt immediate rewarming of the infant. Temperatures below 36 ∘ C are classified as severe hypothermia, which can be life-threatening [ 32 ∘ C 27 ]. Additionally, we defined a level of severe hyperthermia for skin temperatures above . Regarding changes in the central-peripheral temperature difference, we defined a pathology parameter of a cpTD greater than 2 40 ∘ C according to the guideline of the Society for Neonatology and Pediatric Intensive Care Medicine Germany [ ∘ C 25 ]. Additionally, a simulated HR profile can be chosen, which includes the target heart rate in bpm and a fixed HR variability (HRV). The actual HR value H R T (set value) is a cumulative variable, which will be updated every 5 s by adding a pseudorandom integer value H R S r with a maximum step width , in order to enable a random HR variation. Boundary checks make sure that the HR boundaries r max are not surpassed. In our work, we assumed the HR boundaries and maximum step width to be H R Lim and H R Lim = H R T ± 10 bpm for the simulation of a neonate. It should be mentioned that HRV-related pathologies were not in the scope of this work and were thus not further investigated. r max = 10 bpm The HR-related pathologies along with their detection thresholds simulated in this work are listed in Table 2 . The most common indications are tachycardia and bradycardia . As of today, there is no global agreement for an average HR value defined as highest or lowest normal. We used the threshold values suggested by the American Academy of Pediatrics [ 28 ] and in the Heidelberger Guideline for Neonatology [ 29 ]. The presented neonatal phantom was placed inside a closed incubator of type Thermocare Vita (Weyer, Germany), which has an infrared (IR) inspection window ClearIR-4-P (IRISS, USA) inserted into the hood to allow thermal radiation to pass. The setup should be low-cost, highly accurate, and at the same time compact enough to be placed on top of the incubator. A Jetson Xavier NX (NVIDIA, USA) was used as image processing unit for the setup. This embedded GPU is a very powerful yet small system-on-module, which allows running deep neural networks and to process data from multiple camera sensors in real-time. The included 6 Carmel ARM CPUs, 384 CUDA cores, and 48 tensor cores enable a high performance for image processing. The Jetson module was used for image acquisition and processing, as well as ROI detection (cf. Section 3.3 ). The hardware setup was implemented using a low-cost multi-modal recording system consisting of two infrared thermography devices and one RGB camera. For thermal imaging, we integrated two long wave infrared (LWIR) cameras of type Lepton 3.5 (FLIR Systems, USA) into the hardware setup. These low-power, uncooled, FPA microthermal imaging modules are easily integratable into small camera system designs. With respect to the distance of the cameras due to the geometry of the incubator, one Lepton was not sufficient to overview the whole mattress area. Therefore, two thermal sensors were arranged in a line, but slightly tilted. The absolute temperature accuracy is given as and the module includes an on-board shutter for live calibration. Each Lepton has a horizontal field-of-view (HFOV) of 57 ± 5 ∘ C , which in combination allows to guarantee a large enough FOV. ∘ Further, we used one RGB camera module for ROI determination and PPGI extraction. The Arducam MINI High HQ Camera Module (Arducam, China) uses the 12.3 MP SONY IMX477 sensor with an optical format of 1/2.3 and a M12 mount lens, enabling video streaming with up to 4K at 30 fps [ ″ 30 ]. The Arducam uses the camera serial interface (CSI) specification for connection and can be connected directly to the Jetson module. The most relevant properties of both cameras are listed in Table 3 . While a Full-HD resolution was applied for the RGB camera using a frame rate of 30 fps, the IRT device had a slower frame rate of approx. 9 fps (maximum frame rate), which was, however, sufficient for measuring the inert temperature deviations. Since the camera setup is supposed to overview the entire mattress of the incubator, considerations regarding area coverage of the Leptons (in green) and the Arducam (in red) were done as depicted in Figure 3 a. The Lepton cameras were tilted by against the horizontal line, and with their wider viewing angle parallel to the longer axis of the incubator, in order to capture as much of the mattress area as possible. With this arrangement and the usage of two Leptons, the whole scene could be captured, apart from some small cutouts in the overlapping area (cf. 15 ∘ Figure 3 b). The Arducam was centered in between the Leptons and had a large HFOV, providing an overview of the whole mattress. A modular housing, holding all three cameras and the Jetson Xavier NX, was designed using the 3D CAD software Fusion 360 (Autodesk, USA) and 3D-printed using an Ultimaker 3 printer (Ultimaker, The Netherlands). Despite their thermal sensitivity of 0.05 K, the Leptons currently have a nominal absolute temperature accuracy of only ± in the high gain mode (range of −10 to 140 5 ∘ C ). Considering the small size and the low price of this thermal imaging sensor, the accuracy is relatively high. Nevertheless, it should be mentioned that it is about as high as the thermal dynamics, which will be simulated during this work. Therefore, a thermal calibration was performed to improve the absolute measurement accuracy. In fact, in combination with the IR window the Leptons were found to overestimate low temperatures and underestimate higher temperatures, especially after applying the Lepton’s calibration shutter. Thus, a linear temperature calibration according to ( ∘ C 1 ) was chosen to convert the measured surface temperature to the true surface temperature T m . Apart from the slope correction T s , an offset K 1 is assumed. K 2 (1) T s = K 1 · T m + K 2 In order to determine both the slope correction and the offset K 1 of the temperature calibration, a heatable black body was developed and used as an active thermal reference. Therefore, a heating foil (Thermo, Germany) and a more than K 2 emittive, black coated aluminum foil (Advanced Coating, Germany) were integrated into a 3D-printed ABS housing, resisting temperatures of at least 98 % . Both foils are separated by a thin layer of ABS, which is supposed to cause a more homogeneous temperature distribution in the black foil. To obtain the reference temperature, a Weyer skin temperature probe (Weyer, Germany) was placed on the black foil. These adhesive thermistors are clinically used as the gold standard for neonatal skin temperature measurements and have a range of 60 ∘ C – 0 ∘ C . The maximum error of the probes were specified as ± 50 ∘ C [ 0.1 ∘ C 32 ]. The active thermal reference body is shown in Figure 4 . Since image data from several cameras need to be processed simultaneously, the software routine of the setup was designed as a multithreaded process in Python 3. First, the frames were acquired from the multi-modal camera devices. Subsequently, the gain-offset correction for the IRT frames was performed as presented in Figure 5 . The infrared images and the RGB frame were then registered and transformed, allowing both image modalities to have the same Point-of-View (POV). Afterwards, the RGB frame was used to determine the ROIs using a body pose estimation (BPE) algorithm. Before obtaining the desired vital parameters, the thermal correction on the transformed infrared images was done. Finally, the PPGI signal for HR detection and the temperature values were extracted from the RGB and the IR image, respectively. The single steps of the algorithm are explained in more detail in the following section. Regarding the image registration, a manual approach was chosen by selecting ten points on the IRT image and the corresponding feature points on the RGB image. Using the Ransac algorithm [ 33 ] for optimal matching, these feature were taken to determine a 3 × 3 homography matrix H , which can rotate, translate and distort the Lepton images to match the RGB image. As the Leptons have a fixed position in their housing, the manual labeling process described above was only done once. The registration process is shown in Figure 6 . After rescaling of both Lepton frames, they were transformed using the homography matrices and H L 1 to create the combined IRT image. The overlapping region was filled with temperature data from Lepton 1 that mainly records the upper body. H L 2 In order to determine ROIs on hands, feet, the forehead and the chest, we used a state-of-the-art DL-based BPE algorithm. The BPE was executed on the images captured by the RGB camera rather than the IRT camera, because existing open-source models are pre-trained in RGB. During this work, the NVIDIA project trt_pose was used, which enables a BPE on embedded NVIDIA Jetson modules [ 34 ]. No further transfer-learning step using additional data was conducted, but only the pre-trained version has been used. The network architecture is based on the CMU-Pose real-time multi-person 2D pose estimator of Cao et al. [ 15 ]. In contrast to CMU-Pose , the NVIDIA approach works on feature maps extracted from an image by a ResNet-18 feature extractor instead of the 10 first layers of VGG19, as suggested by Xiao et al. [ 35 ]. CMU-Pose is a two-branch multi-stage CNN, with one branch for learning Part Affinity Fields (PAFs) and one for learning Confidence Maps (CMAPs). A CMAP describes the area, where the respective body part can be found. The PAFs represent a 2D vector field which shows the association between two body points. For example, the body part could be the left forearm, connecting the keypoints in the left elbow and the left wrist. Subsequent stages in the CNN receive the CMAPs and PAFs as well as the initial features to refine the solution. In contrast to F CMU-Pose , the trt_pose approach optimized the architecture by preventing the feature exchange between the CMAP and PAF branches, which decreased the computational effort. The matching of keypoints with individuals is performed using a greedy graph matching algorithm, where every association gets a weight and the association with the largest weight was selected [ 15 ]. An overview of the keypoints delivered from the pose estimation and the desired six ROIs for temperature and HR measurements is illustrated in Figure 7 . With the detected ROIs, the skin temperature distribution of the phantom was obtained from the infrared image. Since red LEDs were integrated into the neonatal phantom, the extraction of the heart rate was performed by taking the mean intensity of the red channel inside a head ROI for each RGB frame. A H R PPGI find_peaks function was applied to detect maxima in the signal. Since small peaks caused by noise or the smaller, local maxima of the simulated LED brightness would lead to a corrupted HR, the maxima were compared to the minimum values to select only major peaks. The time distance between the detected peaks was evaluated and irrelevant HRs above 300 bpm and below 36 bpm were filtered out, as they were considered to originate from noise. The use of as mean of the time distance array, which contained only valid measurements from the last 10 s, enabled the calculation of the estimated heart rate T M e a n . H R PPGI The validation measurements were divided into the evaluation of the thermal calibration and pathology detection. Furthermore, the results were organized into simulation along with detection of thermal and HR-related pathologies. All experiments were performed inside an incubator Thermocare Vita (Weyer, Germany). The incubator was heated to a constant set temperature of 30 . This initial temperature was chosen since it enabled a simulation of thermal pathologies in the range between 30 ∘ C and 40 ∘ C . ∘ C The temperature accuracy of both Leptons after temperature correction was examined using an active thermal reference body (cf. Section 3.2 ). Since the measurement range focused on was 30– , only the error (mean of absolute difference) in this band contributed to the thermal calibration and the calculated accuracy. 40 ∘ C In the first step, the heating elements were driven with a voltage of around 4 V and a current, which had been slowly increased and decreased between 0.175 A and 0.575 A. Consequently, the active reference reached temperatures between and 26 ∘ C . The Lepton 1 (cf. 45 ∘ C Section 3.1 ) was used to measure temperatures and determine the slope correction along with the offset of the thermal calibration. The resulting linear fit is given in ( 2 ). (2) T s = 1.82 · T m − 20.18 In the second step, the active reference measurement was repeated, using the Lepton 2 to validate the thermal calibration. Figure 8 shows the validation measurement, as well as the calibrated and reference temperature. The calibrated temperature was well-fitted to the reference temperature, which was recorded using the gold standard temperature probe. Since the thermal calibration was optimized for the temperature range of 30–40 , calibrated temperatures below or above this range deviated more from the reference. In addition to the temperature curves in ∘ C Figure 8 , the mean absolute error (MAE), the standard deviation (STD) as well as maximum (MAX) and minimum (MIN) error of both measurements (Lepton 1 for fitting and Lepton 2 for validation) are presented in Table 4 . The comparison between the calibrated temperatures of Lepton 1 and Lepton 2 revealed that the validation measurement had even smaller MAE, STD, MIN and MAX error than the measurement used to determine the calibration factors. The implemented software was used to monitor the body surface temperature and the HR of the neonatal phantom. Therefore, the set values for both vital signs were adapted during the camera recordings. While the IRT frames were used to extract the surface temperature of different body parts to measure pathological thermoregulatory process and further the cpTD, the RGB images were analyzed for the PPGI signal to derive the simulated HR. An illustrative example was chosen. The results for the temperature simulation and camera-based measurements are illustrated in Figure 9 a. The set temperatures for different body parts were changed during a 120-min simulation to enable pathological cpTDs. The resulting temperature values for central and peripheral body areas are plotted next to the reference temperature from the Pt1000 chest temperature sensor. In Figure 9 b the cpTDs are presented which were measured using the chest for central and the mean of all available arms, hands, legs and feet for peripheral temperature values. The camera-based measurements for the individual body regions differ from their corresponding internal Pt1000 temperature probes, which were integrated on the scaffold during the construction of the neonatal phantom. This temperature difference can also be observed for other body parts. This can be seen exemplary in Figure 9 a for the chest area. The recording can be divided into seven phases, which are listed in Table 5 . The initial temperature progress showed a drop in chest temperature below 36.5 , stabilizing at 34 ∘ C . While this simulated a mild/moderate hypothermia, an induced normothermia in phase II with a resulting fever (skin temperature above ∘ C 37.5 ) in phase III were observed. In the following phase IV, the set temperature was again reduced to simulate a normotherm progress. ∘ C Until the end of phase IV, the cpTD was less than 2 (cf. ∘ C Figure 9 b). The next phases V and VII simulated a rising cpTD by slightly increasing the temperature of central body parts while simultaneously decreasing the set value for the peripheral areas. The progress of the measured cpTD can be observed in Figure 9 b. While phase V showed a cpTD of 4 in the steady state after the cooling of arms and feet, phase VI revealed a cpTD of almost 6 ∘ C due to an increase in central temperature. The final phase VII shows the return to the initial physiological temperature values. ∘ C Next to the simulation of thermoregulatory conditions of the neonatal phantom, the capabilities of a cardiac-related pathology progression were evaluated using the PPG functionality. Thus, the set HR was modified during a recording, while simultaneously measuring the PPGI signal using the pathology detection software. In Figure 10 a, the simulated patterns and the camera-based measurements of the HR are presented. Additionally, Figure 10 b shows the resulting measurement error. In Table 6 , the classification of the simulated phases is provided. In the beginning of the simulation (phase I), a physiological HR of 140 bpm was set. Subsequently, the set HR was reduced to a value less than 60 bpm in order to prove the simulation of a severe bradycardia in phase II. In phases III and IV, the HR was increased to values near a tachycardia (180 bpm) and then to a severe tachycardia (230 bpm). Finally, the HR was changed back to a physiological (140 bpm) in phase V with a simulated HRV. In Figure 10 b, the HR error can be observed. The dashed red lines describe the error margins of ±3 bpm. Since the HR was computed using a sliding-window approach with a window length of 30 s, the prediction error for the extracted HR regularly increased during transient phases. For phases I to IV, a mean absolute error of 0.89 bpm can be observed. In contrast, the mean absolute error increased to 4.62 bpm in phase V with a simulated HRV. The calculated errors only include the time periods, where the measured heart rate already reached the set point. As can be observed in Figure 10 , the results show an accurate camera-based measurement of the HR in the phases using the implemented setup. The absolute temperature accuracy for the Leptons was originally stated as ± in the data sheet [ 5 ∘ C 31 ] within the relevant temperature range of 30– . The measured maximum errors of the Leptons of up to 40 ∘ C (cf. 8 ∘ C Figure 8 ) even exceeded the nominal error, most likely because of the absorption of the IR window, which favors underestimation. As demonstrated in this paper (cf. Table 4 ), proper calibrations of the Leptons with an active thermal reference can lead to an accuracy improvement of at least 79% ( to 8 ∘ C ). 1.64 ∘ C Normally, one would expect that the error is smallest in the measurement that was used to determine calibration factors. However, the calibrated temperature of the validation measurement was found to have a higher accuracy. In contrast to the validation measurement, the temperature data used to determine the calibration showed a thermal hysteresis for the thermal camera. The Leptons measured different temperatures, although the active reference body had the same temperature. One reason could be the different thermal behavior during heating or cooling of the reference body. However, since this behavior was not seen in the validation measurement, a quantitative analysis should verify this in the future. Additionally, the custom-made active reference body and its usage impose a potential error during the measurements. The reference did not have an absolute homogeneous temperature distribution, especially during heat-up, and the skin temperature probe was isolated and contacted by thermal contact fluid. In future studies, a passive reference inside the FOV could be used to perform a Live-Offset compensation. In this case, not only a one-time calibration was conducted to compensate the infrared window, but an offset compensation was performed continuously during the measurements. Finally, research should be conducted concerning the temperature difference between the core and the skin temperature. The results of the temperature measurements demonstrated the feasibility to simulate thermoregulatory processes and the capability of a camera-based detection of pathological conditions. While the camera-based temperatures measured from the skin showed an accurate relative behavior for the chest area, the absolute values were underestimated, with a mean temperature difference of approx. . This can be explained with the position of the Pt1000 sensor, which was located inside the neonatal phantom next to the heating elements, whereas the Lepton recorded lower temperatures from the outer skin. Further, the emissivity of the colored silicone could influence the remote temperature measurement. In future work, the integration of the Pt1000 sensors into the silicone layer needs to be investigated. Additionally, a profound emissivity analysis of the silicone will be conducted. 2.50 ∘ C The analysis of the HR simulation of the neonatal phantom and the monitoring using the implemented setup demonstrated that the developed algorithms enabled the real-time extraction of a PPGI signal. Several pathological HR levels between 60 and 230 bpm were simulated. The analysis revealed a MAE of 0.89 bpm during the phases described in Section 4.2 . The resulted high accuracy can be explained by the reduction of potential external impacts for the PPGI measurement. However, the simulation of a physiological HRV led to errors of up to 4.62 bpm. In this case, the sliding window approach with a window length of 30 s prevented a higher accuracy. Unlike real infants, the phantom was lying still inside the incubator without any movement, which describes one of the biggest problems in camera-based vital signs measurement. In future work, a movement simulation will be added to the neonatal phantom using actuators. Further, the dependencies of PPGI measurements on ambient conditions will be analyzed. During this work, a neonatal phantom was used to simulate various stages of hypothermia and hyperthermia. In addition, cardiac-related pathologies, such as tachycardia and bradycardia, were simulated via LED modulation. The ability of the neonatal phantom to create a temperature distribution and a PPG signal in a controlled manner enabled the development and the validation of a contactless, camera-based monitoring system to measure the simulated vital signs and classify the pathologies. The accuracy of the temperature measurements was improved by at least 79% with a maximum absolute error of less than by using an active thermal reference body, compensating the spectral absorption of the HR window. A DL-based pre-trained human pose estimator was used to determine the ROIs of the hands, the feet, the chest and the head, allowing to semantically match the measured skin temperatures with the areas of the body. Further, the PPGI signal was extracted, allowing to supervise pathological HR conditions. 1.64 ∘ C Even though the presented system achieved promising measurement accuracies and provided a reliable detection of pathologic states, challenges remain, which will be addressed in future work. Since the error for temperature measurement is still relatively high with a maximum error of , it would be feasible to add a passive thermal reference for live offset compensation or use a data-driven approach for temperature correction. Furthermore, the functionality of PPGI recordings could be extended by adding another camera with an IR filter for measuring the oxygen saturation, which can be simulated by the neonatal phantom already. An additional series of measurements should analyze the emissivity of the phantom’s skin to evaluate the impact of the ambient temperature, as well as measurements involving a more realistic temperature and humidity inside the incubator. Finally, the integration of motors into the neonatal phantom to enable the simulation of motion artifacts will be addressed in the future. 1.64 ∘ C The authors gratefully acknowledge the effort of the authors of the COCO human pose dataset and the developers of the NVIDIA tool trt_pose. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Conceptualization, F.V., S.L. (Simon Lyra) and M.L.; methodology, F.V., S.L. (Simon Lyra) and D.B.; software, F.V. and D.B.; validation, F.V. and D.B.; formal analysis, M.L. and S.L. (Steffen Leonhardt); investigation, F.V. and S.L. (Simon Lyra); resources, S.L. (Steffen Leonhardt); data curation, D.B.; writing—original draft preparation, F.V. and S.L.; writing—review and editing, F.V., S.L. (Simon Lyra) and M.L.; visualization, F.V., S.L. (Simon Lyra) and D.B.; supervision, M.L. and S.L. (Steffen Leonhardt); project administration, S.L. (Steffen Leonhardt); funding acquisition, S.L. (Steffen Leonhardt). All authors have read and agreed to the published version of the manuscript. The authors gratefully acknowledge financial support provided by German Research Foundation (Deutsche Forschungsgemeinschaft, LE 817/32-1) and Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, 13GW0441C). Not applicable. Not applicable. The authors declare no conflict of interest. Individual heating regions adapted from [ 23 ]. While the head and the limbs were divided into two heatable areas, the torso was subdivided into three regions. Routine during a temperature increase. The set temperature was adjusted after an update time interval of 30 sec. The routine was applied until the target temperature was reached. ( a ) Side view of the arranged camera setup and field of view. ( b ) Top view of the arranged camera setup and the covered mattress area. ( a ) Inner parts of the reference device. The heating elements was placed under a dissipative layer and an overlying black foil. ( b ) Assembled active thermal reference body with an attached Weyer thermistor. Overview of the pathology detection algorithm. Multithreading was used for parallel data processing. Overview of the registration algorithm. Detected keypoints on the neonatal phantom with extracted ROIs for temperature and HR measurement. Validation measurement for temperature calibration. ( a ) Results for temperature measurements of camera-based setup and internal Pt1000 sensor. ( b ) Resulting central-peripheral temperature difference. ( a ) Validation of HR detection and ( b ) the resulting measurement error. The dashed red lines in ( b ) show the 3 bpm band. Simulated temperature-dependent pathologies. Simulated HR-dependent pathologies. Camera properties and parameters used in this work. Accuracy of the calibrated fitting and validation measurement. Classification of temperature simulation from Figure 9 . Classification of HR simulation from Figure 10 . A Setup for Camera-Based Detection of Simulated Pathological States Using a Neonatal Phantom Levels and Trends in Child Mortality 2020 Caring for Tomorrow: EFCNI White Paper on Maternal and Newborn Health and Aftercare Services Newborns: Improving Survival and Well-Being Preterm Birth The global burden of neonatal hypothermia: Systematic review of a major challenge for newborn survival Thermoregulation and thermography in neonatal physiology and disease Extremely low birth weight preterm infants lack vasomotor response in relationship to cold body temperatures at birth Skin physiology of the neonate and infant: Clinical implications A high-resolution non-contact fluorescence-based temperature sensor for neonatal care No Wires, More Cuddles A broader look: Camera-based vital sign estimation across the spectrum A Deep Learning-Based Camera Approach for Vital Sign Monitoring Using Thermography Images for ICU Patients A neonatal dataset and benchmark for non-contact neonatal heart rate monitoring based on spatio-temporal neural networks Realtime multi-person 2d pose estimation using part affinity fields Neonatal Seizure Detection Using Deep Convolutional Neural Networks Machine Learning of Infant Spontaneous Movements for the Early Prediction of Cerebral Palsy: A Multi-Site Cohort Study Machine learning models for identifying preterm infants at risk of cerebral hemorrhage Continuous Camera-Based Premature-Infant Monitoring Algorithms for NICU Non-contact physiological monitoring of preterm infants in the neonatal intensive care unit Non-contact automatic vital signs monitoring of infants in a neonatal intensive care unit based on neural networks Classification of neonatal diseases with limited thermal Image data A Neonatal Phantom for Vital Signs Simulation Surface body temperature of full-term healthy newborns immediately after Birth—Pilot study Leitlinie der Gesellschaft für Neonatologie und Pädiatrische Intensivmedizin, der Deutschen Gesellschaft für Kinder- und Jugendmedizin, der Gesellschaft für Pädiatrische Gastroenterologie und Ernährung und der Deutschen Gesellschaft für Kinderchirurgie. AWMF Online, AWMF-Leitlinien-Register Nr. 024/008 Arducam MINI High Quality Camera with M12 Mount Lens, 12.3MP 1/2.3 Inch IMX477 HQ Camera Module for Jetson Nano, Xavier NX LWIR Micro Thermal Camera Module 3 & 3.5 Dynamics and complexity of body temperature in preterm infants nursed in incubators Random sample consensus: A paradigm for model fitting with applications to image analysis and automated cartography Real-Time Pose Estimation Accelerated with Nvidia Tensorrt. GitHub Repository Simple baselines for human pose estimation and tracking |
Answer the following medical question. | What does research say about Neonatal plantar response revisited.? | To evaluate plantar response in the early neonatal period in normal, term, healthy newborn infants. This was a prospective study set in the postnatal ward of a tertiary care hospital. The plantar response was elicited in 256 healthy, term, appropriate-for-gestational-age neonates during their first 7 days of life, utilizing the thumb-nail-drag method. The response was tested daily at intervals of 24 h, until the neonate was discharged. A total of 597 observations were made, and the responses were classified as extensor, flexor or equivocal. The overall plantar response was found to be predominantly extensor (73.8%), followed by equivocal (17.3%) and, finally, flexor (8.9%). The plantar response was bilaterally extensor in 72.5%, bilaterally equivocal in 14.2%, and bilaterally flexor in 7.7% of observations, respectively. Asymmetrical plantar response was elicited in 5.4% of observations. No difference was observed in individual categories based on age (<12 h, 12.1-24 h, 24.1-72 h, 72.1 h-7 days) and site of response (right/left foot). The plantar response in healthy, term neonates is predominantly extensor. Further, the relatively high frequency of asymmetrical and symmetrical flexor responses limits its clinical usefulness in the early neonatal period. |
Answer the following medical question. | What does research say about Protocol to Support Skin-to-Skin Care and Closeness Between Parents and Neonates in the NICU.? | Skin-to-skin care (SSC) is essential, can help to prevent separation of parents and the neonate in the NICU, and should be a standard practice. It can safely be integrated into the routine care of preterm neonates, those who require surgery, and those who require all levels of intensive care. Years of experience with the provision of SSC in our NICU influenced our approach to care and resulted in practice guidelines for the safe provision of SSC. In this article, we present our clinical practical guidelines that support SSC and closeness between parents and the neonate to ensure the use of these practices for all neonates in the NICU. |
Answer the following medical question. | What does research say about Effectiveness of neonatal transport systems.? | In order to assess the effectiveness of neonatal transport systems, morbidity on admission and early neonatal mortality of low birth weight infants below 2000 gm were studied. All infants referred to a neonatal department in Munich or Southern Bavaria from 1979 to 1981 were included. The data of infants born in Munich perinatal centers were compared to those of infants delivered in hospitals in the Munich area (radius 30 km) and in other hospitals in Southern Bavaria. Ninety-four percent of 248 LBW neonates born in the Munich perinatal centers, 87.5% of 736 infants and 84.4% of 681 LBW infants from the Munich area and Southern Bavaria respectively survived the first week of life although the morbidity risks of inborn infants were higher than those of the outborn. The presence of a pediatrician at birth and during neonatal transport to an NICU did not improve survival rates of infants delivered outside the perinatal centers. The effectiveness of neonatal transport systems is limited. They should be complemented by a maternal transport system, i.e., an infant transport in utero for cases in which the necessity for intensive neonatal care is expected. |
Answer the following medical question. | What does research say about Fluid homeostasis in the neonate.? | The physiology of the neonate is ideally suited to the transition to extrauterine life followed by a period of rapid growth and development. Intravenous fluids and electrolytes should be prescribed with care in the neonate. Sodium and water requirements in the first few days of life are low and should be increased after the postnatal diuresis. Expansion of the extracellular fluid volume prior to the postnatal diuresis is associated with poor outcomes, particularly in preterm infants. Newborn infants are prone to hypoglycemia and require a source of intravenous glucose if enteral feeds are withheld. Anemia is common, and untreated is associated with poor outcomes. Liberal versus restrictive transfusion practices are controversial, but liberal transfusion practices (accompanied by measures to minimize donor exposure) may be associated with improved long-term outcomes. Intravenous crystalloids are as effective as albumin to treat hypotension, and semi-synthetic colloids cannot be recommended at this time. Inotropes should be used to treat hypotension unresponsive to intravenous fluid, ideally guided by assessment of perfusion rather than blood pressure alone. Noninvasive methods of assessing cardiac output have been validated in neonates. More studies are required to guide fluid management in neonates, particularly in those with sepsis or undergoing surgery. A balanced salt solution such as Hartmann's or Plasmalyte should be used to replace losses during surgery (and blood or coagulation factors as indicated). Excessive fluid administration during surgery should be avoided. |
Answer the following medical question. | What does research say about Providing Expressed Breast Milk to Preterm Neonates Admitted in an Extramural Neonatal Intensive Care Unit: Where do we stand?? | Provision of expressed breast milk (EBM) to premature neonates poses a great challenge in extramural Neonatal Intensive Care Units (NICUs). We conducted a questionnaire-based survey to identify the various challenges faced by the parents to provide EBM to their hospitalized premature infant. 40 preterm neonates (<34 wk gestation and <1500 g weight) planned to be started on EBM were included in the study. The median (range) duration after which EBM was received in NICU after the time it was asked for was 34.5 (13 to 40) hours, and it was received in a clean, sterile and covered container in only 8 (20%) cases. There were multiple hurdles in ensuring early availability of EBM in optimal condition. Sensitization and motivation of families regarding the importance of ensuring early administration of EBM to their prematurely delivered neonate may lead to substantial improvement in outcome of these neonates. |
Answer the following medical question. | What does research say about Improving Skin Integrity in Babies Diagnosed with Neonatal Abstinence Syndrome.? | Neonatal abstinence syndrome (NAS) is becoming a national epidemic. Neonates with NAS display myriad signs during withdrawal from the drugs they were exposed to in utero. One sign is skin excoriation, as well as other skin injuries. While care of the neonate experiencing NAS has been well documented in the literature, the care of the skin of that neonate has not. The purpose of this monograph is to discuss the current literature on neonatal abstinence syndrome, to describe the anatomy and physiology of neonatal skin, and to make recommendations for the prevention and care of the most common neonatal skin injuries seen in infants exhibiting NAS. |
Answer the following medical question. | What does research say about The role of molecular genetics in the pathogenesis and diagnosis of neonatal sepsis.? | Polymorphisms within genes encoding endogenous mediators of inflammation are good candidates for the individual differences in systemic inflammatory responses of neonates to infection. Ina similar manner, polymorphisms in the genes encoding drug metabolizing enzymes, drug transporters, and drug receptors can influence a neonate's risk of an adverse drug reaction or can alter the efficacy of drug treatment. Additionally, molecular tools are proving valuable in the diagnosis of neonatal infection. This article gives an overview of the genetic susceptibility to sepsis, discusses the use of molecular genetics in diagnostic tests for infection, and reviews the potential for more effective and specific therapies for sepsis based on genetic variability. |
Answer the following medical question. | What does research say about Pain in the neonate: focus on nonpharmacologic interventions.? | The assessment and treatment of pain in the neonate, especially preterm neonates, has been a challenge in the NICU for many years. Nurses caring for these vulnerable patients are in a key position to not only recognize when the neonate is experiencing pain but to also work collaboratively with other health care providers in determining the best method to treat and help prevent pain associated with procedures and routine caregiving activities. The American Academy of Pediatrics along with parent groups has recognized the importance of pain-prevention programs in treating pain in the neonate. Nurses, by anticipating and reducing both painful procedures and bedside interruptions, along with innovative nonpharmacologic interventions, can dramatically decrease the neonate's exposure to pain and the potential for long-term effects. An overview of nonpharmacologic interventions in the treatment of neonatal pain is provided for NICU nurses to help them effectively reduce their patient's pain and discomfort. |
Answer the following medical question. | What does research say about Potential NICU Environmental Influences on the Neonate's Microbiome: A Systematic Review.? | Potential NICU Environmental Influences on the Neonate’s
Microbiome: A Systematic Review |
Answer the following medical question. | What does research say about Fluid and Electrolyte Management in the Neonate: Potassium and Phosphorus.? | Maintenance of electrolyte balance in the neonate is challenging in the context of illness or prematurity. Imbalances in potassium and phosphorus can occur in neonates, ranging from benign and clinically insignificant to those that can be life-threatening. An individualized approach to fluid and electrolyte management is based on the neonate's gestational age, day of life, maintenance needs, deficits, and ongoing losses. This article reviews normal and abnormal potassium and phosphorus values along with management strategies. Using a case scenario, the reader can apply concepts outlined in this article to management of critically ill neonates with electrolyte disturbances. |
Answer the following medical question. | What does research say about The Effect of Kangaroo Care on Breastfeeding and Development in Preterm Neonates.? | This study investigated the effect of kangaroo care (KC) on breastfeeding rate and development in preterm neonates in the first six months of life. The study was conducted using a quasi-experimental method with a pretest-posttest control group design. The sample consisted of preterm neonates in the NICU of two state hospitals of Turkey. The experimental group (n =30) was provided with KC by their mothers for 30 min once a day during a postnatal month. The control group (n = 30) received routine care. Feeding patterns and physical development parameters were determined during the transition to exclusive breastfeeding and at discharge, and in the first, third, and sixth postnatal months. Data were collected using a descriptive characteristics questionnaire, a nutrition and physical development follow-up form, and a home KC follow-up form. Percentage distribution, mean, chi-square test, and t-test were used for analysis. The KC group had a significantly higher mean body weight than the control group in the third and sixth postnatal months (p < .05). The KC group had higher breast milk intake and breastfeeding rates than the control group during the transition to exclusive breastfeeding and at discharge, and in the first, third, and sixth postnatal months (p < .05). The KC neonates were breastfed for a more extended period of time than controls. This result suggests that KC improves breast milk intake and breastfeeding rates. Therefore, mothers should be trained in KC in the postnatal period. Healthcare professionals should encourage and follow mothers for kangaroo care. |
Answer the following medical question. | What does research say about Incidence and determinants of neonatal mortality in the first three days of delivery in northwestern Ethiopia: a prospective cohort study.? | Addressing sustainable development goals to reduce neonatal mortality remains a global challenge, and it is a concern in Ethiopia. As a result, the goal of this study was to assess the incidence and determinants of neonatal mortality in the first 3 days among babies delivered in the referral hospitals of the Amhara National Regional State. A hospital-based prospective cohort study was conducted among 810 neonates in the first 3 days of delivery between March 1 and August 30, 2018. The neonates were followed up from the time of admission to 72 h. Interviewer-administered questionnaires and medical record reviews were conducted for data collection. Data were entered into Epi-data manager version 4.4 and analysed using STATA™ version 16.0. The neonate’s survival time was calculated using the Cox-Proportional hazards model. The overall incidence of neonatal mortality in this study was 151/1000 births. Neonatal mortality was significantly higher among neonates whose mothers came between 17 and 28 weeks of gestation for the first visit; among those whose mothers labour was not monitored with a partograph, mothers experienced postpartum haemorrhage and developed a fistula first 24 h, and experienced obstructed labour. However, 39% were less risky among neonates whose mothers were directly admitted and whose mothers had visited health facilities in less than 1-h, both. This study revealed that approximately 1 in 7 neonates died within the first 3 days of life. The determinants were the timing of the first antenatal visit, quality of labour monitoring, maternal complications, and delay in seeking care. Thus, scaling up evidence-based interventions and harmonising efforts to improve antenatal care quality, promote institutional deliveries, provide optimal essential and emergency obstetric care, and ensure immediate postnatal care may improve neonatal survival. The online version contains supplementary material available at 10.1186/s12884-021-04122-8. The newborn period is critical in the miracle of life and death. In 2018, the global neonatal mortality rate was estimated to be 18 deaths per 1000 live births, with 28 deaths per 1000 live births in Sub-Saharan Africa, and in 2016, it was 30 deaths per 1000 live births in Ethiopia [ 1 , 2 ]. According to a systematic review in developing countries, despite more than 99% of neonatal deaths in low and middle-income countries, these settings lack overall or cause-specific neonatal deaths [ 3 ]. The same systematic review also revealed that 57% of neonates died in the first 3 days of life, and two-thirds of these deaths occurred within the first 24 h. Furthermore, this review indicated that among 52% of under-five deaths in the Southeast Asia region, one-third of the neonatal mortality occurred within the first 3 days of life. Among 30% of the under-five deaths in the World Health Organization (WHO) African region, 17% of deaths occur within the first day of life [ 3 ]. The WHO also verifies that the danger of death is most significant in the first 24 h of life, with more than half of all neonatal deaths occurring within the first week of life [ 4 ]. In Ethiopia, a study conducted at a referral specialised teaching hospital revealed that the death of babies aged 1–3 days was riskier than 4–7 days [ 5 ]. In low and middle-income countries, it has been suggested that the scaling-up of evidence-based interventions that begin during the antenatal period, coordinated efforts aimed at improving the quality of antenatal care, promoting institutional deliveries, providing optimal essential and emergency obstetric care, and ensuring immediate postnatal care of neonates are essential [ 3 , 6 ]. Consequently, some countries, including Ethiopia, have substantially improved targeted coverage for some interventions. However, these coverages have not resulted in the expected magnitude of reduction in neonatal mortality rate, specifically neonatal mortality within the first 3 days of life. The lack of a concurrent rise in the coverage of essential interventions in the continuum of care could be one of the possible reasons [ 3 ]. For example, a recent study in Ethiopia indicated that only 12.1% of women completed the continuum of maternal care services, and 25.1% did not receive any care during their recent births [ 7 ]. Although the perinatal mortality rate definition starts at 28 weeks of gestation in low and middle-income countries (LMICs), the mortality rate is higher than the developed countries that stated the definition from 20 weeks of gestation. The perinatal mortality rate includes all stillbirths and neonatal deaths in a given period over the total number of births multiplied by thousands [ 8 ]. In LMICs, there is a lower preterm newborns’ survival rate, and the numerator for perinatal mortality rate includes all fetal deaths with a gestational age of 28 weeks and above and all neonatal deaths within 7 days of life [ 8 ]. However, according to a global network study, in LMIC registries, most neonatal deaths occurred in babies > 37 weeks of gestation, weighing at least 2500 g shortly after birth [ 9 ]. Previous studies have also identified multiple risk factors for perinatal mortality rate in LMICs [ 10 – 14 ]. Poverty contributes to many newborn fatalities, either by increasing risk factors such as maternal infection or limiting access to sufficient care [ 15 ]. Studies have also revealed that the proportions of common causes of perinatal mortality rate include prematurity (17%); asphyxia (25%); infection (37%); tetanus (7%); diarrhoea (3%); congenital malformations (4%); and other causes (7%) [ 16 – 19 ]. Almost all the studies were conducted at the community level and within 28 days of life and recommended prevention through better medical care and hospitalisation in the intrapartum and early neonatal period [ 9 ]. Neonatal mortality rates and determinants in the early neonatal period (the first 3 days of life in this case) are essential for arranging programs and identifying suitable interventions. Local and recent evidence about the spread of the problem could help implement programmatically relevant decision-making [ 10 ]. However, despite a high number of deaths in the first 3 days, data are scarce in the first 3days of life, particularly at the tertiary level of care. Moreover, since both biology and empirical data suggest that the cause of death distribution differs substantially between these periods, separate cause-of-death estimates are required for the first 3 days of life, within the first 7 days, and within 28 days of life [ 10 ]. Therefore, this study aimed to address the incidence and determinants of newborn death in the first 3 days of life among babies delivered in referral hospitals. This study was conducted at the maternity wards of referral hospitals in the Amhara Regional State between March 1 and August 30, 2018. The National Regional State is located between 9° 20′ and 14° 20′ North latitude and 36° 20′ and 40° 20′ East longitude in the Northwestern part of Ethiopia. According to the Central Statistics Agency, the projected total population estimate Amhara Region in 2020/21 is 22,536,999 (11,236,853 males and 11 300,146 females). Of these, 20.08% were urban residents [ 20 ]. According to the annual performance report published by the Federal Ministry of Health of Ethiopia in the 2009 Fiscal Year, the region had 68 hospitals, 841 health centres, and 3342 health posts [ 21 ]. Dessie, Felege-Hiwot, University of Gondar, Debre-Birhan, and Debre-Markos were referral hospitals at the time of data collection for this study. Each referral hospital was expected to serve a population of 5 million people. The University of Gondar Teaching Referral Hospital (UoGH), Felege Hiwot Referral Hospital (FHH), and Debre Markos Referral Hospital (DMH) were selected for this study. The UoGH serves the residents of Gondar town and the neighbouring zones. The NICU was established 20 years ago and serves as the region’s tertiary referral unit, caring for high-risk newborns born at the hospital, referrals from other health facilities and home deliveries. Outpatient clinics, emergency departments, paediatrics and malnutrition wards, and neonatal intensive care units (NICUs) were among the services provided by paediatric and child health departments for rural and urban populations. Although neonatal hospitalisation varies seasonally, the annual average admission rate is 1140. There was no mechanical ventilators or continuous positive airway pressure (CPAP) equipment in this 32-bed NICU, including radiant heaters and nine incubators. On the other hand, Bubble CPAP was locally developed for neonates with respiratory distress syndrome (RDS). There were also four incubators and three phototherapy machines for term babies. The babies were given oxygen via nasal prongs or a nasal catheter connected to oxygen cylinders or concentrators. Ampicillin and gentamicin were the most usually prescribed antibiotics for sepsis treatment. Medications were given through a peripheral vein, with the umbilical vein being used on a few occasions. The NICU has four rooms, which were helpful for preterm and term babies, infectious diseases, and maternity, where relatively stable neonates and newborns require kangaroo mother care. Seven medical interns, two pediatric residents, one paediatrician, and 17 nurses staff the NICU [ 22 ]. Felege Hiwot referral Hospital was a teaching hospital for Bahir Dar University and served the Bahir Dar special zone, west Gojjam zone, Awi zone, South Gondar Zone. More than 7 million people were living in these zones. The FHH was established in 1963 and has been in operation since then. Medical, surgical, gynaecological, orthopaedic, intensive care units, paediatrics, and ophthalmological wards with 375 beds and 561 employees currently provide health care services. Approximately 6300 neonates are diagnosed with various health issues each year. There were 60 beds, five paediatricians, and 20 nurses in the neonatal ward [ 23 ]. Furthermore, the DMH hospital served as a teaching hospital for Debre Markos University was the only referral hospital found in the East Gojjam Zone. This hospital serves a population of over 3.5 million individuals within its catchment area. For extremely ill neonates and those who require neonatal care, the hospital also offers neonatal intensive care. There were 27 nurses, one paediatrician, and two general practitioners working in the NICU. Ten NICU beds, four kangaroo mother care beds, 19 mother side beds, eight radiant warmers, and six incubators were available in the unit. The regular nursing procedures in the NICU were phototherapy, umbilical transfusion, oxygen administration, nasogastric tube insertion, intravenous infusion, urinary catheterisation, lumbar puncture, and CPAP. In 2017, this hospital provided neonatal intensive care services for 1419 neonates [ 24 ]. An institution-based prospective cohort study was conducted among a cohort of term pregnant mothers and newborns admitted to three systematically selected referral hospitals. All term pregnant mothers (≥37 weeks gestational age (GA)) were admitted to the selected referral hospitals included in this study. Additionally, neonates discharged with an appointment and normal status were followed using mothers’ phones and the nearby health extension workers till 3 days of life. Then, they followed up until they gave birth, and their neonates were followed up for a total of 72 h. Cohorts of newborns who were delivered from women aged 15–49 years were included. Those born to women with mental illnesses who could not hear or speak due to their disease and twins were excluded from the study. The sample size of 832 was calculated using Epi-info version 7 stat calc software. The following assumptions of the incidence ratio of early neonatal death of 369 per 2142 deliveries [ 25 ], 95% confidence level, the margin of error 2.75, and 15% lost follow-up. Systematic random sampling was used to identify 832 admitted term pregnant women enrolled in the follow-up study. First, a simple random sampling (i.e., lottery method) technique selected the three hospitals. The study subjects were then allocated the proportion of the expected admitted number of term pregnant women per referral hospital, 300 each for UoGH and FHH, and 210 for DMH. The computed sample was then chosen in order from each referral hospital. Times-to-event, the event of interest was early neonatal death and dichotomised as (alive =1 and died = 0). The determinant variables included socio-demographic and economic factors: ethnicity, religion, place of residence, marital status, education status of the mother, and occupational status of the mother, age of mother, maternal and neonatal related factors: ANC follow up, parity gravidity, mode of delivery gestational age, birth weight, age of neonate at discharge, and sex of neonate. Neonatal illnesses include respiratory distress, perinatal asphyxia, sepsis, congenital malformation, hyaline membrane disease, and meconium aspiration syndrome—care/ service-related factors: Partograph follow-up, length of stay, and obstetric complications. First, we prepared the English questionnaire, translated it to Amharic’s local language, and back to English by different individuals to check its consistency. The survey was pretested on 42 mothers (14 exposed and 28 unexposed cohorts) in Debre Tabor Hospital, which differs from the study hospitals. The questionnaire (Additional file 1 ) was then assessed for its clarity and completeness. Some skip patterns were corrected, and questions difficult to ask were rephrased. The questionnaire had three parts. The first part was socio-demographic factors (i.e., maternal age, body mass index, age at first marriage, age at early pregnancy, age at first delivery, ethnicity, residence, marital status, educational status, husband educational status, occupation, an estimated distance of home from health institution, determining range from primary health institute to referral hospital, religion, and income). The reproductive factors constitute the second part, like gravidity, parity, gestational age, referral status, birth attendant, previous cesarean section, mode of final delivery, antenatal care attendance, number of ANC visits, duration of labour before the presentation, prior history of abortion, and obstetric complications. The third part was that programmatic factors included infrastructure and transportations. The completed questionnaires were checked day-to-day for inclusiveness, correctness, clarity, and consistency by the supervisors and the principal investigators, and necessary corrections and changes were made. During data entry and analysis, complete and consistent variables were checked using frequency distributions, cross-tabulations, sorting in ascending, and descending order. Because of the day and night allocation of data collectors in each hospital, six bachelor (two per hospital) holders experienced midwives collected data interchangeably (by shift), and three general practitioners (1 per each hospital) were supervised the process. Three days of training were given based on the study’s objective and the value of collecting the actual data. The structured questionnaire was discussed in detail, going through every question, and clarification was provided. A field manual was prepared for the supervisors and data collectors for use during data collection. The six data collectors were present in the respective hospitals during the complete 24 h. The data collectors collected the data daily. Medical record review and an interviewer-administered questionnaire were used to collect data on the intended variables of interest until the time of discharge from the hospital or 72 h. We retained only the previously collected data were retained for analysis in cases of readmission. We assessed the neonates for the entire period of hospital stay (both in the maternity ward and neonatal intensive care unit). There was no follow-up after hospital discharge. Early neonatal mortality was the event of interest, coded as “1” for failure and “0” for censored. Time-to-event was considered by subtracting the date of admission from the time of the event. Data entered into Epi-Data manager version 4.4 and analysed using STATA™ version 16.0. for the follow-up time and age of the cohort, we calculated the mean and standard deviation. The cox-Proportional hazard model was used to determine risk factors for newborns’ survival time delivered at the hospitals. A tolerance level with a cut point of 0.2 was used to omit multicollinearity. The Kaplan Meier curves were used to estimate survival time. The log-rank test was used to look at statistical variances between the groups of variables. Statistical significance was declared at p -value < 0.05. A summary statistic of proportions, including hazard ratio and 95% confidence intervals, was used. Screening of risk factors for the newborn’s death employed bivariate Cox regression for each variable one at a period. Those variables with p < 0.25 throughout the bivariate Cox regression analysis were taken as an entrant variable to control possible confounders for the multivariate Cox regression model. Early neonatal mortality: This refers to a neonate’s death within the first 72 h of life. Neonatal survival: is referred to as being alive until the end of the follow-up period (72 h). Term pregnancy: It is defined as a pregnancy lasting between 37 and 42 weeks of gestation. Maternal First Delay refers to the delay after the onset of actual labour to reach a health facility. During the 72 h’ observation, 810 newborns (97.4% of the sample) followed for 37,454 new-borns-hours at the three hospitals. The mean ( + SD) length of stay at the four hospitals was 46.23( + 29.31) hours. Of the 810 newborns, 10.4% were stillbirths, 17.1% were alive but complicated, and 72.5% were alive without complications. Out of the 84 stillbirths, 25 were from primiparous women, 15 deaths in the first 72 h out of the 38 deaths observed among women who gave 2 to 4 births. As Table 1 shows, 81.9% of the newborns who survived were mothers who received antenatal care. Out of 84 stillbirths, 58 of them were diagnosed with intrauterine fetal death before starting actual labour, whereas the rest 26 were fresh stillbirths during delivery (Table 1 ). Table 1 New-borns and maternal clinical characteristics of Amhara regional state referral hospitals, Northern Ethiopia, 2018 Variables Categories Stillbirth Neonates died in the first 72 h Neonatal Survived Frequency(%) Frequency(%) Frequency(%) Parity One child 25(3.1) 13(1.6) 292(36.1) 2 to 4 children 33(4.1) 15(1.8) 292(36.1) 5 children and above 26(3.2) 10(1.2) 104(12.8) Received Antenatal care Yes 71(8.8) 35(4.3) 664(81.9) No 13(1.6) 3(.4) 24(2.9) Place of delivery Health institution 68(8.4) 31(3.8) 599(74.1) Home 15(1.8) 7(0.9) 88(10.9) Newborn birth weight < 2500 52(6.2) 31(3.8) 544(67.2) > = 2500 32(3.9) 7(.8) 144(17.8) APGAR score of the newborn 0–3 69(8.5) 7(0.8) 0(.0) 4–6 2(0.3) 6(.7) 32(3.9) 7–10 13(1.6) 25(3.1) 656(80.9) Fetal outcome in the uterus IUFD 58(7.2) 0(.0) 0(.0) NRFHR 14(1.7) 18(2.2) 184(22.7) RFHR 12(1.5) 20(2.5) 504(62.2) Mode of delivery Vaginal 33(4.1) 18(2.2) 340(41.9) Ceserean section (C/S) 51(6.3) 20(2.5) 348(42.9) IUFD intra-uterine fetal death, NRFH non-reassuring fetal heart rate, RHFR Reassuring fetal heart rate New-borns and maternal clinical characteristics of Amhara regional state referral hospitals, Northern Ethiopia, 2018 IUFD intra-uterine fetal death, NRFH non-reassuring fetal heart rate, RHFR Reassuring fetal heart rate The leading cause of disease in Amhara regional state referral hospitals was neonatal jaundice 52(42.4%), followed by other complications 30(24.6%) like birth trauma, congenital anomalies, and asphyxia 22(17.7%) (Fig. 1 ). Fig. 1 Causes of Neonatal morbidity in the first three days of delivery in Amhara regional state referral hospitals, northwestern Ethiopia Causes of Neonatal morbidity in the first three days of delivery in Amhara regional state referral hospitals, northwestern Ethiopia Of the 688 neonates discharged, 56.7% were discharged alive, 2.5% were discharged with treatment, and 17.3% were referred to the NICU. In contrast, the rest of the 23.5% were discharged with an appointment. During the study period, a total of 15.1% ( n = 122) of neonates deaths were observed, making an overall newborn mortality rate of 151 per thousand births. Of the 122 newborn deaths, 84(68.9%) were stillbirths, 38(31.1%) died in the first 72 h (Table 2 ). The overall incidence of neonates mortality was 1.012 per thousand early neonate hours. Table 2 survival function life table of Amhara regional state referral hospitals, Northern Ethiopia Time Beg Total Fail Net Lost Survivor Function Std Error [95% Conf. Int.] 1 810 82 0 0.8988 0.0106 0.8759 0.9176 6 728 0 117 0.8988 0.0106 0.8759 0.9176 12 611 0 2 0.8988 0.0106 0.8759 0.9176 20 609 1 1 0.8973 0.0107 0.8742 0.9163 24 607 15 95 0.8751 0.0119 0.8498 0.8964 48 497 6 68 0.8646 0.0125 0.8380 0.8871 50 423 1 0 0.8625 0.0126 0.8357 0.8853 52 422 1 0 0.8605 0.0127 0.8333 0.8835 72 421 16 405 0.8278 0.0146 0.7968 0.8544 survival function life table of Amhara regional state referral hospitals, Northern Ethiopia There was a higher mortality level in the first 24 h compared to after 24 to 72 h. This finding indicates a substantial reduction in death after the neonates survive the early 24 h of life in the observation period (Fig. 2 ). Similarly, the curve indicates that neonatal mortality shows substantial decrement among those whose labour was monitored with Partograph (Fig. 3 ). Fig. 2 K-M survival estimate of newborns in Amhara Regional state referral hospitals, Northern Ethiopia Fig. 3 K-M survival estimate of neonates with labour monitored with partograph Amhara Regional state referral hospitals, North-west Ethiopia K-M survival estimate of newborns in Amhara Regional state referral hospitals, Northern Ethiopia K-M survival estimate of neonates with labour monitored with partograph Amhara Regional state referral hospitals, North-west Ethiopia We included the variables with a p -value of less than 0.25 in the Cox proportional hazards regression model’s crude model. Then, after controlling for potential confounders using multivariate Cox proportional hazard regression, the timing of first antenatal care visit, monitoring with partograph, type of admission of the women, and maternal complications within the first 24 h (postpartum haemorrhage, fistula, and obstructed labour) were the variables that determine neonatal survival within the first 72 h of life. Gestational age at the first antenatal care visit was found to be a risk factor for neonatal mortality. Women who came between 17 and 28 weeks of gestation for the first visit were 1.67 times more likely to lose their child [AHR = 1.67: 95% CI: 1.02, 2.73] than those who started the initial antenatal care visit before 16 weeks of gestation. Mothers not monitored with a partograph during labour were 2.66 times the risk of neonatal mortality [AHR = 2.66:95% CI: 1.70, 4.15] compared to their counterparts. Direct admission was 39% less risk of neonatal death than [AHR = 0.61:95% CI: 0.38, 0.97] those admitted from referral to another health facility. Maternal complications within 24 h were also a significant risk factor for newborn mortality. Mothers experiencing postpartum haemorrhage were about three times risky for new-borns death [AHR = 2.88; 95% CI:1.69, 4.89], and those who developed fistula in the first 24 h were also about four times risky for new-borns death [AHR = 3.75; 95% CI: 1.23, 11.43]. Obstructed labour was more than twice risky [AHR = 2.14; 95% CI: 1.35, 3.38] for neonatal mortality and less than 1-h maternal first delay in visiting health facility was 39% less risk of neonatal death [AHR =0.61; 95% CI: 0.37, 0.98] (Table 3 ). Table 3 Bivariate and Multivariate Cox-proportional hazard regression for the first 3 days neonatal mortality in Amhara regional state referral hospitals, Northern Ethiopia Variables Outcome CHR (95%CI) AHR (95%CI) Died Censored Parity 1 child 38(4.69) 292(36.05) 1.0 1.0 2–4 children 48(5.93) 292(36.05) 1.26[.82, 1.93] 1.20[0.74, 1.94] 5 children & above 36(4.44) (104)12.84 2.25[1.43, 3.56] ** 0.92 [0.52, 1.64] Gestational age for the first antenatal care visit ≤16 weeks 34(4.42) 343(44.55) 1.0 1.0 17 to 28 weeks 62(8.05) 307(39.87) 1.84[1.21, 2.80] * 1.67[1.02, 2.73] * > 28 weeks 10(1.30) 14(1.82) 4.49[2.22, 9.10] ** 1.21[0.51, 2.84] Monitored with partograph Yes 63(7.78) 598(73.83) 1.0 1.0 No 59(7.28) 90(11.11) 4.48[3.13, 6.39] ** 2.66[1.70, 4.15] ** Maternal mode of admission Direct admission 44(5.43) 437() .37[.25, .53] ** 0.61[0.38, 0.97] * Referral 78(9.63) 251(30.99) 1.0 1.0 Mothers complications within 24 h Abdominal distension 23(2.84) 68(8.40) 2.63[1.63, 4.26] ** 1.24[.67, 2.32] PPH 34(4.20) 38(4.69) 5.79[3.79, 83] ** 2.88[1.69, 4.89] ** Fistula 5(0.62) 4(0.49) 6.59[2.64, 16.43] ** 3.75[1.23, 11.43] * No complication 60(7.41) 578(71.36) 1.0 1.0 Obstructed Labor Yes 74(9.14) 196(24.20) 2.78[1.93, 4.01] ** 2.14[1.35, 3.38] * No 48(5.93) 492(60.74) 1.0 1.0 Maternal first Delay < 1 h 55(6.79) 560(69.14) .25[.17, .36] ** 0.61[0.37, 0.98] * ≥1 h 67(8.27) 128(15.80) 1.0 ** p < 0.001, * p < 0.05, CHR- crude hazard ratio, AHR-adjusted hazard ratio and CI-confidence interval, the bold indicates significant variables Bivariate and Multivariate Cox-proportional hazard regression for the first 3 days neonatal mortality in Amhara regional state referral hospitals, Northern Ethiopia ** p < 0.001, * p < 0.05, CHR- crude hazard ratio, AHR-adjusted hazard ratio and CI-confidence interval, the bold indicates significant variables Losing a newborn within the first 3 days of life, during which high neonatal mortality occurred, was shocking for the family and community and is devastating globally. Especially in developing countries, addressing this issue was a complex task for several factors. The study aimed to determine the incidence and determinants in the first 3 days among babies delivered in referral hospitals. In this study, 810 neonates born at the referral hospitals were included during the study period, and male predominance was noted in 53.5% of the study participants. Our study finding is in line with studies carried out in Pakistan (63%) [ 26 ], South Africa (57.8%) [ 27 ], in India (63.3%), in St Paul’s Hospital Millennium Medical College (61.1%) [ 28 ] and University of Gondar hospital (58.3) [ 22 ], Ethiopia. Natural selection response to differential survival prospects [ 29 ] and cultural and social factors [ 22 ] discrepancy between female and male babies. Our study’s causes of neonatal deaths were neonatal jaundice, complications such as birth trauma and congenital anomaly, asphyxia, umbilical sepsis, and neonatal sepsis, which are in line with the causes found in Ghana [ 30 , 31 ], and Uganda [ 32 ]. In our study, 122 neonates were lost within the first 3 days of life, giving an overall neonatal mortality rate of 151/1000 total deaths and a stillbirth rate of 103.7/1000 total births. This figure shows a significant decline from a study conducted in the Tikur Anbesa specialised hospital (225/1000 live births) [ 33 ] and (302/1000 live births) [ 22 ]. This decline might be due to the impacts of different interventions for the last 6 years. However, it was much higher than the global neonatal mortality rate in 2016 [ 34 ], and in studies conducted in Southern Ethiopia [ 35 , 36 ], Eastern Ethiopia [ 37 ], Southwest Ethiopia [ 38 ], Sudan [ 39 ], Uganda [ 25 ], Zambia [ 40 ] and Ghana [ 30 ].. Our study finding was also much higher than a finding of a systematic review of perinatal mortality rate in Ethiopia that indicated 75/1000 live births at the institutional level, 43/1000 total births with follow up studies, 59.1/1000 total births in the Amhara region, and 29.5/1000 total births among early newborns (up to 7 days) [ 41 ]. The variances might be attributed to study designs, health service coverage, socioeconomic factors, and PMR’s definition in other studies. In addition, the higher PMR in this study might be because of the admission of complicated mothers and the consideration of perinatal mortality rate up to 3 days in referral hospitals. This finding implies that the situation of neonatal mortality is still not progressing as anticipated in referral hospitals and strengthen the argument made by the study conducted in Jimma Zone [ 38 ] and a previous systematic review [ 6 ], which concluded that “health facility delivery had no significant effect on neonatal mortality.” However, this study’s findings should be interpreted vigilantly because of the stillbirth rate reports among admitted term pregnant women in referral hospitals. Possible misclassification of pregnancy outcomes (e.g., severe asphyxia of neonates) might overestimate the actual burden of stillbirth in the study area. Though there might be differences based on some factors, this implies that there is a need to plan tailored and targeted interventions by all stakeholders at different levels. Regarding the determinants of neonatal mortality within the first 72 h, gestational age at the first antenatal care visit was a risk factor. Women who came between 17 and 28 weeks of gestation for the first visit were 1.67 times more likely to lose their child than those who started the initial antenatal care visit before 16 weeks of pregnancy. This finding is consistent with studies conducted in Tigray regional state [ 42 ], Felege Hiwot referral hospital [ 43 ], and Gaza-Strip [ 44 ]. This result infers that the earlier the start of prenatal care visits, the more the mothers will have time to complete four follow-ups, which will help us a new method of obstetric problems, which suggests the recent WHO recommendation of positive pregnancy experiences [ 45 ]. Thus, this study implies that the early start of the antenatal visit and possible consideration of the new WHO recommendation for antenatal care visits in Ethiopian referral hospitals could play vital roles in reducing early newborn deaths. Maternal complications within 24 h were also a significant risk factor for neonatal mortality. Of these, the experience, postpartum haemorrhage, fistula development within the first 24 h, and obstructed labour were found to be three times, four times, and more than twice risky for neonatal death within the first 72 h of life. Our study’s findings regarding fistula and postpartum haemorrhage as risks for neonatal mortality were unique in this finding. The possible reason for neonatal mortality among mothers facing postpartum haemorrhage and fistula might be intrapartum asphyxia. In cases of maternal complications, the attention of health care providers diverts to saving the mother, and in some cases, neonates would not get adequate care, which leads them to intrapartum asphyxia. However, future research should be conducted to get the exact cause of neonatal mortality in such complications. However, this study’s results, which identified obstructed labour as a risk of neonatal mortality, were similar to studies conducted in Hawassa University hospital, Ethiopia [ 46 ], and tertiary hospitals in Tanzania [ 47 ]. These findings might be due to asphyxia and prolonged labour-related consequences leading to premature neonatal death. Moreover, mothers who were not monitored with partograph during labour were nearly three times the risk of neonatal mortality than their counterparts. This result was supported by a study in Addis Ababa [ 48 ] and Tigray regional state [ 42 ]. This outcome entails that feto-maternal health should be monitored with the start of the active first stage of labour for timely management of prolonged labour, and its consequences will be early identified as prevention and control of early neonatal death. Furthermore, direct admission was 39% less risk of newborn mortality than those admitted from referral to another health facility. In other words, mothers who require a referral were either suffer from severe obstetric problems or transfer time. We extend the time to receive skilled care. Besides, less than 1 h of maternal first delay to visit health was 39% less risk of neonatal death. This result was similar to a study in Tigray Northern Ethiopia, showing that seeking skilled care at the start of labour was protective for perinatal mortality [ 42 ], Uganda [ 32 ], and India [ 49 ]. This result indicates that the first delay in maternal death also contributes to early neonatal death. We suggest that healthcare providers pay attention to newborns’ care with significant intrapartum asphyxia, including respiratory, temperature, and nutritional support. Despite the indications of the Ghanian study [ 30 ], this study has some inherent limitations. First, though this study was unique in addressing the first 3 days of life with a follow-up study design to determine the risk factors of early neonatal mortality, being only at the tertiary level of care may elevate the actual incidence estimate of premature neonatal death in the region. Second, the study was based on tertiary hospitals and may not show the picture of secondary and primary hospitals, and data were only collected up to 72 h of the life of the newborns. Therefore, cases occurring after 72 h were missed. Third, a mixed-method study design should have been used to identify the issues related to mothers and health care providers’ perceptions of the quality of services provided in the referral hospitals. Further longitudinal studies focusing on early neonatal death should explore health system, maternal, and obstetric factors, especially in the first 3 days. We hypothesised high neonatal mortality in tertiary care centres in the first 3 days of life and found that about 1 in 7 newborns died in the first 3 days of life in the tertiary level of care in Northwestern Ethiopia. The leading causes of newborn death were neonatal jaundice, followed by complications like birth trauma, congenital anomalies, and asphyxia. Moreover, the determinants of neonatal mortality were delay for the first ANC visit, more than 1-h maternal first delay to visit a health facility, and health system-related determinants such as not monitoring labour with, admission by referral were the significant factors. Furthermore, obstetric determinants were mothers’ experience of postpartum haemorrhage, fistula development within the first 24 h, and obstructed labour. Therefore, each hospital in the region must start implementing the WHO recommendation on positive pregnancy experience for addressing the health system and obstetric risk factors of newborn mortality. Additionally, awareness creation and adherence to the recommended level of care are essential. Additional file 1. Additional file 1. Adjusted Hazard Ratio Antenatal Care Crude Hazard Ratio Confidence Interval Debre Markos Hospital continuous positive airway pressure machines Ethiopian Birr Felege Hiwot Hospital Gestational Age Standard Deviation Low- and middle-income countries neonatal intensive care unit respiratory distress syndrome university of Gondar hospital World Health Organization Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We want to forward our deepest gratitude to Debre Tabor University. We are also grateful to Amhara National regional state health bureau and respective referral hospitals. Finally, we also need to forward our gratitude to the data collectors and study participants. All authors contributed to the work reported, whether in the conceptualisation, research design, execution, data gathering, analysis, interpretation, or all of these areas. All authors contributed to the manuscript’s drafting, revision, and critical evaluation. Authors given final consent to the version that will be published, have agreed on the journal to which the manuscript will be submitted and agreed to be responsible for all elements of the work. Debre Tabor University supplied the remuneration for data collectors and supervisors. On the other hand, the university played no part in the study design, data collecting, analyses, publication decision, or manuscript preparation. On reasonable request, the corresponding author will provide the datasets generated during the current work. Ethical confirmation was granted from the Institution ethical Review Committee of Debre Tabor University, and all methods were performed following the relevant guidelines and regulations. A letter of formal permission and support was written to the respective administrator office. The aim of the research was undoubtedly clarified to concerned bodies. Mothers were told that they have the right to be involved or not to be involved in the study before they signed written informed consent. The research aims undoubtedly clarified, written informed consent was obtained from all study subjects and their legal guardian(s), confidentiality was ensured, and the study’s process was explained to the neonates’ mothers. Data collectors read the respondents’ consent and mark if they agree for mothers who could not read and write. The study participants knew that data collectors were skilled only to gather evidence, and the data was not being passed to anybody. The confidentiality of the information (personal identification and idea were not used in a way that might threaten the respondent) was maintained, and the study participants’ privacy was respected. There was no payment/incentive for participating in this interview. Not applicable. The authors declare that they have no competing interests. Incidence and determinants of neonatal mortality in the first three days of delivery in northwestern Ethiopia: a prospective cohort study When do newborns die? A systematic review of the timing of overall and cause-specific neonatal deaths in developing countries Predictors of early neonatal mortality at a neonatal intensive care unit of a specialised referral teaching hospital in Ethiopia The effect of health facility delivery on neonatal mortality: systematic review and meta-analysis Women’s retention on the continuum of the maternal care pathway in west Gojjam zone, Ethiopia: a multilevel analysis Neonatal death in low-middle income countries: a global network study Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000–2013 Predictors of neonatal mortality in neonatal intensive care unit at referral Hospital in Southern Ethiopia: a retrospective cohort study Risk factors of neonatal mortality in Ethiopia Teenage motherhood and infant mortality in Bangladesh: maternal age-dependent effect of parity one Maternal complications and perinatal mortality: findings of the World Health Organization multicountry survey on maternal and newborn health Neonatal mortality in Ethiopia: a protocol for systematic review and meta-analysis Does antenatal care service quality influence essential newborn care (ENC) practices? In Bahir Dar City Administration, north West Ethiopia: a prospective follow up study Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the sustainable development goals Cause of neonatal deaths in northern Ethiopia: a prospective cohort study Health Sector TransformationPlan 1 Version 1 Annual Performance Report EFY 2008 (2015/16) Patterns of admission and factors associated with neonatal mortality among neonates admitted to the neonatal intensive care unit of University of Gondar Hospital, Northwest Ethiopia Neonatal mortality in the case of Felege Hiwot referral hospital, Bahir Dar, Amhara regional state, north West Ethiopia 2016: a one-year retrospective chart review Neonatal mortality in the neonatal intensive care unit of Debre Markos referral hospital, Northwest Ethiopia: a prospective cohort study Stillbirths, neonatal deaths and neonatal near-miss cases attributable to severe obstetric complications: a prospective cohort study in two referral hospitals in Uganda Disease patterns and outcomes of neonatal admissions at a secondary care hospital in Pakistan Causes of neonatal admissions and deaths at a rural hospital in KwaZulu-Natal, South Africa Neonatal morbidity and mortality of sick newborns admitted in a teaching hospital of Uttarakhand Gender differences at birth and differences in fetal growth Why are babies dying in the first month after birth? A 7-year study of neonatal mortality in northern Ghana Aetiology of stillbirths and neonatal deaths in rural Ghana: implications for health programming in developing countries Using the three delays model to understand why newborn babies die in eastern Uganda Amha Mekasha, Birkneh Tilahun, Alemayehu Worku: predictors of early neonatal mortality at a neonatal intensive care unit of a specialised referral teaching hospital in Ethiopia Neonatal survival and determinants of mortality in Aroresa district, southern Ethiopia: a prospective cohort study Early days of life are crucial for child survival in Gamo Gofa zone, southern Ethiopia: a community-based study Neonatal mortality and its risk factors in eastern Ethiopia: a prospective cohort study in Kersa health and demographic surveillance system (Kersa HDSS) Determinants and causes of neonatal mortality in Jimma zone, Southwest Ethiopia: a multilevel analysis of prospective follow-up study Neonatal mortality in Sudan: analysis of the Sudan household survey, 2010 Magnitude and trend of perinatal mortality and its relationship with the inter-pregnancy interval in Ethiopia: a systematic review and meta-analysis A facility-based study of factors associated with perinatal mortality in Tigray, northern Ethiopia Neonatal mortality in the case of Felege Hiwot referral hospital, Bahir Dar, Amhara regional state, north West Ethiopia 2016: a one-year retrospective chart review Factors associated with perinatal mortality among public health deliveries in Addis Ababa, Ethiopia, an unmatched case-control study Stillbirths and newborn deaths in slum settlements in Mumbai, India: a prospective verbal autopsy study |
Answer the following medical question. | What does research say about The tortuous diagnosis of one case of neonatal hyperthyroidism.? | To outline the clinical signs, diagnosis, and course of care for a single case of neonatal hyperthyroidism while also summarizing common diagnostic errors related to this condition. Medical records of the neonate of hyperthyroidism were collected and analyzed in combination with literature. The neonate’s mother had thyroid disease, but her thyrotropin receptor antibody (TRAb) levels were not monitored during pregnancy. The neonate exhibited typical symptoms of hyperthyroidism on the day of birth but was not diagnosed until 15 days later. Impaired liver (cholestasis, elevated liver enzymes) and cardiac function (pulmonary hypertension, right heart enlargement) are the main manifestations. Treatment with methimazole (1.0 mg /kg·d) and propranolol (2.0 mg /kg·d) led to recovery, and the neonate stayed in the hospital for 27 days before being discharged with medication. The diagnosis was temporary hyperthyroidism, and the medication was discontinued at 72 days of age. It is important to strengthen the management of high-risk pregnant women with thyroid disease. Monitoring TRAb levels in both mothers and neonates should be done dynamically to enable early prediction and diagnosis of neonatal hyperthyroidism. Most neonates with hyperthyroidism have a good prognosis when timely and appropriate medical treatment is provided. The tortuous diagnosis processes of one case of NH. In the absence of specific clinical manifestations of NH, how to quickly diagnose it. Reminding clinicians of the importance of early identification of NH, as well as the management of pregnant women with abnormal thyroid function. Neonatal hyperthyroidism (NH) is an uncommon condition that affects 1–5% of newborns born to mothers who have active or past Graves’ disease (GD) [ 1 ], and it affects 22% of pregnant women who need to take long-term antithyroid drugs (ATDs) treatment. Autoimmune NH is related to the transplacental passage of maternal anti-thyrotropin receptor antibodies (TRAbs) [ 2 ]. The fetal thyroid gland becomes responsive to thyroid-stimulating hormone (TSH) and TRAbs at around 20 weeks of gestation [ 3 ], those antibodies stimulating the fetal thyroid, cause in-utero and/or postnatal hyperthyroidism. Fetal hyperthyroidism can cause goiter, heart failure with nonimmune hydrops, advanced bone maturation, intrauterine growth retardation, preterm birth, and even fetal death [ 4 ]. When fetal hyperthyroidism is present, there is a high probability of neonatal thyrotoxicosis, which is usually temporary and goes away in 4 to 6 months after birth following clearance of maternal TRAbs. Signs and symptoms of neonatal hyperthyroidism include goiter, tachycardia, poor feeding, irritability, tremors, sweating, and difficulty sleeping [ 5 ]. There are occasional cases of proptosis, craniosynostosis, and microcephaly. Without prompt treatment with antithyroid drugs, cardiac failure and death may occur [ 6 ]. At present, there are only more than 50 cases of NH reported in China. Due to the diversity and lack of specificity of the clinical manifestations of the disease, clinicians lack understanding of the disease, which is easy to be overlooked or misdiagnosed [ 7 ]. To improve knowledge of early identification and treatment of NH, our study presented one case of NH with prominent clinical signs of liver and cardiac dysfunction, whose mother had received GD therapy with radioactive iodine four years prior. This study analyzed one newborn with confirmed hyperthyroidism who was hospitalized in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology and has been discharged. The study was appproved by the Tongji Hospital ethics committee. Informed consent was obtained from the patient’s parents. Clinical, and laboratory data, as well as therapeutic medication and clinical outcomes, were obtained from the electronic medical records. The enrolled newborn in this study was diagnosed with hyperthyroidism, according to the “Practice of Neonatology, 5th Ed”. The diagnostic criteria of NH were as follows: (1) The mother had a history of autoimmune thyroid disease, especially hyperthyroidism. (2) The newborn had typical symptoms and signs [ 8 ]: excitement, irritability, tremors; skin flushing, sweating; increased appetite, accompanied by vomiting and diarrhea, and unsatisfactory weight gain; he or she likes opening eyes, periorbital edema, eyelid contracture, and exophthalmos; goiter may be present; increased heart rate and respiration, hypertension, enlargement of liver and spleen, etc. Severe cases may have a fever, arrhythmia, heart failure and jaundice, liver failure, and coagulation disorders. (3) With laboratory examination: serum T3, and T4 increased, and TSH decreased. This neonate met the diagnostic criteria of NH. The neonate was delivered prematurely at 32 + 6 weeks of gestation as the first offspring of unrelated parents. Her weight measured 2220 g (80%), length measured 47.5 cm (97%) and head circumference measured 28.5 cm (20%). Due to exhibiting symptoms of “moaning and foaming” immediately after birth, she was admitted to the Neonatal Intensive Care Unit (NICU). After admission, the neonate’s blood oxygen saturation was 65% without oxygen inhalation, and her shin wascyanotic, so CPAP (Continuous Positive Airway Pressure) assisted ventilation was given, but her dyspnea persisted after 4 h, and she developed “convulsion”. Consequently, invasive ventilator-assisted ventilation was initiated. The examination findings after admission are presented in Table 1 , encompassing thrombocytopenia; elevated transaminase and total bilirubin, particularly direct bilirubin; hepatosplenomegaly, bile sludge formation; right heart enlargement, and the presence of pulmonary hypertension. The primary diagnoses are neonatal respiratory distress syndrome (NRDS) and intrauterine infection(?). In addition to respiratory support, administration of blood products, anti-infection agents, cardiac and hepatic protection, cholang-removing blood stasis, reduction of pulmonary artery pressure, and enhancement of circulation were implemented. Table 1 The demographic, clinical and biochemical characteristics of the patient Age (Days) 0 1 4 6 8 15 23 40 57 72 93 108 Corrected gestational age (weeks) 32 + 6 33 33 + 3 33 + 5 34 35 35 + 6 38 + 2 40 + 5 42 + 6 45 + 6 48 Weight (g)/%* 2220(80) 2200(77.8) 2020(69.5) 2090(46.1) 2120(46.5) 2060(23.3) 2100(13.1%) 2700(18.5) NA 3600(24.9) NA 5300(67.6) Height (cm)/%* 47.5(97) NA NA 48(95.1) NA 48(85.2) 49.6(90%) 50.1(69.7) NA 55.5(92.2) NA NA Head circumference (cm)/%* 28.5(20) NA NA NA NA NA NA 31.6(6.5) NA 34.2(0.0) NA NA NBNA NA NA NA NA NA NA NA 36 NA 38 NA NA Blood biochemical parameters Leukocytes (3.5–9.5) 10 9 / L 13.5 10.29 7.5 7.47 9 18.45 9.25 NA NA NA NA NA Neutrophils (1.8–6.3) 10 9 / L 10 6.29 3.94 3.2 3.89 7.97 3.37 NA NA NA NA NA Hemoglobin (130–175 g/ L 187 177 190 173 170 167 142 NA NA NA NA NA Platelets (125–350) 10 9 / L 53 63 92 144 195 251 164 NA NA NA NA NA Alanine aminotransferase (9–50) U/ L 86 95 80 94 137 212 175 105 77 93 21 NA Aspartate aminotransferase (15–40) U/ L 366 298 273 334 331 355 232 109 63 71 46 NA Total bilirubin (2-20.4) µmol/ L 149.3 177.1 279.1 326.4 315.6 258.5 173 108.7 42.3 22.2 6 NA Direct bilirubin (2-20.4) µmol/ L 121.7 128 222.9 247.9 252.1 215.6 146.6 93.4 35.6 15.1 5.2 NA C-reactive protein (0-0.5) mg/ dL 1.4 1.5 1.48 1.9 2.15 <0.5 <0.5 TSH (0.27–4.2) uIU/mL < 0.005 < 0.005 < 0.005 0.261 1.19 0.845 2.18 FT3 (3.1–6.8) pmol/L 6.2 5.92 2.68 3.07 3.26 4 3.92 FT4 (12–22) pmol/L 34.9 30.1 9.54 8.7 9.34 9.56 10 Echocardiography Transverse diameter of the right atrium (mm) NA 16 15 NA 17 16 16 12 NA NA NA NA Transverse diameter of the right ventricle (mm) NA 16 16 NA 17 16 15 12 NA NA NA NA Tricuspid regurgitation NA severe severe NA severe severe severe moderate NA NA NA NA Pulmonary artery pressure (mmHg) NA 64 64 NA 64 60 44 37 NA NA NA NA Patent ductus arteriosus (mm) NA 2.5 1.7 NA 1.7 1.4 1.6 NA NA NA NA NA Patent foramen ovale (mm) NA 2.3 2 NA 2 2 2 3 NA NA NA Ejection fraction (%) NA 70 70 NA 64 67 67 70 NA NA NA Abdominal ultrasonography Distance between the right inferior border of the liver and the subcostal margin of the right midclavicular line (cm) NA 4.7 4.8 NA 4.9 3.8 4.2 3.8 NA NA NA Spleen pachydiameter (cm) NA 1.5 1.6 NA 1.5 1.3 1.2 1.7 NA NA NA Biliary sludge NA Yes Yes NA Yes Yes Yes No NA NA NA Gallstone NA No No NA No No Yes Yes NA NA NA Treatment Methimazole → → → Propranolol → → → *Percentile for children of the same gender and gestational age; NBNA: neonatal behavioral neurological assessment; NA: Not available. The demographic, clinical and biochemical characteristics of the patient Distance between the right inferior border of the liver and the subcostal margin of the right midclavicular line (cm) *Percentile for children of the same gender and gestational age; NBNA: neonatal behavioral neurological assessment; NA: Not available. After 2 weeks, the patient no longer requires oxygen assistance. However, there was no notable enhancement in liver and cardiac functionality. Additionally, the patient tended to open her eyes, an increased appetite but inadequate weight gain, and a rapid heart rate. Following consultation and pertinent examinations, we ruled out infection based on normal levels of inflammatory markers, negative results from blood culture, blood NGS-DNA, and a comprehensive panel of viral and other related pathogenic tests. Furthermore, inherited metabolic diseases were excluded based on normal levels of blood ammonia, lactic acid, pyruvate, blood amino acids, and urine organic acids. Lastly, rheumatic immune diseases were ruled out based on a negative complete set of rheumatism and the absence of any history of rheumatic immune system diseases in the patient’s family. We suspected that she had a genetic mutation-caused syndrome, so we advised the family to undergo comprehensive genetic testing. On the 15th day of her hospitalization, we conducted a routine screening for thyroid function and discovered that her TSH levels were below the normal range (TSH < 0.05uIU/mL), while FT4 levels were significantly elevated (34.9ng/dL) (Table 1 ). Additionally, her thyroglobulin levels were above 500 ng/ml (reference range: 3.5–77 ng/ml), thyroglobulin antibody levels were 15.6 IU/ml (reference range: <115 IU/ml), thyroid peroxidase antibody levels were 43 IU/ml (reference range: <34 IU/ml), and Thyrotropin receptor antibody levels were 29.7 IU per liter (reference value, < 1.75IU per liter). A thyroid ultrasound showed an increase in thyroid volume and abundant blood flow, leading to a diagnosis of NH. A thorough examination of the neonate’s mother’s medical history was conducted: her thyroid function (11/26, 2019): TSH 0.01 uIU/mL, T3 14.63 pg/mL, T4 3.56 ng/dL, TPOAb 44 U/mL, TGAb < 15 U/mL. After Iodine 131 treatment, she has been treated with euthyrox orally until now, which further supported the neonate’s diagnosis of hyperthyroidism. Methimazole (0.5 mg/kg/d, Bid) and propranolol (1.8 mg/kg/d, Tid) were promptly added to the treatment regimen, and the neonate’s thyroid function was periodically reassessed. After taking methimazole and propranolol orally for 1 week, the levels of FT3 and FT4 decreased (Table 1 ). Additionally, the patient experienced a decrease in heart rate and an improvement in liver function (as indicated by decreased ALT, AST, and direct bilirubin levels), as well as a significant decrease in pulmonary artery pressure. The patient was discharged with medicine after 27 days of hospitalization. After 25 days of medication, the levels of FT3 and FT4 (except TSH) returned to the normal range (Table 1 ; Fig. 1 A). Methimazole and propranolol were discontinued after 29 days and 36 days of oral medication, respectively. The patient’s thyroid function completely returned to normal 13 days after withdrawal of methimazole, subsequent intermittent reexaminations confirmed the maintenance of normal thyroid function. Fig. 1 The thyroid function ( A ) and liver function ( B ) of the neonate were followed up with age The thyroid function ( A ) and liver function ( B ) of the neonate were followed up with age With the improvement of thyroid function, catch-up growth of body weight and length was achieved. On day 72 after birth (postmenstrual age 42 + 6 weeks), the neonates’ weight and length were at the 24.9 percentile and 92.9 percentile for their sex and gestational age, respectively. The neonatal behavioral neurological assessment (NBNA) score was 38. Notably, the patient’s cardiac function, liver function (Fig. 1 B), and hepatosplenomegaly showed significant improvement. During the whole treatment period of hyperthyroidism, no adverse reactions such as granulocytopenia or liver function damage were observed. In this study, we report a typical case of NH with critical condition and impaired liver and cardiac function as the main clinical manifestations. The patient’s mother had been receiving oral euthyrox treatment since undergoing Iodine 131 radiotherapy for GD four years ago. However, TRAbs levels were not monitored during pregnancy. NH was diagnosed on the 15th day after birth. During the period, a multi-disciplinary consultation was conducted to screen for infectious diseases, inherited metabolic diseases, rheumatic immune diseases, and, other conditions. The diagnosis process was complex, providing valuable experience for future NH diagnoses. The prevalence of hyperthyroidism in pregnancy ranges from 0.7 to 2.8% worldwide [ 9 , 10 ], with GD as the most common etiology [ 11 ]. During pregnancy, thyroid autoantibodies can cross the placenta and either stimulate (thyroid stimulating antibody - TSAb) or block (thyroid blocking antibody - TBAb) the fetal thyroid gland [ 4 ]. Maternally transferred antibodies can temporarily affect the thyroid function of the fetus and newborn until they are metabolized. High levels of TSAb transmission are associated with fetal and neonatal thyrotoxicosis, while maternal TBAb can lead to congenital hypothyroidism [ 12 ]. The impact on thyroid function in the fetus and newborn depends not only on the type of maternal antibodies but also on their levels. Autoimmune hyperthyroidism can also occur in children born to mothers who were treated for GD in the past and still have detectable circulating TRAbs [ 13 ], similar to our patient. TRAbs measurement is not routinely performed in mothers with hyperthyroidism in our hospital, which presents a challenge in identifying those who may develop NH. In our case, the mother’s TRAb levels were not regularly monitored during the 4 years after Iodine-131 radiotherapy, including pregnancy, although she was taking oral euthyrox and had stable thyroid hormone levels within the normal range. Obstetricians and neonatologists often overlook mothers with high-risk factors, leading to misdiagnosis and delayed diagnosis in newborns born to such mothers due to a lack of sufficient understanding in managing these cases. In China, it is recommended that TRAb should be monitored from 20 to 24 weeks of gestation in pregnant women with a history of Graves’ disease or delivery of a newborn with hyperthyroidism, regardless of whether they have received effective treatment. The American Thyroid Association (ATA) 2016 guidelines [ 14 ] recommend that patients with Graves’ disease should be tested for serum TRAb in the first trimester of pregnancy. If TRAb levels are elevated, reexamination should take place at 18–22 and 30–34 weeks of gestation. A TRAb level of ≥ 5 IU/L or > 3 times the upper limit of the reference value indicates a high risk of fetal/neonatal hyperthyroidism. Pregnant women with positive TRAb results should undergo a fetal thyroid ultrasound examination to further evaluate fetal thyroid function. Therefore, for high-risk pregnant women with a history of thyroid disease, it is crucial to detect thyroid function and serum TRAb as early as possible. Close observation of early symptoms of hyperthyroidism is the key to early diagnosis. The clinical manifestations of NH are non-specific and diverse [ 8 ], including tachycardia, irritability, irritability, thrombocytopenia, liver damage, jaundice, shortness of breath, hypoglycemia, hyperhidrosis, premature synostosis, intrauterine growth restriction, growth retardation, goiter, exophthalmia, pulmonary hypertension, hip dysplasia, etc. In severe cases, microcephaly, heart failure, long-term neurodevelopmental delay, and even death may occur. In our study, the neonate presented with growth retardation, tachycardia, cardiac insufficiency, dyspnea, thrombocytopenia, liver injury, and hepatosplenomegaly. Similar cases are often mistaken for intrauterine infection, sepsis, meconium aspiration, and other diseases. The main clinical manifestation in our case is damage to liver and heart function, particularly cholestatic hepatitis [ 15 ], which is rare in NH and complicates the clinical diagnosis. Therefore, the crucial aspect in treating liver damage induced by hyperthyroidism is to manage hyperthyroidism itself. Once diagnosed, prompt administration of anti-hyperthyroidism treatment is essential. Due to the unique nature of the neonatal period, delayed diagnosis and treatment can hurt the physical growth and neurodevelopment of newborns. It is recommended to use ATDs early in neonates showing clinical symptoms of hyperthyroidism, with MMI being the preferred choice. PTU (propylthiouracil) should only be used for a short period in patients experiencing hyperthyroidism crises or severe adverse reactions to MMI. In this case, the patient was administered oral MMI at a dose of 0.5 mg/ kg, Bid. Propranolol (1–2 mg /(kg·d), Bid) can help reduce heart rate and inhibit the conversion of peripheral T4 to T3, especially in patients with increased heart rate. The patient’s heart rate significantly decreased after propranolol was added to her treatment plan. For patients with respiratory and heart failure, it is important to provide respiratory and circulatory support. Short-term glucocorticoids [hydrocortisone 2.5–10 mg /(kg·d), Tid; prednisone 1–2 mg /(kg·d), Bid] can be used to reduce T4 synthesis and peripheral T4 to T3 conversion [ 16 ]. In severe cases, intravenous immunoglobulin (1 g/kg for 2 days) may be administered [ 17 ]. Adequate caloric supply is crucial in the nutritional support of neonatal hyperthyroidism, and the average course of ATDs treatment for NH is 1 to 3 months. During the initial stage of treatment, thyroid function should be regularly monitored every 1 to 2 weeks to adjust the drug dose. The symptoms gradually disappear with the decrease of TRAb concentration, and treatment can be discontinued when TRAb is negative [ 16 ]. In our patient’s case, the total duration of methimazole treatment was 29 days, and the first improvements were FT3 and FT4 levels, with TSH returning to normal levels 13 days after discontinuation of the medication. Pregnancy complicated with hyperthyroidism has hypermetabolism, increased nerve and muscle excitability, which can lead to uterine contraction and vasospasm, affect placental development, and cause intrauterine growth retardation, low birth weight, premature delivery, asphyxia, and even stillbirth or abortion [ 7 , 18 ]. In this particular case, the mother had thyroid disease and gave birth to a test-tube baby who was premature and experienced asphyxia after birth. This suggests that maternal thyroid disease can result in complications for the neonate or fetus. Normally, NH is transient and self-limited, resolving within 3–12 weeks. However, in cases of hyperthyroidism crisis, the mortality rate can be as high as 15-20% [ 6 ]. Persistent cases are rare, mostly caused by gene mutations such as TSHR and GNAS, which can be inherited dominantly or occur as de novo mutations [ 6 ]. Fortunately, in this case, the child was considered to have transient hyperthyroidism, and her thyroid function returned to normal at the age of 57 days without any lasting effects. It is important to regularly monitor the physical and neurodevelopment of children with hyperthyroidism after discharge. NH encompasses gynecology, obstetrics, and neonatology. It is important to enhance the monitoring of thyroid function and TRAb in pregnant women with a history of thyroid disease. This will help assess the risk of neonatal hyperthyroidism. Additionally, it is crucial to promptly screen high-risk infants for thyroid function after birth. Early diagnosis and treatment can then be initiated before clinical symptoms worsen, thereby preventing the occurrence of a hyperthyroidism crisis and any potentially serious consequences. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We thank the patients, their families, referral physicians, and investigators for their cooperation and contribution. Concept and design: Lin Zhu and Wei Liu. Acquisition, analysis, or interpretation of data: Lin Zhu and Jing Wang. Statistical analysis: Lin Zhu. Drafting the paper: Lin Zhu and Jing Wang. None. The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. All procedures performed in studies involving human participants were approved by the ethical standards of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patient’s parents. The authors declare that they have no conflict of interest. NA. The authors declare no competing interests. The tortuous diagnosis of one case of neonatal hyperthyroidism Guidelines of the American thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies Management of fetal and neonatal Graves’ Disease Follow-up of infants born to mothers with Graves’ disease Neonatal screening for hyperthyroidism proof of Concept Neonatal thyrotoxicosis Effect of hyperthyroidism control during pregnancy on maternal and fetal outcome: a systematic review and Meta-analysis ENDOCRINOLOGY IN PREGNANCY: pregnancy and the incidence, diagnosing and therapy of Graves’ disease The prevalence of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women in the third trimester Thyrotoxicosis in pregnancy–a six year review Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies Neonates born to mothers with Graves’ Disease: 15 year experience of a Pediatric Endocrinology Department 2016 American Thyroid Association Guidelines for Diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis The interplay between thyroid and liver: implications for clinical practice Fetal neonatal hyperthyroidism: diagnostic and therapeutic approachment Hyperthyroidism and pregnancy |
Answer the following medical question. | What does research say about An Update on Lung Function of Extremely and Very Preterm Infants in Later Life: The Role of Early Nutritional Interventions.? | Birth occurring at ≤32 weeks’ gestation (“very preterm”) or at ≤28 weeks’ gestation (“extremely preterm”) potentially poses considerable health problems for the neonate, including respiratory sequelae, not only during the immediate newborn period, but throughout childhood and into adulthood. With the progressive improvements in neonatal care, the survival of extremely preterm and very preterm neonates has improved substantially. However, a considerable percentage of these infants suffer dysfunctions that may trigger, at some stage later in life, the onset of respiratory morbidities. The interruption of the normal development of the respiratory tract caused by preterm birth, in combination with postnatal lung injury caused by various interventions, e.g., mechanical ventilation and oxygen therapy, increases the risk ofthe development of long-term respiratory deficits in survivors. Those infants that are most affected are those who develop chronic lung disease of prematurity (also called bronchopulmonary dysplasia, BPD), but impaired lung function can develop irrespective of BPD diagnosis. Apart from indicating abnormal lung function in survivors of extreme prematurity, recent long-term follow-up studies also emphasize the crucial role of early nutritional intake as an effective strategy, which promotes lung growth and repair. This article will update the associations between extremely/very preterm birth with long-term respiratory outcomes. It will also discuss the protective effect of nutritional interventions, focusing on recently published follow-up data. The continuous advances in perinatal care in the last few decades (including the use of antenatal steroids and surfactant treatment), in combination with the less aggressive ventilatory support practices, have resulted in the survival of an increasing number of infants born at gestational ages (GA) ≤ 32 weeks (very preterm) or ≤28 weeks (extremely preterm). Preterm birth results in the interruption of prenatal lung development during the canalicular and saccular/early alveolar stages [ 1 ]. Early exposure to infection and inflammation, as well as mechanical ventilation and hyperoxia may cause additional damage to the immature lung [ 2 ]. A large proportion of preterm infants will eventually develop bronchopulmonary dysplasia (BPD), which is considered one of the gravest sequelae of preterm birth [ 3 ]. The “old” BPD definition provided by Northway and associates [ 4 ] >50 years ago included the characteristics of inflammation, airway smooth muscle hypertrophy, emphysema, and parenchymal fibrosis as a result of exposure to high oxygen concentration and high ventilation pressures. Since then, the cohort of premature infants, the treatment strategies of neonates, and the consequent pulmonary damage have substantially changed. The improved rates of survival among more immature infants, thanks to modern perinatal care, have resulted in the occurrence of a new BPD phenotype (disrupted lung development), which has different disease pathogenesis compared to “old” BPD (acute lung injury) [ 5 , 6 ]. The “new” BPD phenotype is characterized by markedly more immature lung tissue, as well as impaired alveolarization (reduced, large, thin-walled alveoli), dysmorphic pulmonary microvessel growth and less fibrosis, as compared to the “old BPD” [ 7 ]. Lung immaturity, as well as the disruption of alveolarization and the microvascular development in BPD are clinically translated into abnormal gas exchange and lung mechanics [ 8 ]. This new type of chronic lung disease of prematurity poses an additional demanding task to clinicians and researchers besides preventing lung damage, i.e., preserving normal lung tissue development. The exact definition of BPD has been the subject of debate and is currently influenced by the need for supplemental oxygen at 28 days of life, while the severity of the disease is determined by assessing ventilator support and the fraction of the necessary inspired oxygen at 36 weeks postmenstrual age [ 5 , 9 , 10 ]. Overall, about 30–68% of infants <28 weeks’ GA develop BPD [ 3 , 11 ]. This incidence is inversely related to GA and remained unchanged (or even increased) among the most premature infants due to the significant reduction in mortality and the substantial increase in the total number of infants with significant prematurity [ 3 , 11 ]. Large variations in BPD incidence between NICUs reflect population differences and differences in clinical treatment practices [ 12 ]. Previous longitudinal pulmonary function and long-term follow-up studies reported that most extremely/very preterm neonates with BPD present with a low lung function trajectory [ 13 , 14 ] and an increased risk for the future development of a chronic obstructive pulmonary disease (COPD)-like phenotype [ 15 , 16 , 17 ]. Furthermore, former extremely/very premature infants are predisposed to the development of other respiratory morbidities than chronic lung disease, due to factors associated with prematurity [ 18 ]. These infants present with a higher incidence of lower respiratory tract infections requiring re-hospitalizations, impaired lung mechanics, and developmental abnormalities of the airways, leading to recurrent wheezing and asthma. These sequelae may occur from early infancy throughout childhood and until adulthood [ 18 ]. Long-term respiratory outcome studies of extremely/very preterm infants are in need of constant updates due to alterations in patient population, rapid advances in the areas of pulmonary physiology and pathophysiology, as well as improvements in perinatal care practices, including nutritional interventions. In this respect, recent follow-up data highlight the crucial role of nutrition in promoting favorable long-term pulmonary outcomes in extremely/very preterm-born infants [ 19 , 20 ]. In the present manuscript, we review the associations between extremely/very premature birth with long-term pulmonary outcomes, with particular emphasis on the most recent data on the topic, and discuss current evidence, which emphasizes the long-term beneficial effect of nutritional interventions on lung growth and repair. The lung function of prematurely born infants may be compromised during childhood and adulthood; this applies, in particular, to extremely preterm infants, those experiencing BPD or those who have been exposed to mechanical ventilation during the newborn period [ 21 ]. As lung tissue grows postnatally, several parameters related to pulmonary volumes may improve. Nevertheless, pathological changes in pulmonary flows may persist throughout adolescence or into adult life [ 21 ]. Several clinical/experimental studies document that preterm birth disrupts alveolarization, leading to a decrease in the gas exchange surface area of the lung and thereby causing BPD [ 7 , 8 ]. Furthermore, lung immaturity predisposes to respiratory morbidities other than BPD [ 18 ]. Recent data demonstrate that following preterm birth, the airway epithelium is both structurally and functionally impaired, with evidence of epithelial thickening in addition to increased inflammation and apoptosis [ 22 ]. Thus, primarily obstructive pulmonary abnormalities were demonstrated in extremely preterm-born infants receiving contemporary intensive care at term-equivalent age, compared with healthy full-term controls [ 23 ]. Irrespective of BPD, a strikingly abnormal pulmonary function was present at the term-equivalent age, although this was observed more intensely in the BPD group. It is, therefore, suggested that the evaluation of lung morbidity only by diagnosis of BPD or not, is probably not adequate in predicting future respiratory health [ 23 ].Similarly, in a multicenter, longitudinal birth cohort study, extremely low GA neonates receiving ambient air or on low-flow nasal cannula support had abnormal tidal breathing patterns, with no differences noted between infants with and without BPD [ 24 ]. Neither prebronchodilator nor postbronchodilator tidal breathing patterns were associated with post-discharge pulmonary disease [ 24 ]. The authors hypothesized that, besides altered respiratory mechanics, other factors (e.g., respiratory tract viral infections) [ 25 ] may be responsible for the occurrence of respiratory morbidities among preterms. Infants born extremely/very preterm with BPD of either degree of severity were followed-up in a longitudinal cohort study to 6 and 18 months of postnatal age. Respiratory symptoms, such as recurrent/chronic cough and wheezing, were recorded [ 26 ]. Passive lung mechanics and whole-body plethysmography, as well as tidal and raised volume rapid thoraco-abdominal compression techniques, were used to examine respiratory function. Infants with BPD presented with reduced airway function and respiratory compliance. However, mild and moderate/severe BPD differed only in terms of lower respiratory compliance in the latter, possibly as a result of delayed or altered alveolar formulation. Thus, the value of the early classification of BPD severity in predicting future lung function is considered to be very limited [ 26 ]. Gonçalves et al. [ 27 ] reported an increased incidence of impaired respiratory function in very preterm infants of 6–12 months of corrected age compared with same-aged full-term ones, as evaluated by forced expiratory flows using the chest compression technique, and volumes using total body plethysmography. Compromised lung function was associated with the degree of prematurity, restricted fetal growth, mechanical respiratory support and recurrent episodes of wheezing during infancy [ 27 ]. Those infants who survive prematurity are at risk ofaltered pulmonary function during childhood. Only a limited number of follow-up studies have investigated the trajectories of respiratory function in extremely/very preterm-born children and showed a considerable persistent lung function compromise, which warrants follow-up and treatment consideration [ 28 , 29 ]. An earlier follow-up study investigated whether very preterm birth, BPD, and the degree of BPD severity, are predictive of future lung function in school-aged children born in the modern era, which is characterized by antenatal corticosteroids use and surfactant administration [ 30 ]. Preterm children presented with significantly decreased spirometric flow-volume parameters, as well as alveolar diffusion capacity compared with children born at term. The diagnosis of BPD was related to a marked reduction in both spirometry and diffusion capacity. Furthermore, very preterm birth and moderate/severe BPD pose an additive reduction in spirometric parameters of individuals by school age [ 30 ]. Longitudinal data on lung function in a group of extremely premature children born in the post-surfactant era also confirmed a significant airflow limitation, especially striking in BPD survivors who also demonstrated an abnormal airway growth trajectory, followed by a reduction in pulmonary function between 8 and 12 years of age [ 31 ]. Oscillatory mechanics, spirometry, multiple breath nitrogen washout, and diffusing capacity of the lung for carbon monoxide were used to test pulmonary function at 9–11 years of age in children born at term and at ≤32 weeks of gestation in the contemporary era [ 32 ]. In addition, preterm children underwent chest computed tomography (CT) and had their respiratory symptoms recorded. Compared with term controls, preterm children presented with pulmonary obstruction and hyperinflation, in addition to abnormal peripheral lung mechanics. Abnormalities in lung structure were seen in 92% of preterm children and were associated with more intense respiratory obstruction and increased incidence of severe respiratory symptoms, probably implying active lung disease [ 32 ]. A population-based cohort of children born at 22–26 weeks GA and controls born at term between 2004 and 2007 were followed-up at 6½ years of age with spirometry and impulse oscillometry [ 33 ]. It was demonstrated that a large percentage of extremely preterm-born children have impaired airway mechanics and a marked obstructive reduction in pulmonary function. A total of 40% of extremely preterm children and 15% of controls exhibited asthma-like disease. Furthermore, half of the children born at 22–24 weeks GA demonstrated a lung function below the lower limits of normal. Interestingly, severe BPD contributed to pulmonary outcomes only marginally [ 33 ]. Similarly, an earlier meta-analysis of follow-up studies including infants born preterm at 24–36 weeks GA between 1964 and 2000 demonstrated average forced expiratory volume in 1 s (FEV1) reductions of 16% in those with mild BPD and 19% in those with moderate to severe BPD [ 14 ]. The marginally significant (or even non-significant) differences in pulmonary function according to the severity of BPD in these studies suggest that respiratory deficits during childhood are probably related to the degree of prematurity and that the BPD classification is likely of limited value for the prediction of future pulmonary function as evaluated by spirometric parameters [ 14 ]. A recent longitudinal cohort study documented data on lung structure and function, as well as respiratory symptoms throughout childhood in a very preterm cohort born in the contemporary era [ 34 ]. It was reported that preterm children with and without BPD have declining pulmonary function trajectories from 4 to 12 years of age, with greater reductions reported in children with BPD, ongoing respiratory symptoms, and bronchial wall thickening (on chest CT) indicative of inflammation. These children may be predisposed to developing lung disease later in life [ 34 ]. Furthermore, there is evidence suggesting that lung function does not improve over time in very preterm-born children diagnosed with the severe form of either “old” or “new” BPD. By contrast, FEV1 and forced vital capacity (FVC) deteriorate from childhood to adulthood [ 35 ]. In line with these findings, a very recent study aimed to outline alterations in pulmonary function in a contemporary observational group of children born preterm whowere subsequently followedup for post-prematurity respiratory disease with pulmonary function testings [ 36 ]. Very preterm-born children demonstrated worsening obstruction in pulmonary function throughout childhood [ 36 ]. Pulmonary function normally increases during childhood and adolescence, reaches a peak in the mid-20s, and then gradually decreases with age [ 37 ]. This trajectory is modulated by genetic factors, antenatal events, and exposure to multiple events early in life [ 38 ]. A meta-analysis of cohort studies, mainly conducted during the pre-surfactant era, demonstrated that infants born either very preterm or with very low birthweight are at increased risk of not reaching their full lung growth potential during adolescence and early adulthood, a finding which suggests an increased risk of COPD in later adulthood [ 39 ]. Similarly, long-term data obtained in the post-surfactant era showed that survivors born either at a GA less than 28 weeks or with abirthweight less than 1000 g (particularly those who had BPD) will not achieve the normal peak of expiratory airflow by their mid-20 s [ 40 ]. The authors conclude that since nowadays many more infants who were either born at <28 weeks GA or with <1000 gbirthweight are surviving into adulthood since the 1990s, many of them will end up developing symptoms of airway obstruction later in life, especially those who experienced BPD [ 40 ]. A very recently published population-based study [ 41 ] reported lung function trajectories from 10 to 35 years of age in infants who were born extremely preterm. Persistent airflow obstruction was reported in early adult life and throughout the onset of the age-related decline from 25 to 35 years. Lung function after extremely preterm birth was tracked in parallel, but was significantly lower as compared to the trajectories of term-born from 10 to 35 years, including the starting age-related decline from 25 to 35 years. An existing but diminishing long-term importance of BPD was recorded, probably reflecting the recent improvements in perinatal care. However, 30% of these extremely preterm-born infants met the post-bronchodilator spirometry criteria for COPD compared with 5% of term-born infants ( p < 0.001) [ 41 ]. Extremely preterm-born adolescents with “new” BPD presented with poorer lung function compared with extremely preterm-born adolescents without BPD or moderate–late preterm-born ones in a multicenter cross-sectional study [ 42 ]. Extremely preterm-born adolescents with BPD had markedly lower FEV 1 and FVC, as well as significantly higher bronchodilator response and air-trapping. However, BPD adolescents did not demonstrate a higher incidence of asthma symptoms or a poorer quality of life, probably indicating that progress in perinatal care has favored the predominance of milder forms of chronic lung disease of prematurity [ 42 ]. In accordance, recent data demonstrated lower FEV1 in adolescents with BPD born extremely/very preterm, as compared to those without BPD, with lower FEV1 values significantly related to BPD severity [ 43 ]. The results of spirometry and impulse oscillometry measurements in the BPD compared with the non-BPD group indicate airway obstruction including involvement of peripheral airways, probably implying a predisposition to COPD in adult life in the group with severe BPD [ 43 ]. In line with these results, a recent prospective follow-up study reported poorer lung function in adolescents and young adults born extremely premature who experienced BPD, as compared to those without a BPD diagnosis [ 44 ]. Interestingly, 16% of subjects without BPD presented with impaired pulmonary function, suggesting that prematurity by itself has a negative impact on lung function [ 44 ]. Similar results were reported in another study which showed that spirometric parameters were worse during adulthood in those born prematurely without BPD vs. term controls [ 45 ]. Impaired alveolar development blocks lung-diffusing capacity. Disruption of alveolar growth due to extremely preterm birth may lead to COPD in early adulthood [ 46 ]. One controlled population-based report published in 2022 documented the longitudinal development of lung-diffusing capacity after extremely preterm birth from mid-childhood to adulthood [ 47 ]. Two cohorts born at ≤28 weeks GA or birthweight ≤ 1000 g between 1982 and 1985, as well as between 1991 and 1992 were evaluated twice, at ages 18 and 25 years and 10 and 18 years, respectively, and were compared with matched controls born at term. Extremely preterm-born individuals had impaired lung-diffusing capacity. The deficits tracked below (but in parallel) to matched full-term control groups from mid-childhood to adulthood [ 47 ]. Finally, a study investigating the association between prematurity and lung function with COPD in the sixth decade of life showed that severe prematurity is related to obstructive lung function deficits (including COPD) into middle age and that this effect was further aggravated bysmoking [ 48 ]. Overall, there is a paucity of longitudinal respiratory follow-up data after extremely/very preterm birth in the surfactant era, but existing evidence raises considerable concerns about the long-term pulmonary status of survivors of extremely/very preterm birth. Declines in pulmonary function are persistently observed in extremely/very preterm individuals during childhood, adolescence and adulthood and, therefore, a close targeted life-long monitoring of lung health is warranted [ 28 , 29 ]. However, it should be noted that premature birth is not included in authoritative statements, as a risk factor for COPD [ 49 ]. Furthermore, few pulmonologists consider early life factors in their clinical practice [ 49 ]. Studies comparing respiratory outcomes in extremely preterm individuals born from 1980 to 2000 produced conflicting results, with most studies reporting improvements which parallel the remarkable recent advances in perinatal care [ 14 , 41 , 50 , 51 ]. Kotecha et al. compared findings from studies of pulmonary function conducted in the pre- and post-surfactant era, in participants aged between 5 and 23 years. One interesting finding was that the mean FEV1 for subjects with BPD had improved over time from those born in the late 1960s to those born in the early 1990s, indicating that lung impairment during the neonatal period might be less severe with ongoing improvements in neonatal care practices [ 14 ]. Another study from Norway compared respiratory health in extremely preterm-born children between 1991–1992 and 1999–2000 and showed that small airway obstruction and bronchial hyperresponsiveness were still present in children born preterm at the turn of the millennium, but outcomes were better than for children born similarly preterm in 1991–1992, especially after BPD. These data imply that better neonatal care practices improve both survival and long-term pulmonary outcomes [ 50 ].However, in a subsequent longitudinal prospective follow-up of all survivors of extremely preterm births in Victoria, Australia, during three periods (namely, 1991–1992, 1997, and 2005), no significant reduction in oxygen dependence was seen at 36 weeks and no significant improvement in lung function during childhood was detected over time, despite a marked increase in the use of less invasive ventilation after birth [ 51 ]. Finally, a very recently published population-based study addressed possible cohort effects over a period of major advances in perinatal/neonatal care [ 41 ]. Spirometry was repeated in three population-based cohorts born at ≤28 weeks GA or with birthweight ≤ 1000 g during 1982–1985, 1991–1992 and 1999–2000, and in full-term controls matched for age and gender. The deficits of these cohorts compared with term-born infants decreased with each decade of birth from 1980 to 2000 [ 41 ]. Prematurity is a predisposing factor for the development of lung disease. BPD is associated with high morbidity and mortality rates in survivors of severe prematurity [ 52 ]. Irrespective of BPD diagnosis, premature infants are characterized by lung immaturity at birth and deficient control of breathing [ 18 ]. They face adverse pulmonary conditions in the neonatal period and are at risk of pulmonary disorders both in the mid- as well as in the long-term, such as respiratory tract infections during infancy, recurrent wheezing and asthma during childhood and abnormalities of pulmonary function in adulthood [ 18 ]. Thus, it is imperative to identify how early exposures can be modified to decrease the risk of developing BPD or other respiratory pathology before disease progression becomes irreversible. Compelling evidence suggests that the alveoli continue to be formed postnatally throughout childhood and adulthood. Thus, current research should focus on further elucidation of those mechanisms responsible for postnatal lung growth, as well as the development of strategies to stimulate lung regeneration [ 7 , 53 , 54 ]. In this context, nutritional interventions have been proposed to promote postnatal alveolarization and lung growth, offering a unique opportunity to improve respiratory outcomes [ 19 , 55 , 56 ]. Intrauterine malnutrition is a common prenatal risk factor for BPD development when preterm birth occurs [ 57 , 58 ]. Malnutrition may continue postnatally since extreme prematurity poses several difficulties in providing adequate nutrient and energy intake. Both intra- and extra-uterine malnutrition may have devastating effects on the developing lung [ 59 ]. A recent study documented that very preterm infants who developed BPD received a calorie/protein ratio below that recommended for optimal growth during the first 4 weeks of life [ 60 ]. A retrospective cohort of very low birthweight infants also showed markedly lower energy and lipid intake among those who developed BPD during the first week of life [ 61 ]. Interestingly, an energy intake of less than 1778.2 kJ/kg in this time-period was related to a twofold increase in the adjusted risk of developing BPD. The authors emphasize the potential crucial role of early inclusion of lipids in parenteral nutrition, in order to promote (in combination with optimal protein content) an adequate energy intake and, therefore, to reduce the incidence of BPD [ 61 ]. Further retrospective data suggest that high fluid and low caloric intake in extremely preterm infants during the first week of life are associated with BPD severity [ 62 ]. In accordance, several studies pointed out extrauterine growth restriction, secondary to postnatal insufficiency in nutrient and energy intake, as a key risk factor for the development of BPD [ 63 , 64 ]. Due to increased energy expenditure, infants with established BPD have increased and often unmet caloric needs, compared with infants without BPD, which continue after discharge from the hospital [ 65 ]. Therefore, older studies have documented extrauterine growth restriction in BPD infants up to 12 months of age [ 66 , 67 ]. Interestingly, recent prospective data demonstrated poorer growth of very low birthweight infants with BPD until 36 weeks of corrected age but catch up growth accomplished by three months of corrected age, probably due to the continued improvements in nutritional practices applied to BPD infants [ 68 ]. Compelling data suggest a strong association between early nutrition and long-term pulmonary outcomes. In a cross-sectional study of 4- to 8-year-old children who had been born prematurely and were diagnosed with BPD, undernutrition at the age of 2 years was documented as the only factor predisposing to the development of airway distension. It was concluded that nutritional status at 2 years of age in children who were diagnosed with BPD has a significant effect on respiratory outcomes in childhood [ 69 ]. Up to the early 2000s, nutritional policies, applied to hospitalized neonates born with severe prematurity, resulted in significant extrauterine growth restriction [ 70 ]. In 2002, Ziegler et al. introduced a new era in the nutrition of the preterm, by reporting that “aggressive” nutrition, with increased early provision of protein and calories, resulted in better growth [ 71 ]. Nutrition of very preterm infants should ensure optimal growth as reflected in increases in body weight and head circumference. However, a recent whole-population study comprising infants born below 32 weeks of gestation in England and Wales between 2008 and 2019 showed that early postnatal weight loss has decreased, and subsequent weight gain has increased, but the weight at 36 weeks postmenstrual age was consistently below the weight of babies born at full-term. Greater weight at 36 weeks postmenstrual age was dependent on enteral nutritional intake [ 72 ]. It seems that despite significant changes in feeding policies after 2000, extrauterine growth restriction in extremely/very preterm infants remains a considerable concern. Current recommendations suggest an adequate nutritional strategy that includes early “aggressive” parenteral nutrition, while initiating trophic feeding and advancing to concentrated nutritive enteral feeding, i.e., providing high energy in low volume, as soon as possible [ 19 ]. Priority is given to fortified mother’s own milk, followed by fortified donor milk and preterm enriched formulas with a high density of energy and nutrients. Although evidence regarding effectiveness is limited, functional nutrient supplements, such as vitamins, zinc and iron, with a potential protective role against lung damage, are being re-evaluated. Feedings highly enriched in energy and nutrients should be given after discharge, i.e., either fortified breastmilk or enriched formula [ 19 ]. Very recently, the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Committee of Nutrition (CoN) published an expert consensus on recommendations for the nutritional management of preterm infants with a birth weight of <1800 g. The authors emphasize the absence of strong scientific evidence in various topic areas and the need for additional high-quality research, particularly studies that evaluate long-term outcomes [ 73 ]. Until this day, few recent long-term studies have studied the effect of the type of early nutrition on lung function in children born preterm, but they produced interesting results [ 20 , 74 , 75 ]. In this respect, very encouraging findings regarding the impact of intensive early neonatal nutritional support up to 40–44 weeks postmenstrual age (“aggressive nutrition”) and early use of nasal continuous positive airway pressure (nCPAP) on pulmonary function of very preterm neonates at school age were recently reported [ 20 ]. This study documented no significant differences in FEV1 and FVC, as well as in the incidence of lower respiratory tract infections and associated re-hospitalization up to 8 years of age either between very preterm cases and full-term controls or between the two subgroups of preterm infants with and without BPD. It was concluded that “aggressive” nutrition and early use of early nCPAP and their beneficial effect on early postnatal growth probably contributed to normal respiratory function in the study population [ 20 ]. In a 6-year follow-up study, very preterm-born infants breastfed at hospital discharge were subsequently randomized to receive either unfortified or fortified maternal milk, whereas those infants that were not breastfed received a preterm formula until 4 months of corrected age [ 74 ]. Fractional exhaled nitric oxide, airway resistance and occlusion measurements with reversibility were performed at 6 years of age. The results of the study indicated that protein-enriched nutrition after discharge may improve lung function in very preterm-born children [ 74 ]. In a cohort study with a similar design, compared to exclusively breastfed, very preterm infants supplemented with human milk fortifier or fed exclusively a preterm formula for 4 months did not have an increased risk of developing recurrent wheezing during the 1st year of life [ 75 ]. Furthermore, a study comprising infants with BPD aged less than 36 months, demonstrated that a longer duration of breast milk intake is associated with a reduced risk of acute and chronic pulmonary morbidities, such as episodes of cough or chest congestion, a reduced need for systematic administration of steroids and fewer re-hospitalizations. The authors highlight the crucial role of prolonged breast milk consumption among preterm infants with a BPD diagnosis in terms of protection against respiratory morbidities [ 76 ]. Further long-term follow-up studies, with larger populations, are essential in order to elucidate the potential modification of lung function in relation to early nutrition and growth in extremely and very preterm-born children [ 77 ].Moreover, prospective research is urgently needed to investigate whether better extrauterine growth of extremely/very preterm infants achieved by application of the new ESPGHAN CoN consensus-based feeding policies [ 73 ] will positively influence their respiratory outcome, as relevant retrospective data have shown [ 20 ]. Although the respiratory consequences of preterm birth are well-known, they remain poorly understood. BPD remains the most frequent adverse outcome for infants born <30 weeks of GA and the most common chronic lung disease in infancy. Accumulative evidence indicates persistent abnormalities of lung function in survivors of extreme prematurity throughout childhood and into adulthood, irrespective of BPD diagnosis. Long-term follow-up studies suggest that extremely/very premature birth represents an important precursor of chronic obstructive pulmonary disease that needs to be identified by pulmonologists and targeted by researchers. Nutrient intake and nutritional practices seem to have a major impact not only on short-term respiratory morbidities, but also long-term pulmonary outcomes. Efforts should remain focused on the prevention of preterm labor, but novel research should also aim at promoting postnatal alveolarization and lung regeneration. In this context, further follow-up studies focusing on the effect of early nutrition on respiratory health and lung function outcomes of extremely/very preterm individuals are urgently needed. Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. D.D.B. prepared the initial draft; A.M.-P. reviewed and revised the manuscript. All authors have approved the submitted version and agree to be personally accountable for the author’s own contributions and for ensuring that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and documented in the literature. All authors have read and agreed to the published version of the manuscript. Not applicable. Not applicable. Not applicable. The authors declare no conflict of interest. An Update on Lung Function of Extremely and Very Preterm Infants in Later Life: The Role of Early Nutritional Interventions Impact of preterm birth and bronchopulmonary dysplasia on the developing lung: Long-term consequences for respiratory health Understanding the impact of infection, inflammation, and their persistence in the pathogenesis of bronchopulmonary dysplasia Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia Bronchopulmonary dysplasia Chronic lung disease after premature birth Disrupted lung development and bronchopulmonary dysplasia: Opportunities for lung repair and regeneration Bronchopulmonary dysplasia Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia Bronchopulmonary Dysplasia: Executive Summary of a Workshop Short term outcomes after extreme preterm birth in England: Comparison of two birth cohorts in 1995 and 2006 (the EPICure studies) Bronchopulmonary dysplasia: Clinical practices in five Portuguese neonatal intensive care units Bronchopulmonary dysplasia in very low birth weight subjects and lung function in late adolescence Effect of preterm birth on later FEV1, a systematic review and meta-analysis Lung function in adult survivors of very low birth weight, with and without bronchopulmonary dysplasia Bronchopulmonary dysplasia: The earliest and perhaps the longest lasting obstructive lung disease in humans Lung function after preterm birth: Development from mid-childhood to adulthood Respiratory Follow Up of the Premature Neonates-Rationale and Practical Issues The Role of Nutrition in the Prevention and Management of Bronchopulmonary Dysplasia: A Literature Review and Clinical Approach Very preterm neonates receiving “aggressive” nutrition and early nCPAP had similar long-term respiratory outcomes as term neonates Predicting Long-Term Respiratory Outcomes in Premature Infants: Is It Time to Move beyond Bronchopulmonary Dysplasia? Preterm birth impairs postnatal lung development in the neonatal rabbit model Lung function at term in extremely preterm-born infants: A regional prospective cohort study Tidal Breathing Measurements at Discharge and Clinical Outcomes in Extremely Low Gestational Age Neonates Postnatal infections and immunology affecting chronic lung disease of prematurity Lung function at 6 and 18 months after preterm birth in relation to severity of bronchopulmonary dysplasia Pulmonary function in former very low birth weight preterm infants in the first year of life An update on pulmonary and neurodevelopmental outcomes of bronchopulmonary dysplasia Lung growth and pulmonary function after prematurity and bronchopulmonary dysplasia New BPD predicts lung function at school age: Follow-up study and meta-analysis Mid-childhood lung function in a cohort of children with “new bronchopulmonary dysplasia” Altered lung structure and function in mid-childhood survivors of very preterm birth Lung function after extremely preterm birth-A population-based cohort study (EXPRESS) Lung function trajectories throughout childhood in survivors of very preterm birth: A longitudinal cohort study Lung function evolution in children with old and new type bronchopulmonary dysplasia: A retrospective cohort analysis Lung function trajectories in children with post-prematurity respiratory disease: Identifying risk factors for abnormal growth Lung function trajectories in health and disease Lung development and aging Expiratory airflow in late adolescence and early adulthood in individuals born very preterm or with very low birthweight compared with controls born at term or with normal birthweight: A meta-analysis of individual participant data Airway obstruction in young adults born extremely preterm or extremely low birth weight in the postsurfactant era Tracking of lung function from 10 to 35 years after being born extremely preterm or with extremely low birth weight Respiratory outcomes of “new” bronchopulmonary dysplasia in adolescents: A multicenter study Lung function development after preterm birth in relation to severity of Bronchopulmonary dysplasia Influence of bronchopulmonary dysplasia on lung function in adolescents who were born extremely prematurely Respiratory and cardiovascular outcomes in survivors of extremely preterm birth at 19 years Bronchopulmonary dysplasia: What are its links to COPD? Development of lung diffusion to adulthood following extremely preterm birth Association between very to moderate preterm births, lung function deficits, and COPD at age 53 years: Analysis of a prospective cohort study Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: 2020 Report Published in Fontana, WI, USA. 2020 Children Born Preterm at the Turn of the Millennium Had Better Lung Function Than Children Born Similarly Preterm in the Early 1990s Ventilation in extremely preterm infants and respiratory function at 8 years Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia Alveolarization continues during childhood and adolescence: New evidence from helium-3 magnetic resonance Evidence for adult lung growth in humans Impact of Nutrition on Bronchopulmonary Dysplasia Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology, Prevention, and Treatment Fetal Growth Restriction Is Worse than Extreme Prematurity for the Developing Lung Small for gestational age very preterm infants present a higher risk of developing bronchopulmonary dysplasia Enteral Nutrition Support of the Preterm Infant in the Neonatal Intensive Care Unit Assessment of early nutritional intake in preterm infants with bronchopulmonary dysplasia: A cohort study Early energy restriction in premature infants and bronchopulmonary dysplasia: A cohort study Low caloric intake and high fluid intake during the first week of life are associated with the severity of bronchopulmonary dysplasia in extremely low birth weight infants Postnatal Weight Gain in Preterm Infants with Severe Bronchopulmonary Dysplasia Postnatal nutritional deficit is an independent predictor of bronchopulmonary dysplasia among extremely premature infants born at or less than 28 weeks gestation Definition and outpatient management of the very low-birth-weight infant with bronchopulmonary dysplasia Preterm infants with chronic lung disease: Are protein and energy intakes after discharge sufficient for optimal growth? Weight growth velocity of very low birth weight infants: Role of gender, gestational age and major morbidities Adipokines played a limited role in predicting temporary growth differences between very low birthweight infants with and without bronchopulmonary dysplasia Nutritional Status at 2 Years in Former Infants with Bronchopulmonary Dysplasia Influences Nutrition and Pulmonary Outcomes During Childhood Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network Aggressive nutrition of the very low birthweight infant Birthweight and patterns of postnatal weight gain in very and extremely preterm babies in England and Wales, 2008–19: A cohort study Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts Improved lung function at age 6 in children born very preterm and fed extra protein post-discharge Allergic diseases among very preterm infants according to nutrition after hospital discharge Impact of breast milk on respiratory outcomes in infants with bronchopulmonary dysplasia Nutrition and growth in infants with established bronchopulmonary dysplasia |
Answer the following medical question. | What does research say about Infection Risk Reduction in the Intensive Care Nursery: A Review of Patient Care Practices That Impact the Infection Risk in Global Care of the Hospitalized Neonates.? | Neonates are at high risk for developing an infection during their hospital stay in the neonatal intensive care unit. Increased risk occurs because of immaturity of the neonate's immune system, lower gestational age, severity of illness, surgical procedures, and instrumentation with life support devices such as vascular catheters. Neonates become colonized with bacteria prior to or at delivery and also during their hospital stay. They can then become infected with those bacteria if there is a breakdown in the primary defenses such as tissue injury due to skin breakdown, nasal erosion, or trauma to the respiratory tract. Neonates are also at high risk for bacterial translocation due to the altered permeability of the intestinal mucosa, loss of commensal flora, and bacterial overgrowth. The unit-based neonatal care team must implement global care delivery and safety practices, utilize published care guidelines, know and apply evidence-based practices from collaborative quality improvement efforts and other sources, and use auditing and monitoring practices that can identify risks and lead to better practice options to prevent infections. This article presents several aspects of global neonatal care delivery, including vascular access, which may reduce the risk of systemic infection during the hospitalization. |
Answer the following medical question. | What does research say about Neonatal intensive care and radiation.? | Radiography plays an important role in a neonatal intensive care nursery. Diagnostic radiation was measured in 96 newborns. Mean exposure per neonate was 68.1 milliroentgens (mR) (SD = 132.7) with a median exposure per neonate of 28 mR. Radiation received by neonates was low, but further studies are needed to show the safety of radiation or its delayed effects. The measurement of radiation is simple, and routine radiation recording can prove useful in future evaluations of this high-risk population. |
Answer the following medical question. | What does research say about Biopsychosocial risks of parental care for high-risk neonates: implications for evidence-based parental counseling.? | Provide an evidence base for counseling parents of high-risk neonates about the biopsychosocial impact of providing long-term care. A review of the effects of long-term care on families of high-risk neonates. Our search was limited to 1993-2010. We used the terms 'long-term care,' 'family,' 'neonate' and 'technology dependence.' Results were organized based on Engel's biopsychosocial model. Physical-parental caregivers reported more health problems, had fewer health-promoting behaviors and lower vitality.Psychological-parental caregivers had higher rates of post-traumatic stress disorder and depressive symptoms, although some improved with time. Siblings reported greater stress and depression. Social-parental caregivers achieved fewer years of education, higher unemployment and lower incomes. Couples reported greater family strain. The effect on divorce was mixed. Siblings reported disruption in their academic and social lives. Providing long-term care involves biopsychosocial risks. Counseling of parents should identify them and advocate strategies for prevention. |
Answer the following medical question. | What does research say about Outcome of surgical condition of neonates who underwent surgery: A prospective study from a tertiary care center.? | The neonatal period is a highly vulnerable time for an infant, who is completing many of the physiologic adjustments required for extra- uterine survival. If the neonate has a coexisting pathology which needs surgery, this challenge is magnified. Neonatal surgical conditions are unique in their type because some require early diagnosis, prompt surgery and postoperative care to improve the survival and outcome. The aim of this study was to know the clinical profile of congenital surgical conditions and to estimate the burden and outcome in special new born care unit. The study population include 138 surgical neonate admitted in special new born care unit, department of paediatrics, Kamla Raja Hospital, Gajra Raja Medical College, Gwalior (M.P.) from April 2017 to April 2018 including six month follow up period. Total admission in special new born care unit were 5378 out of which 138 (2.5%) neonates of surgical condition were admitted in the study period. Incidence of neonatal surgical condition was found to be 8.48%. Surgery was performed in 57 (41.30%) neonates. The Commonest neonatal surgical condition was constituted by gastrointestinal system (39.13%). Among gastrointestinal system anomalies, tracheoesophageal fistula were 28.6% of total gastrointestinal system cases. The most common surgical condition encountered was meningomyelocele, 23.36% of total cases. The survival of neonatal surgical condition in hospital was 52.89% and after six month follow up was 26.08%. The overall mortality with neonatal surgical condition in this study was 73.91%. Maternal age, antenatal care, history of congenital malformation, socioeconomic status, mode of delivery, prematurity, type of admission, single or multiple surgical condition, inotropic and ventilation support, post operative complication were significantly associated with final outcome of neonatal surgical condition. High mortality was found in neonates suffering from surgical conditions. Commonest anomaly includes conditions of gastrointestinal tract. Maternal age more than 35 year, poor antenatal care, prematurity, vaginal delivery, extra mural neonate, multiple surgical condition, inotropic and ventilation support and post operative complications were associated with increased mortality. |
Answer the following medical question. | What does research say about Surgical procedures performed in the neonatal intensive care unit on critically ill neonates: feasibility and safety.? | Transferring unstable, ill neonates to and from the operating room carries significant risks and can lead to morbidity. We report on our experience in performing certain procedures in critically ill neonates in the neonatal intensive care unit (NICU). We examined the feasibility and safety of such an approach. All surgical procedures performed in the the NICU between January 1999 and December 2005 were analyzed in terms of demographic data, diagnosis, preoperative stability of the patient, procedures performed, complications and outcome. Operations were performed at bedside in the NICU in critically ill, unstable neonates who needed emergency surgery, in neonates of very low birth weight (<1000 g) and in neonates on special equipment like high frequency ventilators and nitrous oxide. Thirty-seven surgical procedures were performed including 12 laparotomies, bowel resections and stomies, 7 repairs of congenital diaphragmatic hernias, 4 ligations of patent ductus arteriosus, and various others. Birthweights ranged between 850 g and 3500 g (mean, 2000 g). Gestational age ranged between 25 to 42 weeks (mean, 33 weeks). Age at surgery was between 1 to 30 days (mean, 10 days). Preoperatively, 19 patients (51.3%) were on inotropic support and all were intubated and mechanically ventilated. There was no mortality related to surgical procedures. Postoperatively, one patient developed wound infection and disruption. Performing major surgical procedures in the the NICU is both feasible and safe. It is useful in very low birth weight, critically ill neonates who have a definite risk attached to transfer to the operating room. No special area is needed in the the NICU to perform complication-free surgery, but designing an operating room within the the NICU would be ideal. Critically ill neonates who require surgery are traditionally transferred to the operating room (OR). The only exception to this approach is the frequently described ligation of patent ductus arteriosus in the neonatal intensive care unit (NICU), which has results similar to that done in the OR. 1 – 3 Transferring these unstable neonates to and from the OR may be associated with significant morbidity, which may alter the outcome in these already compromised patients. Surgery in the NICU can avoid the mishaps that can occur during transport of the neonate, like discontinuation of monitoring, dislocation of artificial airways, accidental removal of vascular access and hypothermia. 4 Another advantage of performing surgery in the the NICU is the continuity of care by the same intensive care team. In contrast, it has been suggested that surgery in the the NICU may increase the risk of infection. 1 We report our experience with critically ill neonates operated on in the the NICU over a 7-year period. A retrospective analysis was undertaken of all neonates who had surgical procedures performed in the NICU at King Khalid University Hospital, Riyadh, Saudi Arabia over 7 years, from January 1999 to December 2005. Our unit had proposed indications for operating on neonates in the NICU, describing the advantages and disadvantages, and submitted this proposal to the ethical committee of the department of surgery, department of anaesthesia, division of neonatology and OR nursing. The proposal was accepted by all. Surgical procedures were performed in the NICU when the patients were clinically unstable and/or weighed less than 1000 g and/or were on a conventional high frequency ventilator (HFV) or on nitrous oxide (NO). All surgeries were done as an emergency. Data were collected from medical records on sex, birth, weight, gestation, age and weight at surgery, underlying diagnosis, clinical stability of the patient, procedure performed, complications and outcome. Our NICU has 22 intensive care beds and 20 fresh filtered air changes per hour, which is similar to that of the OR. All procedures were performed at the bedside with an overhead radiant warmer (Hill-Rom Air Shields, USA). Temporary wall partitions were set-up around the operation site ( Figure 1 ). The theatre staff brought all the necessary equipment, instruments, and drapes to the NICU. A circulating and scrub nurse from the main OR attended the surgery in NICU. Regular activities in the NICU were not suspended during surgery. The surgical team consisted of surgeons, assistants, a neonatologist, an anesthetist, a scrub nurse and a circulating nurse. Monitoring of the patient included continuous pulse oximetry, continuous electrocardiography, continuous heart rate and blood pressure measurements from either an umbilical or peripheral arterial line. Ventilator requirements were monitored and adjusted by the neonatologist. Intravenous anesthetic agents were used in all cases, as no scavenging system for inhalation anesthetics was available. An intravenous opioid (fentanyl) combined with a non-depolarizing muscle relaxant atracurium or vecuronium was used in all cases. The temperature was monitored with a transcutaneous temperature probe. Portable lights provided illumination. Skin preparation and draping was performed as in the OR. Magnification surgical loupes were used in some cases to facilitate surgical technique. Operative and postoperative management did not differ from standard practice. For all the neonates operated on in the NICU, a staff neonatologist remained in continuous attendance with the patient from prior to surgery until its completion and adequate postoperative stabilization of the patient. A total of 37 surgical procedures were performed in the NICU over the period of 7 years. The preoperative characteristics are shown in Table 1 . All the neonates operated on in the NICU were on a mechanical ventilator. Thirty patients were on a conventional ventilator and 7 were on an HFV. Nineteen patients (51.3%) were on inotropic support at the time of surgery. The types of surgical procedures are described in Table 2 . All patients with diaphragmatic hernia were not fit to transfer to OR because all were on HFV and NO. All the laparotomy patients had necrotizing enterocolitis. Miscellaneous procedures done in the NICU included unilateral or bilateral inguinal hernias, insertion of long lines, peritoneal dialysis catheter insertion and muscle biopsies. Body temperature was maintained within the normal range for gestational age. The ventilator settings were perioperatively adjusted to maintain arterial saturation between 90% to 96% depending upon the gestational age. Postoperatively, one patient of low birth weight with a perforated necrotizing enterocolitis developed wound infection and wound disruption. There was no perioperative death. There were three mortalities (none related to surgery). One patient with congenital diaphragmatic hernia died 37 days after surgery due to sepsis and two pre-term babies with perforated necrotizing enterocolitis died in the first week after surgery due to sepsis and respiratory failure. The operating theatre is the ideal location to perform surgical procedures because it provides the required sterility and a natural environment for the surgical and anesthetic team. Stable, full-term neonates who require surgery can often be safely transported to the OR, but the transfer of critically ill, unstable, extremely low birthweight (<1000 g) neonates from the NICU to the OR can cause significant problems and morbidity. 5 Critically ill neonates are transported to the OR in a transport incubator with a transport ventilator and portable monitors. Usually two or three people are required to move the neonate from the transport incubator to the surgical table. These procedures are repeated postoperatively resulting in at least four distinct transfers with a resulting risk of hypothermia, discontinuation of vital treatment, and monitoring, accidental removal of vascular access and dislocation of artificial airways. 5 , 6 The respiratory status of the patient is also a factor even without loss of artificial airways. Many neonates are dependent on complicated ventilators or methods of ventilation such as high frequency or oscillation. These highly sophisticated ventilatory modes cannot be continued during transport. In our series, 7 neonates were on HFV and it was not possible to transfer them to OR for surgery. These patients benefited by having surgery done in the NICU. Incompatibility between monitoring equipment in the OR versus the NICU can be another problem. The journey back from the OR can be particularly hazardous since the baby is often more fragile immediately after surgery. Emergencies such as hemorrhage, arrhythmias, a displaced endotracheal tube or pneumothorax can usually be managed very well in a closely monitored baby on the neonatal unit, but can be a nightmare in a transport incubator being wheeled along the corridor or in a lift between floors. 7 In view of this, some pediatric surgical centers have used the NICU as an alternative place to carry out surgery in critically ill neonates aiming to reduce the morbidity associated with the transfer. Surgical procedures on critically ill patients in the NICU avoid such mishaps and morbidities, 3 with the advantage of doing procedures without interfering with monitoring and vital treatment. An additional advantage of performing procedures in the NICU is the continuity of care by neonatal medical and nursing staffs, which is a great asset not only to the patients but also to the anesthetist who may be unfamiliar with the patient’s ventilatory and circulatory idiosyncrasies. 8 The movement of newborns on extracorporeal membrane oxygenation (ECMO) can be hazardous. 9 A major concern over surgery in the NICU is the higher risk of surgical and postoperative infections. although this assumption is not supported by the literature. Taylor et al 10 and Eggert et al 11 reported no wound infection in a series of 79 and 52 patent ductus arteriosus ligations in the NICU. Lally et al 12 compared the insertion of Broviac catheters in neonates in the OR with those in the NICU and found no difference in the incidence of catheter-associated sepsis or positive blood cultures. Gavilanes et al 13 reported no local or systemic infection associated with surgery and no perioperative mortality related to the procedure in his series of 45 neonates operated on in the NICU. Lago et al 14 compared congenital diaphragmatic hernia newborns who underwent surgery in the NICU versus in the OR. In his series, the NICU group had more infectious complications and mortalities, but the mortalities were not related to surgery. The 18 patients operated on in the NICU were critically ill, on HFV and unsuitable to transfer to OR. In our series, 7 newborns with diaphragmatic hernia were operated on in the NICU. All were unstable and on HFV and NO. There was no infectious complication related to surgery in patients operated on for diaphragmatic hernia in the NICU. Finer et al 4 suggested that surgical procedures can be done in the NICU on unstable critically ill neonates with a morbidity similar to that in the OR. In our series, there was no perioperative mortality, but there was one wound infection in a child with perforated necrotizing enterocolitis. The three deaths in our series were due to pre-existing conditions of the neonates or to a cause not directly related to the place of surgery. In our opinion, successful development of surgery within the NICU requires a clear indication for performing surgery in the NICU, and good planning and cooperation between surgeons, neonatologist, the NICU and OR nursing staffs. To perform emergency surgery in the NICU, no special area is needed. Surgery can be performed at the bedside in the presence of an experienced pediatric surgeon, neonatologist and anesthetist. A designated area, if available, can be used for surgery, and may have higher rate of air circulation, a special ventilation system and no disturbance to routine NICU work. In conclusion, performing major surgical neonatal procedures in the NICU is both feasible and safe. A maximum benefit is observed in very low birth weight and critically ill neonates who have a definite risk attached to transfer to the OR. No special area is needed in the NICU to perform complication free surgery, but designing an operating room within the NICU is ideal. Operating site in the neonatal intensive care unit. Preoperative characteristics of the neonates. Surgical procedures in the neonates. Surgical procedures performed in the neonatal intensive care unit on critically ill neonates: feasibility and safety Feasibility of surgery for patent ductus anteriosus of premature babies in a neonatal intensive care unit Surgical closure of the patent ductus arteriosus in the neonatal intensive care unit Ligattion of the patent ductus arteriosus in newborn respiratory failure In situ emergency pediatric surgery in the intensive care unit Neonatal surgery: Intensive care unit vs. operating room Surgical ligation of patent ductos arteriosus in neonatal intensive care setting is safe and cost effective Surgery of the ill extremely low birthweight infant: Should transfer to the operating theatre be avoided? Operating on critically ill neonates: The OR or the NICU Repair of congenital diaphragmatic hernia during extracorporeal membrane oxygenation Use of neonatal intensive care unit as a safe place for neonatal surgery Congenital diaphragmatic hernia: Intensive care unit or operating room? |
Answer the following medical question. | What does research say about Neonatal cardiac tamponade, a life-threatening complication secondary to peripherally inserted central catheter: a case report.? | Although the use of a peripherally inserted central catheter (PICC) has many advantages for the treatment of neonates, catheter malposition may result in serious complications that could be life-threatening. We report the case of a 10-day-old neonate with cardiac tamponade secondary to a PICC line who was successfully treated by pericardiocentesis. An Iranian (Asian) preterm male neonate was born by Cesarean section with a birth weight of 1190 g and a first-minute Apgar score of 7. Based on an increased respiratory distress syndrome (RDS) score from 4 to 7, resuscitation measures and intubation were performed at the neonatal intensive care unit (NICU). On day 3 after birth, a PICC line was inserted for parenteral therapy. A chest X-ray confirmed that the tip of the PICC line was in the appropriate position. Mechanical ventilation was discontinued 72 h post-NICU admission because of the improved respiratory condition. On the day 10 post-NICU admission, he suddenly developed hypotonia, apnea, hypoxia, hypotension, and bradycardia. Resuscitation and ventilation support were immediately started, and inotropic drugs were also given. Emergency echocardiography showed a severe pericardial effusion with tamponade. The PICC line was removed, and urgent pericardiocentesis was carried out. The respiratory situation gradually improved, the O 2 saturation increased to 95%, and vital signs remained stable. Dramatic improvement of the neonate's clinical responses after pericardial drainage and PICC removal were suggestive of PICC displacement, pericardial perforation, and cardiac tamponade. The online version contains supplementary material available at 10.1186/s13256-022-03506-4. A peripherally inserted central catheter (PICC) made of silicone, polyurethane, or polyethylene provides a prolonged route for administration of parenteral fluids, nutrition, and medications. Preterm neonates admitted to hospital usually require a PICC because of their small and fragile vessels [ 1 , 2 ]. Femoral, subclavian, and internal jugular veins are the most common sites used for PICC catheterization [ 3 ]. Although use of a PICC has many advantages for the treatment of neonates, catheter malposition may result in serious complications that could be life-threatening [ 4 ]. These potential complications (sepsis, embolism, intravascular thrombosis, pleural effusion, and pericardial effusion with tamponade) indicate that insertion of a PICC line requires special medical qualification and follow-up examination to ensure its proper location (the inferior third of the superior vena cava) [ 5 – 8 ]. Of the above complications, tamponade is a rare but fatal condition that occurs following catheter dislocation and pericardial perforation [ 8 ]. Cardiac tamponade is responsible for 47–100% of the mortality rate [ 9 ]. We report here the case of a neonate admitted to a neonatal intensive care unit (NICU) with pericardial effusion and cardiac tamponade secondary to a PICC line that was successfully treated with immediate PICC removal and pericardiocentesis. An Iranian (Asian) pregnant women aged 32 years old with a primary complaint of preterm uterine contraction and vaginal bleeding presented the obstetric ward of Yas Hospital (Tehran-Iran, January 2021). She was a multi-para woman (Gravida: 3, Para: 2, Living: 2, Abortion: 0) with a gestational age of 30 weeks. She did not report any prenatal complications and had received corticosteroid therapy 2 days prior to hospital admission. Upon presentation, magnesium sulfate was immediately administered but she was transferred to the operation room for repeat Cesarean section due to progressive cervical dilation. A preterm male newborn with a first-minute Apgar score of 7 and birth weight of 1190 g was born. Physical examination after birth showed a notable frontal bossing, acrocyanosis, and diffuse head, neck, hand, and leg ecchymosis. Anterior and posterior fontanelles were normal. No congenital anomaly or abdominal organomegaly was observed. Peripheral pulses were palpable and heart sounds were normal without any abnormal sounds. His reflexes were normal, but limb movements were hypotonic. Due to an increase in his respiratory distress syndrome (RDS) score from 4 to 7 and signs of respiratory distress (inter- and subcostal retraction, grunting, and decreased breathing sounds), resuscitation measures were initiated. He was then given nasal continuous positive airway pressure (CPAP) in the operation room that was subsequently switched to mechanical ventilation in the NICU. Intratracheal surfactant and intravenous antibiotic therapy were also initiated in the NICU. Under mechanical ventilation with synchronized intermittent mandatory ventilation (SIMV) setup, his O 2 saturation, blood pressure, and heart rate improved to > 94%, 70/35 mmHg, and 160 beats per minute, respectively. On day 3 post-NICU admission,, a PICC line (Premicath; 1Fr/28 G; VYGON, Écouen, France; Code 1261.080) was also inserted from the auxiliary vein of the right upper extremity for intravenous therapy, delivery of medications, and parenteral nutrition. A chest X-ray showed that the tip of the PICC line was in the appropriate place in the superior vena cava (SVC) (Fig. 1 ). Mechanical ventilation was discontinued 72 h post-NICU admission because of improved respiratory condition and normal automatic breathing. After extubation, low-flow oxygen therapy was continued and low-volume feeding was initiated based on his tolerance. His weight gain was acceptable and the clinical situation improved, including a gradual increase in the feeding volume and respiratory support. On day 10 post-NICU admission, he suddenly developed hypotonia, apnea, hypoxia, and bradycardia. He was gasping, had hypotension, and there was an absence of peripheral pulses. In the first minutes after the alarm signs, resuscitation was initiated and ventilation support provided, together with administration of inotropic drugs (1–3 minutes). Despite the high-frequency setup of the mechanical ventilator, the endotracheal tube was checked for displacement or obstruction due to his persistent critical condition (hypotension and shortness of breath). Pneumothorax and equipment failure were also ruled out. Several medical measures were initiated (approximately at minutes 3–4), including nothing by mouth (NPO), high-dose antibiotic therapy, emergency echocardiography, brain ultrasound, arterial and venous blood sampling, blood cell count, and arterial blood gas analysis. Fig. 1 Chest X-ray findings showing the tip of the peripherally inserted central catheter line at appropriate position Chest X-ray findings showing the tip of the peripherally inserted central catheter line at appropriate position Echocardiography was performed over the next 5–7 minutes (Fig. 2 ), and the results showed SVC perforation caused by the catheter, severe pericardial effusion, right atrial collapse, ventricle dysfunction, and tamponade. The ejection fraction value was 40%, and there was no evidence of atrial septal defect (ASD), pleural effusion, or patent ductus arteriosus (PDA). A peripheral venous catheter was inserted, and the PICC was removed at the same time. Urgent pericardiocentesis was performed through subxiphoid cannulation guided by echocardiography and 10 ml of the pericardial fluid was aspirated (over the next 7–15 minutes) (Electronic Supplementary Material file 1 : Video S1). The aspirated fluid was sent to the laboratory for tests, with the results showing severe acidosis (pH 6.80) and hyperglycemia (Table 1 ). To improve the hyperglycemia and metabolic acidosis, the patient was hydrated with low glucose solution and bicarbonate was initiated. Respiratory support was continued and antibiotics covering Staphylococcus aureus and Gram-negative bacteria were administered. Brain sonography was also performed, which was normal. The workup sequence is shown in Table 2 . Fig. 2 Emergency echocardiography Table 1 Results of arterial blood gas and laboratory blood tests Factors Before pericardiocentesis (range) After pericardiocentesis (range) Arterial blood gas results pH 6.8 7.37 Partial pressure of carbon dioxide (PmmHg) 24 34 Partial pressure of oxygen (mmHg) 55 106 O 2 saturation (%) – 98 HCO 3 (meq/L) – 19.7 Base excess (mEq/L) – − 50 Blood tests Hemoglobin (g/dL) 13 Hematocrit (%) 42.7 Platelet (cells/mcL) 150,000 Mean corpuscular volume (fL) 122.3 Mean corpuscular hemoglobin (pg) 37.2 Mean corpuscular hemoglobin concentration (g/dL) 30.4 White blood cells (cells/mcL) 14,200 Neutrophils (cells/mcL) 42 Eosinophils (cells/mcL) 3 Monocytes (cells/mcL) 5 Lymphocytes (cells/mcL) 50 Creatinine (mg/mL) 0.7 Natrium (mmol/L) 139 Calcium (mg/dL) 9 Potassium (mmol/L) 5.2 Magnesium (mEq/L) 2.3 C-reactive protein (mg/L) 1 Blood sugar (mg/dl) 850 131 Throxine (pmol/L) 9.3 Thyroid-stimulating hormone (mlU/L) 0.6 Free thyroxine (pmol/L) 0.9 Blood culture Negative Negative Table 2 Sequence of performed workups following onset of alarms Sequential steps Measures Time (minutes following first alarm signs) 1 Resuscitation, ventilation supports, administration of Inotropic drugs 1–3 2 Request for medical measures, including nothing by mouth, high-dose antibiotic therapy, emergency echocardiography, brain ultrasound examinations, and blood sampling 3–4 3 Echocardiography examination 5–7 4 Peripheral venous line catheterization, PICC removal, and pericardiocentesis 7–15 5 Hydration and bicarbonate infusion 15–20 6 Initiation of antibiotic therapy 20–23 7 Brain sonography 23-25 PICC Peripherally inserted central catheter Emergency echocardiography Results of arterial blood gas and laboratory blood tests Sequence of performed workups following onset of alarms PICC Peripherally inserted central catheter Under mechanical ventilation the respiratory parameters improved gradually; pericardial drainage and PICC removal occurred concurrently. O 2 saturation increased to 95%, blood pressure elevated, and vital signs remained stable. Analysis of the aspirated pericardial fluid showed a hyperglycemic fluid (Table 3 ). A dramatic improvement in the neonate's clinical responses (after pericardial drainage and PICC removal) was suggestive of PICC displacement, pericardial perforation, and cardiac tamponade. Echocardiography was repeated (× 3) every 12 hours to ensure no further pericardial effusion was present. On day 40 after birth, the patient was still in the hospital but showed weight gain; he was in good condition without requiring respiratory support. Table 3 Results of laboratory analysis of aspirated pericardial fluid Factors Range Glucose (mg/dL) 2233 White blood cell (cells/mcL) – Red blood cell (cells/mcL) 300 Lactate dehydrogenase (units/L) 63 Protein (g/L) 108 Culture Negative Results of laboratory analysis of aspirated pericardial fluid It is commone practice to insert PICC lines for parenteral administration in preterm neonates. Although PICC lines are associated with a number of catheter-related complications, such as infection, catheter block, catheter migration, thromboembolism, and catheter damage, pericardial effusion following PICC insertion is an unusual complication [ 10 ]. In the case presented here, we highlight the potential risk of pericardial effusion with tamponade as a fatal complication in a neonate 1 week after PICC insertion. Although this complication is rare and uncommon following PICC insertion (0.5–2%) [ 11 ], the diagnosis was suspected immediately in our case and confirmed by echocardiography. The patient recovered gradually after urgent removal of the PICC line followed by pericardiocentesis. Regarding the etiology of tamponade, we believe that the catheter tip eroded the catheterized vessel (SVC) and perforated the pericardium, allowing the infused fluid to move into the pericardial space. This flow of fluid into the pericardia space subsequently increased the pressure on the cardiac chambers, resulting in cardiac tamponade. In accordance with our findings, da Silva Dornaus et al . also reported a preterm neonate (30 weeks) with cardiac tamponade secondary to PICC [ 8 ]. The neonate showed episodes of bradycardia, low O 2 saturation, cyanosis, dyspnea, and worsening of clinical condition 5 days after PICC insertion. Radiography and echocardiography examinations revealed that the tip of the catheter was in the cardiac chamber with pericardial effusion and signs of tamponade. These authors also reported improvement in the neonate's clinical situation after immediate cardiac puncture and extraction of 25 mL of fluid similar to the infused solution [ 8 ]. An autopsy study by Warren et al . also showed pericardial effusion with tamponade in five neonates who died unexpectedly and suddenly after receiving parenteral nutrition via PICC. The autopsy findings showed endocardial injury and pericardial filling with permeation of a hyperosmotic parenteral fluid [ 12 ]. Iyer et al . reported cardiac tamponade in a 29-week-old preterm neonate with a sudden arrhythmia, unstable vital signs, and decreased O 2 saturation. The neonate recovered after emergency intubation, administration of inotropic agents, and fluid aspiration from the pericardial space using an echocardiography-guided tap [ 10 ]. It should be noted that in cases with cardiac tamponade, the signs and symptoms may be non-specific and misleading (dyspnea, chest pain, tachycardia, hypotension, and non-palpable peripheral pulses). It is important that all infusions through the PICC must be stopped when tamponade is suspected. It has also been reported that in addition to catheter displacement, other factors, such as the material, length, and size of the catheter, duration of parenteral nutrition, osmolarity, and composition of the infused fluids may severely affect and worsen complications and outcomes related to cardiac tamponade. For example, it was reported in one study that pericardial presence of high-potassium infused fluid resulted in electrocardiogram alterations showing a pattern of hyperkalemia instead of a pattern of cardiac tamponade [ 1 , 9 , 12 ]. Another study also showed that tamponade was frequently observed in cases with PICC inserted through aperipheral vein compared to a central vein [ 4 ]. In conclusion, th case presented here highlights the potential risk of cardiac tamponade following central line insertion with sudden and unexpected symptoms associated with cardiovascular collapse. In such conditions, it is important to rapidly confirm that the catheter tip had migrated into the pericardial space and urgently initiate pericardiocentesis and catheter removal, all of which are effective measures to prevent death. Based on our and previous cases, we strongly recommend using catheters with soft tips, minimizing the movements of the neonates, and checking the catheter position periodically to reduce the risk of perforation and prevent life-threatening complications. Moreover, pericardial effusion with tamponade should be suspected in every case with PICC, and all neonatologists should be aware of this clinical emergency and the steps to be taken [ 1 , 10 ]. Further studies are also needed to suggest other preventive strategies. Additional file 1. Video S1. Additional file 1. Video S1. Atrial septum defect Continuous positive airway pressure Neonatal intensive care unit Nothing by mouth Patent ductus arteriosus Peripherally inserted central catheter Respiratory distress syndrome Synchronized intermittent mandatory ventilation Superior vena cava Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This study was supported by Tehran University of Medical Sciences (TUMS) and the Maternal, Fetal, and Neonatal Research Center. The authors appreciate their kind support. The design, experiment, and preparing the manuscript were carried out by MRZ and MH. The authors approved the content of the manuscript. This study was supported by Tehran University of Medical Sciences and the Maternal, Fetal, and Neonatal Research Center. The datasets are available from the corresponding author on reasonable request. The present investigation was approved by the Institutional Review Board of Tehran University of Medical Sciences based on the Helsinki Declaration of 1964 (IR.TUMS.REC.1400.387). The participant’s parents provided written consent. The information was confidential and no extra expenses were imposed. Written consent was obtained from the patient's parent for publication of this case report and any accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal. The authors declare no competing interests. Neonatal cardiac tamponade, a life-threatening complication secondary to peripherally inserted central catheter: a case report Fatal cardiac tamponade as a result of a peripherally inserted central venous catheter: a case report and review of the literature The extended dwell peripheral intravenous catheter is an alternative method of NICU intravenous access Complications of central venous catheterization in critically ill children Cardiac tamponade associated with a peripheral vein central venous catheter Neonatal percutaneous central venous catheters: equations for the inserted length and locations of the insertion sites The equations of the inserted length of percutaneous central venous catheters on neonates in NICU Percutaneously inserted central catheter-related pleural effusion in a level III neonatal intensive care unit: a 5-year review (2008–2012) Cardiac tamponade due to peripheral inserted central catheter in newborn Peripherally inserted central catheter causing life-threatening cardiac tamponade Cardiac tamponade in a neonate: a dreadful condition—need for functional echo Pericardial effusion and cardiac tamponade in neonates: sudden unexpected death associated with total parenteral nutrition via central venous catheterization |
Answer the following medical question. | What does research say about Presepsin levels in neonatal cord blood are not influenced by maternal SARS-CoV-2 infection.? | Coronavirus disease (COVID-19) can present with various symptoms and can involve multiple organs. Women infected during pregnancy have a higher incidence of obstetrical complications and infants born to "positive" mothers may get the infection with different manifestations. Presepsin seems to be a promising sepsis biomarker in adults and neonates. The aim of this study was to assess if presepsin levels in neonatal cord blood could be influenced by maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 119 neonates born from women with a confirmed diagnosis of SARS-CoV-2 infection were enrolled and presepsin levels of cord blood samples were collected. All neonates were tested for SARS-CoV-2 infection at birth and after 48-72 h. The median presepsin value in umbilical cord blood samples collected after birth was 455 pg/mL. Presepsin levels were not influenced by maternal symptoms of COVID-19, weight for gestational age, or delivery mode, and did not significantly differ between infants with and without adverse neonatal outcomes. Infants hospitalized for more than 5 days had a significantly higher presepsin level at birth rather than those discharged up to 4 days of life. Three infants with positive nasopharyngeal swab at birth had higher Presepsin levels than two infants tested positive at 48 h. This is the first study reporting cord presepsin levels in term and preterm infants born to mothers with COVID-19, that appeared to be not influenced by maternal clinical presentation. However, further studies are needed to explain the mechanisms of P-SEP increase in neonates exposed to perinatal maternal SARS-CoV-2 infection or with an indeterminate/possible SARS-CoV-2 infection in the same neonates. |
Answer the following medical question. | What does research say about Glucose monitoring in neonates: need for accurate and non-invasive methods.? | Neonatal hypoglycaemia can lead to devastating consequences. Thus, constant, accurate and safe glucose monitoring is imperative in neonatal care. However, point-of-care (POC) devices for glucose testing currently used for neonates were originally designed for adults and do not address issues specific to neonates. This review will address currently available monitoring options and describe new methodologies for non-invasive glucose monitoring in newborns. |
Answer the following medical question. | What does research say about Illuminance of neonatal units.? | We have measured the illuminance (brightness) of seven neonatal units during both the day and the night. When the units were lit solely by fluorescent tubes the mean illuminance was 348 lux (range 192-690). During the day the mean illuminance was 470 lux (range 236-905). The high dependency regions in four of the seven units were significantly brighter than the corresponding low dependency nurseries at all times. In two of these units there is a policy of reducing the amount of artificial light in the low dependency areas at night, and in these the normal mean illuminance was 50 lux. We have measured the general levels of illumination to which a neonate might be exposed; the ocular exposure to light of a neonate depends, however, on both physical and biological factors and more research is required before an accurate estimate can be made. Illuminance of neonatal units. |
Answer the following medical question. | What does research say about Immunomodulation. Part IV: Glutamine.? | Glutamine, a nonessential amino acid that appears to be conditionally essential during periods of physiologic stress, plays important physiologic roles in the immune system. However, neither enteral nor parenteral glutamine supplementation makes a difference in the rate of systemic infection or of NEC in very low birth weight infants. Thus, the search for agents to enhance the neonate's immune system and to serve as safe and effective adjuvants to antibiotics continues. Part V, the final article in this immunomodulation series, will explore the use of probiotics to support the neonatal immune system. |
Answer the following medical question. | What does research say about Quantification of neonatal procedural pain severity: a platform for estimating total pain burden in individual infants.? | There is increasing evidence that long-term outcomes for infants born prematurely are adversely affected by repeated exposure to noxious procedures. These interventions vary widely, for example, in the extent of damage caused and duration. Neonatal intensive care unit (NICU) procedures are therefore likely to each contribute differently to the overall pain burden of individual neonates, ultimately having a different impact on their development. For researchers to quantify the procedural pain burden experienced by infants on NICU, we aimed to estimate the pain severity of common NICU procedures using published pain scores. We extracted pain scores over the first minute (pain reactivity) from the literature, using 59 randomized controlled trials for 15 different procedures. Hierarchical cluster analysis of average pain scores resulted in 5 discrete severity groups; mild (n = 1), mild to moderate (n = 3), moderate (n = 7), severe (n = 3), and very severe (n = 1). The estimate of the severity of individual procedures provided new insight into infant pain reactivity which is not always directly related to the invasiveness and duration of a procedure; thus, both heel lance and skin tape removal are moderately painful procedures. This estimate of procedural pain severity, based on pain reactivity scores, provides a novel platform for retrospective quantification of an individual neonate's pain burden due to NICU procedures. The addition of measures that reflect the recovery from each procedure, such as brain activity and behavioural regulation, would further improve estimates of the pain burden of neonatal intensive care. |
Answer the following medical question. | What does research say about Neonatal cancer: a clinical perspective.? | The diagnosis of a neonatal malignancy, while rare, requires complex knowledgeable care from members of the health care team. The neonatal intensive care nurse plays an important role on that team. The types of malignancies found in neonates differ from those in older children, as do the neonate's responses to treatment. A review of the presentation, diagnosis, and management of the more common types of neonatal malignancies provides the context for consideration of the nurse's role in providing specialized care to neonates with cancer. |
Answer the following medical question. | What does research say about Family centred care for the neonate -- the view from Wolverhampton.? | The increased technology of neonatal intensive care has meant that babies born at increasingly lower gestational age are surviving to be discharged home. A family centred approach in neonatal care supports the move toward patient or parent empowerment, which is vital, if babies are to be fully integrated into the family unit. Nurses are essential to the success of this process as they have the most direct and prolonged contact with both family and their baby. Critical care areas such as Neonatal Units (NNU) can be adjusted to support a more family focused philosophy. In Wolverhampton Orems 'Self-Care Model' of self care has been adapted to the family as the self care unit and simple adjustments to the area such as Quiet Times supports families feeling of well being and control. |
Answer the following medical question. | What does research say about An Evidence-Based Practice Project to Provide Standardized Education on Skin-to-Skin Contact and Neonatal Hypoglycemia.? | To develop and examine the implications of formalized education with staff and familial caregivers on skin-to-skin in relation to neonatal hypoglycemia, including the impact on NICU admission rate, exclusive breastfeeding, and glucose gel administration. Evidence-based practice (EBP) project with a comparison of data pre-/postintervention. Implemented at a large health system in the mid-Atlantic, including four hospitals with postpartum care units. The EBP implementation site had approximately 19,400 births in 2021. Participants included 320 postpartum nurses in addition to the familial neonatal caregivers these nurses provided care for. All team members were provided with online education via the HealthStream learning platform, a microlearning introduction video, weekly huddle messages, and unit-specific champions who shared a champion information sheet that included information such as the hypoglycemia protocol, how to perform safe skin-to-skin care, and how to effectively administer glucose gel. Familial caregiver education included a handout given upon admission with an explanation from the postpartum nurse if the neonate met the criteria for the hospital system's neonatal hypoglycemia protocol. We observed a 4% system-wide increase in exclusive breastfeeding rates, a decrease in NICU admissions by 17.3% at 1-month postimplementation at the smallest hospital site (Hospital A), and a 12.3% reduction in NICU admission rates at the largest hospital site (Hospital B). Two hospitals reported a decrease in the need for glucose gel administration to neonates after the educational intervention. This nurse-led project detailed the process of a system-wide EBP project to implement consistent and standardized education regarding neonatal protocols. Although the benefits of skin-to-skin contact are widely known, this project demonstrated that focused, targeted education on skin-to-skin protocols for neonates at risk for neonatal hypoglycemia may be effective at improving outcomes. |
Answer the following medical question. | What does research say about Premedication for Endotracheal Intubation in the Neonate.? | Endotracheal intubation, a common procedure in neonatal intensive care, results in distress and disturbs physiologic homeostasis in the newborn. Analgesics, sedatives, vagolytics, and/or muscle relaxants have the potential to blunt these adverse effects, reduce the duration of the procedure, and minimize the number of attempts necessary to intubate the neonate. The medical care team must understand efficacy, safety, and pharmacokinetic data for individual medications to select the optimal cocktail for each clinical situation. Although many units utilize morphine for analgesia, remifentanil has a superior pharmacokinetic profile and efficacy data. Because of hypotensive effects in preterm neonates, sedation with midazolam should be restricted to near-term and term neonates. A vagolytic, generally atropine, blunts bradycardia induced by vagal stimulation. A muscle relaxant improves procedural success when utilized by experienced practitioners; succinylcholine has an optimal pharmacokinetic profile, but potentially concerning adverse effects; rocuronium may be the agent of choice based on more robust safety data despite a relatively prolonged duration of action. In the absence of an absolute contraindication, neonates should receive analgesia with consideration of sedation, a vagolytic, and a muscle relaxant before endotracheal intubation. Neonatal units must develop protocols for premedication and optimize logistics to ensure safe and timely administration of appropriate agents. |
Answer the following medical question. | What does research say about A Unique Case of Intrauterine Pressure Injury.? | The authors present a review of the literature regarding pressure injuries (PIs) in neonates and a case of a newborn who developed a PI following a prolonged labor process and fetal malposition. A girl born at 35 weeks' gestation to a 34-year-old gravida 7 para 6 mother with a medical history of untreated gestational diabetes, preeclampsia, and COVID-19 was delivered via cesarean section after failure to progress through labor. The premature infant was found to have a 3.2 × 2.3-cm PI at the nape of the posterior neck. Premature infants have a histologically proven, age-dependent decreased thickness of their stratum corneum, epidermis, and dermis, which places them at increased risk of developing PIs that can be painful and lead to infection. In the present case, the neonate's congenital PI was successfully treated with medical-grade honey for approximately a month. |
Answer the following medical question. | What does research say about Effect of early kangaroo mother care on time to full feeds in preterm infants - A prospective cohort study.? | Kangaroo mother care (KMC) is known to reduce neonatal mortality and morbidity. In preterm neonates, KMC is usually initiated only after stabilization. We aimed to assess if early initiation of KMC starting within the first week of life is safe, and reduces the time to full feeds (TFF) in preterm neonates. Prospective cohort study. Preterm neonates (Gestation ≤ 34 weeks, Birth weight ≤ 1250 g). This was studied in two epochs, (epoch 1) which was before early KMC vs. epoch 2 which was after implementation of early KMC even if they needed respiratory support, with umbilical/central lines in situ. The primary outcome of the study was time to establish full feeds (TFF) of 150 ml/kg/day. The neonatal demographic characteristics were comparable between epoch 1 and epoch 2 except for lower gestational age, higher surfactant, and any respiratory support in epoch 2. On univariate analysis, early KMC significantly reduced TFF (12.5 vs. 9 days, P < 0.001). Feed intolerance, duration of parenteral nutrition were significantly reduced, and discharge weight Z score improved significantly in epoch 2. On multivariate regression analysis early KMC, exclusive mother's own milk feeding and blood culture-positive late-onset sepsis were important predictors of TFF. Early KMC was safe and well-tolerated. Early KMC was safe and associated with reduced TFF and other nutritional benefits in moderately ill preterm neonates. |
Answer the following medical question. | What does research say about Transport of the mechanically ventilated neonate.? | Although the primary focus of this article is on interhospital transport, some of the same basic transport principles and management techniques apply to intrahospital transport. The level of care provided during interhospital and intrahospital transport should be based on the neonate's diagnosis, clinical status, anticipated problems, and local, state, and national standards and regulations. The transport team should have policies and procedures to direct their practice. Documentation of the transport process should be initiated with the referral call and continued until the completion of transport. Planning and anticipation of problems are essential, as is care of the family. The transport team should evaluate each neonate's individual response to the transport. |
Answer the following medical question. | What does research say about Patient blood management, what does this actually mean for neonates and infants?? | Patient blood management (PBM) refers to an evidence-based package of care that aims to improve patient outcomes by optimal use of transfusion therapy, including managing anaemia, preventing blood loss and improving anaemia tolerance in surgical and other patients who may need transfusion. In adults, PBM programmes are well established, yet the definition and implementation of PBM in neonates and children lags behind. Neonates and infants are frequently transfused, yet they are often under-represented in transfusion trials. Adult PBM programmes may not be directly applicable to these populations. We review the literature in neonatal (and applicable paediatric) transfusion medicine and propose specific neonatal PBM definitions and elements. |
Answer the following medical question. | What does research say about Prediction of initiation and duration of breast-feeding for neonates admitted to the neonatal intensive care unit.? | Women who desire to breast-feed their sick newborns often encounter obstacles, including insufficient support and education as well as unsupportive hospital practices. The purpose of this study was to describe maternal, neonatal, and outside influences associated with the intention, initiation, and duration of breast-feeding for women whose newborns were admitted to the neonatal intensive care unit. One hundred mothers were interviewed. Most mothers (67%) intended to breast-feed exclusively and this was significantly related to maternal characteristics such as age, education, parity, smoking and marital status, pre-breast-feeding experience, and the influences of the neonate's father and prenatal education. Seventy-eight mothers initiated pumping. Initiation was significantly related to maternal education, smoking, parity, previous breast-feeding experience, the neonate's physician, the neonate's father, and postpartum breast-feeding education. Fifty-four mothers were followed up by telephone after discharge until weaning. Thirty percent were exclusively breast-feeding at 2 weeks after discharge, and 15% were breast-feeding at 1 year. Duration of breast-feeding was significantly associated with education, marital status, ethnicity, income, assistance from nurses and lactation consultants, and feeding method along with milk type and milk volume at discharge. Increased family support, timely breast-feeding information, and a supportive neonatal intensive care unit environment are needed for women to succeed in breast-feeding their hospitalized newborns. |
Answer the following medical question. | What does research say about Evaluation of three pain assessment scales used for ventilated neonates.? | To compare and evaluate the reliability, validity, feasibility, clinical utility, and nurses' preference of the Premature Infant Pain Profile-Revised, the Neonatal Pain, Agitation, and Sedation Scale, and the Neonatal Infant Acute Pain Assessment Scale used for procedural pain in ventilated neonates. Procedural pain is a common phenomenon but is undermanaged and underassessed in hospitalised neonates. Information for clinician selecting pain measurements to improve neonatal care and outcomes is still limited. A prospective observational study was used. A total of 1,080 pain assessments were made at 90 neonates by two nurses independently, using three scales viewing three phases of videotaped painful (arterial blood sampling) and nonpainful procedures (diaper change). Internal consistency, inter-rater reliability, discriminant validity, concurrent validity and convergent validity of scales were analysed. Feasibility, clinical utility and nurses' preference of scales were also investigated. All three scales showed excellent inter-rater coefficients (from 0.991-0.992) and good internal consistency (0.733 for the Premature Infant Pain Profile-Revised, 0.837 for the Neonatal Pain, Agitation, and Sedation Scale and 0.836 for the Neonatal Infant Acute Pain Assessment Scale, respectively). Scores of painful and nonpainful procedures on the three scales changed significantly across the phases. There was a strong correlation between the three scales with adequate limits of agreement. The mean scores of the Neonatal Pain, Agitation, and Sedation Scale for feasibility and utility were significantly higher than those of the Neonatal Infant Acute Pain Assessment Scale, but not significantly higher than those of the Premature Infant Pain Profile-Revised. The Neonatal Pain, Agitation, and Sedation Scale was mostly preferred by 55.9% of the nurses, followed by the Neonatal Infant Acute Pain Assessment Scale (23.5%) and the Premature Infant Pain Profile-Revised (20.6%). The three scales are all reliable and valid, but the Neonatal Pain, Agitation, and Sedation Scale and the Neonatal Infant Acute Pain Assessment Scale perform better in reliability. The Neonatal Pain, Agitation, and Sedation Scale appears to be a better choice for frontier nurses to assess procedural pain in ventilated neonates based on its good feasibility, utility and nurses' preference. Choosing a valid, reliable, feasible and practical measurement is the key step for better management of procedural pain for ventilated newborns. Using the right and suitable tool is helpful to accurately identify pain, ultimately improve the neonatal care and outcomes. |
Answer the following medical question. | What does research say about Oropharyngeal Mother's Milk: State of the Science and Influence on Necrotizing Enterocolitis.? | Oropharyngeal administration of mother's own milk-placing drops of milk directly onto the neonate's oral mucosa-may serve to (ex utero) mimic the protective effects of amniotic fluid for the extremely low birth weight infant; providing protection against necrotizing enterocolitis. This article presents current evidence to support biological plausibility for the use of OroPharyngeal Therapy with Mother's Own Milk (OPT-MOM) as an immunomodulatory therapy; an adjunct to enteral feeds of mother's milk administered via a nasogastric or orogastric tube. Current methods and techniques are reviewed, published evidence to guide clinical practice will be presented, and controversies in practice will be addressed. |
Answer the following medical question. | What does research say about Systemic fungal infections in neonates.? | Systemic fungal infections in neonates |
Answer the following medical question. | What does research say about The best interest principle as a standard for decision making in the care of neonates.? | In neonatal care, decisions are made on behalf of newborn infants by their parents or, in some instances, health professionals. This paper examines how the best interest standard is the most appropriate focus for decision-making concerning neonates. The components of surrogate decision-making are discussed from the perspective of the neonate's interests and the contribution of the various persons involved in caring for neonates. An argument is presented for the use of best interests when making decisions and the interpretation of best interests is explored. By examining the ethical approaches using best interests, an argument is put forward for caring as an expression of best interests. How some nurses use the best interest standard in their practice is described. The unique perspective nurses may have because of their philosophy, circumstances, experience and concern for neonates is discussed. Examples are used from the literature to support the argument for nurses being in roles and relationships where the neonate's interests are the basis of practice. How nurses classify infants on the basis of their future outcome is used to illustrate how nurses can apply the best interest standard. Ethical approaches of care and cure are used to show the best interest standard as applied to neonates. Caring as an expression of best interests is recommended for nursing decisions and actions using infant outcomes as a focus for caring and best interests. |
Answer the following medical question. | What does research say about Impact of a nurse education programme on oral feeding in a neonatal unit.? | Premature neonates often experience feeding difficulties during their hospital stay, and evidence-based interventions have been shown to improve feeding outcomes. This study investigated whether an infant-cue based nurse educational feeding bundle accelerates the achievement of independent oral feeding in neonates in a neonatal intensive care unit. A quality improvement study with a pre, during and post intervention test design. All premature neonates admitted to the unit were eligible. The feeding programme included a four-month nurse training module and nurse coaching. A hundred and twenty-five nurses or nurse assistants attended the programme and 706 neonates were included. The median time to independent oral feeding (IOF) was 40, 36 and 37 days, respectively, for pre, during and post intervention. The reduction in time to IOF observed during the post-intervention period compared with the baseline period was significant (HR = 1.32, CI 95%: 1.01-1.74). No difference was noted in the length of hospital stay between the three study periods. An infant-cue based nurse educational feeding bundle can promote earlier achievement of IOF in preterm neonates. This quality improvement study demonstrates the impact that a nurse-driven intervention in neonatal care can have on improving practice. Feeding interventions involve the early introduction of oral feeding, non-nutritive sucking (NNS), and oral motor stimulation, and should be individualized for each neonate. These individualized feeding interventions applied by all nurses and assistant nurses, can facilitate the achievement of earlier independent oral feeding in preterm infants and should be included in neonatal critical care nurse education programs. |
Answer the following medical question. | What does research say about Hypothyroxinemia and weight velocity in preterm infants.? | Hypothyroxinemia of prematurity (HOP) is characterized by low free thyroxine (FT4) associated with low or normal thyroid stimulating hormone (TSH). The objective of this study is to define FT4 and TSH values in very preterm infants (<32 weeks postmenstrual age, PMA) and correlate hypothyroxinemia and levothyroxine treatment with growth velocity at 28 days and 36 weeks PMA. Preterm neonates <32 weeks PMA admitted to the regional neonatal intensive care unit (NICU) at the Children's Hospital of Georgia (USA) between January 2010 and July 2022 were routinely screened for hypothyroxinemia. FT4 and TSH values were obtained on 589 eligible neonates between day of life (DOL) 4 and 14. Growth velocity (g/kg/day) from DOL 14 to DOL 28 and 36-weeks PMA were calculated for each neonate and potential explanatory variables (PMA, sex, and race) were incorporated into multivariate regression models to identify associations between HOP and growth velocity. In 589 preterm infants, PMA at birth was strongly associated inversely with FT4 (R=0.5845) and modestly with TSH (R=0.2740). Both FT4 and gestational age, but not TSH or levothyroxine treatment, were associated with growth velocity at 28 days of life and at 36 weeks PMA. We provide a large data set for identifying FT4 and TSH measurements and identify hypothyroxinemia of prematurity as a potential mediator of slow postnatal growth in very preterm infants. |
Answer the following medical question. | What does research say about Therapeutic drug monitoring--the appropriate use of drug level measurement in the care of the neonate.? | Neonates and young infants are in a unique and dynamic pharmacokinetic state, in which they undergo relatively rapid maturational changes in drug absorption, distribution, metabolism, and excretion. In addition to these maturational changes, most drug pharmacokinetic studies in neonates show wide interindividual variability despite similar gestational and postnatal ages. Therapeutic drug monitoring is a necessary tool in the neonatal intensive care unit, despite the relative lack of outcome data. This article discusses therapeutic drug monitoring for several frequently used drugs in neonates. |
Answer the following medical question. | What does research say about Should Parents of Neonates With Bleak Prognosis Be Encouraged to Opt for Another Child With Better Odds? On the Notion of Moral Replaceability.? | The notion of moral exchangeability is scrutinized and its proper place in neonatal care is examined. On influential moral outlooks, the neonate is morally exchangeable. On these views, if the parents are prepared to let go of the neonate with a poor prognosis and opt instead for another child who is healthy, this may be the morally right thing for them to do, and neonatal care ought to ease their choice. The notion of moral exchangeability has a different place in different moral theories. Three theories are examined: deontological ethics (insisting on the sanctity of innocent human life), according to which there is no place for the replacement of 1 child for another. It is different, however, with utilitarianism and in the moral rights theory based on self-ownership. According to utilitarianism, we are all replaceable. According to the moral rights theory, neonates are replaceable to the extent that they have not developed personhood. Even a deontological ethicist of a Kantian bent would concur here with the moral rights theory. Because influential moral theories imply that the neonate is morally exchangeable, it is reasonable within neonatal care, as a general rule, to grant the parents a veto against any attempts to save a child with a poor prognosis. In particular, if the parents are prepared instead to have another, healthy child, this is to be recommended. However, this rule cannot be strict. In rare cases, it is necessary to yield to parents who insist that their neonate be saved despite a poor prognosis. |
Answer the following medical question. | What does research say about Outcomes of pregnancy for addicts receiving comprehensive care.? | This study reports pregnancy outcomes for 105 addicted women enrolled in New York Medical College's Pregnant Addicts and Addicted Mothers Program. Three classes of variables are examined: prenatal care variables, obstetrical outcomes, and neonatal outcomes. As a first step, percentage distributions are shown for all variables within each class. With respect to the second and third classes, comparisons are made when possible to findings reported elsewhere on heroin-addicted, methadone-maintained, and drug-free populations. Zero-order correlations are then shown for the prenatal care variables versus the neonatal outcomes. It is found that the mother's number of prenatal medical visits correlates significantly with the neonate's gestational age at birth and birth weight, and that her methadone dose at time of delivery correlates significantly with the neonate's withdrawal status. The effect of the prenatal care variables on the two key neonatal outcomes--gestional age at birth and birth weight--is then examined via a stepwise regression analysis. It is found that two of the variables--gestional duration at first prenatal visit and number of prenatal visits--together account for 18.5% of the variance in birth weight and 26.9% of the variance in gestational age at birth, while maternal methadone dose has virtually no effect on these outcome measures. The findings indicate that better neonatal outcomes are associated with the mother's joining the program relatively early in pregnancy and coming in relatively often for prenatal care. |
Answer the following medical question. | What does research say about Are the current feeding volumes adequate for the growth of very preterm neonates?? | Postnatal growth failure, a common problem in very preterm neonates associated with adverse neurodevelopmental outcome, has recently been shown not to be inevitable. There is a wide discussion regarding feeding practices of very preterm neonates, specifically regarding feeding volumes and nutrients supply to avoid postnatal growth failure. Current guidelines recommend an energy intake of 115–140 kcal /kg per d with a considerably higher upper limit of 160 kcal/kg per d. The feeding volume corresponding to this energy supply is not higher than 200 ml/kg in most cases. From the other side, randomised and observational studies used higher feeding volumes, and these were associated with better weight gain and growth, while no complications were noted. Taking into account the above, nutritional practices should be individualised in each very and extremely preterm infant trying to reduce postnatal growth failure, pointing out that available data are inconclusive regarding the effect of high-volume feeds on growth. Large clinical trials are necessary to conclude in the best feeding practices of very preterm neonates. Despite advances in neonatal care and nutritional practices, postnatal growth failure remains common among very preterm neonates ( . In a multicentre study 1 , 2 ) ( of 1187 infants born at 23–27 weeks of gestation at fourteen neonatal intensive care units in the USA, postnatal growth failure was found in 75 % of these infants at 28 d of life even though the growth velocity rate was above 15 g/kg per d, which is considered an adequate growth velocity for preterm infants 3 ) ( . For many years, the goals of nutritional care are set to approximate the growth and body composition of a healthy fetus although it is recognised that optimal proportions of fat and lean mass accretion will differ 4 – 6 ) ( . 7 , 8 ) Postnatal growth failure is of great concern since there is evidence that it is associated with poor neurodevelopmental outcomes ( . A multicentre cohort study that evaluated 495 infants with 501 to 1000 g birth weight found that the growth velocity had a significant and possibly independent effect on neurodevelopmental and growth outcomes at 18–22 months corrected age 4 , 9 ) ( . Similarly, a study of 219 very low birth weight infants showed that children with postnatal weight gain below the 10th percentile at the age of 2 years were at the highest risk for mental retardation, motor delay, and cerebral palsy, and their developmental outcome was even worse than that of children who were small for gestational age and had insufficient catch-up growth. Therefore, this study concluded that the postnatal growth pattern was the most important factor associated with adverse neurodevelopmental outcomes at the age of 2 years 4 ) ( . However, the association of postnatal weight gain and head growth with later neurocognitive outcomes was reported mainly in observational studies but not in interventional studies 9 ) ( . 10 ) For the last 20 years, there is a discussion regarding the prevention of postnatal growth failure especially in very preterm infants with major morbidities ( . Population-based studies initially proposed that postnatal growth failure was inevitable 11 ) ( . In 2018, Andrews et al analysed data from 396 preterm very low birth weight newborns in a tertiary neonatal unit after the implementation of new nutritional practices. They found that most infants had growth approximating their birth centile, indicating that adequate postnatal growth was not inevitable 12 , 13 ) ( . Several reasons avert very preterm neonates to achieve optimal growth. Embleton et al in 2001 stated in their review that preterm infants had a significant and irreplaceable nutrient deficit in the first few weeks of life that led to postnatal growth failure. This deficit was due to nutritional practices that were based on nutrient maintenance and normal growth but not on catch-up growth 14 ) ( . The problem seems to be more severe in very preterm neonates with co-morbidities such as bronchopulmonary dysplasia (BPD). Very preterm neonates with morbidities had further reduction in growth during hospitalisation, 15 ) ( and this might be due to lower energy administration than that recommended by current feeding practices leading to a further increase in energy deficit 16 ) ( . The observations above indicate that a energy deficit is accumulated, which should be taken into consideration in nutritional practices during hospitalisation. This practice is also emphasised in a recent statement by ESPGHAN who recommended increasing nutrient intakes above estimated target needs during the recovery phase 11 , 17 ) ( . 18 ) Strategies for the prevention of malnutrition and the resulting insufficient growth have been studied including the volume of the feeds. The range of feeding volumes that is discussed in the widely implemented clinical practice 2010 ESPGHAN guidelines lies within 150–180 ml/kg per d (aiming to 110–135 kcal/kg per d energy) with lower and upper limits of 135–200 ml/kg per /d ( . Studies from 127 tertiary neonatal intensive care units reported feeding a wide range of feeding volumes of 140–200 ml/kg per d 19 ) ( . The very recent update of ESPGHAN guidelines 20 ) ( recommends a higher energy supply (115–140 kcal/kg per d 8 ) v .110–135 kcal/kg per d the older guidelines) with a considerably higher upper limit of 160 kcal/kg per d. The feeding volume corresponding to this energy supply is not higher than 200 ml/kg in most cases. Moreover, in the same report, emphasis is given to balance among the several nutrients (energy fractions) for optimal nutrition to promote optimal growth and long-term outcomes ( . Of note, these proposed volumes refer to fortified human milk, which is the best practice or alternatively special formula for very preterm neonates. All but one studies discussed below refer to respective volumes of the above-mentioned type of feeding. 8 ) As ESPGHAN Committee on Nutrition and invited experts in a recent position paper emphasise, these recommendations do not consider changes in energy needs related to acute illness or chronic disease states ( . These conditions are very common in this population. They do not also consider additional nutrient losses or demands of very preterm neonates 8 ) ( . They also conclude that in individual preterm infants, enteral intakes up to 200 ml/kg per d (or higher) may be appropriate and safe depending on current health status, such as the presence of a significant patent ductus arteriosus or BPD 8 ) ( . They also discuss the relevance in specific contexts of the administration of volumes above 200 ml/kg per d, namely in low-middle income countries where access to human milk fortifiers is limited or in infants that do not tolerate full-strength fortification. 8 ) In a randomised clinical trial of 224 infants born very preterm weighing 1001–2500 g at birth, volume feedings of 180–200 ml/kg per d of fortified human milk increased growth velocity, weight, head circumference, length and mid-arm circumference compared with usual-volume feedings of 140–160 ml/kg per d of fortified human milk ( . The average growth velocity of infants in the higher-volume group was 20 g/kg per d, 21 ) ( higher than the 15 g/kg per d that is considered adequate for catch-up growth 21 ) ( . Andrews et al analysed data from 396 preterm neonates and found that optimal nutritional practices led to infants’ growth approximating their birth centiles 5 , 6 ) ( . Another smaller randomised study of sixty-four preterm infants with birth weight < 1500 g found that infants fed on a high volume of expressed breast milk (300 ml/kg per d) had significantly higher daily weight gain compared with infants fed on a maximum of 200 ml/kg per d 14 ) ( . However, this study did not provide any data on the length and head circumference increase between the two groups 22 ) ( . Similarly, in a trial of fifty-four infants born at 24–29 weeks of gestation, volume feedings of 200 ml/kg per d of fortified human milk or preterm formula increased growth velocity, weight gain and arm fat area of infants, compared with those fed at volumes of 150 ml/kg per d 22 ) ( . However, head circumference and length did not differ significantly 23 ) ( . An older study of fifty-nine preterm infants born 1–2 kg birth weight also reported weight gain at the intra-uterine rate with feeding volumes of 250 ml/kg per d of breast milk or standard formula 23 ) ( . The available data indicate that higher feeding volumes led to higher weight gain and optimal growth velocity for catch-up growth. A recent Cochrane review of two randomised controlled trials comparing high 24 ) v . standard enteral feeds for preterm or low birth weight infants concluded that high-volume feeds probably improve weight gain during the hospital stay, yet available data are inconclusive on the effect of high-volume feeds on growth and clinical outcome ( . 25 ) On the other hand, fear of high-volume-related complications, mainly patent ductus arteriosus and BPD ( , leads to hesitation in the advancement of feeding volumes. Available studies find no adverse effects in the higher volume groups regarding fluid retention, haemodynamically significant patent ductus arteriosus, tachypnoea, rate of BPD, duration of respiratory support, necrotising enterocolitis, feeding intolerance and length of stay 19 ) ( . In a recent study of very preterm infants, gradually advancing milk feedings up to 260 ml/kg per d were generally well tolerated and without side effects 21 – 24 , 26 ) ( . Neonates with BPD did not have a significant difference in their respiratory function at 8 years of age compared with very preterm neonates without BPD and term controls when fed with increased milk volumes 26 ) ( . 27 ) Another possible clinicians’ concern is that higher feeding volumes may cause emesis or reflux or even just worsen reflux with a subsequent impact on respiratory status. Current studies assessing higher feeding volumes evaluated preterm infants for signs of feeding intolerance, such as episodes of vomiting and increased aspirates. In the study of Thomas et al, more infants in the high-volume group had feeding intolerance; however, this observation was not statistically significant ( . No difference in feeding intolerance between higher and standard feeding volumes was also noted in two other studies 22 ) ( . A meta-analysis also found that there is little or no difference in feeding intolerance between shorter feeding intervals (smaller milk volumes) and longer intervals (higher milk volumes) in very preterm infants 23 , 28 ) ( . A recent randomised controlled trial of 2804 very preterm or very-low-birth-weight infants found that daily milk increments of 30 ml/kg 29 ) v . 18 ml/kg did not make a difference in survival without moderate or severe neurodevelopmental disability, late-onset sepsis or necrotising enterocolitis ( . A Cochrane review of six trials concluded that data are insufficient to determine how progressive introduction of enteral feeds affects the risk of necrotising enterocolitis (NEC) 30 ) ( . Another recent Cochrane review of fourteen trials involving 4033 infants showed that slow advancement of enteral feed volumes probably has little or no effect on the risk of NEC and overall-cause mortality 31 ) ( . In this review, meta-analyses suggested that slow advancement may slightly increase feed intolerance and the risk of invasive infection; however, this evidence was of low certainty 32 ) ( . 32 ) Another study using a similar intensive feeding policy did not find to affect the BMI and obesity rates at the ages of 2 and 8 years ( . Moreover, rapid weight gain up to term-corrected age in preterm infants had no impact on later metabolic status, while rapid weight gain in later childhood seemed to affect the cardiometabolic status 26 ) ( . Body composition is not routinely estimated in neonatal units, whereas all three anthropometrics namely head circumference, body weight and body length, as a proxy for lean mass accretion, should be taken into consideration. Optimally, growth in the preterm neonates should not lead to excessive fat deposition, and this is addressed in the last ESPGHAN guidelines also 33 ) ( . Low energy intake in the first week of life may be a predisposing factor for complications. A large Swedish retrospective study of 498 infants less than 28 weeks gestation showed that a low energy intake of 102 kcal/kg per d during the first 4 weeks of life was an independent risk factor for the development of severe retinopathy of prematurity, while an increase in energy intake of 10 kcal/kg per d was associated with a 24 % decrease in severe retinopathy of prematurity 8 ) ( . 34 ) Very preterm neonates vary in many aspects such as gestational age, birth weight, sex, perinatal complications, type of feeding (fortified human milk which is the best practice or alternatively special formula or combination), heritability (parental BMI and obesity) and epigenetic factors. Studies in young adults (although reluctance exists when extrapolating adult data to neonates) emphasised the crucial role of heritability and other factors such as gut microbiota in weight gain ( . Based on the above parameters, it seems unlikely that a standard amount of energy fits the needs of each preterm infant to achieve a standard growth pattern and that the amount of feeding should be individualised. Factors such as appetite and satiety regulation which seem to play a crucial role in delineating the true physiological needs to maintain a healthy, normal weight have not so far been studied in preterm neonates 35 , 36 ) ( . There are also no studies assessing the association of nutrition and constitutional factors in the growth of preterm infants. An early study of Kuschel et al demonstrated that almost half of the infants required higher milk intakes to maintain weight gain and the other half required a reduction of milk intake due to feed intolerance. This observation further supports the need for individualisation of feeding 37 ) ( . In corroboration of our notions in the recent ESPGHAN statement, the authors highlight that growth in the 23 ) ex utero environment will never be the same as in utero , that optimal proportions of fat and lean mass accretion will differ, and that optimal nutrient intakes and growth trajectory for an individual infant are impossible to determine ( . 8 ) Currently available guidelines propose feeding the preterm newborn to provide an energy supply of 115–140 kcal/kg per d (maximum 160 kcal/kg per d) which typically represents a feeding volume of 140–180 ml/kg per d (maximum 200 ml/kg per d) ( . In the previous and largely adopted 2010 ESPGHAN statement, whereas slightly smaller volumes have been proposed, the authors state that these feeding volumes may be inadequate for several substrates and have accepted that the nutrient intake above this specified range is not discouraged if justified for a good reason 8 ) ( . Similar concerns are expressed in the current report also, whereas authors acknowledge that neonatal nutrition research is extremely active, and it is likely that alternative approaches and recommendations may be preferable as our knowledge expands. Special preterm formula has a standard concentration with increased protein content; thus, in case of inadequate weight gain, the quantity should be increased since the energy and protein ratio needs to be stable, a necessary issue for protein utilisation. We have observed that very preterm neonates often need higher feeding volumes of fortified human milk or special preterm formula or combination to maintain minimum weight gain. Moreover, we have observed in three tertiary neonatal care units (unpublished observations) that many very preterm infants, immediately after the transition from tube feeding to bottle feeding, consume 19 ) ad libitum milk volumes of 250–300 ml/kg per d or even higher. Recent studies conducted by our research group showed that these higher feeding volumes are usually well tolerated and have not adversely affected BMI at school age, and moreover, very preterm neonates treated with a more intense feeding policy had a good respiratory prognosis at school age ( . Furthermore, healthy bottle-fed full-term neonates and young infants followed up in our outpatient clinic usually consume variable milk volumes ranging between 150 and 250 ml/kg, but their weight gain is also variable and, on several occasions, unrelated to the consumed milk volumes. These observations have also been made by other researchers 26 , 27 ) ( . In a few studies, volumes up to 300 ml/kg per d have been administered earlier but also recently 22 , 24 , 38 , 39 ) ( . One could speculate that reluctance in milk administration exists among many neonatologists in tube-fed premature babies and that many physicians rely on unproven risks to prescribe milk with caution. The interplay between growth factors, genes, epigenetics and nutrient supply, on an individual basis, may affect the early postnatal growth in the preterm infant 22 , 24 , 26 , 38 , 39 ) ( . Nutrient supply is the parameter that we can easily modulate to achieve optimal short-term and long-term outcomes. 40 ) In conclusion, nutritional practices should be individualised in each very preterm infant for ideal growth. Available data are inconclusive regarding the effect of high-volume feeds on growth and later outcomes. There is a need for larger randomised studies that compare higher target feeding volumes in very preterm infants to universally conclude in the optimal feeding practices. None. This research received no specific grant from any funding agency, commercial or not-for-profit sectors C. K. performed the literature search and drafted the manuscript. E. S., D. R. and A. M. contributed to the literature search and drafting of the work. R. S. and M. B. critically revised the manuscript. V. G. proposed the writing of the article, supervised and critically revised the work. A. G. and R. S. contributed to the idea of the article, contributed to literature search and critically revised the manuscript. All authors approved the final version to be published and agreed to be accountable for all aspects of the work. There are no conflicts of interest. Are the current feeding volumes adequate for the growth of very preterm neonates? Cumulative impact of multiple evidence based strategies on postnatal growth of extremely-low-birth-weight infants Very preterm infants admitted to a tertiary neonatal unit in central Vietnam showed poor postnatal growth Nutritional practices and growth velocity in the first month of life in extremely premature infants Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants Longitudinal growth of hospitalized very low birth weight infants An attempt to standardize the calculation of growth velocity of preterm infants-evaluation of practical bedside methods Updates on assessment and monitoring of the postnatal growth of preterm infants Enteral nutrition in preterm infants (2022): a position paper from the ESPGHAN committee on nutrition and invited experts Postnatal growth in VLBW infants: significant association with neurodevelopmental outcome Postnatal growth in preterm infants and later health outcomes: a systematic review Post-natal growth of very preterm neonates Birth weight and longitudinal growth in infants born below 32 weeks’ gestation: a UK population study Weight growth velocity and postnatal growth failure in infants 501–1500 g: 2000–2013 Early postnatal growth failure in preterm infants is not inevitable Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Birthweight and patterns of postnatal weight gain in very and extremely preterm babies in England and Wales, 2008–2019: a cohort study Assessment of early nutritional intake in preterm infants with bronchopulmonary dysplasia: a cohort study Nutritional management of the critically ill neonate: a position paper of the ESPGHAN committee on nutrition Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition Enteral feeding practices in very preterm infants: an international survey Higher- or usual-volume feedings in infants born very preterm: a randomized clinical trial A randomized control trial comparing two enteral feeding volumes in very low birth weight babies A randomized trial of enteral feeding volumes in infants born before 30 weeks’ gestation High volume milk feeds for preterm infants High ‘Aggressive’ feeding of very preterm neonates and body mass index at school age Very preterm neonates receiving ‘aggressive’ nutrition and early nCPAP had similar long-term respiratory outcomes as term neonates Proactive enteral nutrition in moderately preterm small for gestational age infants: a randomized clinical trial Short Controlled trial of two incremental milk-feeding rates in preterm infants Early full enteral feeding for preterm or low birth weight infants Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants Catch-up growth and metabolic outcomes in adolescents born preterm Low energy intake during the first 4 weeks of life increases the risk for severe retinopathy of prematurity in extremely preterm infants Heritability of body size and muscle strength in young adulthood: a study of one million Swedish men Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment Infant feeding, appetite and satiety regulation, and adiposity during infancy: a study design and protocol of the ‘MAS-Lactancia’ birth cohort Continuous intragastric milk feeds in infants of low birth weight Randomised trial of nutrition for preterm infants after discharge Is preterm nutrition a trade-off between head and heart |
Answer the following medical question. | What does research say about Practical pain management in the neonate.? | Neonatal care is advancing to levels where more neonates are now offered more invasive interventions, exposing them to more prolonged hospital care. Consequently, the provision of effective and consistent management of pain in these neonates has become a pressing challenge. Advances in neonatal care have not only increased the number of neonates, who are exposed to noxious stimuli, but, over recent decades, also altered the patterns of exposure. Both procedural and postoperative pain remain distinct in nature, prevalence and management, and need to be addressed separately. Recent advances in the management of neonatal pain have been facilitated by improved methods of pain assessment and an increased understanding of the developmental aspects of nociception. Over the past decade, there have been some advances in the available pharmacological armamentarium, modest clarification of the risks of both untreated pain and aggressive analgesic practice and a greater recognition of non-pharmacological analgesic techniques. However, even advanced health systems fail to consistently articulate pain management policy for neonates, institute regular pain assessments and bridge the gaps between research and clinical practice. |
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