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Answer the following medical question. | What does research say about Bench-to-bedside review: Developmental influences on the mechanisms, treatment and outcomes of cardiovascular dysfunction in neonatal versus adult sepsis.? | Sepsis is a significant cause of morbidity and mortality in neonates and adults, and the mortality rate doubles in patients who develop cardiovascular dysfunction and septic shock. Sepsis is especially devastating in the neonatal population, as it is one of the leading causes of death for hospitalized infants. In the neonate, there are multiple developmental alterations in both the response to pathogens and the response to treatment that distinguish this age group from adults. Differences in innate immunity and cytokine response may predispose neonates to the harmful effects of pro-inflammatory cytokines and oxidative stress, leading to severe organ dysfunction and sequelae during infection and inflammation. Underlying differences in cardiovascular anatomy, function and response to treatment may further alter the neonate's response to pathogen exposure. Unlike adults, little is known about the cardiovascular response to sepsis in the neonate. In addition, recent research has demonstrated that the mechanisms, inflammatory response, response to treatment and outcome of neonatal sepsis vary not only from that of adults, but vary among neonates based on gestational age. The goal of the present article is to review key pathophysiologic aspects of sepsis-related cardiovascular dysfunction, with an emphasis on defining known differences between adult and neonatal populations. Investigations of these relationships may ultimately lead to 'neonate-specific' therapeutic strategies for this devastating and costly medical problem. Sepsis is a significant cause of morbidity and mortality in neonates and adults, and the mortality rate from sepsis doubles in patients who develop cardiovascular dysfunction and septic shock [ 1 ]. Annual combined deaths from sepsis of patients of all ages equal the number of deaths from myocardial infarction [ 2 ], and 7% of all childhood deaths result from sepsis alone [ 3 ]. Sepsis is especially devastating in the neonatal population, as it is responsible for 45% of late deaths in the neonatal intensive care unit, making it one of the leading causes of death for hospitalized infants [ 4 ]. The incidence of sepsis is age-related, and is highest in infants (5.3/1,000) and the elderly over 65 years of age (26.2/1,000) [ 2 ]. Although the incidence is highest in the elderly, both the intensive care unit admission rates (58.5% versus 40%) and the average costs ($54,300 versus $14,600) are higher in infants [ 2 ]. Twenty-one percent of very low birthweight infants will develop at least one episode of culture-proven bloodstream sepsis after the first 3 days of life [ 5 ], and the septic episode will probably be more severe than in adults [ 3 ]. In very low birthweight infants, sepsis increases the hospital stay by 30% and increases mortality 2.5 times [ 5 ]. Unlike adults, little is known about the cardiovascular response to sepsis in the neonate. Baseline neonatal cardiovascular function has not been well defined, and studies of inotrope use to treat hypotension in neonates have failed to show any improvement in short-term or long-term clinical outcomes [ 6 ]. In addition, recent research has demonstrated that the clinical presentation, mechanisms, inflammatory response, response to treatment and outcome of neonatal sepsis vary not only from that of adults, but vary among neonates based on gestational age. The goal of the present article is to review key pathophysiologic aspects of sepsis-related cardiovascular dysfunction, with an emphasis on defining known differences between adult and neonatal populations. The potential impact of these differences on therapeutic strategies is also discussed. Underlying the differences in neonatal and adult sepsis are alterations in the developing immune system. These differences include innate and acquired immunity, immune cell numbers and function, cytokine elaboration and the inflammatory response. The influence of perinatal factors on the development and response to sepsis is unique to newborns. Challenges to the maternal immune system before and during pregnancy have been associated with modulation of the neonatal immune response, and this modulation occurs in both humoral and cell-mediated immunity [ 7 ]. Although proinflammatory cytokines such as TNFα, IL-1β and IL-6 have not been shown to cross the human term placenta [ 8 ], certain immunoglobulins and lymphoid cells can cross the placenta and change fetal and postnatal immune development [ 7 ]. The transplacental transfer of immunoglobulins, however, does not occur until 32 weeks gestation [ 9 ], leading to a relative immune deficiency in extremely premature infants. Labor of any duration may be immunologically beneficial to the neonate, with improved neutrophil survival and lipopolysaccharide (LPS) responsiveness [ 10 ]. Labor itself is a mild pro-inflammatory state and has been associated with delayed neutrophil apoptosis, fetal leukocytosis and elevation of the systemic neutrophil count when compared with cesarean section without labor [ 10 ]. In addition, respiratory burst, CD11b/CD18 and IL-8 receptors have all been shown to be increased after vaginal delivery in comparison with cesarean section [ 11 ]. Severe infection can induce the systemic inflammatory response syndrome and can lead to the development of septic shock, which is associated with elevated levels of proinflammatory cytokines including IL-1β, IL-6, IL-8 and TNFα [ 12 ]. LPS is a cell wall component of Gram-negative bacteria, and is the main endotoxin implicated in the initiation of the proinflammatory response [ 13 ]. If this extreme inflammatory response is not counterbalanced by a competent compensatory anti-inflammatory response syndrome, the resultant exaggerated inflammatory response leads to increased morbidity and mortality during sepsis [ 14 ]. The concentration of proinflammatory cytokines is higher in patients with septic shock than in those with severe sepsis, and elevated levels of IL-1β, IL-6 and IL-8 are associated with an increase in early mortality (<48 hours) [ 12 ]. Sepsis also has the potential to develop into a bimodal disease initially characterized by a proinflammatory state and progressing to a state of immune suppression and immunoparalysis [ 15 , 16 ], which is related to increased production of IL-10 [ 17 ] and decreased HLA-DR expression [ 18 ]. The resultant immune suppression appears to be confined to the blood compartment, however, while a hyperinflammatory state persists in tissues, which makes defining the role of cytokines in sepsis more difficult [ 19 ]. The inflammatory cytokine response to sepsis differs in neonates and adults. Although premature infants were once believed to have deficient production of proinflammatory cytokines, intrauterine fetal cord blood samples taken between 21 and 32 weeks gestation have demonstrated significant synthesis of IL-6, IL-8 and TNFα [ 20 ]. Term and preterm infants have been shown to have a higher percentage of IL-6-positive and IL-8-positive cells than adults, with preterm infants having the highest percentage of IL-8-positive cells [ 21 ]. After stimulation with LPS, this increased percentage of proinflammatory cells in neonates is more pronounced and occurs faster than in adults. In addition, the compensatory anti-inflammatory response system in neonates appears to be immature, with both term and preterm infants demonstrating profoundly decreased IL-10 production and a lower amount of transforming growth factor beta-positive lymphocytes than do adults after LPS stimulation [ 14 ]. Although there is a decrease in the absolute amount of IL-10 produced, an increase in the IL-10:TNFα ratio has been reported in premature infants after LPS exposure; an increased IL-10:TNFα ratio in critically ill adults has been shown to be a negative predictor of outcome [ 22 ]. These perinatal and developmental influences on innate immunity and the inflammatory response may significantly alter the neonate's response to pathogen exposure. In addition to cytokine differences in the neonate, eosinophils, macrophages and polymorphonuclear neutrophils have reduced surface binding components and have defective opsonization, phagocytosis and antigen-processing capabilities, leading to a generally less robust response to pathogen exposure. Polymorphonuclear neutrophil function is the primary line of defense in the cellular immune system, and there is an alteration in both neutrophil function and survival in neonates versus adults. Neonates, especially those born prematurely, display a pattern of infectious diseases similar to the pattern seen in older individuals with severe neutropenia [ 20 ], have a markedly decreased neutrophil storage pool and cell mass [ 23 , 24 ], and are more likely to develop neutropenia during systemic infection [ 25 ]. Functional deficiencies of neutrophils in preterm and stressed/septic neonates include chemotaxis [ 26 ], endothelial adherence [ 20 ], migration [ 27 ], phagocytosis and bactericidal potency [ 20 , 28 , 29 ]. The NADPH oxidase system, however, may be a first-line mechanism of innate immunity as there is a direct negative correlation between oxidative burst product generation and gestational age [ 20 ]. This could, however, have a detrimental effect on preterm infants as exaggerated oxygen free radical formation may contribute to the development of such neonatal diseases as retinopathy of prematurity and broncho-pulmonary dysplasia, as well as to cardiovascular disease. Sepsis is clinically characterized by systemic inflammation, cardiovascular dysfunction, an inability of oxygen delivery to meet oxygen demand, an altered substrate metabolism and, ultimately, multiorgan failure and death [ 30 ]. The mortality rate from sepsis doubles in patients who develop cardiovascular dysfunction and septic shock [ 1 ]. Little is known about the cardiovascular effects of sepsis in the neonate, but the developing cardiomyocyte differs from that of the adult and may lead to differences in the cardiac response to sepsis and inflammation. In addition to underlying differences in the structure of the neonatal cardiomyocyte, functional alterations in proliferative activity [ 31 ] and excitation–contraction coupling [ 32 ] have been identified. These differences may be mediated by alterations in calcium channel expression and activity [ 33 , 34 ], in ATP-sensitive potassium channel function [ 35 ] and in β-receptor coupling [ 36 ], and may contribute to differences in sepsis outcomes and therapeutic responses in neonates versus adults. Cardiac dysfunction and cardiovascular collapse during sepsis result from increased levels of TNFα [ 37 ] and from increased cardiac myocyte production of nitric oxide and peroxynitrite [ 38 ], which leads to further DNA damage and ATP depletion [ 39 ], resulting in secondary energy failure [ 40 ]. In addition, serum from patients with septic shock directly causes a decreased maximum extent and peak velocity of contraction, activates transcription factors for proinflammatory cytokines and induces apoptosis in cultured myocytes [ 41 ]. LPS-induced production of TNFα has been associated with increased apoptosis and cell death in adult cultured cardiomyocytes [ 42 ], and this ventricular myocyte apoptosis has been linked to cardiovascular dysfunction in adult whole animal experiments [ 43 ]. Neonatal cardiomyocytes, however, do not exhibit an increase in apoptosis despite an increase in TNFα production after LPS exposure, suggesting another mechanism for sepsis-associated cardiovascular dysfunction in neonates [ 44 ]. Septic shock is characterized in adults by a hyperdynamic phase with decreased left ventricular ejection fraction, decreased systemic vascular resistance and an increased cardiac index [ 45 , 46 ]. Underlying coronary artery disease, cardiomyopathy and congestive heart failure may contribute to the systolic and diastolic ventricular dysfunction described in the setting of adult sepsis. The resultant myocardial depression does not appear to be related to ischemia, however, as the coronary blood flow and coronary sinus lactate levels have been found to be normal in patients with septic shock [ 47 , 48 ]. Myocardial dysfunction in childhood septic shock reaches its maximum within hours and is the main cause of mortality [ 30 , 49 ]. In comparison with adults, children more often present in a nonhyperdynamic state with decreased cardiac output and increased systemic vascular resistance [ 46 , 50 ] and can develop this nonhyperdynamic septic shock even after fluid resuscitation [ 51 ]. This low cardiac output is associated with an increase in mortality [ 52 , 53 ]. Owing to a limited number of research studies in the very young, the hemodynamic response of premature infants and neonates is not well understood, and the presenting hemodynamic abnormalities are more variable than in older children and adults [ 50 ]. Complicating the clinical evaluation of these patients is the observation that blood pressure is a poor indicator of systemic blood flow in neonates [ 6 , 54 ]. In both premature and full-term infants, left ventricular systolic performance is highly dependent on afterload, which may increase the susceptibility of neonates to sudden cardiac deterioration in the setting of shock and vasoconstriction [ 55 , 56 ]. Newborn infants also have a relatively decreased left ventricular muscle mass [ 57 ] and an increased ratio of type I collagen (determinant of tissue rigidity) to type III collagen (provides elasticity) in myocardial tissue [ 58 ], which may account for the impaired left ventricular diastolic function and the alterations in mid-wall left ventricular fractional shortening seen in premature infants [ 59 ]. These physiologic abnormalities, coupled with the finding that the neonatal left ventricular myocardium already functions at a higher baseline contractile state [ 55 ], may limit the neonate's ability to increase the stroke volume or myocardial contractility in the setting of sepsis. Complicating the cardiovascular response to sepsis in the neonate are additional morbidities, including reopening of a patent ductus arteriosus and the development of persistent pulmonary hypertension of the newborn due to cytokine elaboration, acidosis and hypoxia in the setting of sepsis [ 52 ]. These underlying differences in anatomy, physiology and adaptive cardiovascular function exemplify the need to more specifically identify and understand the cardiovascular response to sepsis in the neonate in order to develop successful therapeutic strategies. The short-term goal of treatment is to optimize the perfusion and delivery of oxygen and nutrients, to correct and/or prevent metabolic derangements resulting from cellular hypo-perfusion and to support organ and body functions until homeostasis is achieved [ 30 , 60 ]. Although our understanding of the pathophysiologic mechanisms of sepsis and septic shock has improved over the past 10 years, the mortality and morbidity associated with sepsis continues to be high [ 2 , 30 , 46 ]. Proinflammatory cytokines have been implicated in the pathogenesis of organ dysfunction during sepsis, but the modulation of single gene products (TNFα, IL-1β, inducible nitric oxide synthase) and nonpeptide mediators (platelet-activating factor, prostaglandin or leukotriene inhibitors) has not been shown to improve mortality in sepsis and septic shock [ 41 ]. Unlike adult and pediatric critical medicine, where there are extensively studied multiple organ dysfunction scores and well-defined algorhythmic guidelines for treatment [ 61 ], there is a large amount of practice variability in neonatal sepsis. The American College of Critical Care Medicine concluded that the adult guidelines for hemodynamic support of septic shock are not applicable to children and neonates, and published guidelines for these younger age groups [ 52 ]. Premature neonates, however, were not specifically addressed. Empiric therapy aimed at the most probable causative pathogens should be started immediately upon suspicion of clinical sepsis, as a delay in the initiation of antibiotics has been associated with an increased risk of mortality in both pediatric [ 30 , 62 ] and adult [ 13 , 63 , 64 ] patients with sepsis. In neonates, special developmental characteristics such as immaturity of the hepatic and renal clearance systems need to be considered when prescribing an antibiotic regimen. Fluid resuscitation is an important mainstay in the resuscitation of patients with septic shock, as marked hypovolemia may result from vasodilation and increased capillary leak. A significant reduction in mortality has been demonstrated when hemodynamic function is optimized within the first few hours after presentation of sepsis [ 60 ]. There has been longstanding debate about the use of colloids or crystalloids, but there is currently no strong evidence supporting the superiority of either fluid agent in the resuscitation of septic shock [ 13 , 65 - 68 ]. The underlying importance is the maintenance of preload and tissue perfusion. Fluid resuscitation is necessary in premature infants, but must be provided with caution due to the risks of developing intraventricular hemorrhage from fluctuations in cerebral perfusion and developing heart failure and/or pulmonary overcirculation from resultant left to right flow through a patent ductus arteriosus [ 52 ]. Adult sepsis is most often characterized by a hyperdynamic state with vasodilation, while neonatal sepsis may be a hypodynamic state with vasoconstriction and may respond better to inotrope and vasodilator therapy [ 30 ]. In both the recent recommendations of the American College of Critical Care [ 69 ] and an extensive evidence-based review of vasopressor support in septic shock [ 70 ], dopamine and norepinephrine are considered first-line agents in adult septic shock. An attenuated response to adrenergic stimulation has been reported in patients with septic shock, which is thought to result from the downregulation of receptors, uncoupling of receptors from adenylate cyclase or decreased production of cAMP [ 46 ]. This impaired effectiveness of exogenous adrenergic stimulation may be augmented in neonates due to a functionally immature autonomic nervous system [ 30 , 71 ] and elevated baseline levels of catecholamines [ 72 - 75 ], especially in premature infants. Randomized controlled trials of vasopressors in neonates are extremely rare. In a recent study investigating dopamine versus epinephrine for cardiovascular support in low birth-weight infants, both agents were found to be efficacious in improving the mean arterial blood pressure – but epinephrine was associated with more short-term adverse effects such as enhanced chronotropic response, hyperglycemia requiring insulin treatment and increased plasma lactate levels [ 76 ]. There is only a weak correlation between blood pressure and systemic blood flow in neonates [ 6 ], and, although a recent metanalysis found dopamine to be superior to dobutamine in improving blood pressure, a randomized controlled trial showed that dobutamine increased systemic blood flow more effectively than dopamine [ 77 ]. According to recently published clinical practice parameters, however, dopamine remains the first-line agent in neonates, and epinephrine may be used in dopamine-resistant septic shock [ 52 ]. If low cardiac output and high systemic vascular resistance persist, dobutamine and/or a type III phosphodiesterase inhibitor may be indicated [ 46 , 52 ]. Phosphodiesterase inhibitors have the additional benefits of TNFα attenuation and decreased myocardial inducible nitric oxide synthase activity [ 46 ], and milrinone has been shown to improve cardiovascular function in pediatric patients with septic shock [ 78 ]. Milrinone is a selective phosphodiesterase type III inhibitor that has proven safe and efficacious in certain clinical scenarios in pediatric patients [ 78 , 79 ]. Many of these studies, however, have been conducted by providing a loading dose of milrinone followed by a continuous infusion. In practice, physicians often forego the loading dose, especially in patients that may have decreased preload to avoid any untoward hemodynamic effects including undue hypotension. The time to reach steady state is therefore prolonged compared with the pharmacokinetics previously described [ 80 ]. Despite this approach, many patients are concomitantly on catecholamine infusions, which have a very short half-life. The glomerular filtration rate in term neonates is 20 ml/min × 1.73 m 2 , which is generally twice that of premature newborns [ 81 ]. The glomerular filtration rate improves over the first several weeks of life in all newborns but the velocity at which it improves is less in premature infants. In term newborns, the glomerular filtration rate doubles in the first 2 weeks of life [ 82 , 83 ]. These differences in glomerular filtration rate values among varying gestational age newborns impact the administration of medications that are primarily eliminated in the renal system. This impact is pertinent in milrinone use, and therefore dosing is often renally adjusted in neonates. In cases of persistent pulmonary hypertension of the newborn associated with sepsis, inhaled nitric oxide may help reduce pulmonary vascular resistance and off-load the right ventricle. Agents such as corticosteroids, pentoxifylline and recombinant human-activated protein C have been studied as adjunctive treatments for sepsis in adults and neonates (Table 1 ). Recombinant human-activated protein C is the only adjunctive therapy approved for the treatment of severe sepsis in adults who have a high risk of death [ 84 , 85 ]. Immunomodulating agents in neonatal and adult sepsis ARDS, acute respiratory distress syndrome; rhG-CSF, recombinant human granulocyte colony-stimulating factor; rhGM-CSF, recombinant human granulocyte–macrophage colony-stimulating factor. The use of corticosteroids in the management of sepsis has evolved with the identification of relative adrenal insufficiency, which occurs in 50–75% of patients with septic shock [ 13 ]. While adult studies of high-dose corticosteroids have not shown a benefit or reduction in mortality [ 86 ], lower doses of steroids given over a longer course may actually decrease mortality in adult patients with sepsis [ 87 ]. The use of corticosteroids in the treatment of sepsis in neonates and children remains relatively untested. A recent study has shown that 44% of children with septic shock are adrenally insufficient [ 88 ], but a large cohort study of steroid administration to children and infants with severe sepsis showed no improvement in outcome and an increase in mortality in a subset of patients [ 89 ]. In neonates, both hydrocortisone and low-dose dexamethasone have been shown to effectively increase blood pressure in refractory hypotension [ 90 , 91 ], but steroids should be used with caution as early administration of high-dose corticosteroids has the additional risk of impaired neurodevelopment and clinically significant disability later in life [ 92 ]. Pentoxifylline is a methylxanthine derivative and nonspecific phosphodiesterase inhibitor that has been shown to be beneficial in the treatment of a variety of illnesses in all age groups, but only a handful of studies have focused on the use of pentoxifylline in the treatment of sepsis in adults and neonates [ 93 ]. In premature neonates with sepsis, pentoxifylline has been shown to decrease IL-6 and TNFα levels, to decrease the clinical symptoms of necrotizing enterocolitis, to reduce the development of cardiac, renal or hepatic failure, to decrease the incidence of disseminated intravascular coagulopathy and to improve blood pressure and survival rates [ 94 ]. Adult studies have shown improved cardiopulmonary and hemodynamic function in severe sepsis [ 95 , 96 ] but did not show a reduction in 28-day mortality [ 96 ]. Both neonatal and adult studies showed no adverse effects of the medication. At least 80% of children and adults develop an acquired deficiency of protein C during severe sepsis, and this deficiency is associated with adverse outcomes, such as multiple organ failure and mortality [ 97 ]. In the PROWESS trial, the use of in the treatment of adults with severe sepsis and a high risk of death showed a relative risk reduction of mortality of 19% [ 84 ]. A large clinical trial in pediatric patients with sepsis was stopped early due to a lack of demonstrated benefit and the finding of an increased risk of intracranial hemorrhage, especially in infants younger than 60 days of life [ 98 ]. In addition to the potential risk for increased bleeding in the neonatal population, the efficacy of recombinant human-activated protein C may also be different in neonates due to underlying developmental differences in the coagulation pathway. The anticoagulant effect of recombinant human-activated protein C has been shown to be decreased in neonatal cord plasma, which is due, in part, to the lower levels of tissue factor pathway inhibitor, antithrombin and protein S in neonatal versus adult plasma [ 84 , 85 ]. The incidence of neonatal sepsis is significant, with suspected sepsis being the most common diagnosis on admission to the neonatal intensive care unit in the United States [ 99 ]. Research regarding neonatal sepsis, and the cardiovascular effects of sepsis in particular, is relatively lacking. The cost of neonatal sepsis is high, with very low birthweight infants and low birthweight infants with sepsis consuming twice as much financial resource than do infants with respiratory distress syndrome [ 3 ]. Future medical and social resource utilization is also increased, as there is a significant increase in the morbidity of infants surviving severe infection, with a 30–400% odds increase of later neuro-developmental impairment [ 100 ]. In the neonate, there are multiple developmental alterations in both the response to pathogens and the response to treatment that distinguish this age group from adults. Differences in innate immunity and cytokine response may predispose neonates to the harmful effects of proinflammatory cytokines and oxidative stress, leading to severe organ dysfunction and sequelae during infection and inflammation [ 14 ]. Underlying differences in cardiovascular anatomy, function and response to treatment may further alter the neonate's response to pathogen exposure. We must therefore gain a greater understanding of these developmental changes in order to adequately understand and treat immune and inflammatory-related cardiovascular compromise in the neonatal population. This remarkably unstudied area of neonatal sepsis is paramount, as cardiac failure remains a main cause of death in this disease state. Translational research will be the cornerstone of this research initiative, as therapeutic agents will need to be developmentally targeted in order to be effective. IL = interleukin; LPS = lipopolysaccharide; TNF = tissue necrosis factor. The authors declare that they have no competing interests. WAL was primarily responsible for the conception and design of the present review, as well as the intellectual content, drafting and revision of the manuscript. TMH and JAB also contributed significantly to the design of the review, added important intellectual content and participated in the drafting and revision of the manuscript. All three authors gave final approval of the version to be published. WAL's research was supported by NIH/NICHD HD043003-04. Bench-to-bedside review: Developmental influences on the mechanisms, treatment and outcomes of cardiovascular dysfunction in neonatal versus adult sepsis Sepsis in European intensive care units: results of the SOAP study Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care The epidemiology of severe sepsis in children in the United States Serial assessment of mortality in the neonatal intensive care unit by algorithm and intuition: certainty, uncertainty, and informed consent Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network Which inotrope for which baby? Maternal modulation of neonatal immune system development Transfer of proinflammatory cytokines across term placenta Molecular and biochemical mechanisms of preterm labour Labor promotes neonatal neutrophil survival and lipopolysaccharide responsiveness Increased respiratory burst and increased expression of complement receptor-3 (CD11b/CD18) and of IL-8 receptor-A in neutrophil granulocytes from newborns after vaginal delivery Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis Sepsis: still going strong Immature anti-inflammatory response in neonates Immunomodulatory therapies in sepsis Sir Isaac Newton, sepsis, SIRS, and CARS Up-regulation of monocytic IL-10 by tumor necrosis factor-alpha and cAMP elevating drugs Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle Markers of inflammation in sepsis Differential maturation of the innate immune response in human fetuses Enhanced interleukin-6 and interleukin-8 synthesis in term and preterm infants Modulation of pro- and anti-inflammatory cytokine production in very preterm infants Neutrophil pool sizes and granulocyte colony-stimulating factor production in human mid-trimester fetuses Low soluble FcRIII receptor demonstrates reduced neutrophil reserves in preterm neonates [letter] Granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor have differential effects on neonatal and adult neutrophil survival and function Mechanisms underlying reduced responsiveness of neonatal neutrophils to distinct chemoattractants Reduced expression of C5a receptors on neutrophils from cord blood Neutrophil production and function in newborn infants Extracellular release of bactericidal/permeability-increasing protein in newborn infants Management of sepsis and septic shock in infants and children Cell proliferation in the growing human heart: MIB-1 immunostaining in preterm and term infants at autopsy Developmental changes of intracellular Ca L- and T-type calcium channels in acutely isolated neonatal and adult cardiac myocytes L-type Ca Expression of ATP-sensitive K Beta 2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes Transforming growth factor-beta1 blocks in vitro cardiac myocyte depression induced by tumor necrosis factor-alpha, interleukin-1beta, and human septic shock serum Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats Metabolic dysfunction and depletion of mitochondria in hearts of septic rats Pediatric septic shock and multiple organ failure Human serum from patients with septic shock activates transcription factors STAT1, IRF1, and NF-kappaB and induces apoptosis in human cardiac myocytes LPS-induced TNF-alpha release from and apoptosis in rat cardiomyocytes: obligatory role for CD14 in mediating the LPS response Expression of apoptosis regulatory factors during myocardial dysfunction in endotoxemic rats The response of neonatal rat ventricular myocytes to lipopolysaccharide-induced stress Sepsis-associated myocardial dysfunction: diagnostic and prognostic impact of cardiac troponins and natriuretic peptides Heart failure in pediatric septic shock: utilizing inotropic support Myocardial dysfunction in sepsis: no role for NO? Myocardial dysfunction in the patient with sepsis Hemodynamic patterns of meningococcal shock in children Circulatory shock in children: an overview Hemodynamic support in fluid-refractory pediatric septic shock Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock Distributions of cardiopulmonary variables in pediatric survivors and nonsurvivors of septic shock Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation Age-related variation in left ventricular myocardial contractile state expressed by the stress velocity relation Maturational changes in left ventricular contractile state Normal right and left ventricular mass development during early infancy The neonatal heart has a relatively high content of total collagen and type I collagen, a condition that may explain the less compliant state Development of left ventricular systolic and diastolic function in preterm infants during the first month of life: a prospective follow-up study Early goal-directed therapy in the treatment of severe sepsis and septic shock What is the role of neonatal organ dysfunction and illness severity scores in therapeutic studies in sepsis? Early treatment with parenteral penicillin in meningococcal disease Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants Randomized evaluation of fluid resuscitation with crystalloid (saline) and colloid (polymer from degraded gelatin in saline) in pediatric septic shock Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or ringer's lactate – does it really make a difference? A comparison of albumin and saline for fluid resuscitation in the intensive care unit Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update Vasopressor and inotropic support in septic shock: an evidence-based review Maturation of the autonomic nervous system: differences in heart rate variability in premature vs. term infants Mode of delivery, plasma catecholamines and Doppler-derived cardiac output in healthy term newborn infants Antenatal dexamethasone treatment decreases plasma cate-cholamine levels in preterm infants Fetal catecholamine release with preterm delivery Developmental changes in myocardial contractile reserve in the lamb Dopamine versus epinephrine for cardiovascular support in low birth weight infants: analysis of systemic effects and neonatal clinical outcomes Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock. A prospective, double-blinded, randomized, placebo-controlled, interventional study Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease A population pharmacokinetic analysis of milrinone in pediatric patients after cardiac surgery Glomerular filtration rate in the first three weeks of life Renal function in preterm neonates Renal function in very low birth weight infants: normal maturity reached during early childhood Efficacy and safety of recombinant human activated protein C for severe sepsis Protein S modulates the anticoagulant action of recombinant human activated protein C: a comparison between neonates and adults Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock Absolute and relative adrenal insufficiency in children with septic shock A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birthweight infants Cardiovascular effects of low-dose dexamethasone in very low birth weight neonates with refractory hypotension Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity Immunomodulation, part I: pentoxifylline Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebo-controlled, double-blind trial Effects of pentoxifylline on hemodynamics and oxygenation in septic and nonseptic patients Effect of pentoxifylline in severe sepsis: results of a randomized, double-blind, placebo-controlled study Recombinant human activated protein C for the treatment of severe sepsis: is there a role in pediatrics? Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial Practice variation in suspected neonatal sepsis: a costly problem in neonatal intensive care What is the role of neonatal organ dysfunction and illness severity scores in therapeutic studies in sepsis? Use of corticosteroids in the sepsis syndrome: what do we know now? Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants Intravenous immunoglobulin for suspected or subsequently proven infection in neonates Intravenous immunoglobulin for treating sepsis and septic shock Immunomodulation, part II: granulocyte colony-stimulating factors G-CSF and GM-CSF for treating or preventing neonatal infections Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis Filgrastim in patients with pneumonia and severe sepsis or septic shock An audit of the use of granulocyte colony-stimulating factor in septic shock Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial A randomized phase II trial of granulocyte–macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction Effect of granulocyte–monocyte colony-stimulating factor therapy on leukocyte function and clearance of serious infection in nonneutropenic patients Drotrecogin alpha (activated) in neonatal septic shock Recombinant human activated protein C for severe sepsis in neonates Recombinant human activated protein C for severe sepsis in a neonate Evaluation of the cost-effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death Pentoxifylline for neonatal sepsis |
Answer the following medical question. | What does research say about Diagnostic challenges in the management of septic arthritis of the neonatal hip: A case report.? | Septic arthritis of the neonatal hip is a very rare pathology. The clinical features may be different from those associated with older children, resulting in diagnostic challenges. Delay in instituting treatment, especially in neonates could be associated with severe dysfunction and deformity in a significant number of affected children. Therefore, treatment should be prompt and comprise broad-spectrum intravenous antibiotic therapy, surgical drainage, and general supportive care. The index patient is a 3-week-old neonate who had left hip arthrotomy on account of septic arthritis. The aim of this report is to highlight the challenges encountered in the diagnosis of septic arthritis of the hip in this patient. |
Answer the following medical question. | What does research say about A systematic review of associations between gut microbiota composition and growth failure in preterm neonates.? | Growth failure is among the most prevalent and devastating consequences of prematurity. Up to half of all extremely preterm neonates struggle to grow despite modern nutrition practices. Although elegant preclinical models suggest causal roles for the gut microbiome, these insights have not yet translated into biomarkers that identify at-risk neonates or therapies that prevent or treat growth failure. This systematic review aims to identify features of the neonatal gut microbiota that are positively or negatively associated with early postnatal growth. We identified 860 articles, of which 14 were eligible for inclusion. No two studies used the same definitions of growth, ages at stool collection, and statistical methods linking microbiota to metadata. In all, 58 different taxa were associated with growth, with little consensus among studies. Two or more studies reported positive associations with Enterobacteriaceae, Bacteroides , Bifidobacterium , Enterococcus , and Veillonella , and negative associations with Citrobacter, Klebsiella , and Staphylococcus . Streptococcus was positively associated with growth in five studies and negatively associated with growth in three studies. To gain insight into how the various definitions of growth could impact results, we performed an exploratory secondary analysis of 245 longitudinally sampled preterm infant stools, linking microbiota composition to multiple clinically relevant definitions of neonatal growth. Within this cohort, every definition of growth was associated with a different combination of microbiota features. Together, these results suggest that the lack of consensus in defining neonatal growth may limit our capacity to detect consistent, meaningful clinical associations that could be leveraged into improved care for preterm neonates. More than 50,000 premature, very low birth weight infants are born in the US each year. Half of these neonates develop malnutrition and postnatal growth failure, the etiology of which is largely unknown. Numerous studies report intriguing associations between the preterm infant gut microbiota and neonatal growth; however, these findings have not yet translated into clinically impactful therapies. A causal link between the gut microbiome and early postnatal growth failure was first identified in studies of Bangladeshi and Malawian 1 infants and children. Malnourished children with kwashiorkor have an “immature” gut microbiome, which is characterized by delayed acquisition of microbial functions 2 , 3 and age-discriminatory bacterial species. 3 Gnotobiotic mouse recipients of these immature microbiota have poor growth compared to mice receiving microbiota from healthy children; 1 growth failure can be prevented by colonization with age- and growth-discriminatory microbes. 3 Interestingly, the growth-promoting potential of microbiota in weanling germ-free mice depends on the developmental stage of the human donor. Mice receiving microbiota from 6-month-old infants grow more compared to those receiving microbes from 18-month-old toddlers, 2 whereas mice receiving meconium microbiota from full-term newborns grow more compared to recipients of meconium microbiota from very preterm newborns. 2 4 Preclinical models highlight mechanisms that may underlie these causal links ( Figure 1 ). Microbes ferment non-digestible dietary substrates into absorbable energy, including short-chain fatty acids (SCFAs) that enhance postnatal growth. Butyrate fed to germ-free mice or produced in the mouse intestine by 5–8 Lacticaseibacillus rhamnosus GG promotes bone growth by inducing regulatory T cells to secrete the bone-anabolic Wnt ligand Wnt10b, whereas acetate produced by specific strains of 8 Bifidobacterium protects mice from death by enterohemorrhagic Escherichia coli in part by blocking translocation of Shiga toxin from the intestine into the bloodstream. Notably, elevated levels of fecal butyrate and propionate are observed among extremely premature infants with severe brain injury; 9 however, SCFA levels can be affected by numerous physiologic changes including altered absorption and colonocyte utilization. 10 Figure 1. Mechanisms by which microbial fermentation of human milk oligosaccharides promote neonatal growth. Numerous factors shape the development of the neonatal gut microbiome. One of the most important factors – nutrition – provides substrates for gut microbes to perform beneficial functions that stimulate neonatal growth. Non-digestible HMOs are metabolized by bacterial enzymes to produce bioavailable energy, growth-promoting metabolites, and anti-inflammatory factors. HMO: human milk oligosaccharides; IGF-1: insulin-like growth factor-1; Wnt10b: Wnt family member 10b. Figure created with BioRender.Com. Mechanisms by which microbial fermentation of human milk oligosaccharides promote neonatal growth. Numerous factors shape the development of the neonatal gut microbiome. One of the most important factors – nutrition – provides substrates for gut microbes to perform beneficial functions that stimulate neonatal growth. Non-digestible HMOs are metabolized by bacterial enzymes to produce bioavailable energy, growth-promoting metabolites, and anti-inflammatory factors. HMO: human milk oligosaccharides; IGF-1: insulin-like growth factor-1; Wnt10b: Wnt family member 10b. Figure created with BioRender.Com. For the neonate, non-digestible dietary substrates include human milk oligosaccharides (HMOs). Based on the finding that HMOs are deficient in breast milk from mothers of malnourished infants in Malawi, milk oligosaccharides were fed to mice or piglets, and this resulted in increased weight gain, bone mineral density, and cortical thickness – but only if gut bacteria were present. Milk oligosaccharides reduce osteoclasts and the bone resorption marker CTX-1 in mice in a microbiota-dependent manner, suggesting that microbial metabolism of HMOs promotes postnatal weight gain in part by inhibiting osteoclastogenesis and bone resorption. 11 HMO fermentation produces other factors that may be growth-promoting, including the anti-inflammatory metabolite indole-3 lactic acid, 12 and might reduce the risk of bacterial translocation via increased expression of colonocyte tight junction proteins. 13 Finally, gut microbes influence the somatotropic axis to promote growth. 14 Drosophila larvae monocolonized by bacteria that are unable to produce acetate exhibit poor growth and altered insulin/insulin-like growth factor (IGF) signaling; acetate supplementation rescues these deficits. Similarly, germ-free mice have reduced levels of IGF-1 and stunted growth compared to conventional mice. Colonizing germ-free mice with microbial communities 6 or with strains of growth-promoting lactobacilli 15 restores somatotropic axis activity, bone growth, and weight gain. These results indicate that in well-defined laboratory conditions, gut microbes and their metabolites regulate postnatal growth. 16 These intriguing preclinical findings instill hope that the newborn gut microbiome could be leveraged in the neonatal intensive care unit, both as a source of biomarkers that identify infants at risk of growth failure and as a growth-promoting therapeutic target. Thus, the purpose of this systematic review is to examine the data associating specific features of the human preterm infant gut microbiome to neonatal growth. Identifying these relationships could open the door for new microbiota-targeted therapies that prevent or treat neonatal growth failure and its short- and long-term consequences. Our literature search identified 860 records, of which 14 met criteria to be included in our qualitative synthesis of studies that report associations between human gut microbial community composition and neonatal growth ( Figure 2 ). Study characteristics are presented in Table 1 . Two studies were randomized controlled trials (one tested enhanced vs standard parenteral nutrition; one tested probiotic 17 Limosilactobacillus reuteri DSM 17938 vs placebo ). Of the 12 observational studies, 10 were prospective cohort studies, 18 one was a nested case-control study, 19–28 and one was a retrospective cohort study. 29 There was geographic diversity, with five studies conducted in China, 30 four each in Europe 23 , 26–29 and the United States, 17–19 , 25 and one in Brazil. 20–22 , 30 Some studies included only extremely preterm infants (< 28 weeks gestation), whereas others included any preterm infant (< 37 weeks), resulting in a range of extremely low birth weight (< 1000 g) to low birth weight (< 2500 g). Newborn diets varied in parenteral and enteral nutrition (mother’s milk, pasteurized donor milk, fortifier, and formula). In two studies, microbiota analyses were limited to a single sample per patient, 24 but in the remainder of studies stool was collected longitudinally. One study determined the abundance of select bacterial taxa using quantitative polymerase chain reaction; 23 , 24 the other 13 studies sequenced subunits of the 16S rRNA gene. None of the studies employed whole metagenomic sequencing. 19 Figure 2. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of studies identified and included. Table 1. Characteristics of studies identified by the systematic review and included in the qualitative synthesis. Author & year Geographic location Study type n = GA at birth Birth weight Neonatal diet Sample collection Sequencing strategy Arboleya et al 2017 Northern Spain Prospective cohort 63 28–33 1085 g − 1580 g Mixed feeding of breast milk and infant formula Fecal samples on day of life 2, 10, and 30 ( n = ~189) qPCR of 8 taxa Grier et al 2017 Rochester, NY, USA Prospective cohort 95 28.83 (mean) 1290 g (mean) − Breast milk or premature formula milk − Fortifiers, parenteral and enteral feeding Meconium and fecal rectal swabs weekly from 24 to 46 weeks PMA ( n = 719) 16S rRNA V3-V4 Younge et al 2019 Durham, NC, USA Prospective cohort 58 26 (median) 800 g (median) − Human milk given as initial diet − Parenteral and enteral feeding Fecal samples weekly for 9 weeks upon reaching full enteral feeding ( n = 385) 16S rRNA V4 Yee et al 2019 Tampa, FL, USA Prospective cohort 83 24–37 < 1400 g − Mother’s milk, donor milk, and formula (> 93% breastfed and > 64% exclusively breastfed) − Fortifiers and enteral feeding Fecal samples at 1–6 weeks, and at 2 and 4 years of age including mother’s ( n = 425) 16S rRNA V4 Li et al 2019 Shenzhen, China Nested case-control 23 < 32 < 1500 g Exclusively breastfed (> 21%), exclusively formula fed (> 34%), or mixed breast milk and formula feeding (> 43%) Swab of meconium and fecal samples at 1 and 28 days of life ( n = 44) 16S rRNA V3-V4 Blakstad et al 2019 Oslo, Norway Randomized controlled trial (Enhanced parenteral nutrition intervention) 45 < 28 < 1500 g − Mother’s milk or donor milk (not pasteurized) − Fortifiers, parenteral and enteral feeding Fecal samples every 1–2 weeks from birth to hospital discharge ( n = 264) 16S rRNA V1-V3 Zhang et al 2019 Shanghai, China Prospective cohort 59 < 30 < 1200 g − Exclusively human milk fed (> 74%), exclusively formula fed (> 10%), human milk mixed with formula (> 6%), or human milk mixed with thickener (> 8%) − Thickener was starch- or carbohydrate-based One fecal sample at discharge ( n = 59) 16S rRNA V3-V4 Terrazzan et al 2020 Porto Alegre, Brazil Prospective cohort 63 < 33 1375 g (mean) Exclusively breastfed (> 14%), exclusively formula fed (> 28%), or breast milk mixed with formula (> 57%) First meconium sample ( n = 63) 16S rRNA V4 Marti et al 2021 Stockholm/Linkoping, Sweden Randomized, double-blind, placebo-controlled trial ( L.reuteri DSM 17938) 132 23 - < 28 < 1000 g − Exclusively mother’s milk or donor milk fed until weight reached 2000 g − Fortifiers, parenteral and enteral feeding Fecal samples at 1–4 weeks of life, 36 weeks PMA, and 2 years of age ( n = 558) 16S rRNA V3-V4 Heida et al 2021 Groningen, Netherlands Prospective cohort 41 26–30 430–990 g Mother’s milk, formula, or mixed Meconium/fecal samples weekly during first 4 weeks of life ( n = 142) 16S rRNA V3-V4 Ding et al 2021 Beijing, China Prospective cohort 22 < 32 Not specified − Breast milk and/or formula − Parenteral feeding when total enteral feeding not achieved Fecal samples at 14 and 28 days of life ( n = 44) 16S rRNA (V region not specified) Shen et al 2022 Guangzhou, China Prospective cohort 118 < 35 < 2000 g Not specified Fecal samples 1–2 times weekly from birth until hospital discharge ( n = 467) 16S rRNA V4 Tadros et al 2022 Tampa, FL, USA Retrospective 34 < 33 < 1500 g − Exclusively breastfed (25%), exclusively formula fed (51%), or mixed feeding (24%) Fecal samples weekly from birth to 28 days of life, additional sample at 36 weeks CGA ( n = not specified) 16S rRNA V4 Huang et al 2022 Shenzhen, China Prospective cohort 67 < 37 < 2500 g − Mother’s milk or donor breast milk − Parenteral and enteral feeding Meconium/fecal samples at day of life 0–1, 3, 4, and weekly for 10 weeks ( n = not specified) 16S rRNA V4 CGA: corrected gestational age; GA: gestational age; PMA: post-menstrual age; qPCR: quantitative polymerase chain reaction; rRNA: ribosomal ribonucleic acid. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of studies identified and included. Characteristics of studies identified by the systematic review and included in the qualitative synthesis. CGA: corrected gestational age; GA: gestational age; PMA: post-menstrual age; qPCR: quantitative polymerase chain reaction; rRNA: ribosomal ribonucleic acid. Each study used different statistical methods to associate microbiota composition with postnatal growth ( Table 2 ). In some cases, microbiota from fecal samples obtained within the first ten days of life were associated with anthropometric indices at a point in time weeks to months later, whereas other studies used various methods to link longitudinally sampled microbiota to rates of growth. 19 , 24 , 29 Only one study identified associations between growth and absolute bacterial abundance based on quantitative polymerase chain reaction. 17 , 20 , 22 Given this heterogeneity of statistical techniques, we sought to determine whether any microbiota features consistently associated with appropriate growth or growth failure – irrespective of how the associations were computed in the individual studies. 19 Table 2. Gut microbiota associations with postnatal growth. Author & year Methods used to determine growth associations Results Arboleya et al 2017 - Microbiota at day of life 2 and 10 associated with weight gained at day of life 30 by univariate and multivariate generalized linear model adjusted for confounders (BW and GA) on forest plot - Growth metric: Fenton - Staphylococcus and Enterococcus negatively associated with weight gain - Weissella positively associated with weight gain - Enterobacteriaceae and Streptococcus at day of life 2 positively associated with weight gain at 30 days of life - Bacteroides at day of life 10 positively associated with weight gain at 30 days of life Grier et al 2017 - Change in weight z-score from birth to hospital discharge associated with “phase” of microbiota using linear mixed-effect regression models - Growth metric: Fenton Delayed transition to “phase 3” (denoted as “Clostridia”) negatively associated with change in weight z-score Younge et al 2019 - Infants grouped into severe postnatal growth failure (defined as weight < 3rd percentile at 40 weeks PMA or hospital discharge) vs appropriate growth - Shannon diversity compared between groups using smoothing spline ANOVA - Taxon relative abundance compared between groups using fitTimeSeries - Beta diversity compared between groups using PCoA on Jensen-Shannon divergences - Catch-up growth (defined as a positive change in weight z-score) associated with relative abundance using zero-inflated Log-normal mixture model - Growth metric: Fenton - Growth failure group associated with low alpha diversity - Increased abundance of Staphylococcus in early weeks of life associated with growth failure - Dominance of Enterobacteriaceae (genus level: Citrobacter , Enterobacter , Serratia , and Klebsiella ) in later weeks of life associated with growth failure - Increased abundance of Veillonellaceae, Streptococcaceae, Peptostreptococcaceae, Micrococcaeae, Lachnospiraceae, and Bacillaceae associated with appropriate growth - Change in weight z-score positively associated with Streptococcus , Bifidobacterium , Clostridiaceae, Clostridiales, Lachnospiraceae, Peptostreptococcaceae, Veillonella , and increased alpha-diversity - Change in weight-z-score negatively associated with Staphylococcus Yee et al 2019 - Shannon diversity correlated with weight gain velocity (g/week) via regression adjusted for PMA - Beta diversity using unweighted UniFrac PCoA and PERMANOVA associated with improved length (a binary variable defined as whether the infant had a length-for-age z-score that was better than expected during the hospital stay) - Regression model that predicts PMA in relation to microbiome composition used to generate associations with improved length - Relative abundance associated with weight gain from birth to hospital discharge using analysis of composition of microbiomes (ANCOM) - Growth metric: Fenton - Weak correlation of increased alpha diversity with overall weight growth rate - Increased “beta diversity volatility” positively associated with length - Reduced microbiome maturity associated with improved length - Klebsiella and Staphylococcus ESVs negatively associated with weight gain Li et al 2019 - Infants grouped into EUGR (defined as weight < 10th percentile at hospital discharge) vs AGA - Group comparisons using LEfSe to identify differences in relative abundance - Growth metric: Clark et al 2003 - Day 1 samples: decreased alpha diversity (Shannon index) in AGA group - Day 1 samples: increased abundance of Parabacteroides , Ruminococcus , Blautia , and Aeromonas negatively associated with growth (increased abundance in EUGR) - Day 1 samples: increased abundance of Aeromicrobium and Serratia positively associated with growth (decreased abundance in EUGR) - Day 28 samples: Increased abundance of Bacteroides , Parabacteroides , Eubacterium , Granulicatella , and Eggerthella negatively associated with growth (more abundant in EUGR) - Day 28 samples: Increased abundance of Salinivibrio positively associated with growth (less abundant in EUGR) Blakstad et al 2019 - Infants grouped into positive or negative change in weight z-score from birth to 36 weeks PMA associated with microbiome features using repeated-measures linear mixed models adjusted for BW or BW z-score and other covariates (i.e. volume of milk intake on first day of life) - Growth metric: Fenton (non-sex-specific) and Sjaerven’s (sex-specific) growth charts - Increased richness (OTUs) and increased relative abundance of Bifidobacterium positively associated with growth - When adjusted for milk intake, no significant differences in richness Zhang et al 2019 - Infants grouped into EUGR (defined as weight < 10th percentile at hospital discharge) or non-EUGR - Differences in relative abundance using multivariate logistic regression models adjusted for potential confounders (i.e. BW, feeding status) and FDR - Growth metric: Clark et al 2003 - Abundance of Rothia , Pantoea , Citrobacter , and Kluyvera negatively associated with growth (increased in EUGR) - Abundance of Streptococcus Parasanguinis _FW21 and Bacterium RB5FF6 negatively associated with growth (increased in EUGR) - Abundance of Acinetobacter sp_V12012 and Enterobacter sp CCBAU 15567 positively associated with growth (decreased in EUGR) - Abundance of Klebsiella ( granulomatis and michiganensis ) and Microbacterium _sp_TSWCW12 negatively associated with growth (increased in EUGR) Terrazzan et al 2020 - Infants grouped into SGA (defined as weight < 10th percentile) vs AGA - Differences in taxon abundances analyzed using DESEq2 adjusted for FDR - Infants later grouped into HC catch-up growth (defined as ≤ 0.67 z-score variation between two consecutive z-scores) by or after 6 months of age - Growth metric: Fenton - Abundance of Proteobacteria, Acidobacteria GP1, Prevotella , and Polynucleobacter positively associated with growth (increased in infants with AGA at birth) - Abundance of Escherichia fergusoni and Streptococcus dentisani positively associated with growth (increased in infants AGA at discharge) - Abundance of Prevotella copri , Roseburia inulinivorans , Staphylococcus sp, Staphylococcus capitis , Sutterella stercoricanis , Corynebacterium tuberculostearicum , and Ruminococcaceae negatively associated with growth (increased in infants with SGA at hospital discharge) - Increased alpha diversity (Shannon index) negatively associated with growth (increased in HC catch-up after 6 months) - Abundance of Bacteroidetes, Proteobacteria, Salmonella , Flavobacterium , and Burkholderia positively associated with growth (increased in HC catch-up by 6 months) - Abundance of Prevotella , Enhydrobacter , Brevundimonas , Bradyrhizobium , and Acinetobacter negatively associated with growth (increased in HC catch-up after 6 months) Marti et al 2021 - Microbial diversity and richness correlated with HC growth velocity (change in z-score) using simple linear regression - Microbiota communities correlated with weight or HC growth velocities using envfit demonstrated on NMDS - Growth metric: Niklasson’s growth chart - Positive association between microbiome diversity at 1 week and richness at 2 weeks of life with HC growth at 4 weeks of life - Positive association of microbial composition in weeks 1 and 3 with head growth at 4 weeks of life and 36 weeks PMA and with weight gain at 2 weeks, 4 weeks of life, and 36 weeks PMA Heida et al 2021 - Microbiota associated with weight at the time of sample collection using simple linear regression and mixed effects regression - Growth metric: Dutch growth curve - Abundance of Enterobacteriaceae positively associated with weight at weeks 3 and 4 of life - Ratio of Enterobacteriaceae to Staphylococcus positively associated with weight Ding et al 2021 - Infants grouped into AGA (control) or EUGR (defined as weight < 10th percentile to corresponding GA or weight loss > 2 SD from birth to 14 or 28 days) - Microbiome differences via LEfSe analysis at 14 and 28 days of life; further analyses compared abundances between groups - Growth metric: Fenton - At week 2 after birth, Enterococcaceae and Enterococcus had an LDA score > 4 in AGA infants and both were more abundant in AGA vs EUGR - At week 2 after birth, Streptococcaceae and Streptococcus had an LDA score > 4 in EUGR infants and both were more abundant in EUGR vs AGA Shen et al 2022 - Microbiome associated with weight gain based on the age (days of life) at which infant reached 2 kg or based on weekly weight gain rate using generalized linear mixed models; further analyses divided infants into high or low groups based on weekly weight gain rate falling < 6% (converted from daily weight gain being < 10 g/kg) - Growth metric: not specified - Abundance of Streptococcus negatively associated with age to reach 2 kg weight - Lower alpha diversity (Shannon index) positively associated with growth (higher weekly weight gain rate) - Abundance of Streptococcus positively associated with growth (decreased in low weekly weight gain rate group) Tadros et al 2022 - Microbiome associated with weight z-score, length z-score, and change in weight and length z-scores using early growth from birth to 4 months of life via regression-based kernel association tests - Growth metric: Fenton In early growth (birth to 4 months): - Abundance of Streptococcus , Veillonella , and Haemophilus positively associated with length z-score (samples from < 14 days of life) - Abundance of Proteus negatively associated with length z-score (samples from 14–28 days of life) - Abundance of Bacteroides and Haemophilus positively associated with weight z-score (samples from < 14 days of life) - Abundance of Gemella negatively associated with weight z-score (samples from 12–28 days of life) - Abundance of Gammaproteobacteria negatively associated with weight z-score (samples from 36 weeks CGA) Huang et al 2022 - Infants grouped into EUGR (defined as weight < 10th percentile at hospital discharge) or control - Microbiome differences between groups identified using LEfSe, multivariate associations with linear models (adjusted for mode of delivery), and Wilcoxon rank-sum tests. - Growth metric: Fenton - Abundance of Proteobacteria (Enterobactericeae and Moraxellaceae) negatively associated with growth (increased in EUGR) - Abundance of Streptococcus negatively associated with growth (decreased in control) - Abundance of Clostridium and Veillonella positively associated with growth (delayed increase in EUGR compared to faster increase in control) AGA: appropriate for gestational age; ANOVA: analysis of variance; BW: birth weight; CGA: corrected gestational age; DEseq2: differential gene sequence; ESV: exact sequence variant; EUGR: extrauterine growth restriction; FDR: false discovery rate; GA: gestational age; HC: head circumference; LDA: linear discriminant analysis; LEfSe: linear discriminant analysis effect size; NMDS: non-metric multidimensional scaling; OTU: operational taxonomic unit; PCoA: principal coordinate analysis; PERMANOVA: permutational multivariate analysis of variance; PMA: post-menstrual age; SD: standard deviation; SGA: small for gestational age; UniFrac: unique fraction metric; VLBW: very low birth weight. Gut microbiota associations with postnatal growth. AGA: appropriate for gestational age; ANOVA: analysis of variance; BW: birth weight; CGA: corrected gestational age; DEseq2: differential gene sequence; ESV: exact sequence variant; EUGR: extrauterine growth restriction; FDR: false discovery rate; GA: gestational age; HC: head circumference; LDA: linear discriminant analysis; LEfSe: linear discriminant analysis effect size; NMDS: non-metric multidimensional scaling; OTU: operational taxonomic unit; PCoA: principal coordinate analysis; PERMANOVA: permutational multivariate analysis of variance; PMA: post-menstrual age; SD: standard deviation; SGA: small for gestational age; UniFrac: unique fraction metric; VLBW: very low birth weight. Gut microbial community characteristics that correlated either positively or negatively with neonatal growth are listed in Table 2 . The Shannon diversity index was the most commonly reported alpha-diversity metric. Interestingly, neonatal growth and Shannon diversity were positively correlated in three studies and negatively correlated in three studies. 18 , 21 , 22 Some studies calculated “microbiota maturity” as an index of a neonate’s postnatal acquisition of age-discriminatory taxa (microbes whose proportional representation define gut microbiota assembly within healthy infants sampled in the same cohort). Microbiota maturity and neonatal growth were positively correlated in one study 24 , 26 , 29 and negatively correlated in another study. 20 22 There was some agreement among the 14 studies correlating the relative abundance of specific taxa with growth ( Figure 3 ). Five studies reported positive associations between Streptococcus and growth, whereas four studies reported negative associations between 19 , 21 , 24 , 26 , 30 Staphylococcus and growth. Several taxa were positively correlated with growth in some studies and negatively correlated with growth in other studies; these included Enterobacteriaceae, Streptococcaceae, 19 , 21 , 22 , 24 Acinetobacter , Bacteroides , Enterobacter , Enterococcus , Serratia , and Streptococcus . In one study, the relative abundance of Prevotella in the first meconium sample positively associated with appropriate weight at birth but negatively associated with growth at hospital discharge. In all, 58 distinct taxa were associated positively and/or negatively with growth. For the 32 taxa positively associated with growth, 26 (81%) were reported in a single study. For the 34 taxa negatively associated with growth, 30 (88%) were reported in a single study. Although all 14 studies identified specific microbiota features that were significantly associated with neonatal growth ( 24 Table 2 ), we found surprisingly little agreement among studies. Figure 3. Microbial taxa positively or negatively associated with growth in studies of human preterm neonates. Blue Venn diagram (left) represents taxa positively associated with postnatal growth. Red Venn diagram (right) represents taxa negatively associated with postnatal growth. Figure created with BioRender.Com. Microbial taxa positively or negatively associated with growth in studies of human preterm neonates. Blue Venn diagram (left) represents taxa positively associated with postnatal growth. Red Venn diagram (right) represents taxa negatively associated with postnatal growth. Figure created with BioRender.Com. We identified many potential reasons for the lack of generalizability of growth-discriminatory microbiota features, including differences in study populations ( Table 1 ), timing of fecal sample collection, timing of neonatal growth measurements, and statistical techniques used to determine associations ( Table 2 ). Most notably, there was little consensus regarding how growth and growth failure were defined. Growth was assessed using combinations of infant weight, length, and head circumference (HC), and these indices were reported as absolute values, percentiles, rates of change (velocity), or z-scores. Infant age was reported as postnatal days or weeks of life, or as post-menstrual age (PMA) or corrected gestational age (CGA). In some cases, microbiota features were regressed linearly against growth over time, and in other cases they were correlated with a single anthropometric measurement at 36 weeks PMA. Some studies assessed appropriate growth versus growth failure as a binary outcome. Among these studies, growth failure was variably defined as weight < 3 rd or < 10 th percentile at 36 weeks PMA, as negative change in weight z-score from birth to 36 weeks PMA, or as weekly weight gain rate < 6 th percentile – all using a variety of published growth charts ( Table 2 ). Thus, the published literature contains a striking variety of definitions of appropriate neonatal growth and postnatal growth failure. To gain insight into how different definitions of postnatal growth can impact growth-associating microbiota signatures, we performed an exploratory secondary analysis of a large, previously published data set of preterm infants born < 32 weeks gestational age (GA) and < 1500 g between 2015 and 2016. This data set included 16S sequencing of 245 fecal samples collected longitudinally throughout the newborn hospitalization. The primary aim of the published study was to determine how the neonatal diet influenced gut microbiota community composition; these microbiota data had not been analyzed with respect to neonatal growth. For our reanalysis, we selected eight definitions of growth failure based on Fenton growth metrics that are both clinically relevant and reported in the literature (all growth velocities and changes were computed from birth to 36 weeks PMA): weight < 10 31 th percentile at 36 weeks PMA; weight gain < 20 g/day; change in weight z-score > −1.2; length velocity < 1 cm/week; change in length z-score > −1.2; HC velocity < 1 cm/week; change in HC z-score > −1.2; and change in status from appropriate for gestational age (AGA) at birth to small for gestational age (SGA; defined as weight < 10 th percentile ) at 36 weeks PMA. 32 These eight growth failure definitions were longitudinally linked to microbial signatures in two different ways – based on the neonates’ PMA and based on the neonates’ postnatal age (weeks of life). Thus, 16 different definitions of growth were explored. A heat map illustrates microbial taxa that were significantly associated with either appropriate neonatal growth or with growth failure according to these 16 definitions ( 32–34 Figure 4 ). Figure 4. Phylum and genus level associations with postnatal growth based on 16 clinically relevant growth indices. in an exploratory secondary analysis of previously published microbiota sequencing from 245 longitudinally-sampled preterm infant stools, we sought to determine how changing the definition of neonatal growth might change the significantly associated microbes. We tested associations between relative abundance change over time and the binary outcome “appropriate growth” versus “growth failure” using eight clinically relevant definitions and analyzed each longitudinally according to PMA quartiles or postnatal week of life. Significant positive (blue) or negative (red) associations between taxa and postnatal growth are illustrated. N = (%) shows that the number of samples from infants classified as having growth failure changes dramatically with each of these 16 definitions. AGA-SGA: change in status from appropriate for gestational age at birth to small for gestational age (weight < 10th percentile) at 36 weeks PMA; HC: head circumference; PMA: post-menstrual age; Week: postnatal week of life. Phylum and genus level associations with postnatal growth based on 16 clinically relevant growth indices. in an exploratory secondary analysis of previously published microbiota sequencing from 245 longitudinally-sampled preterm infant stools, we sought to determine how changing the definition of neonatal growth might change the significantly associated microbes. We tested associations between relative abundance change over time and the binary outcome “appropriate growth” versus “growth failure” using eight clinically relevant definitions and analyzed each longitudinally according to PMA quartiles or postnatal week of life. Significant positive (blue) or negative (red) associations between taxa and postnatal growth are illustrated. N = (%) shows that the number of samples from infants classified as having growth failure changes dramatically with each of these 16 definitions. AGA-SGA: change in status from appropriate for gestational age at birth to small for gestational age (weight < 10th percentile) at 36 weeks PMA; HC: head circumference; PMA: post-menstrual age; Week: postnatal week of life. Our exploratory secondary analysis of this data set revealed that changing the definition of growth failure influenced which microbial taxa positively or negatively correlated with growth. Within our data set, not one taxonomic feature consistently associated with growth across all definitions. In part, this may be due to the different definitions of growth failure identifying different subsets of neonates. For example, when growth failure was defined as HC velocity < 1 cm/week, the majority of stool samples in this cohort (87%) were from infants classified as having growth failure. However, a minority (11%) of the same samples were from infants classified as having growth failure when the definition of change in HC z-score > −1.2 from birth to 36 weeks PMA was used. At the phylum level, the relative abundance of Proteobacteria positively associated with neonatal growth with 4/16 definitions, and the relative abundance of Bacteroidetes negatively associated with growth with 7/16 definitions; this latter association was less frequently observed when age was reported as PMA (1/8) rather than as postnatal weeks (6/8). Most definitions negatively associated three genera with growth: Staphylococcus , Prevotella , and Streptococcus . Conversely, multiple definitions positively associated growth with six genera: Veillonella , Enterococcus , Clostridium sensu stricto, Negativicoccus , Acinetobacter , and Clostridium cluster XI. Importantly, whether these taxa significantly associated with growth depended on the choice of PMA versus postnatal weeks as the measure of time. Unexpectedly, defining growth failure as HC velocity < 1 cm/week, which classified more neonates as having growth failure than any other metric, changed the directionality of the association for the majority of taxonomic features. Sub-analyses of neonates fed a majority of mother’s own milk or a majority of donor human milk revealed similar results, although fewer total taxa were significantly associated with growth among these smaller subgroups (Supplementary Figure S1). Taken together, these data indicate that significant associations between microbiota composition and neonatal growth are highly dependent on how both growth and age are defined. Despite numerous landmark preclinical studies that elucidate mechanisms by which gut microbes regulate postnatal growth, there is a lack of clinically validated biomarkers to predict which preterm newborns are at risk of growth failure, and a lack of microbiota-targeting therapies to prevent and treat this problematic condition. Our systematic review identified 14 studies that have reported relationships between neonatal gut microbiota signatures and postnatal growth. Although every study found significant associations, our qualitative synthesis of this data did not identify any microbiota features that correlated with growth consistently across all (or even most) studies. Each study was designed uniquely, assessing different study populations, different ages at sample collection, different definitions of growth, different sequencing techniques, and different statistical approaches to identify significant microbiota associations. The wide variety of reported definitions of postnatal growth was especially surprising, and our exploratory secondary analysis of a previously published data set illustrates how changing the definition of growth failure dramatically influences which gut microbial taxa positively or negatively correlate with growth. Our systematic review identified increased abundance of Staphylococcus as the most commonly reported microbiota feature in premature infants with growth failure. In full-term infants, Staphylococcus is highly abundant in stool from newborns delivered via cesarean section compared to those born vaginally. Our results are in accord with a study of full-term infants that negatively associates 35 Staphylococcus with body mass index at 3 and 52 weeks of age. However, another study reports a positive association between 36 Staphylococcus and weight gain at 1 month of life among vaginally (but not cesarean) delivered full-term infants. Our review further identified 37 Klebsiella as negatively associated with growth; increased abundance of this genus in preterm infants is associated with sepsis and necrotizing enterocolitis. However, 38 Klebsiella is a diverse genus that is commonly found in preterm infant stool. Very few phenotypic or genomic differences have been identified in Klebsiella strains isolated from sick infants relative to healthy infants. 39 We also identified several microbial taxa that multiple studies found to positively correlate with neonatal growth. Many of these taxa, including Bifidobacterium , Bacteroides , Clostridium , Escherichia , Lactobacillus , Streptococcus , and Veillonella , are abundant in the stool of healthy, full-term newborns. Among the most dominant microbial community members of the full-term infant gut are Actinobacteria (particularly Bifidobacteriaceae or 40 , 41 Bifidobacterium ); however, we identified only two studies that found a positive association between 36 , 37 , 42 , 43 Bifidobacterium and postnatal growth. Our finding could indicate that a consistent link between Bifidobacterium and postnatal growth does not exist. Alternatively, this could reflect the very different, immature gut physiology of preterm relative to full-term neonates; the delayed administration of human milk to preterm neonates, a scenario that provides less of a competitive advantage to HMO-consuming bifidobacteria; or the abnormal initial colonization of premature newborns by microbes native to the neonatal intensive care unit environment. Consequently, microbial associations with preterm growth should be contextualized to factors that impact the development of the preterm infant gut microbiome. 44 Management of preterm infants in the neonatal intensive care unit is challenging, and multiple anthropometric indices are monitored to ensure that postnatal growth is sufficient. Most commonly, growth failure is characterized as growth < 10 th percentile at 36 weeks PMA. Fenton et al. recently outlined reasons why this definition alone is inadequate. Specifically, this definition of growth failure has not been shown to predict adverse outcomes, is based only on body weight irrespective of proportional head and length growth and genetic potential, does not account for postnatal weight loss, and is based on an arbitrary growth percentile cutoff. Clinicians routinely monitor body weight, length, and head circumference over time to ensure adequate trajectories of each and to inform targeted and timely nutritional interventions. As a result, studies of preterm neonates contain complex sets of metadata that typically include dozens of growth measurements recorded longitudinally throughout the newborn hospitalization – which lasts a minimum of 3–4 months for the most premature newborns. 45 Combining longitudinal microbiota sampling with longitudinal growth data presents investigators with a nearly unlimited number of testable associations between gut microbiota features and specific aspects of growth, thus increasing the risk of type I error. Although most software packages contain algorithms to adjust for the possibility of false positives due to testing multiple microbiota features (e.g., false discovery rate), adjustments might not be applied when microbiota data are evaluated repeatedly against multiple definitions of growth or postnatal age. Within our own secondary data analysis, it would be tempting to report microbiota associations by defining growth failure as change in HC z-score > −1.2 and time as PMA (8 significant taxonomic associations), rather than growth failure as length velocity < 1 cm/week and time as postnatal weeks of life (just 2 significant taxonomic associations). Similarly, investigators may account for potentially confounding factors that impact postnatal growth (e.g., co-morbidities including sepsis and necrotizing enterocolitis) in a number of different ways. These factors have been incorporated into statistical models, examined in sub-group analyses, evaluated in metadata tables, built into inclusion and exclusion criteria, or simply ignored. To advance our understanding of relationships between the neonatal gut microbiome and postnatal growth, we offer five recommendations ( Table 3 ). First, protocols of all neonatal microbiome studies, including interventional and observational studies, should be preregistered. The published record should include a thorough description of all statistical techniques that will be used to analyze the complex and typically longitudinal data sets. Second, given the growing number of microbiota-associated variables known to confound comparisons between cases and controls, careful attention must be paid to prenatal and perinatal factors that might explain or confound microbiota associations. A rich metadata set should present factors such as mode of delivery, gestational age at birth, sex, antibiotics and other medications, diet, and co-morbidities. Third, if the metadata set includes multiple growth metrics, all tests of association performed by the investigators should be presented in supplemental material. This will help readers understand how robustly specific microbiome features associate with postnatal growth across multiple indices, lend insight into whether certain microbiome features might associate more strongly with weight versus length versus head development, and provide greater transparency regarding the potential risk of type I error. Fourth, future studies should consider alternative approaches to 16S sequencing (e.g., combining whole metagenomic sequencing with metabolomics) to generate mechanistic insights into specific strains of microbes, genes, or metabolic pathways that underlie the reported associations. Recently developed statistical approaches may be used to integrate multi-omic data sets with clinical metadata; 46 these methods should be documented in the preregistered protocol. This information will generate new mechanistic hypotheses that may be tested in preclinical models. Fifth, the published report should include concise, complete, and organized reporting of all laboratory and bioinformatics elements that are essential to the interpretation and comparative analysis of human microbiome studies. One recommended guideline, the Strengthening The Organization and Reporting of Microbiome Studies (STORMS) checklist, 47 , 48 contains an editable table that can be included with supplemental files. Adherence to these recommendations may accelerate the development of new therapies that confer growth-promoting potential to reduce the burden of growth failure among premature neonates. 49 Table 3. Recommendations to improve future studies examining associations between the neonatal gut microbiome and postnatal growth. 1 Preregister all study protocols including proposed statistical techniques. 2 Capture comprehensive metadata including potentially confounding prenatal and perinatal factors. 3 Present all tested associations using any growth definition or index in supplemental material. 4 Consider alternatives to 16S sequencing (e.g., whole metagenomic sequencing with metabolomics). 5 Use microbiome-specific reporting guidelines to concisely and completely report essential laboratory and statistical details. Recommendations to improve future studies examining associations between the neonatal gut microbiome and postnatal growth. This systematic review was registered in PROSPERO [CRD42022361402] and was conducted according to the guidelines outlined in Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 50 Four databases were searched (PubMed, Web of Science, Cochrane Library, and Medline/Ovid) in September 2022. Studies relevant to gut microbiome associations with preterm infant growth were identified using the following search terms: (“infant,” OR “neonate,” AND “premature,” OR “preterm”), OR “preterm infant,” OR “premature infant,” OR “preterm neonate,” OR “premature neonate,” AND “microbiome,” OR “microbiota,” OR “flora,” OR “gut microbiome,” OR “gut microbiota,” OR “gut microbes,” OR “gut flora,” OR “gastrointestinal microbiome,” OR “gastrointestinal microbes,” OR “gastrointestinal microbiota,” OR “gastrointestinal flora,” OR “intestinal microbiome,” OR “intestinal microbiota,” OR “intestinal microbes,” OR “intestinal flora,” OR “fecal microbiome,” OR “fecal microbiota,” OR “fecal microbes,” AND “growth,” OR “growth failure,” OR “extrauterine growth restriction,” OR “growth faltering,” OR “postnatal growth,” OR “weight,” OR “height,” OR “length,” OR “head circumference,” OR “z-score,” OR “percentile.” Only studies published in the English language were included. Additional records were identified in PubMed searches. Studies were screened according to the following inclusion criteria: (1) study design of prospective, retrospective, longitudinal, cross-sectional, case-control, or randomized controlled trial; (2) studied preterm infants during their newborn hospital admission; (3) evaluated gut microbiome composition; (4) evaluated postnatal growth; and (5) assessed microbiota in relation to growth. Studies were excluded if they met the following criteria: (1) systematic review, narrative review, opinion, perspective, commentary, meta-analysis, animal study, or in vitro study; (2) studies on non-preterm infants; (3) protocol studies, conference abstracts, or studies not yet completed; (4) studies published in a language other than English; and (5) studies that lacked analyses relevant to associations between gut microbiome composition and postnatal growth. Studies identified in the database search were exported and screened using a reference manager (Zotero) based on titles and abstracts. Full-text screens were performed when necessary to determine eligibility. Eligible studies were assessed and the following data were extracted: author, year of publication, geographical location, study type, sample size, gestational age at birth, birth weight, neonatal diet, sample collection methods, microbiome analysis (including DNA extraction) method, and therapeutic interventions when applicable. For each study, we collected data reporting associations of preterm postnatal growth with gut microbiome composition including microbiota alpha diversity, beta diversity, and relative abundance of specific taxa. Because the variability of study methods and outcomes precluded a quantitative data synthesis, we qualitatively depicted microbial taxa that were reported to have positive or negative associations with early postnatal growth in a series of Venn diagrams. These taxa include a range of classifications from phylum to genus, as reported in the individual studies. When individual studies reported multiple statistical associations within the same data set, only associations that remained significant after adjusting for confounding factors and false discovery rate are included in our qualitative synthesis. A taxon was excluded from our qualitative synthesis if the same study reported both positive and negative associations between that taxon and growth. Venn diagrams were created with the BioRender.com platform. The secondary analysis in this report was generated from the Ford et al. study, a prospective cohort study ( 31 NCT02573779 ) conducted at Texas Children’s Hospital – Pavilion for Women and approved by the Institutional Review Board at Baylor College of Medicine. This study enrolled 125 very low birth weight preterm infants < 32 weeks gestational age. Stool samples, including the first meconium sample, were collected every week during the first 6 weeks of life. Inclusion/exclusion criteria, baseline demographics, and clinical outcomes are described in the previous report. In all, 249 stool samples were included in the secondary analysis. Associations between the gut microbiota and neonatal growth had not been investigated in the published study. For our secondary analysis, we incorporated anthropometric indices that classify infants as having “growth failure” or “appropriate growth.” Growth failure definitions include: weight at 36 weeks PMA < 10 th percentile using Fenton 2013 growth curves; weight velocity from birth to 36 weeks PMA < 20 g/day; length and HC velocities from birth to 36 weeks PMA < 1 cm/week; change in weight, length, or HC z-score > −1.2 from birth to 36 weeks PMA; 33 and infants who were born AGA then became SGA (weight < 10 34 th percentile at 36 weeks PMA ). Infants who were not classified as growth failure were classified as having appropriate growth. In the original prospective study, two infants died before 36 weeks PMA; therefore, their stools were excluded from the secondary analysis, resulting in a total of 245 stool samples analyzed in this report. 32 Raw sequences of the V4 region of the 16S rRNA gene were generated and processed as previously described. Analyses presented in this review were performed with ATIMA (Agile Toolkit for Incisive Microbial Analysis), a microbiome visualization tool developed by the Alkek Center for Metagenomics and Microbiome Research (CMMR) at Baylor College of Medicine. Data were rarified to 1015 reads per sample as done in the source study. For each definition of growth and neonatal age, all stools were categorized using the binary outcome growth failure versus appropriate growth, and taxonomic trends over time were analyzed either by week of life or by post-menstrual age (PMA). Statistical significance was determined by the Kruskal-Wallis test adjusted for false discovery rate. The taxonomic mean abundance was set at a threshold of ≥ 0.05%, unclassified taxa were excluded, the top 4 phyla and top 9 genera were ranked by the significance of the p-value, and these data were extracted. Taxa with relative abundances that changed significantly over time in one binary growth outcome but not the other were depicted in a heat map constructed in Microsoft Excel. Taxa with increasing abundance in growth failure or decreasing abundance in appropriate growth were designated as negatively associated with growth, whereas taxa with increasing abundance in appropriate growth or decreasing abundance in growth failure group were designated as positively associated with growth. 31 Click here for additional data file. We are grateful to Steven Ford, M.D. and Ruth Ann Luna, Ph.D. for their contributions to the original study that provided the microbiota sequencing data for our secondary analysis. No potential conflict of interest was reported by the author(s). All data and concepts described arise from the analysis of the literature detailed above (DOI: 10.1093/ajcn/nqz006). Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2190301 A systematic review of associations between gut microbiota composition and growth failure in preterm neonates Persistent gut microbiota immaturity in malnourished Bangladeshi children Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children Gut microbiomes of Malawian twin pairs discordant for kwashiorkor Preterm infant meconium microbiota transplant induces growth failure, inflammatory activation, and metabolic disturbances in germ-free mice Comparative effect of orally administered sodium butyrate before or after weaning on growth and several indices of gastrointestinal biology of piglets Drosophila microbiome modulates host developmental and metabolic homeostasis via insulin signaling Butyrate supplementation to gestating sows and piglets induces muscle and adipose tissue oxidative genes and improves growth performance The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B Expression Bifidobacteria can protect from enteropathogenic infection through production of acetate Aberrant gut-microbiota-immune-brain axis development in premature neonates with brain damage Sialylated milk Oligosaccharides promote microbiota-dependent growth in models of infant undernutrition Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition Preterm infant fecal microbiota and metabolite profiles are modulated in a probiotic specific manner Bifidobacteria isolated from infants and cultured on human milk oligosaccharides affect intestinal epithelial function Gut microbiota induce IGF-1 and promote bone formation and growth Enhanced nutrient supply and intestinal microbiota development in very low birth weight infants Effects of Lactobacillus reuteri supplementation on the gut microbiota in extremely preterm infants in a randomized placebo-controlled trial Intestinal microbiota and weight-gain in preterm neonates Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth Disrupted maturation of the microbiota and metabolome among extremely preterm infants with postnatal growth failure Longitudinal microbiome composition and stability correlate with increased weight and length of very-low-birth-weight infants Whiteson KL ed Association between extrauterine growth restriction and changes of intestinal flora in Chinese preterm infants Meconium microbiome and its relation to neonatal growth and head circumference catch-up in preterm infants Weight shapes the intestinal microbiome in preterm infants: results of a prospective observational study The gut microbiome of preterm infants treated with Aminophylline is closely related to the occurrence of feeding intolerance and the weight Gain Disrupted establishment of anaerobe and facultative anaerobe balance in preterm infants with extrauterine growth restriction Effect of intestinal microecology on postnatal weight gain in very preterm infants in intensive care units Characteristics of the intestinal microbiota in very low birth weight infants with extrauterine growth restriction Postnatal growth and gut microbiota development influenced early childhood growth in preterm infants Improved feeding tolerance and growth are linked to increased gut microbial community diversity in very-low-birth-weight infants fed mother’s own milk compared with donor breast milk A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants An attempt to standardize the calculation of growth velocity of preterm infants—evaluation of practical bedside methods Identifying malnutrition in preterm and neonatal populations: recommended Indicators Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns Intestinal microflora and body mass index during the first three years of life: an observational study Levels oF predominant intestinal microorganisms in 1 month-old full-term babies and weight gain during the first year of life Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella, and fimbriae-encoding bacteria Preterm infants harbour diverse Klebsiella populations, including atypical species that encode and produce an array of antimicrobial resistance- and virulence-associated factors Microbial succession in the gut: directional trends of taxonomic and functional change in a Birth Cohort of Spanish Infants Development of the intestinal flora in very low birth weight infants compared to normal full-term newborns Association between breast milk bacterial communities and establishment and development of the infant gut microbiome Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort The developing premature infant gut microbiome is a major factor shaping the microbiome of neonatal intensive care unit rooms “Extrauterine growth restriction” and “postnatal growth failure” are misnomers for preterm infants Host variables confound gut microbiota studies of human disease Gut microbiota profiling: metabolomics based approach to unravel compounds affecting human health The gut microbiome-metabolome dataset collection: a curated resource for integrative meta-analysis Reporting guidelines for human microbiome research: the STORMS checklist The PRISMA 2020 statement: an updated guideline for reporting systematic reviews |
Answer the following medical question. | What does research say about Comparison of neonatal skin sensor temperatures with axillary temperature: does skin sensor placement really matter?? | Appropriate thermoregulation affects both morbidity and mortality in the neonatal setting. Nurses rely on information from temperature sensors and radiant warmers or incubators to appropriately maintain a neonate's body temperature. Skin temperature sensors must be repositioned to prevent skin irritation and breakdown. This study addresses whether there is a significant difference between skin sensor temperature readings from 3 locations on the neonate and whether there is a significant difference between skin sensor temperatures compared with digital axillary temperatures. The study participants included 36 hemodynamically stable neonates, with birth weight of 750 g or more and postnatal age of 15 days or more, in a neonatal intensive care unit. Gestational age ranged from 29.6 to 36.1 weeks at the time of data collection. A method-comparison design was used to evaluate the level of agreement between skin sensor temperatures and digital axillary thermometer measurements. When the neonate's skin sensor was scheduled for routine site change, 3 new skin sensors were placed-1 each on the right upper abdomen, left flank, and right axilla. The neonate was placed in a supine position and redressed or rewrapped if previously dressed or wrapped. Subjects served as their own controls, with temperatures measured at all 3 skin sensor sites and followed by a digital thermometer measurement in the left axilla. The order of skin sensor temperature measurements was randomly assigned by a computer-generated number sequence. An analysis of variance for repeated measures was used to test for statistical differences between the skin sensor temperatures. The difference in axillary and skin sensor temperatures was calculated by subtracting the reference standard temperature (digital axillary) from the test temperatures (skin temperatures at 3 different locations), using the Bland-Altman method. The level of significance was set at P < .05. No statistically significant differences were found between skin temperature readings obtained from the 3 sites (F2,70 = 2.993, P = .57). Differences between skin temperature readings and digital axillary temperature were also not significant when Bland-Altman graphs were plotted. For hemodynamically stable neonates in a supine position, there were no significant differences between skin sensor temperatures on abdomen, flank, or axilla or between skin sensor temperatures and a digital axillary temperature. This may increase nurses' confidence that various sites will produce accurate temperature readings. |
Answer the following medical question. | What does research say about Epidemiology of painful procedures performed in neonates: A systematic review of observational studies.? | Procedural pain in neonates has been a concern in the last two decades. The purpose of this review was to provide a critical appraisal and a synthesis of the published epidemiological studies about procedural pain in neonates admitted to intensive care units. The aims were to determine the frequency of painful procedures and pain management interventions as well as to identify their predictors. Academic Search, CINAHL, LILACS, Medic Latina, MEDLINE and SciELO databases were searched for observational studies on procedural pain in neonates admitted to intensive care units. Studies in which neonatal data could not be extracted from the paediatric population were excluded. Eighteen studies were included in the review. Six studies with the same study duration, the first 14 days of the neonate life or admission in the unit of care, identified 6832 to 42,413 invasive procedures, with an average of 7.5-17.3 per neonate per day. The most frequent procedures were heel lance, suctioning, venepuncture and insertion of peripheral venous catheter. Pharmacological and nonpharmacological approaches were inconsistently applied. Predictors of the frequency of procedures and analgesic use included the neonate's clinical condition, day of unit stay, type of procedure, parental presence and pain assessment. The existence of pain protocols was not a predictor of analgesia. Painful procedures were performed frequently and often with inadequate pain management. Unlike neonate clinical factors, organizational factors may be modified to promote a context of care more favourable to pain management. |
Answer the following medical question. | What does research say about Randomised study showed that recorded maternal voices reduced pain in preterm infants undergoing heel lance procedures in a neonatal intensive care unit.? | Alleviating pain in neonates should be the goal of all caregivers. We evaluated whether recorded maternal voices were safe and effective in limiting pain in preterm infants undergoing heel lance procedures in the neonatal intensive care unit of an Italian children's hospital. This prospective, controlled study took place from December 2013 to December 2015. We enrolled 40 preterm infants, born at a 26-34 weeks of gestation, at a corrected gestational age 29-36 weeks and randomised them to listen or not listen to a recording of their mother's voice during a painful, routine heel lance for blood collection. Changes in the infants' Premature Infant Pain Profile, heart rate, oxygen saturation and blood pressure during the procedure were compared by analysis of variance. Possible side effects, of apnoea, bradycardia, seizures and vomiting, were also recorded. Both groups showed a marked increase in PIPP scores and decrease in oxygen saturation during the procedure, but infants in the treatment group had significantly lower PIPP scores (p = 0.00002) and lower decreases in oxygen saturation (p = 0.0283). No significant side effects were observed. Using recorded maternal voices to limit pain in preterm infants undergoing heel lance procedures appeared safe and effective. |
Answer the following medical question. | What does research say about Normative blood pressure data in the early neonatal period.? | There has been a temporal trend towards increased birth weight over the past three decades. This increase in birth weight may have resulted in an increase in neonatal blood pressure. Neonatal hypertension is becoming more common, especially in neonatal intensive care unit survivors. Current normative values are required to assist in diagnosis and appropriate management of neonatal hypotension and hypertension. The objective of this study was to determine normative blood pressure readings in healthy term neonates. Term neonates from the postnatal ward were enrolled from August 2003 to August 2005. Exclusion criteria included infants of mothers with preeclampsia, hypertension of any cause, gestational diabetes, type 1 diabetes mellitus and illicit substance use, infant congenital or chromosomal anomaly, admission to the neonatal intensive care unit or possible sepsis. Of the 406 infants enrolled, 218 were male. The median systolic, diastolic and mean blood pressures on day 1 of life were 65 mmHg, 45 mmHg, and 48 mmHg, respectively. On day 4, these values had increased to 70 mmHg, 46 mmHg and 54 mmHg. There was a significant elevation in blood pressure from day 1 to day 2 of life. There was no significant difference in blood pressure readings with respect to birth weight or length. The only significant difference between the sexes was a lower mean and diastolic pressure on day 2 in boys. This study has provided current normative blood pressure readings of healthy term neonates that can be used to assess both hypotension and hypertension in the term neonate. No increase in blood pressure was noted from previous studies. |
Answer the following medical question. | What does research say about Quantitative ultrasound assessment of bone health in the neonate.? | For a number of reasons there is a need to explore reliable non-invasive methods for assessing bone health in neonates and young infants. Epidemiological studies suggest that early events in life may predispose the adult to degenerative diseases such as osteoporosis. Preterm infants have an increased risk of low bone mass because of limited bone mass accretion in utero and a greater need for bone nutrients. Despite improvements in neonatal care fractures still occur. The diagnosis of osteopaenia of prematurity remains difficult as there is no screening test which is both sensitive and specific. Biochemical indices are non-diagnostic, and plain X-rays in the absence of fractures are poor at diagnosing bone disease. Although dual energy X-ray absorptiometry is increasingly used to assess bone mineral status in newborn infants, the size and immobility of the scanner, the length of time to perform the scan and use of ionising radiation make it unsuitable for routine use in the setting of the fragile very low birth weight infant. Quantitative ultrasound (QUS) was first developed in 1984, as a non-ionising, portable and low cost method of assessing bone health. The measurements obtained from QUS are thought to be related not only to the mineral density of the bone but also to reflect parameters of bone quality and strength. Preliminary studies suggest that this technique may be a useful method of assessing changes in bone health in preterm infants, but the data need to be interpreted carefully. This review will concentrate on the methodology of QUS and the studies that have already been performed in neonates. |
Answer the following medical question. | What does research say about Risk factors of infection and digestive tract colonization by Candida spp. in a neonatal intensive care unit.? | In this study we determined the risk factors for infection and colonization by Candida spp. in our Neonatal Intensive Care Unit (NICU). We designed a cohort study in the NICU of the La Paz University Hospital. Over a one year period, 153 neonates admitted to the NICU were studied. In the bivariable analysis, hospitalization period, central catheterization, parenteral feeding, parenteral lipid feeding, respiratory support and premature rupture of the membranes (PRM) were statistically associated with infection and colonization; age was only associated with infection. Logistic regression was used to control the confusing factors. The hospitalization period was a risk factor for infection and colonization. PRMs were also colonization risk factors. We developed a statistical equation that predicts the probability of infection or colonization by Candida spp. that are related to a neonate's specific characteristics. The equation helps us to develop preventive procedures. |
Answer the following medical question. | What does research say about Comparison of the analgesic effect of inhaled lavender vs vanilla essential oil for neonatal frenotomy: a randomized clinical trial (NCT04867824).? | Communicated by Peter de Winter It is necessary to treat neonatal pain because it may have short- and long-term adverse effects. Frenotomy is a painful procedure where sucking, a common strategy to relieve pain, cannot be used because the technique is performed on the tongue. In a previous randomized clinical trial, we demonstrated that inhaled lavender essential oil (LEO) reduced the signs of pain during neonatal frenotomy. We aimed to find out whether inhaled vanilla essential oil (VEO) is more effective in reducing pain during frenotomy than LEO. Randomized clinical trial with neonates who underwent a frenotomy for type 3 tongue-ties between May and October 2021. Pain was assessed using pre and post-procedure heart rate (HR) and oxygen saturation (SatO2), crying time, and NIPS score. Neonates were randomized into “experimental” and “control” group. In both groups, we performed swaddling, administered oral sucrose, and let the newborn suck for 2 min. We placed a gauze pad with one drop of LEO (control group) or of VEO (experimental group) under the neonate’s nose for 2 min prior to and during the frenotomy. We enrolled 142 neonates (71 per group). Both groups showed similar NIPS scores (2.02 vs 2.38) and crying times (15.3 vs 18.7 s). We observed no differences in HR increase or in SatO2 decrease between both groups. We observed no side effects in either of the groups. Conclusions : We observed no appreciable difference between LEO and VEO; therefore, we cannot conclude which of them was more effective in treating pain in neonates who underwent a frenotomy. Trial registration : This clinical trial is registered with www.clinicaltrials.gov with NCT04867824 . What is Known: • Pain management is one of the most important goals of neonatal care as it can have long-term neurodevelopmental effects . • Lavender essential oil can help relieve pain due to its sedative, antispasmodic, and anticolic properties . What is New: • Lavender and vanilla essential oils are safe, beneficial, easy to use, and cheap in relieving pain in neonates who undergo a frenotomy for type 3 tongue-ties . What is Known: • Pain management is one of the most important goals of neonatal care as it can have long-term neurodevelopmental effects . • Lavender essential oil can help relieve pain due to its sedative, antispasmodic, and anticolic properties . What is New: • Lavender and vanilla essential oils are safe, beneficial, easy to use, and cheap in relieving pain in neonates who undergo a frenotomy for type 3 tongue-ties . Neonates routinely undergo painful procedures such as blood sampling for the early diagnosis of inborn errors of metabolism. According to the International Association for the Study of Pain, “pain” is as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage [ 1 ]. Over the last years, neonatal units have shown an increasing interest in studying neonatal pain. Historically, newborns were thought to have no pain due to the immaturity of their nervous system [ 2 ]. Evidence however demonstrated that newborns feel pain and may even have increased sensitivity to it and to its long-term negative effects due to this immaturity. Repeated, unrelieved pain can cause adverse physiologic effects in all systems, including the brain, potentially affecting long-term development [ 3 ]. This fact has driven development-based care, a model which promotes individualized care based on the observation of the neonates’ behaviors and on the knowledge of their physical and family environment. Developmental care focuses on avoiding painful procedures such as blood sampling as much as possible, grouping interventions in order to minimally manipulate the newborn, and managing pain, either by administering analgesia, physically restraining the patient, or combining both [ 4 ]. It is important to recognize pain and relieve it because it may lead to hemodynamic instability, decreased oxygen saturation, and increased intracranial pressure [ 5 ]. Non-pharmacological pain relief interventions are important in neonatology because there is evidence that they reduce pain (even though they do not eliminate it) and distress but also because pharmacological treatments have potential adverse effects. They include the following: sensory stimulation (positioning or swaddling, vestibular action or rocking, aromatherapy, non-nutritive sucking, musical therapy), and nutritive (oral sweet solutions) and maternal interventions (maternal odor and voice, breastfeeding, skin-to-skin contact) [ 4 , 6 – 11 ]. Olfaction is essential for neonatal behavioral adaptation in many mammals, including humans [ 12 ]. Olfactory signals help the newborn baby localize and attach to the nipple at the first sucking bout [ 13 ]. Aromatherapy uses the healing effects of volatile essential oils in different ways and has been widely used for centuries in traditional and modern medicine as complementary therapy [ 6 , 14 , 15 ]. Aroma stimulates the olfactory bulb, anatomically close to the limbic system which is responsible for the emotions. Effects of essential oils on the limbic system lead to encephalin, endorphin, and serotonin release [ 16 ]. Lavender essential oil (LEO), of all the essential oils, has been studied most by healthcare professionals [ 17 ]. LEO may relieve pain [ 8 , 14 , 16 ] through inhibition of nociceptive stimuli by stimulating the olfactory system, inducing relaxation and stimulating endogenous opioids [ 7 ]. In our service, we perform painful techniques following administration of oral sucrose, performing swaddling, and allowing neonates to breastfeed or suck, which helps prevent crying. However, these measures are not enough during frenotomies because they are performed in the mouth and neonates cannot suck during the procedure. We have a high prevalence of neonatal ankyloglossia (32.5%) in our center, for which frenotomy is a common treatment [ 18 ]. In a former clinical trial ( NCT04877392 ), we compared the use of common pain control strategies (swaddling, administration of oral sucrose, and suck for 2 min prior to the procedure) with the use of those plus inhaled LEO and observed that signs of pain (duration of crying and NIPS score) were lower in the experimental group. From that moment on, we have routinely used inhaled LEO when performing a frenotomy [ 19 ]. Other authors have observed the benefits of using vanilla ( Vanilla fragrans ) essential oil (VEO) for pain control in neonates [ 20 , 21 ]. The aim of this study was to demonstrate if the use of inhaled VEO was more effective than inhaled LEO ( Lavandula angustifolia ssp angustifolia ) in reducing signs of pain during frenotomy in healthy, full-term neonates. Our hypothesis was that signs of pain (crying time and NIPS score) would be lower in the experimental group than in the control group. We chose LEO (control group) and VEO (experimental group) because these are the fragrances for which more studies have been performed in neonates and infants [ 6 – 8 , 14 , 19 , 21 – 29 ]. As far as we know, there are no previous studies which have analyzed the potential benefit of LEO vs VEO to relieve pain in neonatal frenotomy. We conducted a blinded randomized clinical trial (registered at https://clinicaltrials.gov with the identifier NCT04867824 , under the title “The Use of Lavender vs Vanilla Essential Oil as Complementary Analgesia for Frenotomy in Healthy Newborns”). Our hospital Ethics Committee (CEIm-PSMAR) reviewed and approved this study on May 4, 2021 (approval number: 2021/9731/I). This study was conducted according to the ethics code of the Barcelona Medical Association and the principles of the Helsinki-Fortaleza Declaration 2013. This study was conducted at the neonatal unit of a tertiary care hospital in Barcelona, Spain, which experiences approximately 1400 births per year from a multiethnic population with Spanish, Pakistani, and Bangladeshi being the most frequent nationalities of our patients [ 30 ]. We have high breastfeeding rates: around 85% at discharge from the maternity ward (86.8% in 2018) [ 18 ], 82% at the age of 3 months, and 54% at 6 months. We assess for the presence of ankyloglossia as part of the routine neonatal evaluation and classify it based on Coryllos’s criteria [ 31 ] and the Hazelbaker tool [ 32 ]. A lingual frenulum is symptomatic if it scores eight points or less in appearance and/or 11 or less in function according to Hazelbaker. Advice and help with positioning and attachment for breastfeeding are provided to all the mothers by lactation support providers. During the study period, if we identified a symptomatic neonate with a type 3 tongue-tie which affected breastfeeding, we offered the neonate’s parents to participate. We considered a tongue-tie to be symptomatic if it scored 8 points or less in appearance and/or 11 points or less in function according to Hazelbaker and the mother experienced nipple pain or bruises, or if the neonate had problems latching onto the breast after a neonatal nurse assessed feeding and corrected other reasons for maternal pain such as retrognathia, micrognathia, incorrect positioning, insufficient mouth opening, and latching onto the nipple only. We chose type 3 tongue-ties because they are the most common in our population [ 18 ] and, due to their anatomical features (thick and submucosal), they seem to make breastfeeding more difficult. Neonates were enrolled if their parents agreed to and signed a written informed consent prior to the procedure, and then they were allocated into the experimental or the control group by simple random sampling using the program OxMAR (Online Minimization and Randomization for Clinical Trials) [ 33 ]. Prior to recruitment, we generated a list of 142 numbers, where each number was randomized to either the “VEO” or “control (LEO)” group. Neonates were enrolled in numerical order and assigned into the pre-determined group. The group into which a neonate had been enrolled was not known by the attending personnel until the moment of performing the frenotomy. To perform the frenotomy, the neonate was taken to the neonatal unit and monitored with a pulse-oximeter (COVIDIEN Nellcor Portable SpO2 Patient Monitoring System PM10N, Covidien Ireland Limited, IDA Business & Technology Park, Tullamore, Ireland) while preparing the neonate for the frenotomy, throughout the procedure and until 5 min after completing it. For both groups, we swaddled, administered 1 mL of oral sucrose, and let the newborn suck for 2 min prior to the procedure. The control group had a 7 × 7 cm gauze pad with one drop of 100% pure LEO (Pranarôm España S.L.) placed 2 cm under their nose for 2 min prior to starting the frenotomy and for the duration of the procedure, whereas in the experimental group, the drop on the gauze pad was of 100% pure VEO (Pranarôm España S.L.) instead. The bottles of both LEO and VEO have a dropper that always dispenses the same amount of oil per drop. We did not start the procedure until the neonates were calm and had a NIPS score of 0. Frenotomy was performed by one of the three staff neonatologists by placing a sterile groove director under the tongue holding the frenulum in place with visualization of tongue base and frenulum, then snipping the frenulum with a blunt tip scissor along the underside of the tongue to its base just proximal to the genioglossus muscle until a full release was achieved [ 31 ]. We assessed pain by means of crying time and the highest Neonatal Infant Pain Scale (NIPS) score in the 5 min post procedure, and whether there was an increase in heart rate (HR) and decrease in oxygen saturation (SatO2) (comparing pre- and post-procedure HR and SatO2). NIPS evaluates facial expression, crying, breathing pattern, arm and leg position, and state of arousal on a scale from 0 to 7, where 0–2 means no pain to mild pain, 3–4 mild to moderate pain, and > 4 severe pain [ 34 ]. A blinded neonatologist who did not perform the frenotomy evaluated vital signs through the screen of the pulse-oximeter, NIPS score, and crying time from a neighboring room through a glass, for which he/she could not smell or see which oil was being used. Vital signs, whether the baby cried or not, the seconds crying lasted, and the post procedure NIPS score were recorded on a data collection sheet. A chronometer was started when the neonate started crying and was stopped once he/she completely stopped crying. If he/she restarted crying after having initially stopped, the chronometer was started again and all the crying time was added up. If a neonate cried, the attending staff who performed the frenotomy provided calming techniques such as holding, swaddling, and sucking regardless of which essential oil was being used. These persons were not blinded. Once the procedure was completed, we removed the gauze pad and returned the neonate to the mother for breastfeeding. In an exploratory preliminary study prior to the intervention, we observed a mean (SD) crying time of 19.80 (21.14) s. We used this data as our baseline. In order to detect a difference of 10 s in crying time, we calculated that we needed a sample size of 71 neonates per group to be able to draw conclusions with a confidence interval ( CI ) 95% and a power of 80%. We used crying time to calculate sample size because it is an objective way to measure pain, whereas NIPS could be more person-specific. The observer (a blinded neonatologist) saw the procedure from a neighboring room through a glass, from which the screen of the pulse-oximeter and the neonate were perfectly visible. This person recorded demographic (sex, gestational age, birth weight, age in hours at the time of frenotomy) and clinical data (HR and SatO2 before, during, and after the procedure, whether the neonate cried or not during the procedure, length of crying time in seconds, presence of side effects during the procedure (apnea, desaturation, distress, vomiting, changes in skin color), and highest NIPS score within the first 5 min after the procedure) on a data collection sheet. The primary outcome was difference in crying time between the experimental and the control group, and secondary outcomes were as follows: difference of NIPS score, HR, and SatO 2 pre and post-procedure between the experimental and the control group. Participants’ confidentiality was maintained because neither the name nor the medical record number was recorded on the data collection sheet. Quantitative variables are described using the mean, standard deviation, and 95% CI ; the experimental and the control groups were compared with a Student’s t test. Qualitative variables are presented in percentages and compared using Fisher’s exact test. We compared NIPS scores between both groups using the Wilcoxon rank-sum (Mann–Whitney) test. Statistical significance was set for a P < 0.05. To perform statistical analyses, we used STATA version 16.1 (StataCorp, College Station, TX, USA). We enrolled 142 neonates until we reached 71 neonates in each group from a total of 155 potential candidates between May 10, 2021, and October 9, 2021. Thirteen were excluded for the following reasons: eight parents refused to participate in the study, there was a language barrier with four parents, and one was isolated due to maternal COVID-19 infection. There was no follow-up period; therefore, we did not lose any participants to follow up. All the neonates were analyzed for the primary and secondary outcomes. We included 77 male (54.2%) and 65 female (45.8%) newborns. Globally, mean (SD) gestational age was 39 6/7 (1 1/7 ) weeks, and mean (SD) birth weight, 3328.58 (488.04) g. The mean (SD) age at the time of the procedure was 43.0 (32.9) hours. Table 1 shows the demographic characteristics of both groups. There were no differences between the two groups in terms of sex, birth weight, gestational age, or age at the moment of the frenotomy. Table 1 Demographic characteristics of the experimental group and the control group Variables Experimental group (VEO) n = 71 (%) Control group (LEO) n = 71 (%) P value Male newborn 38 (53.5) 39 (54.9) > 0.99 a Birth weight (grams) (mean, SD) 3277.97 (494.71) 3379.20 (479.41) 0.217 b Gestational age (weeks) (mean, SD) 39 6/7 (1 1/7 ) 39 6/7 (1 2/7 ) 0.909 b Age at frenotomy (hours) (mean, SD) 43.6 (31.1) 42.4 (34.8) 0.819 b LEO lavender essential oil, VEO vanilla essential oil a Fisher’s exact test b Student’s t -test Demographic characteristics of the experimental group and the control group LEO lavender essential oil, VEO vanilla essential oil a Fisher’s exact test b Student’s t -test Mean (SD) HR pre-procedure was 125.4 (17.3) bpm, and post-procedure 155.3 (16.8) bpm; mean (SD) HR increase was 29.9 (15.6) bpm. Mean (SD) SatO 2 pre-procedure was 99.3 (1.2) %, and post-procedure, 96.4 (3.1) %; mean (SD) SatO2 decrease was 2.9 (3.0) %. A total of 140 neonates cried (99.3%) with a mean (SD) crying time of 17.0 (19.5) seconds. Mean (SD) NIPS score was 2.20 (1.05). There were no differences between the two groups in terms of baseline HR. There were statistically different baseline SatO2 that had no clinical significance. Table 2 presents the outcomes of the experimental group and the control group. Table 2 Outcomes of the experimental group and the control group. Control group is the reference Variables Experimental group n = 71 (%) Control group n = 71 (%) P value 95% CI d Crying (yes, %) 71 (100%) 70 (98.6%) > 0.99 a - Crying (seconds) (mean, SD) 15.3 (16.5) 18.7 (22.0) 0.297 b −9.88 to + 3.04 NIPS score (mean, SD) (range) 2.02 (0.97) (1–4) 2.38 (1.11) (0–4) 0.114 c −0.63 to + 0.07 Heart rate (bpm) pre-procedure (mean, SD) post-procedure (mean, SD) 125.1 (13.1) 155.8 (16.5) 125.8 (17.3) 154.9 (17.2) 0.781 b 0.762 b −5.83 to + 4.39 −4.74 to + 6.46 Increase in heart rate post-procedure (bpm) (mean, SD) 31.3 (16.1) 30.6 (15.5) 0.549 b −3.62 to + 6.77 Oxygen saturation (%) pre-procedure (mean, SD) post-procedure (mean, SD) 99.1 (1.5) 96.1 (3.3) 99.6 (0.9) 96.7 (2.9) 0.024 b 0.277 b −0.87 to − 0.06 −1.62 to + 0.47 Decrease in oxygen saturation post-procedure (%) (mean, SD) 2.3 (2.7) 2.4 (2.9) 0.826 b −1.13 to + 0.90 Presence of adverse effects (yes, %) 0 (0.0%) 0 (0.0%) - - a Fisher’s exact test b Student’s t -test c Wilcoxon rank-sum (Mann–Whitney) test d 95% CI : 95% confidence interval of the difference between the experimental and the control group Outcomes of the experimental group and the control group. Control group is the reference Heart rate (bpm) pre-procedure (mean, SD) post-procedure (mean, SD) 125.1 (13.1) 155.8 (16.5) 125.8 (17.3) 154.9 (17.2) 0.781 b 0.762 b −5.83 to + 4.39 −4.74 to + 6.46 Oxygen saturation (%) pre-procedure (mean, SD) post-procedure (mean, SD) 99.1 (1.5) 96.1 (3.3) 99.6 (0.9) 96.7 (2.9) 0.024 b 0.277 b −0.87 to − 0.06 −1.62 to + 0.47 a Fisher’s exact test b Student’s t -test c Wilcoxon rank-sum (Mann–Whitney) test d 95% CI : 95% confidence interval of the difference between the experimental and the control group There were no differences between the experimental group and the control group in terms of crying time, NIPS scores, HR increase, or SatO 2 decrease. Almost all neonates cried in both groups. We observed no adverse effects with the use of LEO or VEO. Goubet conducted the first study of aromatherapy with neonates in 2003 [ 35 ]. Aromatherapy has been used to treat pain in infants, showing an objective improvement in neonatal pain scale scores, decreased heart rate, shorter crying time, and prevention of decreased oxygen saturation [ 6 – 8 , 14 , 19 , 22 ]. The main aromas used in neonatology are lavender, vanilla, amniotic fluid, and human milk [ 6 , 36 ]. LEO may alter the perception of pain by inhibiting nociceptive stimuli by means of stimulating the olfactory system and inducing relaxation, providing a pleasant environment, distracting the mind from the pain, and stimulating endogenous opioids [ 7 ]. Its sedative, antidepressant, and antispasmodic and anticolic properties make it capable of relieving the symptoms of pain [ 8 , 14 ]. Inhaled LEO has demonstrated benefits in reducing pain during neonatal blood sampling, heel puncture [ 7 , 8 , 22 ], and vaccination at the age of 2 months [ 23 ]. Several studies concluded that the use of a familiar odor (mainly breast milk, but also vanillin, present in VEO) helps to reduce agitation, apneas, and stress and adverse effects of neonatal pain [ 29 , 37 , 38 ]. Vanillin seems to be hedonically pleasant for full-term and preterm neonates, seems to influence pain reaction, and may even be analgesic, especially if the infant has been previously exposed to its odor [ 28 , 29 , 35 , 39 ]. We did not sensitize neonates with the aroma of VEO because we performed the frenotomy when it was indicated, and thus, there was no time to sensitize them prior to the procedure. Goubet observed that VEO has soothing effects on premature neonates during venipuncture but not during heel stick [ 35 ], whereas some authors have observed that it is effective in full-term neonates during heel stick [ 21 , 28 , 39 ], venipuncture [ 20 ], and arterial puncture [ 40 ]. Sadathosseini observed that crying lasted significantly less and that variation in SatO 2 was lower when the odor of VEO was familiar [ 40 ]. Other studies have found no effects of VEO in soothing pain in full-term infants if the patients have not been previously exposed to this odor [ 26 ]. Neshat et al. found no differences on prematures’ heart rate and SatO 2 during venipuncture even though the neonates had been previously familiarized with VEO [ 25 ]. We are aware that the prevalence of ankyloglossia we found in our population is higher than reported [ 18 ]. This can be explained by the fact that we designed a study to prospectively evaluate all the neonates for the presence of a tongue-tie. Most studies have focused their attention to the “anterior tongue-ties,” whereas the true prevalence of “posterior tongue-ties” remains unknown [ 41 ]. Most clinicians recognize an anterior frenulum and recommend a frenotomy if it affects breastfeeding. Posterior ankyloglossia is often undiagnosed, as it does not have the usual appearance of the traditional, anterior frenulum, and it is a relatively newly recognized entity [ 42 ]. To the best of our knowledge, this is the first study to evaluate the effect of inhaled LEO vs VEO as pain relief during neonatal frenotomy. In a previous clinical trial, which we conducted, we observed a significant decrease in crying time and NIPS scores in the LEO-exposed group when compared to the control group and traditional pain control measures [ 19 ]. When planning this clinical trial, we chose VEO because it is the second most used aroma (apart from breastmilk) in neonatology. In this study, we observed no difference in crying time or the NIPS scores between the LEO and VEO groups. Thus, we can assume that VEO is a suitable alternative for LEO in treating neonatal pain during frenotomy. None of the prior aromatherapy studies performed in infants has described any side effects, for instance nausea, vomiting, or chills [ 24 , 27 , 29 , 40 ]. In keeping in line with them, we also have observed no side effects from its use. Therefore, we conclude that using inhaled LEO and VEO for frenotomy is safe. Our study is easily reproducible. One positive note is that the use of inhaled essential oils is cheap. A 10-mL bottle of Pranarôm LEO or VEO costs $7.60 US, and contains approximately 200 drops. We used one drop per neonate, which represents approximately $0.04 US. We acknowledge that the study has limitations. The team who performed the frenotomies was not blinded, because the smell of LEO and VEO is too obvious to ignore. However, the person who recorded the data was blinded, as described in the “ Patients and methods ” section. Some candidates (8.39%) were not eligible to participate primarily because eight parents did not consent and four parents had language barrier issues for which they were not offered to participate. Another limitation is that more than one person performed the frenotomies, for which the technique could have minimal variations; however, all three staff neonatologists have similar experience and training. In conclusion, we observed no differences in the signs of pain between the experimental and the control group. For this reason, we cannot conclude that LEO or VEO are more effective in treating pain in the neonates who underwent a frenotomy for type 3 tongue-ties. We observed no side effects from its use. Heart rate Lavender essential oil Neonatal Infant Pain Scale Oxygen saturation Vanilla essential oil Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We would like to thank Jennifer Bricker-Bolton for proofreading this manuscript and helping with the English language. We would like to thank Pranarôm España S.L. for providing the samples of lavender and vanilla essential oils used in the present study at no cost. Dr. SM designed the study, collected data, analyzed the results, and drafted the initial manuscript. Dr. MF designed the study, analyzed the results, and drafted the initial manuscript. Ms. RL reviewed the literature and helped draft the initial manuscript. Drs. JC, JG and ML collected data, and helped draft the initial manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Our database is accessible from the authors upon request. Our Ethics Committee approved the study (reference number: 2021/9731/I), which was conducted in accordance with the Declaration of Helsinki. Yes. N/A. We declare that we have no conflicts of interest to disclose. Comparison of the analgesic effect of inhaled lavender vs vanilla essential oil for neonatal frenotomy: a randomized clinical trial ( The reality of neonatal pain and the resulting effects Long-term effects of neonatal pain Effect of sucrose analgesia, for repeated painful procedures, on short-term neurobehavioral outcome of preterm neonates: a randomized controlled trial Culturally based practice in neonatal procedural pain management: a mini review The effectiveness of familiar olfactory stimulation with lavender scent and glucose on the pain of blood sampling in term neonates: a randomized controlled clinical trial Sweet solutions to reduce procedural pain in neonates: a meta-analysis Combined non-pharmacological interventions for newborn pain relief in two degrees of pain procedures: a randomized clinical trial Olfaction and human neonatal behaviour: clinical implications Does the newborn baby find the nipple by smell? The effectiveness of aromatherapy massage using lavender oil as a treatment for infantile colic Exploring pharmacological mechanisms of lavender (Lavandula angustifolia) essential oil on central nervous system targets Varieties of alternative experience: complementary care in the neonatal intensive care unit Prevalence of neonatal ankyloglossia in a tertiary care hospital in Spain: a transversal cross-sectional study Comparative effect of the smells of amniotic fluid, breast milk, and lavender on newborns’ pain during heel lance Lavender bath oil reduces stress and crying and enhances sleep in very young infants Effects of breast milk and vanilla odors on premature neonate’s heart rate and blood oxygen saturation during and after venipuncture The effects of olfactory stimulation and gender differences on pain responses in full-term infants Olfactory stimulation prevents apnea in premature newborns Systematic review on phytotherapy in neonatology Validation of a neonatal skin color scale OxMaR: open source free software for online minimization and randomization for clinical trials The development of a tool to assess neonatal pain Olfactory experience mediates response to pain in preterm newborns Activation of olfatory cortex in newborn infants after odor stimulation: a functional near-infrared spectroscopy study Olfactory stimulation by vanilla prevents apnea in premature newborn infants Impact of the odors of vanilla extract and breast milk on the frequency of apnea in preterm neonates The calming effect of a familiar odor on full-term newborns The effect of a familiar scent on the behavioral and physiological pain responses in neonates Ankyloglossia and Other Oral Ties Breastfeeding difficulties and oral cavity anomalies: the influence of posterior ankyloglossia and upper-lip ties |
Answer the following medical question. | What does research say about Kangaroo care is effective in diminishing pain response in preterm neonates.? | To test the efficacy of maternal skin-to-skin contact, or kangaroo care (KC), on diminishing the pain response of preterm neonates to heel lancing. A crossover design was used, in which the neonates served as their own controls. Subjects Preterm neonates (n = 74), between 32 and 36 weeks' postmenstrual age and within 10 days of birth, who were breathing without assistance and who were not receiving sedatives or analgesics in 3 level II to III neonatal intensive care units in Canada. In the experimental condition, the neonate was held in KC for 30 minutes before the heel-lancing procedure and remained in KC for the duration of the procedure. In the control condition, the neonate was in the prone position in the isolette. The ordering of conditions was random. The primary outcome was the Premature Infant Pain Profile, which is composed of 3 facial actions, maximum heart rate, and minimum oxygen saturation changes from baseline in 30-second blocks. Videotapes, taken with the camera positioned on the neonate's face so that an observer could not tell whether the neonate was being held or was in the isolette, were coded by research assistants who were naïve to the purpose of the study. Heart rate and oxygen levels were continuously monitored into a computer for later analysis. A repeated-measures analysis of covariance was used, with order of condition and site as factors and severity of illness as a covariate. Premature Infant Pain Profile scores across the first 90 seconds from the heel-lancing procedure were significantly (.002<P<.04) lower by 2 points in the KC condition. For preterm neonates who are 32 weeks' postmenstrual age or older, KC seems to effectively decrease pain from heel lancing. Further study is needed to determine if younger neonates or those requiring assistance in breathing, or older infants or toddlers, would benefit from KC, or if it would remain effective over several procedures. Given its effectiveness, and that parents of neonates in critical care units want to participate more in comforting their children, KC is a potentially beneficial strategy for promoting family health. |
Answer the following medical question. | What does research say about Emotional disorganization: The prominent experience of Iranian mothers with preterm neonate: A qualitative study.? | When a preterm neonate is born and needs to be taken care of in the neonatal intensive care unit (NICU), the mother experiences a different process of mothering. A grounded theory study was conducted to explore the maternal role attainment in mothers of preterm infants. The authors of this paper report the most prominent experience of Iranian mothers with preterm neonates during their stay in the NICU that emerged as part of the process of maternal role attainment. Data were collected through in-depth semi-structured interviews with mothers in the NICU. We found four categories as emerged from experiences that formed the concept of "emotional disorganization". We argue that these findings can help caregivers and nurses to provide sensitive and supportive care to mothers of preterm neonates. |
Answer the following medical question. | What does research say about The Pathophysiology, Diagnosis, and Management of Wolff-Parkinson-White Syndrome in the Neonate.? | Wolff-Parkinson-White (WPW) is a congenital defect of the cardiac conduction system (CCS), with proliferation of extra embryologic conduction pathways and rapid conduction of electrical impulses. The estimated neonatal incidence of 0.1% to 0.2% may be misrepresented secondary to missed or misdiagnosis. Undiagnosed WPW can result in sudden cardiac death. To discuss the pathogenesis, manifestations, diagnosis, management, and lifespan implications of WPW in the prenatal and postnatal periods. A literature review was conducted using PubMed, CINAHL, and Google Scholar (2013-2019). Search terms included (newborn OR infant), wolff parkinson white, pathogenesis, management, and ventricular preexcitation. After removal of duplicates, 267 references were identified, abstracts reviewed, and 30 publications fully evaluated. Separation of the heart chambers begins around 7 weeks' gestation with formation of the annulus fibrosis complete after term. The unknown external environmental influence on the development of the preterm infant's CCS places neonates at risk for persistent atrioventricular reentrant tachycardia with WPW development. Ensuring an appropriate diagnosis is crucial, as an incorrect diagnosis could mean death. Due to the rarity of WPW, any fetal or neonatal supraventricular tachycardia requires further evaluation with an electrocardiogram and involvement of an experienced cardiologist for diagnosis. One episode of supraventricular tachycardia warrants evaluation for WPW, as recurring episodes may result in irreversible damage. The recommendations for treatment of WPW in the prenatal and immediate postnatal periods are based heavily on standards of care for the adult population. A paucity of evidenced-based literature exists and future research is crucial to understand the true incidence, physiologic effects, and lifespan implications of WPW on neonates. |
Answer the following medical question. | What does research say about Early arterial lactate and prediction of outcome in preterm neonates admitted to a neonatal intensive care unit.? | In the present study early arterial lactate samples were examined to predict adverse outcome in preterm neonates. 88 preterm neonates (mean gestational age 29.8 weeks, mean birth weight 1,225 g) had arterial lactate levels measured from indwelling arterial catheters within the first 3 h of life. An adverse outcome was defined as death or abnormal neurodevelopment. The positive (PPV) and negative predictive value (NPV) of early arterial lactate levels for an adverse outcome (death or neurodevelopmental abnormalities) were calculated using receiver operating characteristic analysis. PPV and NPV of arterial lactate within 3 h after birth were 0.47 and 0.92, respectively, with a cutoff value of 5.7 mmol/l. Umbilical blood gas values and 1 and 5 min Apgar scores had much lower PPVs. Arterial lactate levels within 3 h of life can be used to select preterm neonates who are at risk of an adverse outcome. |
Answer the following medical question. | What does research say about Neonatal management at limits of viability: hypothesis based on review of literature and clinical observations.? | Advances in the surfactant era have resulted in a dramatic rise in the survival of 23-26 week old neonates. For the group as a whole, survival is 50% with a 50% morbidity in survivors. Current literature includes a few 'small baby protocols' suggesting guidelines for management based on institutional experiences. Adopting these with or without any modifications may not be appropriate for other institutions due to the diversity of the patient population involved and the available resources. A review of literature on ELBW neonates reveals an interesting fact that almost all the management strategies and optimal goals in the most critical first few weeks of life involve two numbers--'fifty' and 'eight'! The relevance of these two numbers (or their multiples) in simplifying the management of ELBW neonates is highlighted. |
Answer the following medical question. | What does research say about Accuracy of a spontaneous breathing trial for extubation of neonates.? | Prevalence of extubation failure in neonates may be up to 80%, but evidence to determine if a neonate is ready for extubation remains unclear. We aim to evaluate a spontaneous breathing trial accuracy with minimum pressure support to predict success in neonates' extubation and identify variables related to failures. This is a diagnostic accuracy study based on a cohort study in an intensive care unit with all eligible newborn infants subjected to invasive mechanical ventilation for at least 24 hours submitted to the trial for 10 minutes before extubations. The outcome was failures of extubations, considered if reintubation was needed until 72 hours. The incidence of failure was 14.7%among 170 extubations. There were 145 successful extubations; of these, 140 also passed the trial with a sensitivity of 96.5%(95%CI: 92.1-98.9). Of the 25 extubations that eventually failed, 16 failed the test with a specificity of 64.0%(95%CI: 42.5-82.0). The negative predictive value was 76.2%, and the positive predictive value was 94%. In stratifying by weight, the accuracy was >98.7%for neonates weighting >2500 g, but 72.5%for those weighing <1250 g. Extubation failures occurred more frequently in smaller (p = 0.01), preterm infants (p = 0.17), with longer ventilation time (p = 0.05), and having a hemodynamically significant persistent arterial duct (p = 0.01), compared with infants whose extubation was successful. The spontaneous breathing trial with minimum pressure support ventilation seems to predict extubation success with great accuracy in full-term and larger neonates. |
Answer the following medical question. | What does research say about The Effect of Breastfeeding, Kangaroo Care, and Facilitated Tucking Positioning in Reducing the Pain During Heel Stick in Neonates.? | Invasive intervention can negatively affect prognosis, behavior, environmental adaptation in neonates. Some nonpharmacological pain management methods are used for effective pain treatment. This study investigated the effect of breastfeeding, kangaroo care, and facilitated tucking positioning on heel-stick pain in neonates. A quasi-experimental design was employed. The study was conducted in three family health centers in Kütahya/Turkey. The sample consisted of 140 healthy neonates with the gestational age of 37 weeks or more, birth weight greater than 2500 g, and no sucking problems. The sample was divided into four groups (breastfeeding, kangaroo care, facilitated tucking position, and control). Data were collected using a Baby-Mother Characteristics Questionnaire, a Physiological Parameter Follow-up Form, and the Neonatal Infant Pain Scale. Data were analyzed using chi-square, the one-way analysis of variance (ANOVA), Kruskal-Wallis, Student t-test, and Mann-Whitney U tests. The research adhered to ethical principles. The facilitated tucking position group cried less and experienced less pain during heel stick than the other groups (p < 0.05). Breastfeeding, kangaroo care, and facilitating tucking help reduce heel-stick pain but facilitating tucking causes less crying and imposes less pain on neonates than the other methods. Facilitated tucking position may be preferred to reduce pain during heel stick. Using facilitated tucking positions and breastfeeding methods can assist healthcare professionals as supportive methods in pain management. |
Answer the following medical question. | What does research say about Initial resuscitation and stabilization of the periviable neonate: the Golden-Hour approach.? | There is a paucity of data to support recommendations for stabilization and resuscitation of the periviable neonate in the delivery room. The importance of delivery at a tertiary center with adequate experience, resuscitation team composition, and training for a periviable birth is reviewed. Evidence for delayed cord clamping, delivery room temperature stabilization, strategies to establish functional residual capacity, and adequate ventilation as well as oxygen use in the delivery room is generally based on expert consensus, physiologic plausibility, as well as data from slightly more mature extremely low gestational-age neonates. Little is known about optimal care in the delivery room of these most fragile infants, and thus the need for research remains critical. |
Answer the following medical question. | What does research say about How we decide when a neonate needs a transfusion.? | The decision to transfuse a neonate can be approached by addressing a series of questions that cover the cause of anaemia, alternatives to transfusion, the need for transfusion and the risks. Recent clinical trials of red cell transfusions have started to inform evidence-based transfusion practice, but have raised uncertainties about neurological outcomes when policies advocating use of fewer red cell transfusions at lower haemoglobin concentration (Hb) thresholds were tested. Red cell transfusions should be considered when the Hb <120 g/l for premature neonates requiring mechanical ventilation support, with lower thresholds applying for oxygen-dependent neonates not requiring ventilation or for late anaemia (Hb <70-100 g/l, depending on gestational and post-natal age). There is no recent high quality evidence to inform thresholds for prophylactic platelet transfusions in stable non-bleeding premature neonates with platelet count levels of 50 × 10(9) /l, although common practice has become more restrictive, using lower safe thresholds for platelet transfusion between 20 and 30 × 10(9) /l. A more appropriate transfusion strategy for fresh frozen plasma (FFP) in neonates is one that emphasizes the therapeutic use of FFP in the face of bleeding, rather than prophylactic use in stable non-bleeding neonates who often have mild to moderate apparent abnormalities of standard coagulation tests, after allowing for appropriate reference ranges. |
Answer the following medical question. | What does research say about Review demonstrates that less invasive surfactant administration in preterm neonates leads to fewer complications.? | Surfactant treatment of neonatal respiratory distress syndrome (RDS) was introduced in Europe during the 1990s. Meta-analyses have indicated that using less invasive surfactant administration techniques on preterm neonates receiving continuous positive airway pressure (CPAP) results in improved survival rates without bronchopulmonary dysplasia. Surfactant should be administered early and ventilator settings adapted to changing oxygen requirements and lung mechanics. Side effects including initial bradycardia, oxygen desaturation, tube obstruction and isolated cases of pulmonary haemorrhage have been reported. Less invasive surfactant therapy improves pulmonary outcomes in preterm neonates with RDS and should ideally be administered in combination with CPAP. |
Answer the following medical question. | What does research say about Unobtrusive Monitoring of Neonatal Brain Temperature Using a Zero-Heat-Flux Sensor Matrix.? | The temperature of preterm neonates must be maintained within a narrow window to ensure their survival. Continuously measuring their core temperature provides an optimal means of monitoring their thermoregulation and their response to environmental changes. However, existing methods of measuring core temperature can be very obtrusive, such as rectal probes, or inaccurate/lagging, such as skin temperature sensors and spot-checks using tympanic temperature sensors. This study investigates an unobtrusive method of measuring brain temperature continuously using an embedded zero-heat-flux (ZHF) sensor matrix placed under the head of the neonate. The measured temperature profile is used to segment areas of motion and incorrect positioning, where the neonate's head is not above the sensors. We compare our measurements during low motion/stable periods to esophageal temperatures for 12 preterm neonates, measured for an average of 5 h per neonate. The method we propose shows good correlation with the reference temperature for most of the neonates. The unobtrusive embedding of the matrix in the neonate's environment poses no harm or disturbance to the care work-flow, while measuring core temperature. To address the effect of motion on the ZHF measurements in the current embodiment, we recommend a more ergonomic embedding ensuring the sensors are continuously placed under the neonate's head. |
Answer the following medical question. | What does research say about Chylothorax: A Stepwise Approach to Diagnosis and Treatment.? | Chylothorax, a lymphatic flow disorder characterized by an abnormal circulation of lymph fluid into the pleural cavity, is the most common cause of pleural effusions during the neonatal period. This condition affects 1/15,000 neonates every year. Affected neonates often manifest with respiratory distress, electrolyte imbalances, sepsis, and even immunodeficiencies. Mortality risk is highest among neonates undergoing cardiac surgery as well as those with associated hydrops fetalis. Conservative treatment options include bowel rest with administration of parenteral nutrition, followed with medium-chain triglyceride enteral feedings, and octreotide therapy. Severe or persistent cases require surgical intervention. This can involve a unilateral or bilateral pleurectomy and thoracic duct ligation, with or without pleurodesis. Early identification and successful treatment of this condition is contingent upon awareness of the most current evidence and a timely cross-disciplinary approach to care. |
Answer the following medical question. | What does research say about Association of Hospital Adoption of Probiotics With Outcomes Among Neonates With Very Low Birth Weight.? | Accepted for Publication: February 21, 2023. Published: May 12, 2023. doi: 10.1001/jamahealthforum.2023.0960 Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Agha L et al. JAMA Health Forum . Author Contributions: Prof Agha had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Agha, Staiger, Soll, Horbar, Edwards. Acquisition, analysis, or interpretation of data: Agha, Staiger, Brown, Soll, Edwards. Drafting of the manuscript: Agha, Staiger, Brown, Soll. Critical revision of the manuscript for important intellectual content: Agha, Staiger, Horbar, Edwards. Statistical analysis: Agha, Staiger, Brown. Obtained funding: Agha. Administrative, technical, or material support: Agha, Soll, Edwards. Supervision: Horbar. Conflict of Interest Disclosures: Prof Agha reported receiving grants from the National Institute on Aging (NIA) during the conduct of the study. Dr Staiger reported receiving grants from the NIA during the conduct of the study and being a founder of, having an equity interest in, and consulting for ArborMetrix outside the submitted work. Mr Brown conducted work on this project while he was a student at Dartmouth College, prior to his employment with AEA Investors. Dr Soll reported being the vice president and director of clinical trials and follow-up and the director of Cochrane at the Vermont Oxford Network (VON) Institute for Evidence-Based Practice and an unpaid member of the VON Board of Trustees. Dr Horbar reported being the chief executive officer, president, and chief scientific officer of and receiving a salary from VON and being an uncompensated member of its board of directors outside the submitted work. Dr Edwards reported receiving grants from VON to the University of Vermont during the conduct of the study. No other disclosures were reported. Funding/Support: Prof Agha and Dr Staiger were supported by P01-AG19783 from the NIA. Dr Edwards received salary support from VON. 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 2 . Additional Contributions: We thank our colleagues who submitted data to VON on behalf of neonates and their families. This cohort study examines changes in probiotic use among neonates with very low birth weight in US neonatal intensive care units (NICUs) between 2012 and 2019 and the association of routine probiotic use in this population with health outcomes. Did probiotic use change in US neonatal intensive care units (NICUs) between 2012 and 2019, and is use of probiotics associated with improved health outcomes in neonates with very low birth weight (VLBW)? In this cohort study of 307 905 neonates with VLBW in 807 NICUs from 2012 to 2019, 17% of NICUs had adopted routine use of probiotics by 2019. Incidence of necrotizing enterocolitis declined by 18% at adopting NICUs vs nonadopting NICUs, and probiotic adoption was not associated with significant changes in mortality or sepsis. In this study, probiotic use increased in US NICUs, and probiotic use was associated with a decline in necrotizing enterocolitis but not with sepsis or mortality rates. For neonates with very low birth weight (VLBW), randomized clinical trials (RCTs) indicate that probiotic treatment decreases the risk of necrotizing enterocolitis (NEC), with smaller decreases in the risk of sepsis and death. There is little evidence on the rate of probiotic adoption in US neonatal intensive care units (NICUs) and whether the benefits seen in trials have materialized in practice. To estimate changes in probiotic use among neonates with VLBW and to test whether neonates with VLBW treated at NICUs adopting routine probiotic use experience better outcomes compared with neonates treated at nonadopting NICUs. This cohort study used Vermont Oxford Network data on neonates with VLBW in US NICUs from January 1, 2012, to December 31, 2019. Data were analyzed from January 2022 through February 2023. Probiotics adoption vs nonadoption. Adopting NICUs were defined as those that currently or previously treated at least 20% of neonates with VLBW with probiotics. The primary outcomes were rates of NEC, in-hospital mortality, and sepsis, defined as bacterial or fungal infection occurring after day 3 from birth. A difference-in-differences analysis compared changes in VLBW infant outcomes between adopting and nonadopting NICUs before and after hospital-level adoption of probiotics. Additional analyses used the proportion of neonates treated with probiotics in each neonate’s birth NICU and year. The analysis included 307 905 neonates with VLBW (mean [SD] gestational age, 28.4 [2.9] weeks; 50.0% male) at 807 US hospitals. The rate of probiotic treatment of neonates with VLBW rose from 1572 of 38 296 neonates (4.1%) in 2012 to 4788 of 37 910 (12.6%) in 2019. Only 123 of 745 NICUs (16.5%) adopted probiotics by 2019, with 4591 of 6017 neonates with VLBW (76.3%) receiving probiotics in 2019 at adopting NICUs. Incidence of NEC declined by 18% at adopting NICUs (odds ratio [OR], 0.82; 95% CI, 0.70-0.95; P = .10) compared with nonadopting NICUs. Probiotic adoption was not associated with a significant reduction in sepsis (OR, 1.11; 95% CI, 0.98-1.25; P = .09) or mortality (OR, 0.93; 95% CI, 0.80-1.08; P = .33). In this cohort study, adoption of routine use of probiotics increased slowly in US NICUs and was associated with lower NEC risk but not with sepsis or mortality among neonates with VLBW. The findings for probiotic adoption and NEC, sepsis, and mortality were smaller than would have been predicted by the totality of RCT evidence but are consistent with a meta-analysis restricted to studies at low risk of bias. Although the incidence of necrotizing enterocolitis (NEC) has decreased, affected preterm infants remain at high risk for death, neurodevelopmental disabilities, repeated surgeries, and long-term tube feeding. Three recent meta-analyses, summarizing 30 to 56 randomized clinical trials (RCTs), evaluated use of enteral probiotics among infants with very low birth weight (VLBW). 1 , 2 These studies found that probiotics were associated with a 43% to 45% reduction in NEC, 11% to 14% reduction in sepsis, and 23% to 24% reduction in mortality, 3 , 4 , 5 although sensitivity analyses of trials with low risk of bias found more modest changes in NEC and no significant associations with sepsis or mortality. 3 , 4 , 5 In response to this research, there have been recent calls for widespread adoption of probiotics in newborn intensive care units (NICUs). 5 Nevertheless, the American Academy of Pediatrics does not recommend universal administration of probiotics to preterm infants given the lack of US Food and Drug Administration (FDA)–regulated products and conflicting safety and efficacy data. 6 , 7 , 8 , 9 10 There is little evidence on how US NICUs have responded to this research and the conflicting expert guidance. Both the extent of probiotic adoption and the effectiveness of probiotic treatment under clinical conditions remain unknown. There is additional clinical uncertainty about the benefits of probiotic supplementation for infants with extremely low birth weight (ELBW), and the benefits may depend on whether infants are exposed to beneficial bacteria or probiotics through vaginal delivery 5 or breast milk 11 in the absence of supplementation. A 2015 survey suggested that there were low levels of probiotic adoption in NICUs, 12 but recent, large-scale estimates of probiotic use are not available. 13 As new treatments diffuse into practice, the benefits demonstrated in clinical trials may not always materialize. Effective treatments may diffuse slowly, and there may be a gap between efficacy under ideal conditions and effectiveness in practice. 14 Effectiveness is a particular concern for probiotics, which have not been approved as a treatment by the FDA and for which production is less carefully regulated than would be the case for an approved drug. 15 Monitoring the health effects of probiotics as they diffuse into practice is a crucial component of evaluating their safety and effectiveness. 7 This study investigated the diffusion and clinical benefits of probiotic use among neonates with VLBW in NICUs when probiotic adoption occurred outside a clinical trial context. We used data from NICUs in the US to study changes in the rates of NEC, sepsis, and mortality, comparing the experiences of NICUs that did and did not adopt probiotics. This cohort study used data from the Vermont Oxford Network (VON), a voluntary learning community dedicated to improving newborn care. Research in support of the VON mission is funded by membership fees. VON has members in 49 states and is estimated to include data on over 85% of infants with VLBW born in the US. The University of Vermont’s institutional review board determined that use of VON’s deidentified research repository for this analysis was not human participants research and thus deemed the study exempt from institutional review board approval, with a waiver of informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( 15 STROBE ) reporting guideline for cohort studies. The analysis included all eligible VON members in the US. Participating centers are listed in eTable 5 in Supplement 1 . Member NICUs submit standardized data to VON on all neonates with VLBW treated at their facility within 28 days of birth. We used data for all neonates born weighing 501 g to 1500 g from January 1, 2012, to December 31, 2019. The sample was limited to neonates with a length of hospital stay of at least 3 days and with nonmissing data on neonate characteristics, probiotic treatment status, and outcomes. Probiotic use was defined as formulas containing probiotics or probiotic supplements added to formula or breast milk feeds. For each neonate, the data also included health outcomes (NEC, in-hospital mortality, and bacterial or fungal infection after day 3 from birth) and factors associated with those outcomes recorded at birth (sex, race and ethnicity, birth weight, gestational age, 1-minute Apgar score, multiple birth, congenital malformation, whether the neonate was small for gestational age, and whether the neonate was transferred to the NICU from an outside hospital). Detailed definitions of the variables can be found in the eMethods in 16 Supplement 1 . Probiotic use at a neonate’s NICU was defined as the proportion of all other neonates born in the same year and admitted to the same NICU who were treated with probiotics. To study patterns of probiotic adoption across hospitals, we followed a long history of research on technology diffusion and defined initial adoption using a threshold level of probiotic use. Specifically, the year that a NICU first adopted probiotics was defined as the first year in our data when at least 20% of neonates with VLBW received probiotics. 17 The decision to treat an individual neonate with probiotics may be endogenously related to the neonate’s health status, length of NICU stay, and survival. To avoid confounded comparisons of neonates who received probiotics and those who did not, our cohort study used a difference-in-differences approach that compared neonate outcomes across adopting and nonadopting hospitals before and after hospital-level adoption of probiotics. This approach yielded unbiased estimates of probiotic treatment outcomes under the assumption that in the absence of probiotic adoption, adopting and nonadopting hospitals would have had parallel trends in the evolution of NEC, sepsis, and mortality outcomes. 18 Probiotic diffusion was characterized by the percentage of all neonates with VLBW receiving probiotics and the number of hospitals newly adopting probiotics over time. For hospitals that had adopted probiotics by 2019, we calculated the percentage of neonates receiving probiotics in those hospitals in the 4 years before and 4 years after adoption. We used fixed-effects logistic regressions to estimate the association between neonate outcomes and hospital-level probiotic adoption. The unit of observation was at the neonate level. All regressions included hospital-level intercepts (fixed effects) to account for fixed differences in outcomes across hospitals and individual year effects to account for temporal trends in outcomes. All regressions further controlled for neonate factors associated with NEC, in-hospital mortality, and sepsis that have been previously validated, including birth weight, gestational age, small for gestational age, race and ethnicity, sex, multiple birth, location of birth, 1-minute Apgar score, and major birth defect. Race and ethnicity were reported by the mother if possible and otherwise from the birth certificate or medical record and categorized as American Indian or Alaska Native, Asian, Black, Hispanic, non-Hispanic White, and other (if none of the race and ethnicity categories applied). 19 To estimate changes in neonate outcomes each year before and after a hospital adopted probiotics, we conducted an event study analysis. Specifically, we estimated a fixed-effects logistic regression including indicator variables for each event year relative to the hospital’s adoption year; year 0 was defined as the first year that the NICU achieved at least 20% probiotic use. The coefficients on the event-year indicators estimated how neonate outcomes changed before and after probiotic adoption at adopting NICUs compared with changes at nonadopting units. For our final analysis, we replaced the event-year variables with a single treatment variable that captured continuous NICU-level variation in the extent of probiotic adoption: the proportion of all other neonates with VLBW born in the same year and at the same NICU who were treated with probiotics. This analysis extended the logic of our difference-in-differences approach but used the continuous variation in NICU-level probiotic use, rather than dichotomizing adoption status. Regression coefficients directly scaled to estimate probiotic effects per treated neonate, which allowed us to compare the magnitude of our estimates directly with the RCT findings. 3 , 4 , 5 In exploratory analyses, we interacted NICU-level probiotic use with 3 neonate characteristics to test whether probiotic use had different associations with health outcomes in subgroups: whether the neonate was born via cesarean delivery, received breast milk prior to discharge, or had ELBW (defined as <1000 g). Statistical significance was set at P < .05 using a 2-sided t test of whether the odds ratio (OR) associated with NICU probiotic use was equal to 1, indicating no association between NICU probiotic use and neonate outcomes. Additional details about the estimation approach are given in the eMethods in Supplement 1 . Data analysis was performed from January 2022 through February 2023, using Stata, version 15 (StataCorp LLC). The sample included 307 905 neonates with VLBW with a length of stay of at least 3 days and nonmissing data on neonate characteristics, probiotic treatment status, and outcomes (mean [SD] gestational age, 28.4 [2.9] weeks; 50.0% female and 50.0% male; 0.8% American Indian or Alaska Native, 4.9% Asian, 30.3% Black, 18.2% Hispanic, 43.2% non-Hispanic White, and 2.0% other). These neonates were treated at 807 NICUs located in the US. Probiotic use diffused slowly over our study period, with use remaining low at most hospitals. Figure 1 shows that national probiotic use for neonates with VLBW rose from 1572 of 38 296 neonates (4.1%) in 2012 to 4788 of 37 910 (12.6%) in 2019. In 2012, only 36 of 645 hospitals (5.6%) treated at least 20% of their neonates with VLBW with probiotics; by 2019, 123 of 745 hospitals (16.5%) had achieved this threshold. At probiotic-adopting hospitals, 4591 of 6017 neonates with VLBW (76.3%) received probiotics in 2019. Bars show the number of hospitals adopting probiotics in each year of the sample. The adoption year was defined as the earliest year that at least 20% of in-sample neonates with very low birth weight (VLBW) received probiotics. The dashed line shows the proportion of neonates with VLBW in the sample who received probiotics each year; this proportion was calculated using data from all in-sample hospitals regardless of probiotic adoption status. The Table reports summary statistics contrasting neonates at 680 nonadopting NICUs, 91 newly adopting NICUs that exceeded 20% probiotic use for neonates with VLBW for the first time between 2013 and 2019, and 36 early-adopting NICUs that were already providing probiotic treatment to more than 20% of neonates with VLBW in 2012. Nonadopting NICUs reported a mean (SD) of 7.8 (0.9) years of neonate data over our 8-year sample period. For newly adopting NICUs, our data covered a mean (SD) of 3.6 (2.1) preperiod years and 4.1 (2.0) postperiod years. Infants at adopting and nonadopting NICUs had similar mean birth weight, gestational age, and 1-minute Apgar scores. Probiotic adoption rates were higher in the West census region and lower in the Northeast (eTable 1 in Supplement 1 ). Trends over time in probiotic use, NEC, sepsis, and mortality rates are reported in the eFigure in Supplement 1 . Abbreviations: NA, not applicable; NICU, neonatal intensive care unit. Data are presented as the number (percentage) of neonates unless otherwise indicated. Defined as less than 1000 g. Respondents were instructed to report race and ethnicity as “other” if none of the other categories applied. Figure 2 plots probiotic use at adopting hospitals relative to the year of probiotic adoption (the first year with ≥20% use within the NICU); this year is indicated as year 0 in the graph. Probiotic use remained below 5% in the years prior to adoption and climbed steeply thereafter, reaching 80% in year 1. Year 0 is defined as the probiotic adoption year, the earliest year when at least 20% of in-sample neonates with VLBW received probiotics at a hospital. The sample included hospitals that first adopted probiotics between 2013 and 2019. Figure 3 plots difference-in-differences event-study estimates of the change in neonate outcomes in each year before and after hospitals adopted probiotics compared with hospitals that did not adopt probiotics. The indicator variable for the year immediately preceding adoption (event year −1) was omitted from the regression and used as the reference category. The incidence of NEC declined by 18% at adopting NICUs (OR, 0.82; 95% CI, 0.70-0.95; P = .01) compared with trends at nonadopting hospitals, differencing the mean regression coefficient for the postevent years (0 through 3) from the mean coefficient for the pre-event years (–4 through –1). Figure 3 B and C show that probiotic adoption was not associated with any significant reduction in sepsis (OR, 1.11; 95% CI, 0.98-1.25; P = .09) or mortality (OR, 0.93; 95% CI, 0.80-1.08; P = .33). The plotted points are regression coefficients on a series of indicator variables for years before and after the hospital first reached at least 20% probiotic use (normalized to year 0); whiskers indicate 95% CIs. All regressions control for calendar-year fixed effects, hospital fixed effects, and neonate characteristics (birth weight, gestational age, small for gestational age, race and ethnicity, sex, multiple birth, location of birth, 1-minute Apgar score, and major birth defect). The odds ratio (OR) for 1 to 4 years after adoption vs 1 to 4 before adoption was 0.82 (95% CI, 0.70-0.95) for necrotizing enterocolitis (A), 1.11 (95% CI, 0.98-1.25) for sepsis (B), and 0.93 (95% CI, 0.80-1.08) for in-hospital mortality. Additional details are given in the eMethods in Supplement 1 . Figure 3 also allowed us to assess whether adopting and nonadopting hospitals were on parallel trends prior to probiotic adoption. The stable preperiod coefficients suggest that there were not differential trends at adopting hospitals prior to probiotic adoption. For each health outcome, an F test of the joint significance of the preperiod relative-year coefficients found that they were not statistically distinguishable from 0 ( Figure 3 ). Figure 4 plots estimates from models using the proportion of neonates receiving probiotics in each hospital and year as the exposure variable; detailed results are reported in eTable 2 in Supplement 1 . Probiotic treatment was associated with lower rates of NEC, with an OR of 0.74 (95% CI, 0.64-0.87; P < .001). There was no significant association of probiotic exposure with sepsis risk (OR, 1.06; 95% CI, 0.94-1.20; P = .34) or mortality (OR, 1.05; 95% CI, 0.91-1.21; P = .52). To compare these results to meta-analyses reporting relative risk ratios (RRs), we rescaled the ORs using the mean outcome risk in nonadopting hospitals: NEC with an RR of 0.75 (95% CI, 0.65-0.88); sepsis with an RR of 1.05 (95% CI, 0.94-1.18); and mortality with an RR of 1.05 (95% CI, 0.91-1.21). Estimated effects from logit regressions are shown. The independent variable of interest in the overall regressions was the rate of probiotic use among other neonates in the same neonatal intensive care unit–year. For the subsequent specifications, the probiotic use rate was interacted with neonate characteristics. All regressions controlled for calendar-year fixed effects, hospital fixed effects, and neonate characteristics (birth weight, gestational age, small for gestational age, race and ethnicity, sex, multiple birth, location of birth, 1-minute Apgar score, and major birth defect). Data markers represent point estimates, and error bars indicate 95% CIs. Additional details are given in the eMethods in Supplement 1 . ELBW indicates extremely low birth weight and OR, odds ratio. Our approach relied on changes over time in NICU-level probiotic adoption rates rather than a conventional analysis directly comparing treated and untreated neonates. Direct comparisons of treated and untreated neonates would likely have been biased by unobserved confounding variables. Infants treated with probiotics had lower birth weight and Apgar scores and younger gestational age and were more likely to have a major birth defect (eTable 3 in Supplement 1 ). In contrast, changes in hospital-level probiotic use were not associated with changes in these factors (eTable 3 in Supplement 1 ), suggesting that our difference-in-differences analysis was less subject to confounding. Figure 4 reports results of exploratory tests for heterogeneity in the association of unit-level probiotic adoption with neonate outcomes depending on whether the neonate had ELBW (birth weight, <1000 g), was born via cesarean delivery, or received any breast milk at discharge. Probiotics were estimated to confer smaller benefits for neonates with ELBW compared with those who did not have ELBW. The association of probiotics with neonate outcomes was not significantly different for neonates delivered vaginally or via cesarean or for neonates who did or did not receive breast milk. In sensitivity analyses, we restricted to NICUs that remained in the sample for every year of the study period (eTable 4 in Supplement 1 ) and excluded NICUs that had already achieved 20% adoption of probiotics by 2012 (eTable 4 in Supplement 1 ) and found similar results. We also confirmed similar results for our binary adoption analysis when using a 10% (rather than 20%) probiotic use threshold to define adoption (eTable 4 in Supplement 1 ). In this cohort study of 807 NICUs, only 12.6% of neonates with VLBW were receiving probiotics and only 16.5% of NICUs had adopted probiotic treatment as of 2019. Initially, these low rates of probiotic diffusion present a puzzle. A recent Cochrane review and meta-analysis of more than 50 published RCTs studying the outcomes of probiotics for infants with VLBW found that this body of evidence suggests benefits of probiotics for NEC, sepsis, and mortality, although the evidence was rated as low certainty due to small trial sample sizes and unreliable methods used in many of the trials. 5 Our findings suggest that NICU adoption of probiotics was associated with smaller benefits than those found in meta-analyses of RCTs. The NEC reduction associated with infant-level treatment with probiotics in clinical trials (RR, 0.54 [95% CI, 0.45-0.65]) 3 , 4 , 5 was larger than our estimated reduction (RR, 0.75 [95% CI, 0.65-0.88], based on our results in 5 Figure 4 and rescaling OR to RR) and even lay outside the 95% CI for our estimate. Similarly, in the trial meta-analysis, the RRs of probiotics for sepsis (0.89 [95% CI, 0.82-0.97]) and mortality (0.76 [95% CI, 0.65-0.89]) were larger than our estimates for these outcomes (sepsis: RR, 1.05; 95% CI, 0.94-1.18; mortality: RR, 1.05; 95% CI, 0.91-1.21) and lay outside our 95% CIs. Both the meta-analysis and our own analysis found weak evidence that probiotics benefit neonates with ELBW compared with neonates with VLBW. 5 There are many reasons why probiotics may be less effective in practice than in published clinical trials. First, prior research suggests risk of bias in the published studies on probiotics. In the Cochrane review, 5 , 20 sensitivity meta-analyses of trials at low risk of bias did not show associations with mortality or infection and found smaller reductions in NEC risk (RR, 0.70 [95% CI, 0.55-0.89]), more in line with our findings. Second, patients enrolled in trials may differ systematically from patients treated in a NICU, although we found limited evidence of heterogeneity in the association between outcomes and probiotic adoption across neonate subgroups. Finally, other practices that are associated with the effectiveness of probiotics may differ from the RCT context. Probiotics used in trials and in practice may vary in timing, dose, and formulation of the probiotic feedings. This may be particularly true in US NICUs, where probiotics have not been approved by the FDA and production is less carefully regulated than for an approved drug. 5 10 Studying the impact of probiotics (and other medical innovations ) as they diffuse into clinical practice through postmarket surveillance is critical to developing a body of evidence on benefits in general clinical practice. Our analysis demonstrates that the difference-in-differences approach can provide a useful framework for estimating treatment outcomes in observational data in settings where patient-level comparisons may be confounded. 21 Uncertainty about the quality of commercially available probiotics may contribute to lagging adoption rates. Developing direct evidence of their outcomes in practice, as we did in this study, is an important step toward establishing safety and efficacy for routine use. Another possible avenue to increased adoption may be the commercial entry of an FDA-regulated probiotic product. We speculate that a major hurdle is that probiotic formulations cannot easily gain patent protection ; by protecting the entrant’s initial monopoly power, patent protection can be a crucial incentive to encourage costly market entry. 22 Without the safety, quality, and efficacy assurances that accompany the FDA drug review process, NICUs are left to interpret evidence and assure product integrity independently. Our results suggest lessening barriers to probiotic adoption and widening access could spur important reductions in NEC for neonates with VLBW. 23 This study has limitations. As with all observational studies, the association between probiotic adoption and outcomes for neonates with VLBW could be confounded by unmeasured factors associated with hospital adoption of probiotics. The difference-in-differences approach does not rely on individual-level comparisons of treated and untreated neonates within the same NICU and year, where treatment choices are likely confounded by differences in neonate health status. The model also accounted for differences across hospitals that were fixed over time but did not account for time-varying factors that changed at the hospital level. Because our event-study analysis suggests that there were no differential trends in patient outcomes prior to adoption of probiotics, and changes in patient outcomes for NEC occurred at the same time as adoption of probiotics, any time-varying confounder would need to have coincided with probiotic adoption. For example, a harmful treatment could confound our estimates if it was always adopted at the same time as probiotics and tended to offset the benefits, although there is no direct evidence of such a confounder. We were not able to investigate many potential reasons for the gap between the efficacy of probiotics in clinical trials and the effectiveness of probiotics as they have diffused in practice. The VON data do not track the timing, dose, or formulation of the probiotic feedings, each of which may influence the potential benefits of this treatment. We did not know the timing of NEC or sepsis relative to probiotic administration; both were defined as occurring at any time and not necessarily at the specific hospital where probiotics were given. Efficacy may also depend on each neonate’s preexisting gut microbiome. Investigating these factors remains a crucial avenue for future research. 24 , 25 In this cohort study of outcomes for neonates with VLBW in NICUs that adopted routine probiotic supplementation and those that did not adopt probiotics, we found that probiotic adoption was associated with lower NEC risk but not lower risk of sepsis or mortality among neonates with VLBW. The associations of probiotic adoption with NEC, sepsis, and mortality were smaller than would have been predicted based on clinical trial evidence, although they were consistent with a meta-analysis restricted to trials at low risk of bias. 5 These findings highlight the importance of monitoring the effectiveness of probiotics as they diffuse into neonatal practice beyond the setting of clinical trials. The analysis also suggests a framework that might be applicable to postapproval effectiveness evaluations for other new clinical treatments, providing insight into how a technology affects patient outcomes as it diffuses into routine clinical practice. 5 eMethods eFigure. Trends Over Time in Probiotics Use, NEC, Sepsis, and Mortality by NICU Adoption Status eTable 1. Descriptive Data on Characteristics of Nonadopting, Newly Adopting, and Early-Adopting Hospitals eTable 2. Complete Regression Results and Standard Errors for Specifications Graphed in Figure 4 eTable 3. Association of Infant Risk Factors With Infant and NICU Use of Probiotics eTable 4. Alternative Regression Specifications, Varying Sample and Definition of Probiotic Adoption eTable 5. Vermont Oxford Network Members Click here for additional data file. Data Sharing Statement Click here for additional data file. Association of Hospital Adoption of Probiotics With Outcomes Among Neonates With Very Low Birth Weight Prioritizing Research to Reduce Mortality for Infants and the Broader US Population. Severe neurodevelopmental disability and healthcare needs among survivors of medical and surgical necrotizing enterocolitis: a prospective cohort study Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: a multicenter cohort analysis The “golden age” of probiotics: a systematic review and meta-analysis of randomized and observational studies in preterm infants Probiotic supplementation and late-onset sepsis in preterm infants: a meta-analysis Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants Probiotics for preterm neonates: what will it take to change clinical practice? Probiotic supplementation in preterm infants: it is time to change practice Global health: probiotic prevents infections in newborns Probiotics for preterm infants—time to end all controversies Use of probiotics in preterm infants The impact of probiotics, prebiotics, and synbiotics during pregnancy or lactation on the intestinal microbiota of children born by cesarean section: a systematic review Probiotics in human milk and probiotic supplementation in infant nutrition: a workshop report Survey and evidence based review of probiotics used in very low birth weight preterm infants within the United States Vermont Oxford Network: a worldwide learning community Hybrid corn: an exploration in the economics of technological change Methods for evaluating changes in health care policy: the difference-in-differences approach Revalidation of the score for neonatal acute physiology in the Vermont Oxford Network Comparison of publication of pediatric probiotic vs antibiotic trials registered on ClinicalTrials.gov Evaluating agreement between bodies of evidence from randomised controlled trials and cohort studies in nutrition research: meta-epidemiological study Probiotics and the microbiome—how can we help patients make sense of probiotics? Do firms underinvest in long-term research? evidence from cancer clinical trials Probiotics for preterm infants: which one(s) to choose? Probiotics reduce mortality and morbidity in preterm, low-birth-weight infants: a systematic review and network meta-analysis of randomized trials |
Answer the following medical question. | What does research say about Evaluation of the impact of the S.T.A.B.L.E. Program on the pretransport care of the neonate.? | To determine whether the S.T.A.B.L.E. Program increases health care providers' confidence and clinical abilities in pretransport stabilization and to assess the care of transported neonates before and after S.T.A.B.L.E. Program education. A descriptive design was used to evaluate health care providers ' confidence about pretransport stabilization and to assess infant outcomes before and after S.T.A.B.L.E. education. Sixty-four participants in the S.T.A.B.L.E. Program in Nova Scotia participated in this study over a 13-month period. Thestudy evaluated the charts of all neonates transported tothe IWK Health Centre over two one-year periods, before and after the S.T.A.B.L.E. Program. Perceived confidence and incorporation of S.T.A.B.L.E. Program principles among regional health care provide:rs and neonatal stability at time of transfer were measured. Ninety-six percent of participants indicated that the course was relevant and useful. Ninety percent indicated that they felt more confident about their ability to provide neonatal pretransport stabilization, and 86.5 percent reported adoptionof the S.T.A.B.L.E. Program principles into their practice. There were no differences in infant outcomes between the pre- and post-S.T.A.B.L.E. time periods. |
Answer the following medical question. | What does research say about Newborn physiological immaturity: a concept analysis.? | Most standardized nursing care plans for healthy neonates include multiple nursing diagnoses to reflect nurses' judgments on the infant's status; however scientific literature concerning this issue is scarce. Newborn physiological immaturity is a concept in the ATIC terminology (architecture, terminology, interface, information, nursing [infermeria], and knowledge [coneixement]) to represent the natural status of vulnerability of the healthy neonate. To identify the essential attributes of the concept and provide its conceptual and operational definition, using the Wilsonian approach. The concept under analysis embeds a natural cluster of vulnerabilities and environmental interactions that enhance the evolving maturation process. The use of this diagnosis may simplify the process of charting the nursing care plans and reduce time needed for documentation while maintaining the integrity of the information. Consistent development and use of nursing concepts is essential for knowledge building. Studies on the actual use of nursing diagnoses are needed to inform decision making. Nurses have used concept analyses to examine fundamental components of disciplinary phenomena, guide clarification by proposing operational definitions, and reduce ambiguity in order to inform clinical practice and theory development. Concept analysis is associated with research design of philosophical inquiry, an integrated part of terminology work where concepts, their characteristics, and relations to other concepts are clarified. It uses intellectual analysis to clarify meanings, obtain well-differentiated concepts, establish coherent and systematic relationships among them, identify operational definitions, and build appropriate concepts for their use in a context. 1 The Wilson method to guide concept analysis is designed in a stepwise format and explicated in 11 steps: (1) isolating questions of concept, (2) finding right answers, (3 to 7) case examples, (8) social context, (9) underlying anxiety, (10) practical results, and (11) results in language. This last procedure is considered particularly valuable when a concept may have more than one meaning. 1 Newborn physiological immaturity is a concept included in the diagnosis axis of a nursing terminology that name yields the acronym of 6 key concepts, in the Catalan spelling: architecture, terminology, interface, information, nursing ( infermeria ), and knowledge ( coneixement ) (ATIC). The ATIC terminology is a controlled vocabulary where concepts are based on the natural language that nurses employ in their daily practice, subsequently revised for theoretical refinement. This terminology has been submitted to a formal validation process and it is used in different practice settings. 2 – 7 This article focuses on the evaluation of the concept newborn physiological immaturity by using the Wilsonian concept analysis approach. During the first weeks of extrauterine life, infants experience transitions and changes as part of the developmental and adaptive-to-environment processes. They confront a myriad of unique adaptation challenges to support life, and the ongoing maturation process will extend beyond the neonatal period. 8 The authors hypothesized that healthy, full-term neonates exhibit an appropriate normal functioning and development that may be explained using the concept of newborn physiological immaturity . Nevertheless, in the scientific literature, immaturity is a concept mainly used to illustrate preterm and very low-birth-weight infants' status. 9 Similarly, scholarly literature on the use of nursing diagnoses in healthy newborns is scarce, although most of the published standardized nursing care plans include some nursing diagnoses to reflect judgments on the infant' status on the basis of the North American Nursing Diagnosis Association International Nursing Diagnosis Classification. 10 , 11 Although the North American Nursing Diagnosis Association International includes some specific diagnoses for the neonatal period, it does not completely encompass the range of diagnoses identified by nurses in practice. Standardized nursing language systems have been found to lack alignment with terms commonly used by nurses in the clinical settings. 12 Likewise, classification systems may fail in representing the “normal” status of maturation for human infants during this early period of life. Fragmenting the neonates' status into many nursing diagnoses may not match with the idea of a holistic approach to the neonatal nursing care process. The identification of a concept that could inform this phenomenon may contribute to better reflect neonatal nurses' judgments on healthy, full-term newborns' status, while ensuring the provision of safe and comprehensive care to this vulnerable group. This article is aimed at clarifying the phenomenon of newborn physiological immaturity and providing a conceptual and operational definition. A literature search was conducted in PubMed ( http://www.ncbi.nlm.nih.gov/pubmed ) and SCIELO ( http://www.scielo.org/php/index.php ), from 2013 back to 1990, language limited to English, French, Spanish, Italian, and Portuguese. This resulted in a paucity of publications on the topic, where immaturity was mainly related to premature births and physiological immaturity hardly found. No research article focusing newborn physiological immaturity as hypothesized in our study was located, therefore a concept analysis was conducted, following the steps of the Wilson method as described by Avant. 1 According to the Wilsonian technique, questions are classified into 3 categories: concept, fact, and value. Questions of concept are about meaning, the way they are answered depends on the angle from which they are explored. Questions of fact can be answered with already available knowledge and evidence. Question of value should be answered on the basis of on moral principles. 1 In this inquiry, the first is a question of concept (meaning): What is the nature of newborn physiological immaturity ? The second is a question of concept and fact, as it implies explanations on the differences and similarities between concepts: Does newborn physiological immaturity differ from prematurity ? The third is a question of concept and fact, since it is about meaning and may be answered on the basis of available evidence: What are the features of newborn physiological immaturity ? The last is a question of fact and value, because its answer depends on knowledge and moral principles: Does newborn physiological immaturity require nursing interventions ? This stage of the Wilsonian method is aimed at identifying the primary uses that are central to the concept. Because there is no definition of newborn physiological immaturity as one word in the dictionary, each term of the concept was isolated and addressed. The concepts newborn and neonate were found in the Online Merriam-Webster's Collegiate Dictionary, 13 displaying the following definitions: (1) recently born , (2) born anew , and (3) a newborn child, especially a child less than 1 month . For the purposes of this analysis, this last definition was considered. In this same publication, the term physiological is defined as (1) of or related to physiology , (2) characteristic of or appropriate to an organism's healthy or normal functioning , and (3) differing in, involving or affecting physiological factors . The second definition was considered optimal to illustrate the concept of study. The definition of immaturity revealed 2 uses. The first clearly referred immaturity as a concept very close to prematurity. The second use referred to a state of incomplete growth or development. According to the Online Merriam-Webster's Collegiate Dictionary, immature has 2 related definitions: (1) lacking complete growth, differentiation, or development and (2) having the potential capacity to attain a definitive form or state . Both these definitions were found useful to inform the concept of immaturity because they involve associated ideas of potentiality for growth and development and maturation-dependent vulnerability. The use of immaturity to describe the exhibition of less-than-expected degree of maturity for extrauterine survival better matches the idea of prematurity. The concept premature is defined as happening, arriving existing, or performed before the proper, unusual or intended time; especially, born after a gestation period of less than 37 weeks . 13 Therefore, immaturity (“incomplete maturity”) involves having the potential capacity to attain or being ready to complete neonatal growth and development, whereas prematurity (“previous to maturity”) indicates a stage of significant or extreme degree of immaturity, which is less than expected to survive the extrauterine life, that is, out of the standard time and maturation range or nonphysiological. Case examples are used to identify the essential elements of the concept of interest. Wilson utilizes 5 types of cases: (1) A model case that must contain all the attributes of the concept. (2) A contrary case includes opposite clues. (3) A related case promotes a better understanding of the similarities and differences of the concept under study from others in the same conceptual network. (4) A borderline case that reflects unsureness whether a case fits an example of the concept and contains some of the essential elements of the concept analyzed and some features indicating the need for differential diagnosis. (5) An invented case should only be described when ordinary experiences do not provide instances to clarify the concept. 1 Newborn Physiological Immaturity. Albert H. is a 2-day healthy term infant, rooming with his mother in the ward. Born via vaginal delivery, his Apgar test scored 9 and 10 at minutes 1 and 5, respectively. Measurements were body weight, 3.530 kg; length, 52 cm, and cranial circumference, 34 cm. Mother's and infant's blood type was O Rh+. Serum glucose was 45 mg/dL; hematocrit, 53%; and bilirubin, 4.5 mg/dL. Now, his respiratory rate is 40; blood pressure, 60/35 mm Hg; heart rate, 130; temperature, 36.9°C; and body weight, 3.350 kg. His skin is warm, dry, and slightly jaundiced, and capillary refill is 2 seconds. His urine output is 2 mL/kg/h after several hours of oliguria. His mother talks to him calmly while changing the diaper and the sleeper. He keeps his eyes open and responds to his mother's voice. He strongly cries when the nurse obtains blood sampling for metabolic screening, glucose monitoring, and laboratory tests. Soft pressure is applied to the site with a gauze wrap, comfort measures continued, and bleeding of the site ruled out. All test results are within normal limits (Table 1 ). His mother caresses him, sings him a song while holding and breastfeeding him. He breastfeeds well, with proper sucking-swallowing-breathing coordination. Later, he falls asleep in his mother's arms. Abbreviations: BUN, blood urea nitrogen; WBC, white blood cell. In this case, vital signs are within the expected range for a well newborn, reflecting physiological neonatal breathing and circulation mechanisms to adapt the extrauterine environment. 8 , 14 Blood pressure levels also reflect cerebral autoregulation, perfusion, and parasympathetic predomination to protect the neonate against hyper- and hypotension. 8 Neonates are at high risk for heat loss; protecting clothes and warming environment of the room contribute to maintain his body temperature and minimize thermal stress. 15 After birth, infants normally lose up to 10% of body weight because of loss of extracellular fluid, which is an expected component of normal postnatal adaptation. 16 Similarly, in the first hours of life, urine output may be very low (or event absent) in well neonates because of poor renal perfusion, improving with circulatory adaption; after the first 24 hours, urine output should be greater than 1 mL/kg/h. Neonates' limited ability to concentrate the urine and reduced glomerular filtration rate make the infant susceptible to both dehydration and fluid overload. 8 Glucose is at normal range; cerebral metabolism and functioning depends upon an adequate blood glucose supply that provides for most of the brain's energy requirements. 17 His “slightly jaudiced” skin and serum bilirubin reveal the normal rise of unconjugated bilirubin levels during the first 48 to 72 hours of life, because of the rapid breakdown of fetal hemoglobin and poor conjugating ability of the immature liver. Bilirubin levels will gradually fall during the next 15 days, with jaundice being rare beyond this period. 8 , 18 Neonates' platelet counts are within the adult range, but platelet function is impaired and vitamin K-dependent clotting factors are initially low because of transition to bone marrow hematopoiesis and immature hepatocyte function. Vitamin K prophylaxis is administered to protect the infant against hemorrhage. 19 Although breastfeeding may protect the infant against gastrointestinal and respiratory infections, immature hematopoiesis and humoral system increases the risk for infection. 20 , 21 Effective sucking enhances breast milk production and proper infant nutrition and hydration. An adequate coordination of sucking, swallowing, and breathing is crucial to avoid respiratory complications such as desaturation, apnea, or pulmonary aspiration. 22 , 23 The infant in the model case is able to respond to noxious stimuli. He initiates a need and receives loving attention from his mother. He responds to stimuli, with states of consciousness and within a dynamic reciprocal interaction with a caretaking environment. Mother holding, cuddling, visual contact, and touch may stimulate immunological maturation, strengthen attachment, and enhance neurobehavioral organization, including habituation to environment, consolability, orientation, and motor performance. 24 – 26 Neonatal behavioral organization is a reciprocal, evolving process of information exchange between the infant and the environment that has been described as selective and purposeful. The neonate seeks stimuli and influences the caregiver by communicating different cues. The infant is able to coordinate sensory, motor, and behavioral functions and social interaction systems, develop consolability and resiliency, and encourage and discourage interaction, while maintaining stability to enhance developmental maturation. Sleep is essential to brain development, general maturation, and physical growth in infants. 27 – 29 Multiorgan Congenital Immaturity. An infant was delivered at 34 weeks' gestational age by emergency cesarean section. His mother was 36 years old, blood group O Rh+, with no relevant obstetrics history, chronic conditions, allergies, or toxic habits. The pregnancy had been normal with no complications. Amniocentesis for chromosomal screening tests at 16 gestation weeks resulted in karyotype 46,XY. At gestation week 34, an echography revealed mediastinal shift due to ccupation of right hemithorax by fluid. A Doppler echography revealed reverse diastolic flow in the umbilical artery. She was immediately transferred to the operating room for an emergency cesarean section. The infant's Apgar scored 1 and 0 at minutes 1 and 5, respectively. His measurements were as follows: body weight, 2.620 kg; length, 44 cm; and cranial circumference, 37.6 cm. The neonate's resuscitation was unsuccessful. His skin was cold and extremely pale; general swelling of the body and dysmorphias were evident. The autopsy led to the diagnosis of multiple malformation syndrome including macrocephalia, pulmonary hypoplasia, atrial communication, pleural and pericardial effusion, gastroschisis, and generalized visceral immaturity. Karyotyping allows the examination of chromosomes in sample cells to identify genetic problems causing defects or diseases. The amniotic fluid karyotyping tests are performed to rule out fetus chromosome problems. Normal results include 44 autosomes and 2 sex chromosomes, that is, 46,XX for human females and 46,XY for human males. Severe congenital defects may cause fetal death or prevent normal transition and adaption to extrauterine life to occur. Advances in genetics and neonatology have contributed to improve survival rates; however, severe multiple congenital malformation syndromes are rare diseases and prevalence data depend on their etiology. Many neonates with malformation syndromes, either caused by trisomies (3 instances of a particular chromosome instead of the normal 2), other genetic defects, or unknown etiologies, need medical assistance from the moment of birth because they usually achieve low mean Apgar test scores (<6 at minute 1 and 3 at minute 5). Prognosis can be usually poor and death is generally associated to severe cardiorespiratory or neurological conditions. 30 – 32 At birth, the neonate in the contrary case has none of the attributes of newborn physiological immaturity; he exhibits multiple malformations preventing adaption and survival. Prematurity. Sarah P. is a very low-birth-weight preterm infant (29 weeks' gestational age). At birth, her Apgar test scored 7 at minutes 1 and 5, respectively. Measurements were as follows: body weight, 1.200 kg; length, 39 cm; and cranial circumference, 27 cm. Mother's and infant's blood type was O Rh+. She received 2 doses of surfactant via an endotracheal tube during the first hours of life and was admitted to the NICU where she received intensive care for 2 months (up to 37 weeks' corrected gestational age). The NICU nursing discharge report contained the following information: The infant was on mechanical ventilation for 2 weeks. She was monitored in a double-wall incubator kept at a neutral thermal environment appropriate for gestational age and a decreasing schedule for humidity level during the first week (from 80% day 1 to 56% day 7 and on). Nesting and positioning were applied and environmental stimuli minimized. The infant weaned to open crib at 34 weeks' corrected age, with no episodes of temperature instability. She was initially provided with double phototherapy for 2 days and simple phototherapy for 1 day to correct hyperbilirubinemia (7 mg/dL) achieving normal values (2 mg/dL). From the first hours of life, she received trophic feeding administered using a nasogastric tube, with a progressive increase of 10 to 20 mL/kg/d. A central venous line was used to administer parenteral nutrition for several weeks and then she was fed with enteral feeding and initiated to full breastfeeding transition. Her parents were actively involved in Sara's care, interacting with her to enhance development. Kangaroo technique and infant massage were used to foster attachment. Prematurity refers to an insufficient degree of maturity of organs to allow normal postnatal physiological adaptation and survival. The premature infant is immature in the sense that developing organs are not mature enough for extrauterine life. Neonatal intensive care is needed to create a protective environment to prevent, promptly detect, and manage life-threatening potential complications and to promote infant development. At the same time, this environment may add stressors to the premature infant, because of the infant's lack of neurological and sensory maturity to modulate external environmental factors. 33 , 34 Immature integumentary and immune systems do not provide competent defense against microorganisms. 35 Lung immaturity and poor lung compliance from lack of surfactant limits the infant's capacity for gas exchange. 36 Barotrauma of ventilation for the immature lung places the premature infant at risk for bronchopulmonary dysplasia. Enzymatic immaturity of the digestive system challenges absorption of nutrients; however, trophic and enteral feeding improves milk tolerance and reduces the risk for sepsis and necrotizing enterocolitis. 37 Double-wall incubator may provide metabolic advantages to the preterm infants, although scientific evidence on this issue is inconclusive. Phototherapy is aimed at reducing bilirubin level by transforming bilirubin into isomers that can be eliminated without conjugation in the liver. 38 Family-centered care contributes to meeting the needs of parents and contributes to infant development, interaction, and attachment. 39 Term Infants With Minor Congenital Anomalies. Hillary K. is a 27-day-old, full-term infant. Her mother carefully places her into the stroller to go to the pediatric ambulatory clinics for immunization and routine consultation. She explains the nurse that her daughter “is so good, she sleeps almost 5 hours without interruption, only wakes up to eat and suckles properly while breastfed. She passes odorless urine and stools at regular intervals, receiving 8 to 12 diaper changes per day. She enjoys the bath time; she seems to hear me, to look at me, somehow to understand what I tell her. Physical examination findings include body weight, 4.090 kg; length, 53 cm. Posterior fontanel is closed. Face is symmetrical. Hard palate is intact with high arch. Skin is dry and pink, and no rashes are present. Capillary refill is 2 seconds. Abdomen is rounded; no swelling is observed and no organomegaly present. Cord is healed. Body temperature is 37°C; respiratory and heart rates are 30 and 129 per minute, respectively. Heart sounds are abnormal: a harsh murmur masks the first heart sound (S1); the second sound (S2) is normal. She is scheduled for further medical examination and echocardiogram, which lead to the diagnosis of small ventricular septal defect. Ventricular septal defect (VSD) is the most common form of congenital heart disease. It results from a delay in closure of the intraventricular septum beyond the first 8 weeks of intrauterine life, leading to an abnormal opening between the left and right ventricles. Although critical congenital heart diseases may be detected using pulse oximetry within the first day of extrauterine life, small VSDs are often detected between 2 and 8 weeks' age. Moderate and large VSDs produce symptoms and complications, and require medical and surgical treatments; in contrast, small VSDs are asymptomatic and rarely need treatment but medical follow-up and bacterial endocarditis prophylaxis. Spontaneous closure of small VSD is reported in many cases in the first 2 years of life. 40 , 41 The infant in the borderline case shows most of the attributes of newborn physiological immaturity, with normal growth, development, and adaption to extrauterine environment; however, the attribute of normal organ (heart) development is altered. Congenital VSD may not be classified as physiological. In this case the infant has a small VSD; she will not probably need hospitalization or cardiac surgery; however, she will require more medical and nursing attention and follow-up, as well as prophylactic antibiotic treatment to prevent complications. Small VSDs are not expected to affect infants' general development; however, surveillance beyond the standard guidelines for healthy neonates will be required. In the Wilsonian method, when researchers are not able to discover a sufficient number of different instances to clarify a concept, an invented case can be presented. 1 Because in this analysis different instances have been identified, no invented case is strictly necessary. The concept of newborn physiological immaturity is nurtured by the advances in neonatology and basic science research. Scientific evidence has expanded our understanding of the physiological maturation of the newborn: from the first breath to lung mechanics and ventilation; cardiac and circulatory adaption changes, thermoregulation and the influence of a thermoneutral environment, the hepatic and renal adaption, fluid hemostasis and requirements, immunocompetency development, and nutritional and metabolic processes, as well as nervous system maturation and neurobehavioral organization in reciprocal interaction with a caring environment. Environment is a key aspect to support life and promote newborn healthy growth and development. Further support for the notion of newborn physiological immaturity as a cluster nursing diagnosis concept has been gained from the literature examining the outcomes of healthy neonates and mothers receiving episodic nursing care during the neonatal period. 42 A cluster nursing diagnosis is a judgment on the patient' status where a number of related potential problems sharing a common etiology are aggregated. The neonate is challenged by continuous new stimuli, adaptation to home and social environment and adaption to ongoing immunological challenges. Underlying anxiety for the parents and the family unit is related to properly protecting the infant from perils, face an adaptation process to include the new member into the family dynamics, and promote growth and development. For health care professionals, underlying anxiety is mainly associated with contributing to the infant's successful transition to extrauterine life and also might be influenced by the social context and a perceived need to intervene. Across the globe, nurses provide care interventions to well newborns and health education to parents regarding their infant's care. However, with the growing nursing shortage and the shrinking public money for preventive health care programs, these essential health care services are threatened. 43 Health care interventions should be oriented to prevention and education, in order not to medicalize the natural maturation process of the newborn. This may be the reason why so many well baby nursing care plans contain many nursing diagnoses: an underlying anxiety that leads some nurses to think they have to demonstrate through the documentation, that they are thinking of and doing everything for the infant. Nevertheless, it is probable that the same can be formally represented in a neonate's chart, using a single nursing diagnosis concept: newborn physiological immaturity . This analysis has shown that the concept newborn physiological immaturity embeds a natural cluster of vulnerabilities, involving several vital processes of progressive adaptation, habituation, and organization, a ready-to-adapt organic, functional and maturational development, that enhance neonatal survival, internal homeostasis, and environmental interaction. This conceptualization might assist professionals in determining when to intervene and when to withhold unnecessary interventions. The essential structure of the concept embeds that newborn physiological immaturity is an expected, natural, status of vulnerability of the full-term healthy neonate, to adaption for life in the extrauterine environment. It includes the physiological maturation-dependent potential problems including risks for respiratory fatigue and impaired gas exchange (hypoxemia and hypoxia), the potential for aspiration, the risks of impaired cardiac rhythm (propensity to bradycardia) and blood pressure alteration, the risks for dehydration and fluid overload, the potential for hemorrhage and infection, and the risks of hypothermia and dysthermia, as well as the risks of hyperbilirubinemia, hypoglycemia, constipation, impaired metabolic homeostasis, delayed growth, and development and behavioral disorganization. The caretaking environment plays a vital role to enhance a positive, evolving maturation process, protecting the infant from risks and promoting healthy interactions between the neonate and the macroenvironments. Although much of the essential maturation is achieved within the first month of life, some of the maturation processes will extend beyond this period. Newborn physiological immaturity differs from prematurity. The healthy full-term neonate is equipped with ready-to-adapt extrauterine environment mechanisms, whereas the premature infant is not. The essential structure of the concept embeds that newborn physiological immaturity is an expected, natural, status of vulnerability of the full-term healthy neonate, to adaption for life in the extrauterine environment. It includes the physiological maturation-dependent potential problems including risks for respiratory fatigue and impaired gas exchange (hypoxemia and hypoxia), the potential for aspiration, the risks of impaired cardiac rhythm (propensity to bradycardia) and blood pressure alteration, the risks for dehydration and fluid overload, the potential for hemorrhage and infection, and the risks of hypothermia and dysthermia, as well as the risks of hyperbilirubinemia, hypoglycemia, constipation, impaired metabolic homeostasis, delayed growth, and development and behavioral disorganization. The caretaking environment plays a vital role to enhance a positive, evolving maturation process, protecting the infant from risks and promoting healthy interactions between the neonate and the macroenvironments. Although much of the essential maturation is achieved within the first month of life, some of the maturation processes will extend beyond this period. Newborn physiological immaturity differs from prematurity. The healthy full-term neonate is equipped with ready-to-adapt extrauterine environment mechanisms, whereas the premature infant is not. The concept of newborn physiological immaturity may be used to represent the well infant's status in the nursing documentation and may be considered a cluster nursing diagnosis. In the clinical settings, the use of this type of diagnoses may simplify the process of charting the nursing care plans and reduce time needed for documentation while maintaining the integrity of the information because the cluster concept embeds all its related diagnoses. The use of a lineal view of the nursing process where each nursing intervention is related to one diagnosis and each diagnosis is conceived independent from the whole situation might be useful for novice nurses or nursing students; however, it hardly reflects the complexity of proficient nurses' clinical reasoning, where overall information is captured and integrated as one unit. 44 , 45 In this case, the use of the concept newborn physiological immaturity as a cluster nursing diagnosis allows the prescription of preventive and health-promoting interventions as well as interventions to support the caretaking environment and therefore, they may be charted linked to a single nursing diagnosis. This analysis may contribute to consistent usage of the concept in health care research, education, and practice; however, the Wilsonian method of concept analysis has been criticized for the absence of empirical methods and the lack of comprehensiveness; although it is based on philosophical design, a literature study and an intellectual analysis, these limitations should be considered when interpreting the results of our inquiry. It would be interesting to explore this concept using different methods of analysis. Meanwhile, our findings provide clarity and contribute to the advancement of a better understanding of the fundamental concept newborn physiological immaturity . Immaturity is a term commonly used in neonatal care, mainly related to premature births Standardized nursing care plans for well babies usually contain many nursing diagnoses The concept newborn physiological immaturity needs clarification The usefulness of this expanded concept of physiological immaturity in the practice settings Nurses should be educated to recognize newborn physiological immaturity as a healthy maturation-dependent vulnerability status of the neonate regardless of the gestational age The cluster nursing diagnosis of physiological immaturity could be useful to represent nursing judgments on the healthy newborn's status The authors declare no conflicts of interest. Newborn Physiological Immaturity Philosophical and theoretical foundations for the development and validation of a nursing interface terminology. Part I Inductive evaluation of a Nursing Interface Terminology: conceptualization of the nursing process Mapping the diagnosis axis of a new interface terminology to the NANDA International Taxonomy Is the ATIC terminology oriented to nursing phenomena? What patients' problems do nurses e-chart? Longitudinal study to evaluate the usability of an interface terminology Basic nursing care: retrospective evaluation of communication and psychosocial interventions documented by nurses in the acute care setting Adaptation for life: a review of neonatal physiology Transitions in the early-life of late preterm infants: vulnerabilities and implications for postpartum care Nursing diagnoses in in-rooming units The usefulness of nursing languages to communicate a clinical event Encyclopaedia Britannica Company, 2013 Hypoxia in the term newborn: part two-primary pulmonary disease, obstruction, and extrinsic compression Keeping infants warm. Challenges of hypothermia Early additional food and fluids for healthy breastfed full-term infants Hyperbilirubinemia in neonates. Prevention, early identification and treatment Urinary excretion of vitamin K metabolites in term and preterm infants: relationship to vitamin K status and prophylaxis Optimal duration of exclusive breastfeeding Neonatology in the emerging countries: the strategies and health-economics challenges related to prevention of neonatal and infant infections Longitudinal changes in suck-swallow-breathe, oxygen saturation, and heart rate patterns in term breastfeeding infants Mechanics of sucking: comparison between bottle feeding and breastfeeding Massage and touch therapy in neonates: the current evidence A randomized placebo-controlled trial of massage therapy on the immune system of preterm infants The importance of touch in the development of attachment Concept clarification of neonatal neurobehavioural organization Social regulation of the stress response in the transitional newborn Promoting and protecting infant sleep Natural history of fetal trisomy 18 after prenatal diagnosis Prenatal diagnosis and postnatal follow-up of a child with mosaic trisomy 22 with several levels of mosaicism in different tissues Mortality and morbidity of VLBW infants with trisomy 13 or trisomy 18 The effects of environmental noise and infant position on cerebral oxygenation Preterm infants' biobehavioral responses to caregiving and positioning over 24 hours in a neonatal unit in Taiwan The developing human preterm neonatal immune system: a case for more research in this area Oxygen use for preterm infants: factors that may influence clinical decisions surrounding oxygen titration Preventing necrotizing enterocolitis with standardized feeding protocols: not only possible, but imperative Fundamentals of phototherapy for neonatal jaundice How can family centred care be improved to meet the needs of parents with a premature baby in neonatal intensive care? Neonate with cardiac issues Role of pulse oximetry in examining newborns for congenital heart disease: a scientific statement from the AHA and AAP Update on well-baby and well-child care from 0 to 5 years: What's new in the Rourke Baby Record? Public health and nursing: a natural partnership Expertise threshold required for nursing competency performance The effects of time pressure and experience on nurses' risk assessment decisions: a signal detection analysis |
Answer the following medical question. | What does research say about Use of Lactobacillus casei subspecies Rhamnosus GG and gastrointestinal colonization by Candida species in preterm neonates.? | Candida species increasingly cause morbidity and mortality in the premature infant in neonatal intensive care units, and the gut reservoir is the site from which dissemination most frequently starts in such patients. Specific antifungal prophylaxis is the most suitable strategy with which to limit the severity and the frequent neurodevelopmental impairment in survivors that is associated with neonatal invasive fungal infections. Recent interest has focused on the use of probiotics for the treatment of several diseases in neonatal patients. Pilot studies have implicated these organisms in necrotizing enterocolitis, sepsis, and urinary tract infections. Other applications of probiotic therapy in preterm neonates may also include the prevention of fungal colonization and of Candida-related disorders. Probiotics could provide an innovative and less invasive approach because they modify the bowel flora by colonizing the gastrointestinal tract. Basic research has shown that in mice models, the Lactobacillus casei subsp Rhamnosus GG (LGG) is effective in preventing Candida gut colonization and systemic dissemination. A pilot, randomized, double-blind, placebo-controlled trial in human preterm neonates has demonstrated that LGG administered in the first month of life significantly reduces enteric Candida colonization. The present article summarizes the state of the art about probiotics and Candida-related diseases in the preterm neonate and emphasizes the need for further investigations to determine unequivocally the possible role of LGG in the prevention and management of the fungal diseases in preterm neonates. |
Answer the following medical question. | What does research say about [Fractures in full-term neonates].? | It has recently been suggested in the media that fractures in full-term neonates might be caused by non-accidental injury. It is well known that a traumatic birth can result in fractures in the neonate. To evaluate the incidence of unexplained fractures in full-term neonates, we analysed data from the Netherlands Perinatal Registry, containing admission data on neonates from all 10 Neonatal Intensive Care Units and 60% of the level II hospitals. In 1997-2004, 158,035 full-term neonates were admitted. In 1174 of these (0.74%), fractures were demonstrated. In 227 of these 1174 neonates (19%), no cause for the fracture could be found: obvious trauma during birth or congenital bone disease was excluded. In 12 of the 227 full-term infants with an uneventful birth a fracture of the humerus was found, and in 3 a fracture of the femur. In all other cases there was a fracture of the clavicle. The authors conclude that fractures can occur in full-term neonates even after an uneventful vaginal birth or elective caesarean section. A neonate with pain may have a fracture, also after a normal birth. |
Answer the following medical question. | What does research say about [Research progress on brain functional near-infrared spectroscopy technology in the field of neonates].? | 杨骞 ，男，大学本科。 功能性近红外光谱技术（functional near-infrared spectroscopy, fNIRS）是一种新兴的神经影像学检查工具，根据神经血管耦合机制，通过监测脑氧代谢的变化反映脑部神经元的活动功能，无创便捷，尤其适合新生儿脑功能监测。该文对新生儿语言、音乐和情绪的脑网络发育规律，新生儿护理的脑网络成像，静息态脑网络连接规律，以及疾病状态下脑功能成像特点等方面的fNIRS相关研究进行综述。 Functional near infrared spectroscopy (fNIRS) is an emerging neuroimaging tool that reflects the activity and function of brain neurons by monitoring changes in brain oxygen metabolism based on the neurovascular coupling mechanism. It is non-invasive and convenient, especially suitable for monitoring neonatal brain function. This article provides a comprehensive review of research related to the developmental patterns of brain networks concerning language, music, and emotions in neonates using fNIRS. It also covers brain network imaging in neonatal care, resting-state brain network connectivity patterns, and characteristics of brain functional imaging in disease states of neonates using fNIRS. 脑功能性近红外光谱技术在新生儿领域中的研究进展 |
Answer the following medical question. | What does research say about Is Cronobacter sakazakii infection possible in an exclusively breastfed premature neonate in the neonatal intensive care unit?? | Cronobacter species are Gram-negative rods that may cause life-threatening infections in neonates and infants. They belong to the family of Enterobacteriaceae. The first case was published in 1961 in England and about 150 cases have been reported thus far in the literature. The worst form of infection results in meningitis, leaving survivors with devastating neurological sequelae. We present the case of a premature neonate who was exclusively gavage fed with non-fortified breast milk and developed culture positive sepsis for Cronobacter sakazakii with clinical signs of meningitis at 18 days of life. She had a very traumatic course and survived the illness, but questions remain as to how she obtained this infection and her future neurodevelopmental outcomes. |
Answer the following medical question. | What does research say about Fetal and neonatal neurologic case histories: assessment of brain disorders in the context of fetal-maternal-placental disease. Part 2: Neonatal neurologic consultations in the context of adverse antepartum and intrapartum events.? | The more conventional role of the pediatric neurologist involves the evaluation of the child after birth. Although the pediatric neurologist rarely attends the delivery of the neonate, consultation by the neurologist should begin immediately following stabilization by the neonatal resuscitation team. Four interrelated aspects of the neurologist's clinical assessment will be discussed in the context of reaching a consultative opinion, which must incorporate knowledge of chronologic events before as well as during labor and delivery. This evaluation encompasses an assessment of levels of arousal, increased or decreased muscle tone, presence of seizures, and effects of systemic diseases on the central nervous system, which are the essential elements of a complete neurologic examination. Documentation of the neonate's neurologic condition, together with knowledge of maternal, fetal, and placental diseases, will help anticipate neuroresuscitative decisions, as well as subsequent neurologic deficits. |
Answer the following medical question. | What does research say about A randomized controlled trial protocol in modifying neuromotor behavior of hospitalized preterm neonates using multimodal stimulations: MMS trial.? | Noxious sensory inputs from the neonatal Intensive Care Unit (NICU) and lack of placental support negatively impact neuronal organization which has implications later in life. Evidence regarding early interventions (EI) on preterm neonates (PN) at high risk for developmental motor disorders is limited and inconclusive. This study focuses on neuromotor changes following Multimodal stimulations (MMS) with sensory and motor interventions among stable hospitalized PNs. This single-center, non-blinded pre-test post-test control group study will recruit 60 PNs admitted to the Level II and III NICU of a recognized tertiary care teaching hospital by convenience sampling method into two groups by block randomization. Group A (n = 30) will receive MMS trial lasting for 30 minutes per session for five days per week, until discharge of the neonate from the NICU; Group B (n = 30) will receive regular lifesaving care from the NICU. Anthropometric evaluation, physiological status, and Infant Neurological International Battery (INFANIB) will be the outcome measures used to analyze the neuromotor behavioral modifications among the hospitalized PNs. All the outcome measures will be recorded at baseline, after every five days (to compare trajectories of scores between the groups), and at the end of the intervention at the time of discharge of neonate from the NICU. Demographic and outcome measures will be assessed for their normality using the Shapiro-Wilk test. Within and between-group comparisons will be analyzed by the repeated measures analysis of variance/Friedman test and independent t-test/Mann-Whitney U test respectively. MMS, which includes both sensory and motor interventions, will, to the best of the authors' knowledge, be the first trial for modifying the neuromotor behavior of hospitalized PNs. If successful, the clinical effects of this protocol could be revolutionary in mitigating developmental impairments of PNs. |
Answer the following medical question. | What does research say about Neurocardiovascular coupling in congenital diaphragmatic hernia patients undergoing different types of surgical treatment.? | The effect of peri-operative management on the neonatal brain is largely unknown. Triggers for perioperative brain injury might be revealed by studying changes in neonatal physiology peri-operatively. To study neonatal pathophysiology and cerebral blood flow regulation peri-operatively using the neuro-cardiovascular graph. Observational, prospective cohort study on perioperative neuromonitoring. Neonates were included between July 2018 and April 2020. Multicentre study in two high-volume tertiary university hospitals. Neonates with congenital diaphragmatic hernia were eligible if they received surgical treatment within the first 28 days of life. Exclusion criteria were major cardiac or chromosomal anomalies, or syndromes associated with altered cerebral perfusion or major neurodevelopmental impairment. The neonates were stratified into different groups by type of peri-operative management. Each patient was monitored using near-infrared spectroscopy and EEG in addition to the routine peri-operative monitoring. Neurocardiovascular graphs were computed off-line. The primary endpoint was the difference in neurocardiovascular graph connectivity in the groups over time. Thirty-six patients were included. The intraoperative graph connectivity decreased in all patients operated upon in the operation room (OR) with sevoflurane-based anaesthesia ( P < 0.001) but remained stable in all patients operated upon in the neonatal intensive care unit (NICU) with midazolam-based anaesthesia. Thoracoscopic surgery in the OR was associated with the largest median connectivity reduction (0.33 to 0.12, P < 0.001) and a loss of baroreflex and neurovascular coupling. During open surgery in the OR, all regulation mechanisms remained intact. Open surgery in the NICU was associated with the highest neurovascular coupling values. Neurocardiovascular graphs provided more insight into the effect of the peri-operative management on the pathophysiology of neonates undergoing surgery. The neonate's clinical condition as well as the surgical and the anaesthesiological approach affected the neonatal physiology and CBF regulation mechanisms at different levels. NL6972, URL: https://www.trialre-gister.nl/trial/6972 . KEY POINTS A novel computational model, the neurocardiovas-cular graph (which focuses on the neonatal brain), unravelled changes in peri-operative neonatal physiology. The linical condition of the neonate undergoing surgery as well as the anaesthesia technique utilised and surgical approach might influence the neonatal physiology and homeostasis. The network analysis approach using the neuro-cardiovascular graph could be a potentially useful technique for other researchers. A novel computational model, the neurocardiovas-cular graph (which focuses on the neonatal brain), unravelled changes in peri-operative neonatal physiology. The linical condition of the neonate undergoing surgery as well as the anaesthesia technique utilised and surgical approach might influence the neonatal physiology and homeostasis. The network analysis approach using the neuro-cardiovascular graph could be a potentially useful technique for other researchers. Despite ‘state of the art’ peri-operative monitoring, the outcome after noncardiac neonatal surgery can be complicated by significant acute and long-term sequelae. Structured analysis revealed a high incidence (48% in full term, 75% in preterm) of brain injury on MRI after noncardiac neonatal surgery. 1 Furthermore, interdisciplinary follow-up studies showed delayed neurodevelopment after neonatal surgery. 2 To date, the effect of peri-operative management on the neonatal brain is largely unknown. 3 – 6 Triggers for peri-operative brain injury might be revealed by studying peri-operative changes in the neonatal physiology. To this end, a new approach in neuromonitoring is needed, which includes neuromonitoring combined with computational models. 2 An overview of the co-ordinated interaction between the brain and the cardiovascular and cardiopulmonary systems can be created by extending standard monitoring with measurements of cerebral tissue oxygenation (rScO 2 )and cerebral activity (EEG). This provides insight into the regulation of cerebral blood flow (CBF), including neurovascular coupling (NVC), cerebrovascular pressure autoregulation (CAR), cerebral oxygen balance and heart rate passivity (HRP). 7 Impairment in regulation results in inadequate brain perfusion, which may cause hypoxic ischemic encephalopathy, 8 – 11 intraventricular haemor-rhage 12 and periventricular leukomalacia. 13 14 An advanced computational approach is needed to capture the status of the CBF regulation mechanisms as numerous multimodal signals need to be included. To achieve this, we used a model based on signal interaction graphs. 7 We applied the signal interaction graph framework peri-operatively to neonates diagnosed with congenital diaphragmatic hernia (CDH). These neo-nates were stratified into different groups based on different types of peri-operative management. The aim was to determine whether the resulting graphs, referred to as neurocardiovascular graphs, provided crucial information about the neonatal pathophysiology and the CBF regulation mechanisms peri-operatively. More specifically, the primary endpoint of this study was the difference in neurocardiovascular graph connectivity, per group over time. Secondary endpoints included the coupling between the vital parameters and the interactions corresponding to CBF regulation, per group over time. 15 , 16 This was a multicentre, observational, prospective study on peri-operative neuromonitoring in neonates with CDH undergoing surgery in one of two tertiary paediatric centres: the Erasmus MC-Sophia Children's Hospital (Rotterdam, the Netherlands), and the Mannheim University Hospital (Mannheim, Germany). The neonates were managed according to the revised 2016 CDH-EURO consortium guidelines. Measurements were performed after institutional research board approval and written informed consent from both parents. Approval was provided by the Medical Ethics Committee of the Erasmus University Medical Center, Rotterdam, The Netherlands on 14 August 2017 (Chairpersons Professor HJ Metselaar and Professor HW Tilanus, protocol number MEC 2017–145) and the Medical Ethics Committee of the University of Heidelberg, Mannheim, Germany on 6 July 2018 (Chairperson Professor JP Striebel, protocol number 2018–578N-MA). Trial registration NL6972. 17 Neonates with CDH, a major noncardiac congenital anomaly, were studied as they present a unique profile of clinical needs. Neonates with CDH show pulmonary hypoplasia and abnormal morphology of the pulmonary vasculature, resulting in severe respiratory insufficiency and an increased risk of developing persistent pulmonary hypertension (PPHN). A larger diaphragmatic defect leads to more severe pulmonary hypoplasia, and neonates with a (partial) intra-thoracic liver are more prone to develop PPHN. Venoarter-ial extracorporeal membrane oxygenation (VA-ECMO) treatment is imperative when therapy-resistant PPHN occurs. CDH neonates were eligible for inclusion between July 2018 and April 2020 if scheduled to receive surgical treatment within the first 28 days of life. Exclusion criteria were a major cardiac or chromosomal anomaly, or a syndrome associated with altered cerebral perfusion or major neurodevelopmental impairment. 18 Five peri-operative settings were compared: thoraco-scopic surgery in the operation room (OR), conversion from thoracoscopy to laparotomy in the OR, laparotomy in the OR, laparotomy in the neonatal intensive care unit (NICU) and laparotomy in the paediatric ICU (PICU) during VA-ECMO. The subjects were stratified into groups based on clinical condition (Fig. 1 ): thoracoscopic surgery in the OR if the neonate was cardiopulmonary-stable and did not have a herniated liver; laparotomy in the OR if the patient was cardiopulmonary-stable and had a herniated liver; surgery in the ICU if the patient was not cardiopulmonary-stable. Reasons for conversion were the need for a patch in case of a large diaphragmatic, or a ventilation problem (hypoxia or hypercapnia). The patients are stratified in five groups based on their clinical conditions. Five perioperative strategies were compared. These are indicated by the small coloured squares: thoracoscopy in the OR (blue), conversion from thoracoscopy to laparotomy in the OR (orange), laparotomy in the OR (yellow), laparotomy in the NICU (purple), and laparotomy on VA-ECMO in the PICU (green). The location of surgery defined the anaesthesiological approach (Table 1 ). In the operation room, general anaesthesia was performed by continuous administration of inhaled sevoflurane with a bolus of fentanyl and rocuro-nium, performed by a paediatric anaesthesiologist. In the NICU, neonates received continuous midazolam, bolus of fentanyl and rocuronium (Rotterdam) or continuous fentanyl and vecuronium (Mannheim), guided by a neonatologist or paediatric intensivist. Neonates on VA-ECMO were operated on in the PICU and received continuous midazolam and morphine with a bolus of fentanyl and rocuronium, guided by a paediatric intensivist. Patient characteristics Data are median [IQR], n (%) o/e LHR, observed to expected lung area to head circumference ratio; VIS, vasoactive inotropic score. Data are presented as median [IQR]. Defect size is presented as a score from A (small) to D (very large) . 17 On the days before and after the day of surgery, each patient received a cranial ultrasound, performed by an experienced paediatric radiologist or neonatologist, to screen for intracranial abnormalities and brain injury. Patient demographics were collected in accordance with the standardised reporting about CDH (Table 1 ). For each patient, seven signals were measured; heart rate (HR), mean arterial blood pressure (MABP) (indwelling arterial catheter) and peripheral oxygen saturation (SpO 17 2 ) were measured at 1 Hz (Primus, Draeger, Luebeck, Germany). Two frontal rScO 2 channels, measured using near-infrared spectroscopy (NIRS), were recorded at 1 Hz (neonatal sensor, INVOS 5100C, Covidien, Boulder, Colorado, USA). Two EEG channels, left (C3–P3) and right (C4–P4), were measured at 256 Hz (Rotterdam: BrainRT, OSG, Rumst, Belgium; Mannheim: Brain-trend, Fritz Stephan GMBH, Gackenbach, Germany). Measurements started the day before surgery and continued until 24 h postoperatively. After acquisition, the signals were preprocessed to reduce artefacts (Fig. 2 ). This procedure consisted of filtering the EEG (0.5 to 32 Hz), removing amplitudes outside of the physiologic range (negative values and saturation above 100), and detecting motion artefacts, defined as epochs in which the moving standard deviation exceeds 3. The data processing pipeline to translate the raw measured signals to a signal interaction graph, referred to as the neurocardiovascular graph. EEG, electroencephalogram; HR, heart rate; MABP, mean arterial blood pressure; rScO 2 , cerebral tissue oxygenation; SpO 2 , peripheral oxygen saturation. To match the temporal scale of the rapidly changing EEG with the hemodynamic signals, the EEG was processed as a running estimate of the power in the delta frequency band (0.5 to 4 Hz). The delta oscillations regulate basic homeostatic needs, such as blood flow circulation and normotension enforcement. 19 Signal interaction graphs were computed in a sliding window of 15 min, which was found to be the minimum length required to estimate signal interaction in a robust way. In each window, the signal interaction was assessed between every pair of signals. This corresponds to the computation of a signal interaction graph. In such a graph, the signals define the nodes, whereas the links define the coupling between every pair of signals. Transfer entropy was used as a measure of coupling. Transfer entropy is a nonlinear, effective measure, which can detect the direction of the interaction. In the transfer entropy framework, a signal 7 X interacts with a signal Y if the past of X facilitates the prediction of the present of Y , to a better extent than the past of Y predicts its own present. The practical implementation used binning and nonuniform embedding. Finally, the transfer entropy values were normalised as 0 (no coupling) to 1 (perfect coupling) following a procedure previously outlined. 20 21 The signal interaction graph used in this study is referred to as the neurocardiovascular graph as it captures the status of the regulation mechanisms affecting CBF (Fig. 3 ). The coupling between HR and MABP in which HR reacts to changes in MABP, presents a measure for baroreceptor reflexes. As the barorecep-tor reflexes couple HR and MABP, large interaction values are expected. CAR is defined as the coupling between MABP and rScO 22 2 . As CBF should be independent of cerebral perfusion pressure, baseline coupling between MABP and rScO 2 is low. HRP was recently defined as the coupling between HR and rScO 2 . As high values of HRP have been associated with poor outcome, low interaction values are expected. Lastly, the coupling between EEG and rScO 11 2 presents a measure for NVC, which is properly functioning if cerebral oxygenation and cerebral activity are highly coupled. The overall connectivity of the neurocardiovascular graph was quantified as the average over all graph links (average degree). 7 The neurocardiovascular graph translates the complex regulation of cerebral blood flow into one straightforward model. This regulation includes baroreflex (BR, highly coupled), cerebral pressure autoregulation (CAR, weakly coupled), heart rate passivity (HRP, weakly coupled), and neurovascular coupling (NVC, highly coupled). EEG, electroencephalogram; HR, heart rate; MABP, mean arterial blood pressure; rScO 2 , cerebral tissue oxygenation; SpO 2 , peripheral oxygen saturation. To balance data and remove transitional effects, such as artefacts of transport and care and the effect of intrao-peratively administered medication, the graphs were computed in five time windows: the preoperative window (6 to 3 h before surgery), the surgical period and three postoperative windows: 3 to 6, 9 to 12 and 15 to 18 h after surgery, respectively. Linear mixed effects models were used to test the primary endpoint. Post hoc analysis was done using estimated marginal means with Tukey correction. Data re presented as median [IQR] and n (%). The coefficient of determination (R2) was also calculated. Statistical computations were carried out in R. Data are presented a median [IQR] and number (%). 23 Forty-eight neonates were enrolled in the study, of whom 11 neonates were excluded following the absence of multiple signals because of data transfer and storage problems. One neonate was excluded because of cardiopulmonary resuscitation intraopera-tively, leaving 36 patients included (Fig. 1 ). Preopera-tively, data of the thoracoscopic repair and conversion groups were merged in later analysis (Fig. 4 ) as they included the most stable patients with similar characteristics (Table 1 ). The neurocardiovascular graph is strongly influenced by both the patient group (rows) and the clinical time window (columns). Graphs are presented as a median over all patients in a group. The regulation mechanisms are highlighted in red whereas all other graph connections are presented in grey. EEG, electroencephalogram; HR, heart rate; MABP, mean arterial blood pressure; rScO 2 , cerebral tissue oxygenation; SpO 2 , peripheral oxygen saturation. The connectivity of the graphs was not affected by gestational age, birth weight, sex, position of the liver, and the size of the diaphragmatic defect, whereas the clinical time window and the clinical group influenced the graph connectivity (both P < 0.001). Neonates selected for thoracoscopic repair had the largest connectivity of 0.33 [0.26 to 0.37] preoperatively (Figs. 4 and 5 f). During surgery, the connectivity of the neuro-cardiovascular graph dropped, reaching values of 0.12 [0.08 to 0.15], P < 0.001, which increased again to 0.24 [0.23 to 0.33], P < 0.001, 0.26 [0.25 to 0.36] and 0.32 [0.32 to 0.32] postoperatively. Overview of heart rate (a), mean arterial blood pressure (b), peripheral oxygen saturation (c), regional cerebral oxygen saturation (d), EEG (e), graph connectivity (f), baroreflex (g), cerebral pressure autoregulation (h) and neurovascular coupling (i). Each surgical setting is represented by a different colour, as indicated in (a). Each subfigure (a to h) contains five columns, which correspond to the five monitoring periods: pre-operative, intra-operative, 3 to 6, 9 to 12 and 15 to 18 h postoperative. In each column, a dot represents the mean value for one patient. The bar and the shaded area represent the median and interquartile range, respectively. n.u., normalised units between 0 and 1. Preoperatively and postoperatively, there was intact and strong interaction between the vital parameters and a functioning baroreceptor reflex (Fig. 5 g), CAR (Fig. 5 h) and NVC (Fig. 5 i) and (Table 2 ). During surgery, CAR remained intact whereas both baroreceptor reflex and NVC disappeared. Main findings ‘+’ or ‘−’ indicate the presence or absence of a particular cerebral blood flow regulation mechanism, respectively. BR, baroreflex; CAR, cerebral pressure autoregulation; ICU, intensive care unit; NVC, neurovascular coupling; OR, operation room; VA-ECMO, venoarterial extracorporeal membrane oxygenation. The main finding was that largest reduction in connectivity was observed in the thoracoscopic repair group (Fig. 4 and Table 2 ). During surgery, graph connectivity slightly decreased to 0.31 [0.24 to 0.34]. After surgery, connectivity further decreased to 0.27 [0.23 to 0.31], P < 0.001, after which it increased again to 0.33 [0.26 to 0.34] and 0.32 [0.30 to 0.34], P = 0.014 (Figs. 4 and 5f). The interaction between the vital parameters dropped intraoperatively, after which it steadily increased postop-eratively (Table 2 ). CAR and NVC remained intact over the peri-operative period. Baroreceptor reflex dropped intraoperatively but restored again after surgery. The main finding here was that the connectivity in the conversion group was larger than that in the open repair operation room group. In the open repair operation room group, the connectivity was 0.28 [0.20 to 0.36] preoperatively, then slightly dropped intraoperatively to 0.25 [0.12 to 0.28], P < 0.001, and increased to 0.25 [0.15 to 0.31], P = 0.037, 0.27 [0.12 to 0.30], and 0.30 [0.18 to 0.32] postoperatively (Figs. 4 and 5 f). The interaction among the vital parameters was strong preoperatively, dropped intraoperatively, and reached baseline values again postoperatively (Table 2 ). CAR remained intact over the peri-operative period. The same holds true for baroreceptor reflex and NVC, although they were associated with slightly lowered values during surgery. The main finding here was that the open repair OR group is the only group in which baroreceptor reflex, CAR and NVC remained intact over the peri-operative period. The graph connectivity remained stable for neonates on open surgery in the NICU, reaching values of 0.30 [0.23 to 0.34], 0.34 [0.26 to 0.38], 0.26 [0.22 to 0.33], 0.32 [0.24 to 0.37] and 0.28 [0.27 to 0.36] for the five consecutive time windows, respectively (Figs. 4 and 5 f). Interaction among the vital parameters, including baro-receptor reflex, was absent over the entire peri-operative period (Table 2 ). CAR was intact over the entire perioperative period, as was NVC, and had the largest values compared with all other groups over all time windows. The main finding here was that NVC had the largest values in the open repair NICU group. Neonates on VA-ECMO had the lowest connectivity before surgery; that is, 0.27 [0.23 to 0.30]. The connectivity increased to 0.34 [0.28 to 0.41] during surgery. Postoperatively, the connectivity was 0.30 [0.30 to 0.32], 0.21 [0.20 to 0.23], P < 0.001) and 0.28 [0.26 to 0.31], P <0.001 (Figs. 4 and 5 f). Strong interaction among the vital parameters, intact CAR, and NVC was observed throughout the peri-operative period (Table 2 ). CAR values only increased slightly intraoperatively, and in the first hours after. The baroreceptor reflex was absent, especially in the preop-erative period, as well as in the postoperative windows of 9 to 12 and 15 to 18 h after surgery. The main finding here was that a strong interaction among vital parameters was observed in the ECMO group. During sevoflurane anaesthesia, increased sevoflurane concentration correlated with increased BR ( R = 0.34) and decreased HRP ( 2 R = 0.32); increased fentanyl dose correlated with increased HRP ( 2 R = 0.60), increased CAR ( 2 R = 0.41) and decreased EEG to MABP coupling ( 2 R = 0.42) and increased partial pressure of CO 2 2 ( P a CO 2 ) correlated with increased HRP ( R = 0.33). 2 During midazolam sedation, increased midazolam dose correlated with increased CAR ( R = 0.47) and increased interaction between MABP and the two EEG signals ( 2 R = 0.39 for the left channel, and 2 R = 0.34 for the right channel); and increased fentanyl dose correlated with increased MABP to EEG coupling ( 2 R = 0.33 for the left channel and 2 R = 0.37 for the right channel). 2 Increased P a CO 2 correlated with decreased baroreceptor reflex during both sevoflurane and midazolam anaesthesia. Both the anaesthesiological and the surgical approaches highly influenced the connectivity of the neurocardio-vascular graph (Fig. 4 ). Despite the small sample size and the novelty of the methodology used, some observations can be made, which will have to be validated in future studies. The largest reduction in connectivity, which included an absence of baroreceptor reflex and NVC, was observed during thoracoscopic surgery (Table 2 ). This was striking, as neonates selected for thoracoscopic repair were the most cardiopulmonary stable patients (Table 1 ). The conversion group was characterised by a larger connectivity compared with the open repair operation room group, most likely as the neonates in the conversion group were clinically more stable (Table 1 ). Yet, the open repair operation group was the only group in which all CBF regulation mechanisms remained intact. Of all groups, the open repair NICU group had the largest NVC values whereas the ECMO group had a significantly larger interaction among the vital parameters intraoperatively. CAR remained stable in all groups (Table 2 ). NVC remained functioning in all groups, except during thoracoscopic surgery. The majority of the drugs used in NICUs are unlicensed or off-label. Intravenous midazolam for sedation has been used for decades in NICUs. 24 , 25 Nonetheless, a recent Cochrane review raised concerns about the safety of midazolam in neonates. 26 One study reported statistically significant higher rates of adverse neurological events (death, grade III or IV intraventricular haemorrhage, periventricular leukomalacia) in neonates treated with midazolam compared with morphine. 27 Two studies observed a (transient) decrease in middle cerebral artery blood flow velocity and transient cerebral hypoperfusion after a bolus of midazolam in preterm neonates. 28 Our data showed a more impaired CAR with increasing midazolam dose. 29 , 30 In general, the literature reports a negative effect of general anaesthesia on neonatal physiology. In the present study, we observed a stronger baroreceptor reflex and less HRP with increasing sevoflurane concentration during sevoflurane anaesthesia, which might indicate that a higher sevoflurane concentration does not adversely affect regulation. Sevoflurane mediates a decrease in myocardial contractility and mean arterial blood pres-sure. 31 In the brain, sevoflurane mediates vasodilation, suppresses somatosensory-evoked potentials and reduces cerebral metabolism. 32 33 Increasing the fentanyl dose during induction, however, was associated with a more pronounced HRP, a more impaired CAR and a stronger, directed coupling between EEG and MABP in the intraoperative period, aspects, which are all associated with adverse outcomes in neo-nates. 11 , 34 , 35 Thoracoscopic surgery is popular because of its potential benefits, including fewer postoperative ventilator days, a reduced requirement for analgesics and a shorter hospital stay. A drawback is that an artificial CO 36 – 39 2 -pneumo-thorax is needed to create a surgical workspace and this results in hypercapnia and acidosis. Signal interaction was highly affected during thoracoscopic surgery, which might be because of increased CO 40 2 or the increased intrathoracic pressure the latter affects venous return. An increase in P a CO 2 correlated with a less functional baroreceptor reflex, and a more pronounced HRP. The observed increase in HR might indicate a compromised venous return, although MABP did not decrease (Fig. 5 ). Open surgery leads to fewer oxygenation and ventilation problems for the anaesthesiologist to deal with, but our data showed that graph connectivity decreased anyway. Although ECMO is associated with (intracranial) haemor-rhagic and thrombotic complications, our results suggest that ECMO might help to preserve the signal interactions intraoperatively. Peri-operative management, including ICU management, anaesthesia and surgery, could cause undesirable changes in the neonatal physiology, which might trigger peri-operative brain injury. So far, most of the studies on this subject have focused on the analysis of one of the CBF regulation mechanisms, and lack information about other physiology parameters. Advanced computational approaches need to be developed to quantify and understand the impact of peri-operative management on neonatal physiology. 2 – 4 In this study, we applied a computational framework (with visual and graphical feedback) that permitted handling of multiple concomitant signals, and thereby enabled the study all major regulation mechanisms in one straightforward model. 7 As numerous signals are measured from the same physiological system, a strong, coordinated interaction should exist between them. The neurocardiovascular graph captures continuous information about the ability of the autonomic nervous system to react to changes in MABP (baroreceptor reflex), and about the ability of the brain to regulate CBF independently of fluctuations in MABP (CAR) but dependently on cerebral metabolism (NVC). Therefore, neurocardiovascular graph provides insights about cerebral perfusion. As HR, MABP and SpO 16 2 are included, the coordinated interactions between the brain and the cardiopulmonary systems can also be analysed. Clinical decisions should be based on precise, qualified and selected information. Information overload in perioperative medicine is a major concern. New monitoring strategies, which integrate different information sources in one straightforward, visual model could help to reduce information overload. The neurocardiovascular graphs provided new information on how the neonatal physiology and the CBF regulation mechanisms are affected by the actions of the clinicians, even in the most cardiore-spiratory stable patients. Therefore, this approach could assist clinicians in making timely decisions about the optimal surgical and anaesthesiological approach, thereby making clinical practice more patient-specific and potentially preventing brain injury. 41 7 The framework was applied in a very specific pathology during major, high-risk surgery. This approach needs further validation in other pathologies as well as in cardiorespiratory healthy neonates with and without anaesthesia. The severity of the critical illness also differed between the groups, in addition to the surgical and the anaesthesiological approach. Exposure to medication was compared based on dosages instead of their plasma concentrations. We showed that neurocardiovascular graphs provide new and important information about the effect of the perioperative management on the pathophysiology of neo-nates undergoing surgery. The neonate's clinical condition and the surgical and anaesthesiological approach affected neonatal physiology and CBF regulation mechanisms at different levels. This new approach may assist clinicians in making patient-specific decisions about the optimal peri-operative management, aiming to prevent brain injury and possibly impaired neurodeve-lopmental outcomes. At this stage, however, given the limited patient numbers in each group and the novelty of our approach, it is still too early to couple our results directly to changes in clinical management. Assistance with the study: none. Financial support and sponsorship: research supported by Bijzonder Onderzoeksfonds KU Leuven (BOF): C24/15/036 ‘The effect of perinatal stress on the later outcome in preterm babies’, EU: H2020 MSCA-ITN-2018: ‘Integrating Functional Assessment measures for Neonatal Safeguard (INFANS)’, funded by the European Commission under Grant Agreement #813483. This research received funding from the Flemish Government (AI Research Program). Sabine Van Huffel and Dries Hendrikx are affiliated to Leuven. AI to the KU Leuven institute for Artificial Intelligence, B-3000, Leuven, Belgium. DH is a SB Ph.D. fellow at Fonds voor Wetenschappelijk Onderzoek (FWO), Vlaanderen, supported by the Flemish government. This project was performed by three centres participating in ERNICA, the European Reference Network for rare Inherited and Congenital Anomalies. Conflicts of interest: none. Presentation: none. DH and SAC contributed equally as co-first authors. Neurocardiovascular coupling in congenital diaphragmatic hernia patients undergoing different types of surgical treatment Associations of neonatal noncardiac surgery with brain structure and neurodevelopment: a prospective case-control study Neonatal surgery for noncardiac congenital anomalies: neonates at risk of brain injury Neurodevelopmental outcomes after neonatal surgery for major noncardiac anomalies Risk factors of impaired neuropsychologic outcome in school-aged survivors of neonatal critical illness Longitudinal neurodevelopmental and neuromotor outcome in congenital diaphragmatic hernia patients in the first 3 years of life Memory deficits following neonatal critical illness: a common neurodevelopmental pathway Measurement of neurovascular coupling in neonates Neurovascular coupling in humans: physiology, methodological advances and clinical implications Neonatal cerebrovascular autoregulation The use of hemodynamic and cerebral monitoring to study pharmacodynamics in neonates Heart rate passivity of cerebral tissue oxygenation is associated with predictors of poor outcome in preterm infants Novel wavelet real time analysis of neurovascular coupling in neonatal encephalopathy Consequence of intraventricular hemorrhage on neurovascular coupling evoked by speech syllables in preterm neonates Neurobiology of periventricular leukomalacia in the premature infant Using graph theory to assess the interaction between cerebral function, brain hemodynamics, and systemic variables in premature infants Network physiology: how organ systems dynamically interact CDH EURO Consortium. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium Consensus -2015 Update Time-frequency analysis of electroencephalogram series. III. Wavelet packets and information cost function Nonuniform multivariate embedding to assess the information transfer in cardiovascular and cardiorespiratory variability series Evaluating information transfer between auditory cortical neurons Development of baroreflex influences on heart rate variability in preterm infants Unlicensed and off label drug use in neonates Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands Clinical pharmacology of midazolam in neonates and children: effect of disease—a review Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial Haemodynamic responses and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn Effects of anesthesia with isoflurane, ketamine or propofol on physiologic parameters in neonatal rhesus macaques (Macaca mulatta) A review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anaesthesia Effect of general anesthesia on neonatal aEEG — a cohort study of patients with noncardiac congenital anomalies Coupling between mean blood pressure and EEG in preterm neonates is associated with reduced illness severity scores Cerebral blood flow autoregulation and dysautoregulation Thoracoscopic versus open repair of CDH in cardiovascular stable neonates Beyond feasibility: a comparison of newborns undergoing thoracoscopic and open repair of congenital diaphragmatic hernias Minimal access surgery for repair of congenital diaphragmatic hernia: is it advantageous? - an open review Congenital Diaphragmatic Hernia Study Group. Minimally invasive repair ofcongenital diaphragmatic hernia Hypercapnia and acidosis during open and thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia: Results of a pilot randomized controlled trial Information overload in emergency medicine physicians: a multisite case study exploring the causes, impact, and solutions in Four North England national health service trusts |
Answer the following medical question. | What does research say about Changes in skin barrier over the first four days of life: a cross-sectional study.? | We aimed to evaluate the trajectory of skin barrier properties in full-term newborns during the first four days after birth. Based on the MKNFOAD cohort (NCT02889081), transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin pH, and sebum content at five anatomical sites (cheek, forehead, volar forearm, abdomen, and dorsal lower leg) were examined once within 96 h after birth in 384 full-term infants. Multivariable linear regression analysis was performed to assess variations in these skin barrier parameters with age adjusted for gestational age, neonate's sex, parents' allergy history, delivery mode, amniotic fluid characteristics, and birth weight. The regression coefficient (ß) and 95% confidence interval were reported. We analyzed a total of 384 neonates including 198 (51.6%) boys. TEWL values remained stable and showed no significant association with age (days). pH values exhibited a declining trend with age (p for trend <0.001). Both SCH values and sebum content grew with age (p for trend <0.001). During the first four days after birth, the skin TEWL remained stable, pH decreased, and the SCH and sebum content increased over time. These findings provide insights into the neonatal skin physiological development at the beginning of life. From birth to 96 h, TEWL was stable, pH showed a steep decline, SCH and sebum content increased. This study provides the first evidence of skin adaptation in the newborn due to changes in utero to after birth in the first 4 days of life in an Asian population. These findings will provide a new theoretical basis for neonatal skin physiology and clinical strategies for guiding newborn skin care. |
Answer the following medical question. | What does research say about Associations between salivary testosterone and cortisol levels and neonatal health and growth outcomes.? | Tel.: +1 205 934 4680; fax: +1 205 934 3100. Tel.: +1 205 934 2355; fax: +1 205 996 7183. Tel.: +1 205 939 9107; fax: +1 205 939 9821. Conflict of interest The authors declare that they have no conflict of interest. Male vulnerability in health and growth outcomes has often been reported in very low birth weight (VLBW) preterm neonates. On the basis of gender-difference theories, possible associations were explored between the levels of postnatal salivary testosterone/cortisol and the outcomes of neonatal health/growth. This study used an exploratory and comparative research design. One-hundred-one mother–VLBW preterm neonate pairs were recruited from the neonatal intensive care unit (NICU) of a tertiary medical center in the Southeastern, US. Demographic information, health and growth variables of neonates, and pregnancy and labor variables of mothers were obtained from the medical record reviews and interviews of mothers. Saliva samples from each pair were collected between 9 and 60 days of age. The levels of testosterone and cortisol were determined by using an enzyme immunoassay methodology. Linear regression analysis showed that neonatal health problems were positively associated with the levels of postnatal salivary testosterone and cortisol, while growth delays were positively associated with the levels of postnatal salivary testosterone after adjusting for the characteristics of neonates and mothers and day of saliva sampling. The salivary levels of testosterone and cortisol were higher in neonates than in mothers. A positive correlation between the levels of testosterone and cortisol was found in neonates and in mothers. The level of postnatal salivary testosterone is a more reliable marker in assessing neonatal health and growth outcomes compared to salivary cortisol. Further research on both testosterone and cortisol measurements at various stages during the neonatal period may elucidate further these associations. Associations between salivary testosterone and cortisol levels and neonatal health and growth outcomes |
Answer the following medical question. | What does research say about Recent advances toward defining the benefits and risks of erythrocyte transfusions in neonates.? | Like many treatments available to small or ill neonates, erythrocyte transfusions carry both benefits and risks. This review examines recent publications aimed at better defining those benefits and those risks, as means of advancing evidence-based neonatal intensive care unit transfusion practices. Since decisions regarding whether to not to order an erythrocyte transfusion are based, in part, on the neonate's blood haemoglobin concentration, the authors also review recent studies aimed at preventing the haemoglobin from falling to a point where a transfusion is considered. |
Answer the following medical question. | What does research say about Developing a Small Baby Program for the Extremely Low Birth Weight: The Wee CARE Team.? | The Children's Hospital at Providence (TCHaP) is a hospital within a hospital, in the heart of Alaska's biggest city, Anchorage. TCHaP admits up to 60 extremely low birth weight (ELBW) neonates per year. The ELBW population, although small in number, contributes disproportionately to rates of death or serious morbidities. Nationally, ELBW is defined as a neonate born at a gestational age between 22 and 29 weeks. In 2014, only 38 percent of neonates born in Alaska <28 weeks survived without experiencing major morbidities. For those born <26 weeks, morbidity-free survival dropped to 25 percent. Discussions were held among NICU nursing leaders, clinical nurses, and physicians about current co-morbidities and potentially best practices to improve outcomes. Subsequently, the group decided to develop best practices for managing the care of the ELBW, which started by organizing a group of specialists. This group at TCHaP is called the Wee CARE team. |
Answer the following medical question. | What does research say about Perioperative care of the neonate.? | The neonate is a unique individual with his/her own needs. This article deals with the adjustments the neonate has to make to extrauterine life; some of the differences between neonates and older children and adults, and the special needs of the neonate who needs surgery. |
Answer the following medical question. | What does research say about Early Interventions to Achieve Thermal Balance in Term Neonates.? | Hypothermia is one of the most recognized and potentially avoidable reasons for transfer of a term neonate to the NICU. Physiologic and physical factors involved in the loss of heat affect a neonate's ability to thermoregulate in extrauterine environments. At the same time, these processes are interdependently affected by hypothermia, hypoglycemia, and respiratory distress. Underlying principles and preventive measures to avoid hypothermia are presented with practical application to practice. The implementation of best practices will decrease NICU admissions that separate mothers and neonates at this critical time. Preventive measures, competent assessment guides, and early interventions offer measures to avert avoidable hypothermia-related admissions to the NICU. |
Answer the following medical question. | What does research say about Induced hypothermia for neonates with hypoxic-ischemic encephalopathy.? | Hypoxic-ischemic encephalopathy causes significant morbidity and mortality in neonates. Preventing the secondary reperfusion injury that occurs following a hypoxic-ischemic event is paramount to ensuring the best possible neurologic outcome for the neonate. Induced hypothermia is currently being studied in various institutions as a means of neuroprotection for neonates at risk of severe brain injury following a hypoxic-ischemic event. This article highlights the pathophysiology of hypoxic-ischemic encephalopathy and the rationale behind the effectiveness of induced hypothermia. Nursing care and management of neonates being treated with induced hypothermia are discussed. |
Answer the following medical question. | What does research say about Pneumothorax in a Preterm Neonate: A Case Report.? | A pneumothorax is an abnormal collection of air in the pleural space between the lung and chest wall. Although this condition commonly occurs in adults, it can also present as complication in neonates requiring assisted ventilation and has high morbidity and mortality. Chest tube placement and needle drainage are some common approaches in management. A late preterm infant born at 35+2 weeks of gestation was admitted in Neonatal Intensive Care Unit for the management of respiratory distress. He was kept on mechanical Continuous Positive Airway Pressure owing to worsening respiratory distress. Chest X-ray revealed pneumothorax that was successfully managed with venous catheter drainage on second intercostal space with underwater seal. He was discharge on 10th day of Neonatal Intensive Care Unit admission with stable vitals and normal breathing pattern. Pneumothorax is a condition where there is free air in the pleural space. In preterm neonate, it has been associated with an increased risk of intraventricular hemorrhage and mortality. Although the use of postnatal surfactant has reduced the risk of pneumothorax in neonates, 1 , 2 it remains an important complication. Timely diagnosis and appropriate treatment are crucial to reduce complications and mortality due to pneumothorax. Here, we present a case of management of pneumothorax with a venous catheter inserted in second space with underwater seal in a late preterm with respiratory distress that was kept on mechanical continuous positive airway pressure. 3 , 4 A preterm male neonate was delivered to multipara mother at 35 weeks and two days of gestation via emergency lower segment caesarean section for fetal distress. Baby had an APGAR score of 8/10 and 9/10 at 1 minute and 5 minutes respectively and birth weight of 2.2kg. Baby was admitted in NICU for further management. Baby developed tachypnea up to 80 breaths per minute for which baby was kept on Mechanical Continuous Positive Airway Pressure (CPAP) at Positive End Expiratory Pressure (PEEP) of 5 cm of H 2 O. Surfactant was not considered as the baby was maintaining oxygen saturation at FiO 2 of 25% and chest X-ray was normal. IV antibiotics Ampicillin and Amikacin were started as per unit protocol in view of raised C-reactive protein. Other parameters of initial sepsis screening were normal. At 19 th hour of life, baby had worsening respiratory distress with increased tachypnea, severe intercostal, sub-costal and supra-sternal retractions. The FiO 2 requirement increased up to 50%. An urgent chest X-ray was done which revealed a right-sided pneumothorax along with mediastinal and tracheal shift to the opposite side which was suggestive of tension pneumothorax ( Figure 1 ). As tension pneumothorax is an emergency condition it was managed with IV cannula drainage at second intercostal space and which was later connected to an underwater seal. Respiratory distress began to subside significantly. Antibiotics was upgraded to Piperacillin/Tazobactam and baby was kept nil per oral. The IV cannula placed in the chest was removed accidently at 42 nd hour of life. There was no worsening of tachypnea, chest retraction and laboured breathing. FiO 2 requirement and Silverman score significantly decreased. Chest X-ray was repeated after four hours which showed resolving pneumothorax ( Figure 2 ). Feeding was gradually increased without complications and kept on full feed. As the respiratory distress settled and FiO 2 requirement decreased, baby was weaned to nasal prong on 5 th day of life, baby was comfortable on room air on 7 th day of life. Baby was successfully discharged on 10 th day with stable vitals, normal respiratory pattern and activity. Pneumothorax in preterm neonates with respiratory distress vary from 3% (receiving mechanical ventilation) to 9% (receiving CPAP support). Worsening tachypnea, chest retractions, nasal flaring, grunting and cyanosis are few clinical signs of pneumothorax in a neonate. Respiratory distress syndrome, meconium aspiration syndrome, pneumonia and transient tachypnea of newborn are some of the risk factors. Mortality is very high when pneumothorax is untreated or treatment is delayed. The development of a pneumothorax with ensuing hypoxia and hypercapnia is a potentially life-threatening condition and 30% of the infants die in NICU. 6 In our case, early recognition and treatment of pneumothorax was key in good outcome. Pneumothorax is most commonly encountered in the first three days. This is probably due to high transpulmonary pressure caused by the onset of new breathing. 7 Our case was identified as pneumothorax at 19 8 th hour of life. Chest tube placement is the most common treatment approach in management of severe neonatal pneumothorax. It involves surgical procedure and various complications. Few trials support insertion of a venous catheter as a safe alternative to chest tube placement as a method of draining air from neonates with pneumothorax. This is an easy and quick bedside procedure and is particularly useful for neonates that require immediate air drainage. As compared with chest tube drainage, needle aspiration decreased hospital stay and decreases surgery related complication. Our case was also managed with insertion of 22-gauge cannula connected to an underwater seal. There was significant improvement in respiratory rate, chest retraction, Silverman score and Fi02 requirement after needle insertion. It also avoided chest tube insertion and patient was discharged on 10 9 th day of hospital admission. Another alternative to chest tube placement in neonate is high-frequency oscillatory ventilation that provides a conservative management in a case of significant pneumothorax in a preterm neonate who is hemodynamically stable and requires mechanical ventilation. 10 Pneumothorax in a neonate is a serious condition with high morbidity and mortality which requires early identification and prompt management. Venous catheter with underwater water seal can be considered as an alternative to chest tube drainage to minimize surgical complication and hospital stay. None. JNMA Case Report Consent Form was signed by the patient and the original article is attached with the patient's chart. Pneumothorax in a Preterm Neonate: A Case Report Relationship of pneumothorax to occurrence of intraventricular hemorrhage in the premature newborn Prognostic implications of age at detection of air leak in very low birth weight infants requiring ventilatory support Pneumothorax after mechanical ventilation in newborns Systematic review of prophylactic vs rescue surfactant Trends in mortality and morbidity for very low birth weight infants, 1991-1999 Nasal CPAP or intubation at birth for very preterm infants Is pneumothorax size on chest x-ray a predictor of neonatal mortality? Evaluation of neonatal pneumothorax Treatment of pneumothorax in newborns: use of venous catheter versus chest tube Management of pneumothorax in hemodynamically stable preterm infants using high frequency oscillatory ventilation: report of five cases |
Answer the following medical question. | What does research say about Intimate partner violence during pregnancy and adverse neonatal outcomes in low-income women.? | Intimate partner violence (IPV) affects an estimated 1.5 million U.S. women annually. IPV impacts maternal and neonatal health with higher rates of depression and low birth weight (LBW). Less studied is experiencing IPV and delivering a small for gestational age (SGA) baby. SGA neonates are at increased risk of developmental and behavioral problems. The negative sequelae persist into adulthood with increased rates of diabetes mellitus and coronary heart disease. Background: In a sample of 239 pregnant women experiencing IPV, in urban and rural settings, we examined cross-sectional associations of severity of IPV and neonatal outcomes (i.e., birth weight and gestational age). Severity of IPV was measured by the Conflict Tactics Scale 2 and neonatal outcomes were collected at the time of delivery. Methods: Outcomes were collected on 194 neonates; 14.9% ( Results: n =29) were classified as LBW, 19.1% ( n =37) classified as SGA, and 9.8% ( n =19) as LBW and SGA. Women reporting higher severity of IPV during pregnancy had a greater likelihood of delivering an SGA neonate (odds ratio [OR] 4.81; 95% confidence interval [95% CI] 1.86–12.47), and LBW neonate (OR 4.20; 95% CI 1.46–12.10). In a sample of pregnant women experiencing perinatal IPV, women experiencing greater severities of IPV were more likely to deliver a neonate with an adverse outcome. Early recognition and intervention of IPV is essential to reduce disparities in birth outcomes and long-term health outcomes for these neonates. Conclusions: Intimate Partner Violence During Pregnancy and Adverse Neonatal Outcomes in Low-Income Women |
Answer the following medical question. | What does research say about Neonatal Health Psychology [NNHP]: theories and practice.? | By 1994, Health Psychology had been established as a discipline, and defined by Marie Johnston as the scientific study of the psychological processes and behaviour in health, illness and health care. Health Psychology, so far, has mainly related to the adult population, although increasing attention is now being paid to both pediatric and broadly-based child health psychology. It is noteworthy that attention devoted to pediatric and child health psychology has increased dramatically, but the great majority of published work refers to the child and not to the preterm neonate; yet being preterm means being born early, and sometimes too small, and is a stressful life event. In the field of Medicine, Neonatology has appeared as a sub-discipline, and both investigates and cares for at-risk babies, including risk for developmental disabilities. The time is consequently opportune for psychology to make an effective contribution to both the theory and care of the preterm neonate, viewed as a unique, emergent, coactional and hierarchical human being. The formal framework for this is Neonatal Health Psychology (NNHP), which is defined in the article as 'the scientific study of biopsychosocial and behavioural processes in health, illness, and health care of the preterm (and fullterm) neonate during his/her first 28 days of life, and the relationship of such processes with later outcome.' Early work in this category has shown that NNHP has profound interdisciplinary connotations, not least because of the diverse ways in which information has to be derived from the non-verbal neonates. The pathways and scope of NNHP are identified, and many examples of work with preterm neonates are summarised in the article. In making the case for the professional formalization of NNHP, descriptions are given of Neonatal Assessments and very-early interventions; the interdisciplinary character of much of the early work is shown to have been essential. Indication of theoretical frameworks for NNHP is given. |
Answer the following medical question. | What does research say about Noise and Critical Sound Levels During Non-Invasive Ventilation of a Preterm Infant in the Incubator.? | Preterm birth and the subsequent necessary treatment in neonatal intensive care units (NICU) subjects the preterm infant to non-physiological noise exposure with potentially adverse consequences for short- and long-term development. Adjusters to improve the acoustic environment for the preterm infant need to be defined. Sound pressure level measurements during routine procedures in a NICU were performed by ¼" microphones placed inside and outside the incubator. The microphones need to be suitably positioned to measure sound pressure levels that are representative for the sound field inside and outside the incubator. The sound pressure level spectra generated by respiratory support and corresponding monitor alarms were compared. Inside the incubator, higher sound level pressures (in dBA) were generated primarily by the use of the system components of the incubator itself than outside, whereas when the incubator was closed, it had an insulating effect on sounds generated in the NICU. Non-invasive ventilation resulted in an increase in sound pressure levels from 50 to 60 dBA in the neonate's environment, with sound pressure levels increasing particularly in the frequency range above 1 kHz. Preterm infants are exposed to high sound levels, especially in the non-physiological high-frequency range, particularly during non-invasive ventilation. The continuous sound exposure could be further reduced to some extent by an optimized design of the incubator. Frühgeburt und die anschließend notwendige Behandlung auf der Neugeborenen- Intensivstation (NICU) setzen das Frühgeborene einer unphysiologischen Schallexposition mit potentiell nachteiligen Folgen für die kurz- und langfristige Entwicklung aus. Stellschrauben zur Verbesserung der akustischen Umgebung für das Frühgeborene müssen definiert werden. Schalldruckpegelmessungen während der Routineabläufe auf einer NICU wurden durch inner- und außerhalb des Inkubators angebrachte ¼“ Messmikrophone durchgeführt. Dabei müssen die Mikrofone so platziert werden, dass die gemessenen Schalldruckpegel repräsentativ für die Schallfelder innerhalb und außerhalb des Inkubators sind. Die durch Atemunterstützung, Routinemanipulationen und Monitoralarme erzeugten Schalldruckpegelspektren wurden vergleichend dargestellt. Im Inkubators entstanden während der Routineversorgung z. B. durch das Türenöffnen und die Höhenverstellung höhere Schallpegeldrücke (in dBA) als außerhalb, während der Inkubator bei geschlossenen Türen schallabsorbierend auf Umgebungsgeräusche wirkte. Nicht-invasive Beatmung führte zu einer Erhöhung des Schalldruckpegels von 50 auf 60 dBA in der Umgebung des Frühgeborenen, wobei der Schalldruckpegel insbesondere im Frequenzbereich oberhalb von 1 kHz anstieg. Frühgeborene sind besonders bei nicht-invasiver Beatmung einer hohen Schallbelastung vor allem im unphysiologischen Hochtonbereich ausgesetzt. Die Schallbelastung könnte durch eine optimierte Bauweise des Inkubators weiter verringert werden. |
Answer the following medical question. | What does research say about Major abdominal surgery of the neonate: anaesthetic considerations.? | The anaesthetic handling of neonates scheduled for major abdominal surgical procedures is one of the most demanding tasks that can confront an anaesthesiologist. This chapter will review the specific physiological characteristics of the newborn with relevance to anaesthesia and will also provide robust guidelines for the anaesthetic handling of the most frequent diagnoses that need major abdominal surgery during the neonatal period. |
Answer the following medical question. | What does research say about Implementation of Bubble CPAP in a Rural Ugandan Neonatal ICU.? | Respiratory distress is a leading cause of neonatal death in low-income and middle-income countries. CPAP is a simple and effective respiratory support modality used to support neonates with respiratory failure and can be used in low-income and middle-income countries. The goal of this study was to describe implementation of the Silverman-Andersen respiratory severity score (RSS) and bubble CPAP in a rural Ugandan neonatal NICU. We sought to determine whether physicians and nurses in a low-income/middle-income setting would assign similar RSS in neonates after an initial training period and over time. We describe the process of training NICU staff to use the RSS to assist in decision making regarding initiation, titration, and termination of bubble CPAP for neonates with respiratory distress. Characteristics of all neonates with respiratory failure treated with bubble CPAP in a rural Ugandan NICU from January to June 2012 are provided. Nineteen NICU staff members (4 doctors and 15 nurses) received RSS training. After this, the Spearman correlation coefficient for respiratory severity scoring between doctor and nurse was 0.73. Twenty-one infants, all < 3 d of age, were treated with CPAP, with 17 infants starting on the day of birth. The majority of infants (16/21, 76%) were preterm, 10 (48%) were <1,500 g (birthweight), and 13 (62%) were outborn. The most common diagnoses were respiratory distress syndrome (16/21, 76%) and birth asphyxia (5/21, 24%). The average RSS was 7.4 ± 1.3 before starting CPAP, 5.2 ± 2.3 after 2-4 h of CPAP, 4.9 ± 2.7 after 12-24 h of CPAP, and 3.5 ± 1.9 before CPAP was discontinued. Duration of treatment with CPAP averaged 79 ± 43 h. Approximately half (11/21, 52%) of infants treated with CPAP survived to discharge. Implementing bubble CPAP in a low-income/middle-income setting is feasible. The RSS may be a simple and useful tool for monitoring a neonate's respiratory status and for guiding CPAP management. |
Answer the following medical question. | What does research say about Neonatal complications in newborns with an umbilical artery pH < 7.00.? | Our purpose was to determine the significance of an umbilical artery pH < 7.00 in relation to neonatal morbidity and mortality. Between 1986 and 1993 acid-base assessment of the umbilical artery was performed routinely in 10,699 deliveries. In a retrospective cohort study 84 nonanomalous neonates with an umbilical artery pH < 7.00 were individually matched with 84 neonates with an umbilical artery pH > 7.24. Matched variables included year of delivery, gender, parity, maternal age, delivery mode, fetal presentation, gestational age, and birth weight. Differences in morbidity between the two groups during the neonatal period (until 28 days after delivery) were investigated. Neonates with an umbilical artery pH < 7.00 versus > 7.24 showed significant differences in the following: neonatal condition directly post partum; neurologic, respiratory, cardiovascular, and gastrointestinal complications; and neonatal intensive care unit admissions. No significance was found in renal dysfunction and mortality rate. The proportion of premature infants (< 37 weeks) was 17% in both groups. In the acidotic group a 1-minute Apgar score < or = 3 and a 5-minute Apgar score < 7 was predictive for neonatal complications. Severe intrapartum asphyxia, quantified by an umbilical artery pH < 7.00, poses a threat to the neonate's health. |
Answer the following medical question. | What does research say about A single case study of the communication development of a high-risk neonate, from birth to discharge from a neonatal intensive care unit.? | Since preterm and low birth weight infants display a high-risk for communication disorders or delays, the Neonatal Intensive Care Unit (NICU) provides the earliest opportunity where family-centered early communication intervention (ECI) services can be initiated. Extensive knowledge about high-risk neonates exists, but there appears to be limited knowledge about the emergence of early communication skills in these neonates. The aim of the study was to provide a systematic description of the successive communication developmental steps of a high-risk neonate on a weekly basis, from birth to discharge from a NICU, in order to guide further research on a larger scale. An A-type single case study design was used to collect prospective data over 14 sessions during the participant's 51-day stay in the NICU. Using a comprehensive data-collection protocol, rich data sets were gleaned over time. The results are described as a chronology of events contributing to the participant's risk status and influencing his early communication development. The successive emergence of the different components of language skills in the participant provided new insights into the communication development of a preterm neonate and should be further investigated. An ECI programme and guidelines for implementation in the NICU are discussed as a treatment option. |
Answer the following medical question. | What does research say about [Weigth Loss in a Neonate- A Case of Hypoaldosteronism].? | The Neonatal weight loss is a common problem which most physicians who take care of newborns should recognise. The most common reason is insufficient dietary intake. However the reason can also be an underlying disease. Aldosterone insufficiency in neonates is a rare disease and if not treated correctly can be life threatening. It presents with serious electrolytes abnormalities and metabolic acidosis. It is therefore important to distinguish between serious and benign causes of weight loss in neonates. |
Answer the following medical question. | What does research say about Toxic excipients in medications for neonates in Brazil.? | The aim was to describe the exposure to excipients among neonates hospitalised in the neonatal intensive care unit (NICU) of a public hospital in Brasilia, Brazil. This was a retrospective study based on medicines that were prescribed electronically to neonates (≤28 days) who were admitted to the NICU of a hospital in Brasilia between January 1 and March 31, 2012. Excipients were identified from the medicine package leaflets and were classified according to toxicity. Seventy-nine infants received a total of 1,303 prescriptions comprising 77 formulations and 70 active drugs. Eighty-six excipients were identified, of which, 9 were harmful excipients (HE) and 48 were potentially harmful excipients (PHE). Almost all the neonates (98.7 %) were exposed to at least one HE and PHE. Preterm neonates (n = 64; 1,502 neonate days) presented high risk of exposure to polysorbate 80 (3.26/100 neonate days), sodium hydroxide (3.39), PG (3.19) and propylparaben (3.06). Full-term neonates (n = 15; 289 neonate days) presented risks in relation to phenol (4.84), ethanol (3.8) and sodium citrate (3.46). Neonates in NICUs in Brazil are exposed to a wide variety of HE and PHE with unpredictable results. Safer alternatives are needed, as well as further studies on the subject. |
Answer the following medical question. | What does research say about Nutritional care of the surgical neonate.? | The function of the nutritionist was to identify and anticipate nutritional problems, to facilitate complete care for each infant, and to serve as an educational resource to staff, patients, and families. Neonatal nutrition is an open and challenging field for nutritionists. An expanded role for the nutritionist as a member of the physician-nutritionist team, as demonstrated in this article, may provide direction for the organization of such a team in other health care facilities with neonatal intensive care units. |
Answer the following medical question. | What does research say about Mothers' perceptions of their neonates' in-hospital transfers from a neonatal intensive-care unit.? | This study explored mothers' perceptions of their neonates' in-hospital transfers from a neonatal intensive-care unit. A convenience sample of 15 mothers was selected, and the researchers interviewed each mother once within a week after her neonate's transfer. Three themes emerged from the data: (1) the mothers expressed feelings of relief accompanied by concern, fear of the unknown, and feelings of alienation; (2) the mothers depended on familiar things and people; and (3) the mothers experienced feelings of helplessness. The mothers' perceptions of their preparation for transfer and continuity of care were mainly negative. |
Answer the following medical question. | What does research say about [Nursing management of neonatal opiate abstinence syndrome].? | Caring for infants with neonatal opiate abstinence syndrome is a challenge for nursing staff. These infants are at high risk for many complications. Nurses should be aware of the influences on neonates of maternal opium addiction during pregnancy. This article discusses clinical manifestations of neonatal opiate abstinence syndrome, common assessment tools for neonatal abstinence syndrome, and a variety of medical treatments and nursing interventions. In order to obtain adequate medical care for the neonates and safely alleviate their neonatal abstinence system, nurses should develop a comprehensive discharge plan and seek community support for the neonate's family. |
Answer the following medical question. | What does research say about Incidence and Predictors of Mortality Among Preterm Neonates Admitted to Jimma University Medical Center, Southwest Ethiopia: a Retrospective Follow-Up Study.? | Edited by: Jean Tenena Coulibaly , Félix Houphouët-Boigny University, Côte d’Ivoire Reviewed by: Ramesh Poluru , INCLEN Trust, India Hongzhao You , Chinese Academy of Medical Sciences and Peking Union Medical College, China Tigabu Kidie Tesfie , Debre Markos University, Ethiopia One reviewer who chose to remain anonymous ORCID: Temesgen Mohammed Toma, orcid.org/0000-0001-8849-6722 ; Hailu Merga, orcid.org/0000-0001-7536-4755 This study aimed to assess incidence and predictors of mortality among preterm neonates in Jimma University Medical Center, Southwest Ethiopia. A retrospective follow-up study was conducted among 505 preterm neonates admitted to the Neonatal Intensive Care Unit of Jimma University Medical Center from 01 January 2017, to 30 December 2019. Data were collected from medical records using a data collection checklist. Data were entered into Epi-Data 3.1 and analyzed with STATA 15. Cox-regression analysis was fitted to identify predictors of preterm neonatal mortality. Variables with p -value <0.05 were declared a statistical significance. The cumulative incidence of preterm neonatal death was 25.1%. The neonatal mortality rate was 28.9 deaths (95%CI: 24.33, 34.46) per 1,000 neonate-days. Obstetric complications, respiratory distress syndrome, neonatal sepsis, perinatal asphyxia, antenatal steroid exposure, gestational age at birth, and receiving kangaroo-mother care were predictors of preterm neonatal mortality. Preterm neonatal mortality rate was high. Hence, early detection and management of obstetric and neonatal complications, use of antenatal steroids, and kangaroo-mother care should be strengthened to increase preterm neonatal survival. Preterm birth, births earlier than 37 weeks of gestational age, is a global public health priority that is linked with high neonatal morbidity and mortality, mainly in developing countries [ 1 – 4 ]. The preterm birth rate is increasing and great inequalities exist in a quality, access to care, and survival across countries [ 1 ]. The risk of dying is highest in the first 4 weeks of life for all babies, but preterm babies are acutely so and they need special care just to remain alive [ 1 , 3 ]. Preterm birth affects nearly fifteen million people worldwide each year, with a rate of around 11% [ 1 ]. Prematurity is the leading cause of neonatal mortality and the second leading cause of death among children under the age of five worldwide. Prematurity is also the leading cause of multiple health risks in both the short and long term [ 1 , 3 ]. Asia and Sub-Saharan Africa accounted for nearly 80% of all preterm births [ 5 ]. More than 35% of all neonatal mortality globally results from preventable and treatable preterm birth complications [ 3 , 4 , 6 ]. Nearly one million neonates die each year from preterm birth complications [ 7 ]. The survival chance of preterm neonates varies significantly based on where they were born. More than three-fourths (75%) of preterm babies could be saved with the feasible and cost-effective practice of quality care, and further reductions are possible with intensive neonatal care [ 1 , 4 ]. The consequence of being born preterm extends beyond the neonatal period. They need proper care and treatment as they face greater risks of lifetime disability as well as a deprived quality of life [ 1 , 7 ]. Moreover, mothers of preterm neonates experience significant psychological distress and families also endure substantial financial hardship [ 8 , 9 ]. Prematurity is associated with higher healthcare costs, particularly within the first year after birth, suggesting that the implementation of appropriate programs and strategies to prevent premature delivery is beneficial from a medical as well as a healthcare expenses perspective [ 10 ]. Different findings identified mainly that mother and her neonate socio-demographic factors, maternal medical-related factors, and obstetric and gynecologic-related factors as the predictors of mortality among preterm neonates [ 11 – 18 ]. Ethiopia was one of the top ten countries with a high burden of preterm births globally. In Ethiopia, more than three hundred thousand neonates were born prematurely every year, and the rate of preterm birth was 12% [ 5 , 19 ]. As a result, Ethiopia has adopted the new WHO recommendations for improving preterm neonatal outcomes in clinical practice [ 20 ]. Besides, the country has developed a national newborn and child survival strategy from 2015 to 2020 which aims to improve the survival of neonates, mainly preterm neonates, through the inclusion of high-impact life-saving neonatal interventions and intends to end all preventable newborn and child deaths by 2035 [ 21 ]. Despite these efforts, prematurity is the first leading cause of neonatal mortality and the fourth leading cause of mortality among children below the age of five in Ethiopia [ 22 , 23 ]. Conversely, sustainable development goals (SGDs) three place a high priority on reducing newborn mortality, with a target of 12 neonatal deaths per 1,000 live births by 2030 [ 24 ]. Hence, prematurity should be addressed to curb neonatal death globally and attain SDGs [ 5 ]. There is a dearth of recent evidence on incidence and predictors of mortality among preterm neonates to inform programs and policies in Ethiopia, particularly in a study area. This significantly limits understanding of the extent and depth of the problem for evidence-based intervention. It is a dual agenda to prevent preterm delivery and address the survival gap of preterm neonates which necessitates comprehensive research to end the preventable deaths of neonates and children below 5 years. The study will help healthcare providers to identify the main predictors of preterm neonatal mortality and intervention areas, and in the timely detection of high-risk babies to give maximum efforts for their survival. Hence, this study aimed to assess the incidence and predictors of mortality among preterm neonates admitted to neonatal intensive care unit (NICU) in Jimma University Medical Center (JUMC) in Southwest Ethiopia. A retrospective follow-up study was conducted among preterm neonates admitted to NICU at JUMC between 1 January 2017, and 30 December 2019. JUMC is found in Jimma town 352 km away from Addis Ababa, the capital city of Ethiopia, in the southwestern part of the country. JUMC currently provides a range of services for approximately 15 million people. The NICU unit is one of the intensive care unit services currently in operation at the hospital which has 26 neonatal and 16 kangaroo-mother care beds. The unit also has 20 radiant warmers, four continuous positive airway pressure (CPAP), six photo-therapy machines, oxygen concentrator machines, pulse oximetry, a glucometer, and neonatal resuscitation equipment. On average, nearly 1,500 neonates are admitted annually to NICU of JUMC. The functional capability of JUMC is level three NICU [ 25 ]. The data collection period was from March 11 to 20 April 2020. The source population for this study was all preterm neonates admitted to the NICU of JUMC from 1 January 2017, to 30 December 2019. All randomly selected preterm neonates admitted to the NICU of JUMC from 1 January 2017, to 30 December 2019, and fulfilling the eligibility criteria were the study population. All alive-born preterm neonates at admission who were registered on the neonatal registry book from 1 January 2017, to 30 December 2019, in the NICU of JUMC were included in the study. However, preterm neonates with incomplete information on medical records regarding outcome status, a time when neonates were admitted to NICU, and a time when death or censoring occurred were excluded. The sample size was determined for survival analysis by considering preterm neonates who have jaundice using STATA Version 15 statistical software based on the following assumptions: 5% level of significance (α) (two-sided), 80% power, adjusted hazard ratio of 1.62 for preterm neonates who have jaundice, overall probability of preterm neonatal death (d) of 0.288 [ 15 ], and 0.5 variabilities of covariates of interest. It was assumed that no subjects were anticipated to withdraw from the follow-up, and a 10% contingency was added for incomplete records. Hence, the total sample size for this study was 516. The medical registration number (MRN) of preterm neonates over three 3-year period from 1 January 2017, to 30 December 2019, was taken from the NICU logbook to create a sampling frame. A total of 957 preterm neonates were admitted to NICU. A computer-generated simple random sampling technique was employed to select 516 participants for the study as follows: The sampling frame that was created using the MRN was entered into SPSS version 25 software. Then, a 516 sample was selected randomly using the SPSS select case procedure. Medical records of preterm neonates attached to selected MRNs were reviewed, and those records that met eligibility criteria were included in the analysis. Time to death of preterm neonates was the dependent variable (death was an event and coded “1,” and censored observation coded “0”). Socio-demographic related variables such as sex of neonate, neonatal age at admission, maternal age, and residence; maternal medical condition-related variables like maternal febrile illness/disease, anemia, diabetes mellitus, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS); obstetric and gynecologic related variables like gravidity, antenatal care visit, birth type, history of bad obstetric and/or gynecologic outcome, mode of delivery, presentation, place of delivery, antenatal steroid use, and obstetric complications; and preterm neonates related variables such as gestational age at birth, birth weight, weight class for gestational age, fifth minute APGAR score, kangaroo-mother care, initiation of breastfeeding, method of feeding, congenital malformation, temperature, respiratory distress syndrome, neonatal sepsis, perinatal asphyxia, hypoglycemia, anemia, and jaundice were independent variables. Data were collected from preterm neonatal medical records and registers by three trained bachelor’s degree holder midwives and supervised by one bachelor’s degree holder senior nurse. A data collection checklist adapted from the Global Neonatal Database data collection form for the Ethiopian Neonatal Network was used to collect the data [ 26 ]. Modifications were made to the checklist based on NICU registration format, and through reviewing relevant literature. The starting point for follow-up was the first NICU admission date and followed until the last neonatal period (28th days of life), which was the endpoint of the study. ➢ Survival status : An outcome of the neonate during follow-up from the medical records and is considered as “death” if neonate died during follow-up, as “lost to follow-up” if the mother or caregiver was not available and unable to reach their address. It was considered as “Withdrawal” if the mother refused the follow-up due to inconvenience, as “refereed” if the neonate was referred to other institutions for better management, and “alive” if the preterm neonate survival was assured at the last follow-up period [ 27 ]. ➢ Censored : Preterm neonates who were alive at the end of follow-up, lost to follow-up, withdrawal, or referred to other health institutions without knowing the outcome status [ 27 ]. ➢ Survival time : Measure of the follow-up time (in days) from the date of admission in the NICU up to the date of death, censored, or the end of the study (28th day of life) [ 28 ]. ➢ Time-to-death: Death of a preterm neonate on a specific day in the first 28 days of life [ 27 ]. Survival status : An outcome of the neonate during follow-up from the medical records and is considered as “death” if neonate died during follow-up, as “lost to follow-up” if the mother or caregiver was not available and unable to reach their address. It was considered as “Withdrawal” if the mother refused the follow-up due to inconvenience, as “refereed” if the neonate was referred to other institutions for better management, and “alive” if the preterm neonate survival was assured at the last follow-up period [ 27 ]. Censored : Preterm neonates who were alive at the end of follow-up, lost to follow-up, withdrawal, or referred to other health institutions without knowing the outcome status [ 27 ]. Survival time : Measure of the follow-up time (in days) from the date of admission in the NICU up to the date of death, censored, or the end of the study (28th day of life) [ 28 ]. Time-to-death: Death of a preterm neonate on a specific day in the first 28 days of life [ 27 ]. Data quality was assured by the careful designing of the data collection checklist, recruiting data collectors, and supervisor who have previous experience. A preliminary chart review was done on 26 randomly selected records (5% of the sample size) before the commencement of the actual study, and relevant clarifications and amendments were taken on the checklist. Training for 2 days was given on principles of research ethics, data collection checklist, and procedures for data collectors and a supervisor. Data collectors were supervised closely by the supervisor daily throughout the data collection period. Data were cleaned, coded, and entered into Epi-Data version 3.1, and analysis was done using STATA version 15.0. Descriptive statistics such as frequencies, percentages, summary measures, and rates were computed to describe categorical and continuous variables as supposed necessary. The incidence rate of neonatal mortality was computed by dividing the number of preterm neonates who died during the follow-up period by the total neonate-days at risk of observation. The Kaplan-Meier (KM) method was used to estimate median survival time and compare survival experience between categories of variables. Log-rank test was used to compare statistically significant differences in survival experience among groups. The Cox proportional hazard model was used to identify predictors of time to death. A bivariable cox-proportional hazard model was fitted first, and variables with a p -value <0.25 in this analysis entered into the multivariable cox-proportional hazard model. To identify independent predictors of time to death, a stepwise backward likelihood ratio method was used to fit a multivariable cox-proportional hazard model. An adjusted hazard ratio with a 95% confidence interval was computed to determine the strength of the association. Variables with a p -value <0.05 in the final model were considered significant predictors of the time to death of preterm neonates. The proportional hazard assumption was checked by the Schoenfeld residual test and was satisfied (Global test X 2 = 5.13, p -value = 0.92). Multicollinearity was checked by looking at the variance inflation factor (VIF) and the highest observed VIF value was 2.06, indicating that there was no multicollinearity threat. The goodness of model fitness was evaluated by using the Cox-Snell residual test. In this study, the Nelson-Aalen cumulative hazard function follows the 45° diagonal line very closely, indicating that it almost has an exponential distribution with a hazard rate of one. Hence, for the residual test, it was possible to conclude that the final model fits the data very well ( Figure 1 ). Cox-Snell residual Nelson-Aalen cumulative hazard function among preterm neonates admitted to the Neonatal Intensive Care Unit of Jimma University Medical Center, Southwest Ethiopia, 2020. A total of 516 preterm neonate medical records were reviewed, and 505 records that met eligibility criteria were included in the analysis with a response rate of 97.8%. Eleven medical records which did not fulfil the eligibility criteria were excluded. From excluded records, 6 records had incomplete data on outcome status, 3 records had an unknown date when the outcome of interest happened, and 2 records had an unknown date of admission to NICU ( Supplementary Material S1 ). Near to nine-tenth of neonates, 433 (85.7%), had less than 24 h of age at admission and more than half, 279 (55.2%), of them were males. The median age of the mother was 27 years (an interquartile range (IQR) of 8 years). Most mothers of the neonates, 398 (78.8%), were between the ages of 20 and 34. Nearly two-thirds, 339 (67.1%), of preterm neonates were rural residents ( Table 1 ). Socio-demographic characteristics of preterm neonates and their mothers at Neonatal Intensive Care Unit of Jimma University Medical Center, Jimma, Southwest Ethiopia, 2020 (N = 505). Of the participants, 66 (13.1%) mothers had known or been diagnosed with a medical disease, and more than nine-tenths of the mothers, 467 (92.5%), had antenatal care visits during the current pregnancy. Almost a quarter, 124 (24.6%), of the mothers had used antenatal steroids. Nearly three-fourths, 372 (73.7%), of the mothers had spontaneous onset of labor, and the majority of the delivery, 462 (91.5%), had a cephalic presentation. Almost half, 250 (49.5%), of the mothers had an obstetric complication ( Table 2 ). Maternal medical, obstetric, and/or gynecologic characteristics of a study participant in the Neonatal Intensive Care Unit of Jimma University Medical Center, Jimma, Southwest Ethiopia, 2020 (N = 505). Diabetes mellitus, HIV/AIDS, cardiac disease, renal disease, and STIs. Neonatal death, stillbirth, abortion, and intrauterine fetal death. Cord prolapse, oligohydramnios, polyhydramnios, and prolonged labor. Almost four-fifths of the neonates, 399 (79%), were moderate preterm, and more than two-thirds of neonates, 349 (69%), had low birth weight. Out of the cohort, 454 (89.9%) had not initiated breastfeeding within 1 hour of birth. More than three-fourths of neonates, 397 (78.6%), were diagnosed with hypothermia followed by respiratory distress syndrome 295 (58.4%), and hypoglycemia 167 (33.1%). Kangaroo-mother care (KMC) was provided to nearly one in every ten neonates (30.7%). More than three-fifths of neonates, 59.6%, received nasal CPAP ( Table 3 ). Neonatal-related characteristics of preterm neonate admitted to Neonatal Intensive Care Unit of Jimma University Medical Center, Jimma, Southwest Ethiopia, 2020 (N = 505). Meningitis, ophthalmic neonatorum, necrotizing enterocolitis, pulmonary hypertension, HIV, exposed, meconium aspiration syndrome, hospital-acquired infection, and birth trauma. During the follow-up, the cumulative incidence of preterm neonatal death was 127 (25.1%). Of all deaths, 15.7% died in the first 24 h of life, and 81.1% of deaths occurred within 7 days of life. Out of the cohort, 352 (69.7%) improved and were discharged to home, 15 (3.0%) lost to follow-up, 6 (1.2%) were referred to other hospitals, and the remaining 5 (1.0%) were withdrawn from the follow-up. A cohort contributed a total of 4,386 neonate days at risk of observation. The overall neonatal mortality rate (incidence density) was 28.9 deaths per 1,000 neonate-days (95% CI: 24.33, 34.46). The neonatal mortality rate (NMR) was 67.3 deaths per 1,000 neonate-days in the first 24 h of life (95% CI: 48.11, 94.23). Early NMR (death within 7 days of life) was 40 deaths per 1,000 neonate-days (95% CI: 33.08, 48.33); however, the late NMR was 11.7 deaths per 1,000 neonate-days (95% CI: 7.55, 18.13). Preterm neonates were followed for different periods: a minimum of 1 day and a maximum of 28 days. The overall median length of follow-up was 7 (IQR = 8) days. The cumulative survival probability at the end of the follow-up was 54.94% (95% CI: 41.83, 66.27). The cumulative probability of survival at the end of the first, seventh, 14th, and 21st days was 93.27% (95% CI: 90.71, 95.14), 76.89% (95% CI: 72.73, 80.51), 71.8% (95% CI: 66.79, 76.19), and 66.96% (60.54, 72.58), respectively. The overall mean survival time was 20.42 neonate days (95% CI: 19.27, 21.56). Preterm neonates born from mothers who used antenatal steroids had higher survival experiences compared to their counterparts (chi-square = 5.17, p -value = 0.023). Likewise, preterm neonates who received KMC had a higher survival experience than neonates who didn’t receive KMC (chi-square = 14.18, p -value = 0.0002). However, preterm neonates born from mothers with obstetric complications had lower survival experience than their counterparts (chi-square = 11.71, p -value = 0.001). Neonates having respiratory distress syndrome (RDS) had lower survival experiences than neonates without RDS (chi-square = 11.14, p -value = 0.001). Preterm neonates with neonatal sepsis had lower survival experiences than their complements (chi-square = 7.55, p -value = 0.006). Neonates with perinatal asphyxia (PNA) had lower survival experiences than their counterparts (chi-square = 7.51, p -value = 0.003) ( Figure 2 ). (A) The Kaplan-Meier survival curves by antenatal steroid use among preterm neonates admitted to the Neonatal Intensive Care Unit at Jimma University Medical Center, Southwest Ethiopia, 2020 ( n = 505). (B) The Kaplan-Meier survival curves by KMC service among preterm neonates admitted to the Neonatal Intensive Care Unit at Jimma University Medical Center, Southwest Ethiopia, 2020 ( n = 505). (C) The Kaplan-Meier survival curves by obstetric complication among preterm neonates admitted to the Neonatal Intensive Care Unit at Jimma University Medical Center, Southwest Ethiopia, 2020 ( n = 505). (D) The Kaplan-Meier survival curves by respiratory distress syndrome among preterm neonates admitted to the Neonatal Intensive Care Unit at Jimma University Medical Center, Southwest Ethiopia, 2020 ( n = 505). (E) The Kaplan-Meier survival curves by neonatal sepsis among preterm neonates admitted to the Neonatal Intensive Care Unit at Jimma University Medical Center, Southwest Ethiopia, 2020 ( n = 505). (F) The Kaplan-Meier survival curves by perinatal asphyxia among preterm neonates admitted to the Neonatal Intensive Care Unit at Jimma University Medical Center, Southwest Ethiopia, 2020 ( n = 505). In the multivariable cox-regression model; antenatal steroid use, obstetric complication during the current pregnancy, an increment in gestational age at birth, receiving KMC, having RDS, neonatal sepsis, and PNA were found to be predictors for time to death of preterm neonates at p -value <0.05. Preterm neonates born from mothers who used antenatal steroids during current pregnancy had 45% fewer hazard of death compared to neonates born from mothers who didn’t use antenatal steroids (AHR = 0.55; 95% CI:0.34, 0.90). Preterm neonates born from mothers with an obstetric complication had a 1.84 times higher hazard of death compared to those who were born from mothers without obstetric complication (AHR = 1.84; 95% CI: 1.20, 2.82). As the gestational age of preterm neonates at birth increases by 1 week, the hazard of death decreases by 19% (AHR = 0.81; 95% CI: 0.75, 0.87). Preterm neonates who had RDS had 1.52 times more hazard of death than those without RDS (AHR = 1.52; 95% CI:1.01, 2.29). Preterm neonates who had neonatal sepsis had about 1.71 times greater hazard of death than neonates without neonatal sepsis (AHR = 1.71; 95% CI: 1.18, 2.49). Preterm neonates who had PNA had 2.44 times more hazard of death compared to those neonates without PNA (AHR = 2.44; 95% CI: 1.33, 4.49). Preterm neonates who received KMC had 52% lesser hazard of death as compared to their counterparts (AHR = 0.48; 95% CI: 0.30, 0.77) ( Table 4 ). Bivariable and multivariable cox-regression model for predictors of preterm neonatal mortality in Neonatal Intensive Care Unit of Jimma University Medical Center, Jimma, Southwest Ethiopia, 2020 (N = 505). Abbreviations: AHR, adjusted hazard ratio; APGAR, appearance, Pulse, Grimace, Activity, and Respiration; CHR, crude hazard ratio; CI, confidence interval; CPAP, continuous positive airway pressure; C/S, caesarean section; GA, gestational age; HIV/AIDS, Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome; IQR, interquartile range; JUMC, jimma university medical center; NGT, nasogastric tube; NICU, neonatal intensive care unit; PPROM, preterm premature rupture of membrane; SDGs, Sustainable Development Goals; SSA, Sub-Saharan Africa; SVD, spontaneous vaginal delivery. This study showed that 25.1% of preterm neonates died during the follow-up with an overall neonatal mortality rate of 28.9 deaths per 1,000 neonate days. This finding is consistent with studies reported from Nigeria 27.7% [ 29 ], Tigray Region 32.1% with an incidence of 36.6 per 1,000 person days [ 14 ], Gondar 32.9 deaths per 1,000 neonate-days [ 15 ], and Addis Ababa 25.3% and 36.4 deaths 1,000 neonates-day [ 12 , 30 ]. However, this finding is higher than studies reported from Australia 7.7% [ 31 ], China 1.9% [ 32 ] and Uganda 8% [ 11 ]. This discrepancy between studies might be explained by variation in a study setting as there might be a high quality of neonatal care in Australia and China. A study from Australia was conducted in a hospital with a level four NICU while this study was conducted in a hospital with a level three NICU. Preterm neonates born in developed countries like Australia and China might receive improved care during pre-pregnancy, pregnancy, antepartum, and postnatal periods. Partly, this disparity might result from a difference in sample size, study design, and those reported studies were multicenter studies. Conversely, this study finding is lower than studies reported from India 33.5% [ 33 ], Southern Ethiopia 47.7 deaths per 1,000 neonatal days [ 17 ], Mizan Tepi 62.15 deaths per 1,000 neonate-days [ 13 ] and Jimma, Ethiopia 34.9% [ 28 ]. This discrepancy might result from variation in study design as a study reported from India was a multicenter prospective study conducted on a large sample size. The difference could result from variations in the study settings. The inconsistency with the finding from Jimma might be due to variation in the timing of the study as there was some improvement in antenatal and delivery care from a skilled provider and institutional delivery [ 22 ]. Partly, this might result from the fact that the NICU is organized in a good manner, and access to trained healthcare providers increased comparatively since special attention was given to preterm neonates by national neonatal and child survival strategy [ 21 ]. This finding implies that ongoing commitment and interventions need to be considered by focusing preterm neonatal survival intervention/management more on the intrapartum, immediate postpartum as well as early neonatal periods. In this study, early NMR (40 per 1,000 neonate-days) was higher as compared to late NMR (11.7 per 1,000 neonate-days). This finding is consistent with a study reported from Gondar, Ethiopia [ 15 ]. This might be attributed to the reason that most of the preterm neonatal mortality in the resource-limited setting is related to practice during the intrapartum and immediate postpartum period, the need for intensive medical care, and timely referral of high-risk neonates. But, this finding is lower than the study conducted in Addis Ababa [ 30 ]. This inconsistency could be due to a study from Addis Ababa was a multicenter prospective study conducted on a small sample and it is a setting that receives high-risk neonates referred from different regions of the country. The finding of this study shows the need to focus preterm neonatal survival interventions more on the intrapartum as well as the immediate postpartum period, and early neonatal periods. In the current study, preterm neonates born from mothers who used antenatal steroids had a lesser hazard of mortality than those neonates born from mothers who did not use antenatal steroids. This finding is in line with studies reported in the United States [ 34 ] and China [ 32 ]. This could be explained by the fact that the administration of steroids for mothers who had imminent preterm delivery enhances fetal lung maturity and decreases the risk of developing respiratory distress syndrome and intraventricular hemorrhage, and consequently might reduce the risk of neonatal death [ 35 ]. In this study, preterm neonates born from mothers who had an obstetric complication during their current pregnancy had a higher hazard of neonatal death compared to their counterparts. This finding is comparable with studies reported from Addis Ababa [ 12 ] and Southern Ethiopia [ 17 ]. This might be explained by the fact that obstetric complications affect the pregnancy status and placental blood transfusion, and can result in preterm delivery with subsequent preterm-related life-threatening complications which might increase the hazard of neonatal death. In this study, an increment in gestational age at birth by 1 week decreases the hazard of preterm neonatal deaths by 19%. This finding is in line with studies reported from Gondar [ 15 ], and Addis Ababa, Ethiopia [ 30 ]. A possible reason for this might be as the gestational age of the neonates at birth increases, the maturity of the fetus will be enhanced, and the risk of developing life-threatening complications related to prematurity decreases which might contribute to a reduced risk of preterm neonatal death. In the current study, preterm neonates who had RDS had a greater hazard of neonatal mortality compared to their counterparts. This finding is consistent with studies reported from different parts of Ethiopia: Bahir Dar [ 18 ] and Jimma [ 28 ]. This might be because of similarities in settings that lack postnatal surfactant administration. Partly, it could be explained by the fact that preterm neonates had immature lungs, and might consequently develop life-threatening complications like respiratory failure. Different literatures reported that RDS was the primary cause of preterm neonatal death [ 36 ]. In this study, preterm neonates who had neonatal sepsis had a higher hazard of neonatal mortality than preterm neonates without neonatal sepsis. This finding is in line with a study reported from Jimma [ 28 ]. This might result from the fact that preterm neonates were more likely to be born with or acquire an infection because they had immature immune defences supplemented with poor calorie intake, which might increase the risk of death [ 37 ]. In the current study, preterm neonates who had PNA had a greater hazard of neonatal mortality than those preterm neonates without PNA. This finding is consistent with studies reported from China [ 32 ], Gondar [ 15 ], Bahir Dar [ 18 ], and Jimma, Ethiopia [ 28 ]. This consistency might be elucidated by similarity in study design and follow-up period. This finding might be supported by the fact that PNA can lead to hypoxia with subsequent development of acidosis, leading to hypotension and hypoxic-ischemic encephalopathy, which further compromise oxygen delivery to the brain and might increase the risk of death [ 38 ]. In the present study, a preterm neonate who received KMC had a 52% lesser hazard of neonatal mortality compared to preterm neonates who did not receive KMC. This finding was in line with studies reported from Uganda [ 11 ], Gondar [ 15 ], and Bahir Dar, Ethiopia [ 18 ]. This consistency might be due to the similarity of the study setting, study design, and sample size. The finding was reaffirmed by the fact that receiving KMC protects neonates from the risk of hypothermia by decreasing body surface area to the external environment. Partly, it might also be explained by the fact that KMC promotes early initiation of breastfeeding, and may be used even when babies on formula-fed, which helps to prevent hypoglycemia. Moreover, KMC helps to reduce neonatal mortality by protecting them from sepsis [ 39 , 40 ]. This study has some limitations. Since the data were accessed from a secondary source, some important predictors such as maternal educational status, maternal nutritional status, birth interval, birth order, duration of rupture of membrane, and first-minute APGAR score were not available in the medical records and their effect on preterm neonatal mortality was not investigated. The study did not address the probable care and service-related predictors of mortality among preterm neonates due to the nature of the study design. Additionally, the study covers only JUMC which limits generalizability to other settings found in the Oromia region and Ethiopia. The incidence rate of preterm neonatal mortality was found high. Most preterm neonatal mortality occurs in the early phase of the neonatal period, which requires due attention to meet the national newborn and child survival and SDG-3 in Ethiopia. Obstetric complications, respiratory distress syndrome, neonatal sepsis, and perinatal asphyxia were found to be predictors of preterm neonatal mortality. Whereas, antenatal steroid exposure, an increment in gestational age at birth, and receiving kangaroo-mother care were preventive predictors for preterm neonatal mortality. Hence, special emphasis and close follow-up are highly warranted, especially during the early neonatal period. It is better to strengthen obstetrics and use of antenatal steroids for women having an imminent preterm delivery. Early detection and management of obstetric as well as preterm neonatal complications is highly demanding. Encouraging and supporting mothers to practice kangaroo-mother care, and ensuring a continuum of care are also crucial to enhance preterm neonatal survival. We would like to thank all neonatal intensive care unit and medical record staff members of Jimma University Medical Center for their cooperation and for providing the necessary information. We would also like to thank data collectors and supervisors. Ethical approval was obtained from the Institutional Review Board (IRB) of the Institute of Health of Jimma University with a reference number of IRB000/01/2020 before the commencement of the study. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because the study was based on anonymized patient records without contacting patients since the study was retrospective (conducted through patient chart review), which was waived by the IRB. However, after explaining the aim of the study, informed written consent was obtained from Jimma University Medical Center’s medical director on behalf of the patients to get full access to patient information and medical records. To ensure confidentiality, identifiers of preterm neonates and healthcare providers who examined the neonate were not recorded on the data collection checklist. All data collected from the respondents’ records were kept confidential by locking it with a password. After completing data entry, filled checklists were locked on the shelf. All study procedures followed the Declaration of the Helsinki Convention. TT conceived the study and contributed to the work in study design, execution, data analysis, interpretation, report writing, drafting, and revising of the manuscript. HM and LD were involved in the conception, design, data analysis, and revising of the manuscript. All authors contributed to data analysis, drafting, and revising the paper and agreed to be accountable for all aspects of the work. All authors contributed to the article and approved the submitted version. The authors declare that they do not have any conflicts of interest. The Supplementary Material for this article can be found online at: https://www.ssph-journal.org/articles/10.3389/ijph.2024.1606897/full#supplementary-material A flow chart of selecting preterm neonates admitted to the NICU of JUMC, Southwest Ethiopia, 2020. Incidence and Predictors of Mortality Among Preterm Neonates Admitted to Jimma University Medical Center, Southwest Ethiopia: a Retrospective Follow-Up Study Global, Regional, and National Estimates of Levels of Preterm Birth in 2014: A Systematic Review and Modelling Analysis Global, Regional, and National Causes of Under-5 Mortality in 2000–15: An Updated Systematic Analysis With Implications for the Sustainable Development Goals Patterns of Psychological Distress in Mothers of Preterm Infants Mothers' Depression, Anxiety, and Mental Representations After Preterm Birth: A Study During the Infant's Hospitalization in a Neonatal Intensive Care Unit Cost Effects of Preterm Birth: A Comparison of Health Care Costs Associated With Early Preterm, Late Preterm, and Full-Term Birth in the First 3 Years After Birth Survival Time and its Predictors in Preterm Infants in the Post-Discharge Neonatal Period: A Prospective Cohort Study in Busoga Region, Uganda Survival Status and Predictors of Mortality Among Preterm Neonates Admitted to Neonatal Intensive Care Unit of Addis Ababa Public Hospitals, Ethiopia, 2021. A Prospective Cohort Study Survival Status and Predictors of Mortality Among Preterm Neonates Admitted to Mizan Tepi University Teaching Hospital, South West Ethiopia Survival and Predictors of Mortality Among Preterm Neonates in Northern Ethiopia: A Retrospective Follow-Up Study Survival and Predictors Among Preterm Neonates Admitted at University of Gondar Comprehensive Specialized Hospital Neonatal Intensive Care Unit, Northwest Ethiopia Survival and Mortality of Preterm Neonates in a Neonatal Intensive Care Unit in Northern Ethiopia: A Retrospective Cohort Study Predictors of Time to Death Among Preterm Neonates Admitted to Neonatal Intensive Care Units at Public Hospitals in Southern Ethiopia: A Cohort Study Predictors of Survival Among Preterm Neonates Admitted to Felege Hiwot Comprehensive Specialized Hospital, Northwest Ethiopia Survival of Preterm Infants Admitted to Tikur Anbessa Hospital Nicu, Addis Ababa Survival of Neonates and Predictors of Their Mortality in Tigray Region, Northern Ethiopia: Prospective Cohort Study Modeling Determinants of Time-To-Death in Premature Infants Admitted to Neonatal Intensive Care Unit in Jimma University Specialized Hospital Determinants of Neonatal Survival Following Preterm Delivery at the University of Maiduguri Teaching Hospital, Maiduguri, Nigeria Survival of Preterm Neonates and its Determinants in Teaching Hospitals of Addis Ababa University Causes of Death in Very Preterm Infants Cared for in Neonatal Intensive Care Units: A Population-Based Retrospective Cohort Study Care Practices, Morbidity and Mortality of Preterm Neonates in China, 2013-2014: A Retrospective Study Causes of Death in Preterm Neonates (<33 Weeks) Born in Tertiary Care Hospitals in India: Analysis of Three Large Prospective Multicentric Cohorts Exposure to Any Antenatal Corticosteroids and Outcomes in Preterm Infants by Gestational Age: Prospective Cohort Study Antenatal Corticosteroids for Accelerating Fetal Lung Maturation for Women at Risk of Preterm Birth Major Causes of Death in Preterm Infants in Selected Hospitals in Ethiopia (SIP): A Prospective, Cross-Sectional, Observational Study Why Are Preterm Newborns at Increased Risk of Infection? The Effect of Asphyxia on Neonatal Death: A Meta-Analysis The Effects of Kangaroo Mother Care on the Time to Breastfeeding Initiation Among Preterm and LBW Infants: A Meta-Analysis of Published Studies Kangaroo Mother Care in Resource-Limited Settings: Implementation, Health Benefits, and Cost-Effectiveness |
Answer the following medical question. | What does research say about Nursing the preterm surgical neonate.? | The preterm neonate's response to surgery manifests in all body systems. Necrotising Enterocolitis (NEC) is an acute gastro-intestinal emergency requiring surgical intervention. Severe NEC may require the removal of infarcted bowel. Examining the response to surgery in the preterm neonate with NEC offers nurses a rationale for their post-operative care. Both physiological and psychological responses need to be understood in the light of family centred care. |
Answer the following medical question. | What does research say about Surveillance Practice for Sonographic Detection of Intracranial Abnormalities in Premature Neonates: A Snapshot of Current Neonatal Cranial Ultrasound Practice in Australia.? | There are no publications reporting on scan duration and Doppler use during neonatal cranial ultrasound scans. We investigated current practice of neonatal cranial ultrasound at four large tertiary neonatal intensive care units in Australia. Cranial scans were prospectively recorded between March 2015 and November 2016. Variables, including total number of scans, scan duration and frequency and duration of colour and spectral Doppler mode, were extracted. A total of 196 scans formed the final cohort. The median (range) number of scans for each neonate was 1 (1-12). The median (range) overall total scan duration was 309 (119-801) s. Colour mode with or without spectral Doppler mode was used in approximately half of the cohort (106/196, 54%). Our findings comport with our hypotheses. Operators performing neonatal cranial scans in Australia have low overall scan durations. Although the use of Doppler mode during neonatal cranial scans is not standard practice in all neonatal intensive care units, it is used widely irrespective of the degree of prematurity or the presence of brain pathology. Further efforts are required to incorporate recommendations on scan duration and the routine use of Doppler mode during neonatal cranial scans. This is especially imperative given that the most vulnerable neonates with the greater neural tissue sensitivity are likely to be scanned more often. |
Answer the following medical question. | What does research say about Enteral nutrition and infections: the role of human milk.? | Human milk (HM) is known as the best nutrition for newborns and support the optimal growth of infants, providing essential substances, nutrients, bioactive and immunologic constituents. HM also grants a favorable microbial colonization with attendant priming/maturation of the gut. The bioactive and immunologic elements of HM demonstrated to protect offspring against infection and inflammation and contribute to immune maturation. Some of these elements are being investigated in order to be used to ameliorate formula milk. A formula milk similar to breast milk may help neonatal gut to build a microbiota near to the one of the breast fed infants, improving the neonate's protection against pathogens. The aim of this review is to summarize the most significant bioactive constituents of HM that own natural anti-infectious properties and contribute to neonatal immune defense. |
Answer the following medical question. | What does research say about blaOXA-48 carrying clonal colistin resistant-carbapenem resistant Klebsiella pneumoniae in neonate intensive care unit, India.? | Bacteria resistant to colistin, a last resort antibiotic reflect the pre-antibiotic era. In this study, colistin resistance carbapenem-resistant K. pneumoniae (COL |
Answer the following medical question. | What does research say about Effect of cup, syringe, and finger feeding on time of oral feeding of preterm neonate's: a randomized controlled clinical trial.? | The oral nutrition is big challenge for preterm neonates. Since the best oral feeding method for preterm neonates is not yet known, the present study aimed to evaluate the effect of cup, syringe, and finger feeding methods on reaching the time of full oral feeding and weight gain among preterm neonates. This randomized clinical trial study was conducted on 99 preterm neonate’s, born at 30–34 weeks gestation, admitted to the neonatal intensive care unit (NICU) of Al-Zahra and Taleghani Therapeutic-Educational Centers in Tabriz, Iran. Subjects were assigned into finger feeding ( n = 33), cup feeding ( n = 33), and syringe feeding ( n = 33) groups in the allocation ratio of 1:1:1 using block randomization with a block size 6 and 9. They were studied in terms of reaching the time of full oral feeding and weight gain. The data were analyzed using SPSS/version21 software, and ANOVA, chi-square, and ANCOVA tests. There was no significant difference in the mean score of reaching the time of full oral feeding among cup, finger, and syringe feeding groups ( p = 0.652). The mean score of daily weight gain, oxygen saturation (SaO 2 ), and heart rate after feeding was not significantly different among the three groups ( p > 0.05). The effect of confounding variables, including birth weight and age, arterial oxygen saturation, and heart rate before feeding, was controlled. Based on the results, one of the cup, finger, and syringe feeding methods can be applied in the NICU, considering the staff’s proficiency in feeding neonates. Trial registration IRCT20150424021917N11. What is known Safe and efficient feeding method is one of the most important challenges in preterm newborns` life. Preterm neonate’s cannot coordinate breathing, Sucking, and swallowing, for oral feeding Safe and efficient feeding method is one of the most important challenges in preterm newborns` life. Preterm neonate’s cannot coordinate breathing, Sucking, and swallowing, for oral feeding What is new Results of this study showed that There was no significant difference in the reaching the time of full oral feeding among cup, finger, and syringe feeding methods. There was no difference in daily weight gain among neonates who fed with using of cup, Finger or syringe feeding methods Results of this study showed that There was no significant difference in the reaching the time of full oral feeding among cup, finger, and syringe feeding methods. There was no difference in daily weight gain among neonates who fed with using of cup, Finger or syringe feeding methods Acquiring safe and efficient feeding skills, is a challenging stage of life for preterm neonate. [ 1 ], which is one of the main and important components of emergency care for neonate’s [ 2 , 3 ]. The factors influencing the effective feeding ability of preterm neonate’s include neurobehavioral maturity, physiological stability of the control of muscle tone, organization of behavioral state, swallowing, and coordinated breathing [ 4 , 5 ]. Oral feeding requires the maturity of the sucking, swallowing, and breathing mechanisms. Preterm neonate’s cannot coordinate breathing, sucking, and swallowing, thanks to the dearth of physiological and neurological maturity [ 6 ]. Although the ability to suck and swallow is present by the 28 weeks gestation, the coordination of these abilities is not developed until the 32–34 weeks gestation. Therefore, neonate’s younger than 32 weeks of gestation cannot breastfeed or bottle feed efficiently and are fed by the gavage [ 7 ]. The appropriate nutrition for neonates is breastfeeding, which is achieved by successful sucking. However, preterm newborns fail to suck, due to the anatomical and physiological immaturity of the organs and systems and many problems they face. Therefore, alternative methods, such as using feeding tubes or supportive nutritional interventions, including cup, syringe, bottle, dropper, and finger feeding are suggested to prepare preterm neonate’s for breastfeeding [ 8 , 9 ]. In cup feeding, the neonate is kept in a sitting or semi-sitting position with head and body coordination, as the rim of the cup is placed on his or her lower lip to lap or sip milk with forward movements of the tongue [ 10 ]. The World Health Organization (WHO) introduced cup feeding as a method of transfer or oral feeding complementation for preterm neonate’s, since it does not cause nipple confusion and does not affect the suction of preterm neonate’s [ 11 – 13 ]. The cup feeding allows the neonate to adjust the suction, control breathing, and swallow more easily, as it requires little energy [ 8 ]. The finger feeding is planed as another methodology within the nutrition transfer. During this technique, milk is transferred to the preterm neonate by suction through the nasogastric tube (NG tube) connected to a syringe attached to the little finger of the gloved hand, that is fastened in situ. Although this technique is widely used in different neonatal units, a few studies have been conducted on finger feeding, its indication and use, and its advantages and disadvantages [ 11 , 12 , 14 , 15 ]. The sensory stimulation caused by the stiffness of finger is more like a nipple and facilitates the development of oral motor skills, which should be exist during breastfeeding [ 11 , 15 – 17 ]. To our knowledge, there are few studies available on the use of syringe and only information exists on how to administer it. In finger feeding method, the milk is directed to the inner part of the neonate’s cheek and its piston is pressed only when the preterm neonate is sucking and not when swallowing or breathing [ 16 ]. The study results of comparing the effectiveness of the finger and syringe feeding methods indicated that the transition time to breastfeeding was significantly shorter and the weight gain was higher in the finger feeding group compared to the syringe feeding group [ 18 ]. In a study, neonates received gavage feeding at 26–32 weeks gestation were compared in terms of the time to start full oral feeding in the syringe and bottle feeding groups, and the time of transition to breastfeeding and the time of discharge were significantly short in the syringe group [ 19 ]. Owing to lack of sufficient evidence about comparing three mentioned nutrition method, this study was designed and carried out to response questions in this regard. This randomized clinical trial study was done on 99 preterm neonate’s, born at 30–34 weeks gestation, admitted to the NICU of Al-Zahra and Taleghani Educational Centers in Tabriz. The sampling was carried out after obtaining the code of ethics from the Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1399.819) and registering on the website of the Iranian Registry of Clinical Trials (IRCT, 20150424021917N11). Participants in this stusy were neonate’s at 30–34 weeks gestation with a stable clinical condition at the time of sampling, neonate’s swallow ability for two days, Apgar score higher than 7 at the 5th minute, and obtaining permission from the relevant neonatologist. The neonates with intraventricular bleeding and sepsis, neonate’s using continuous positive airway pressure (CPAP) or ventilator, and the presence of congenital malformation, Down syndrome, and neuromuscular diseases were not eligible. The researcher attended the selected centers for daily sampling, and subjects were selected using convenience sampling method. Before the start of the study, the researcher attended the educational-therapeutic centers and selected the neonate’s at 30–34 weeks. After checking the inclusion and exclusion criteria, their mothers were invited to participate in the briefing session. In the briefing session, more complete information was provided regarding the goals, study method, importance and benefits of participating in the study, then the initial registration of people interested in participating in the study was done and the check list of entry criteria for these neonate’s was completed. Informed written consent was provided to the mother of the neonate’s who met the conditions for inclusion in the study. The neonate profile questionnaire and the personal social profile questionnaire were completed. The researcher visited these centers daily and selected the eligible neonates as available. Participants were assigned into finger feeding ( n = 33), cup feeding ( n = 33), and syringe feeding ( n = 33) groups in the allocation ratio of 1:1:1 by block randomization using the random allocation software (RAS) with a block size 6 and 9. For allocation concealment, the type of intervention was written on a piece of paper and placed inside sealed opaque envelopes that were numbered sequentially. The envelopes were opened by a non-involved person (a nurse working in the NICU) in sampling neonate’s who met the conditions to be included in the study, informed written consent was provided to the mother, the neonate and the mother profile questionnaires were completed. The data were collected using the neonate checklist, including heart rate, bradycardia, apnea, and oxygen saturation, neonate and mother’s socio-demographic characteristics questionnaire, including age, gender, neonate’s weight, birth grade, and mother’s age, Parental satisfaction with intervention questionnaire, which was measured using a Likert scale at the end of the intervention, and a checklist of adverse events, including any adverse events occurred to neonates during the intervention. The neonate’s weight was measured at the beginning of the study and then, daily before and after feeding at a specific time in the morning shift using the scale available in the ward. Breast milk or pasteurized donor milk was used to feed the neonate. The amount of milk prescribed for each neonate was according to the protocol prescribed by the neonatologist. The feeding speed in the syringe feeding method was on average, 1.5 cc per minute [ 16 ]. Before starting the study, mothers were given the necessary training related to cup, finger, and syringe feeding methods. According to the hospital protocol, the gavage tube will not be removed from the neonate until reaching the full oral feeding. In this research, reaching the time of full oral feeding (oral feeding 8 times a day or two-thirds of the total number of feedings per day) is regarded as the primary outcome and weight gain, average heart rate, and arterial oxygen saturation as the secondary outcomes. Oxygen saturation and heart rate were measured every day in the morning shift once at the beginning and then, at the end of breastfeeding. Further, the occurrence of apnea, bradycardia (heart rate reduction to less than 100 beats per minute), and chocking were monitored at each feeding time. The study continued until the neonate reached the independent oral feeding. Holding the syringe, finger or cup (disposable 50 ml plastic cup) on the neonate’s lips was considered as the onset and the completion of the milk prescribed by the neonatologist as the its termination. In all three groups, the neonate’s body was placed in a half-lying position with a 45-degree incline, and the head and neck were held with the other hand. At the end of the research, the intervention satisfaction questionnaire was provided to the mothers for completion. The primary outcome of this study was to compare the average time to oral feeding and weight gain in 3 groups for 5 days with the adjustment of birth weight using a newborn questionnaire. The secondary outcome of the study was the comparison of the average heart rate, oxygen saturation, and the incidence of chocking, bradycardia, and apnea between the groups for 5 days of intervention. The mentioned variables were recorded once before and once immediately after the intervention in the morning shift for 5 days. The sample size was calculated 33 subjects per group based on the study of Rahmani et al. [ 20 ]. Considering m 1 = 5.1 (the mean duration to achieve full oral feeding in the syringe feeding group) and m 2 = 4.0 (the mean day to reach full oral feeding in the cup feeding group), SD 1 = 2.7, SD 2 = 1.6, α = 0.05, β = 0.8, power = 80%, and two-sided hypothesis. The data were analyzed using SPSS/version 21 software, ANOVA test was used to compare the quantitative variables of socio-demographic characteristics, and the chi-square was employed to compare the qualitative variables of socio-demographic characteristics among the three groups. In addition, ANCOVA test was applied to compare the time passed to reach oral feeding, weight gain, oxygen saturation, and heart rate after feeding. Birth weight, oxygen saturation, and heart rate before feeding were included into the statistical model as confounding variables. The chi-square test was used to compare side effects (chocking, bradycardia, and apnea) and mothers’ satisfaction with feeding methods by intervention groups. In all stages, the P-value was considered 0.50 and the data were analyzed using the Intention to treat method. This study was conducted from February to October 2021. The characteristics of 610 neonate’s were checked initially and 511 neonates were excluded from the study, due to not fulfilling the eligibility criteria (Fig. 1 ). Finally, a total of 99 preterm neonate’s were entered in the cup feeding ( n = 33), finger feeding ( n = 33), and syringe feeding ( n = 33) groups. One neonate in the syringe feeding group was excluded from the study due to bradycardia. The mean (SD) age of the neonate’s was 30.6 (2.1) weeks and the birth weight was 1560.45 (432.23) gr. Fig. 1 Study flowchart Study flowchart Table 1 indicates the socio-demographic characteristics of neonate’s and mothers. The results of the ANOVA test demonstrated a significant difference in the neonates’ birth weight and age among the three groups. Tukey’s tests revealed that cup feeding neonates had significantly higher birth weight ( p = 0.045) and age ( p = 0.002) compared to finger feeding neonate’s. Table 1 Individual and social characteristics of the study participants Groups Cup feeding Finger feeding Syringe feeding p value ** Variable N = 33Mean (SD)* N = 33Mean (SD)* N = 33Mean (SD)* Mother's age (years) 29.06(7.41) 27.24(4.82) 29.51(5.38) 0.268 Neonate’s age at recruitment (days) 13.36(11.19) 21.09(15.31) 18.51(13.82) 0.068 Gestational age (weeks) 31.48(1.87) 29.66(2.13) 30.84(2.19) 0.002 Neonate’s birth weight (grams) 1661.36(399.57) 1407.57(382.22) 1612.42(485.10) 0.040 Mother’s job Housewife 31(93.9) 31(93.9) 30(90.9) 0.858 Employed 2(6.1) 2(6.1) 3(9.1) Education Illiterate/elementary 3(9.1) 1(3.0) 3(9.1) 0.545 Middle school/high school 9(27.3) 5(15.2) 7(21.2) Diploma/University 21(63.6) 27(81.8) 23(69.7) Gravid 1–2 22(66.7) 23(69.7) 21(63.6) 0.706 3–4 23(69.7) 10(30.3) 10(30.3) > 4 2(6.1) 0(0.0) 2(6.1) Delivery 1–2 25(75.8) 28(84.8) 25(75.8) 0.580 3–4 8(24.2) 5(15.2) 8(24.2) Delivery type Vaginal 9(27.3) 6(18.2) 6(18.2) 0.580 Cesarean section 24(72.7) 27(81.8) 27(81.8) Gender of the neonate Female 19(57.6) 15(45.5) 15(45.5) 0.524 Male 14(42.4) 18(54.5) 18(54.5) Receive breastfeeding education Yes 33(100) 33(100) 33(100) No – – – – *Mean (standard deviation) ** ANOVA test and chi-square test and chi-square test Individual and social characteristics of the study participants *Mean (standard deviation) ** ANOVA test and chi-square test and chi-square test Table 2 represents the time to reach oral feeding and weight gain during the study. The results of ANCOVA indicated no difference in the neonate’s weight among three groups after adjusting the effect of weight. Table 2 Comparison of the time to reach full oral feeding and daily weight gain according to the study groups Group Time (day) Mean(SD)* Weight (gram) Mean(SD)* ADM(95%CI)¥ p value** Time to reach oral feeding Cup feeding ( n = 33) 6.27(5.03) 0.652 Finger feeding ( n = 33) 9.12(6.53) Syringe feeding ( n = 33) 7.96(5.17) Comparison of groups Cup with finger feeding − 1.1(− 4.4 to 2.26) 0.212 Cup with syringe feeding − 1.03(− 2.10 to 4.17) 0.652 Syringe feeding with finger 0.076(− 3.38 to 3.23) 0.325 Daily weight gain (grams) Cup feeding 14.31 (6.11) 0.127 Finger feeding 12.90 (4.7) Syringe feeding 15.55 (4.83) Comparison of groups Cup with finger feeding 1.13(− 2.10 to 4.37) 0.781 Cup with syringe feeding − 1.19(− 4.1 to 1.72) 0.691 Syringe feeding with finger 2.32(− 0.93 to 5.58) 0.237 *Mean (standard deviation) ¥ Adjusted mean difference (95% confidence interval) **ANCOVA test with adjustment of weight, gestational age and birth weight Comparison of the time to reach full oral feeding and daily weight gain according to the study groups *Mean (standard deviation) ¥ Adjusted mean difference (95% confidence interval) **ANCOVA test with adjustment of weight, gestational age and birth weight Table 3 illustrates the average heart rate and oxygen saturation after feeding by the study groups. Based on the results of ANCOVA, there was no difference in neonates’ age at birth among three groups after adjusting the effect of weight. However, the heart rate of neonates in syringe feeding group was significantly higher than that in cup feeding group ( p = 0.026). Table 3 Comparison of oxygen saturation and heart rate after feeding by intervention groups Group Arterial oxygen mean(SD)* Heart rate mean(SD)* ADM(95%CI)¥ p value** Arterial oxygen Cup feeding ( n = 33) 96.60(1.38) 0.337 Finger feeding ( n = 33) 96.12(0.90) Syringe feeding ( n = 33) 96.16(1.92) Comparison of groups Cup with finger feeding 0.32(− 0.50 to 0.57) 0.998 Cup with syringe feeding 0.31(− 0.22 to 0.84) 0.406 Syringe feeding with finger − 0.27(− 0.81 to 0.25) 0.508 Heart rate Cup feeding 142.11(9.47) 0.233 Finger feeding 145.28(8.48) Syringe feeding 145.05(6.37) Comparison of groups Cup with finger feeding − 1.45 (− 3.39 to 0.48) 0.200 Cup with syringe feeding − 3.60(− 5.55 to − 1.65) 0.200 Syringe feeding with finger 2.14(0.19 to 4.10) 0.026 *Mean (standard deviation) ¥ Adjusted mean difference (95% confidence interval) **ANCOVA test with adjustment of oxygen saturation and heart rate from feeding Comparison of oxygen saturation and heart rate after feeding by intervention groups *Mean (standard deviation) ¥ Adjusted mean difference (95% confidence interval) **ANCOVA test with adjustment of oxygen saturation and heart rate from feeding In the present study, no case of apnea was reported in any of the groups. In the syringe feeding group, one person suffered from bradycardia and 13, 11, and 14 cases of chocking occurred in the cup feeding, finger feeding, and syringe feeding groups, respectively. The current study aimed to compare the cup, syringe, and finger feeding methods on reaching the time of full oral feeding and weight gain among the preterm neonate’s. To the best of our knowledge, no study has compared the effect of the cup, syringe, and finger feeding methods on reaching the time of full oral feeding and weight gain among preterm neonate’s. In most of the studies, two feeding methods have been compared and in some of them, three methods have been compared with other variables. The mean duration to reach full oral feeding did not show a significant difference between the study groups, only the time to reach full oral feeding in the cup feeding group was slightly less than that in the other groups. Although the weight gain was slightly higher in the syringe feeding group, there was no significant difference among the three groups. Nunes et al. [ 21 ] in a clinical trial study evaluated the provision of a diet with cup feeding and finger probe simultaneously with breastfeeding and indicated additional weight gain and longer length of hospital stay in the cup feeding group. The more weight gain was probably due to the longer length of stay in the hospital. There was no statistically significant distinction among the study groups in terms of oxygen saturation and heart rate. In line with the results of the present study, the findings of the study of Mirjalili et al. [ 22 ] discovered that the mean weight of neonate’s and therefore trend of changes within the mean weight were not considerably completely different in the cup, finger, and dropper feeding methods ( p = 0.25). Achieving full oral feeding is an important step for preterm infants, given that it is an important criteria in order to discharge of newborn and shows the maturity and health of the preterm infant [ 23 ], Any delay in achieving this crucial physiological function will lead to delay in discharge from the neonatal intensive care unit and might result in growth failure, and poorer neurodevelopmental outcomes [ 24 – 26 ]. Çamur et al. [ 27 ] reported that the bottle and cup feeding methods were equally effective in reaching the time of full oral feeding and there was no statistically significant difference between the mentioned groups. However, the study results of Say et al. [ 19 ] illustrated that the transition time to full oral feeding was significantly shorter in syringe-fed preterm neonate’s compared to bottle-fed preterm neonate’s. There is insufficient evidences comparing dietary transition techniques in respect to O2 Saturation and heart rate [ 21 ]. It is possible that the type of feeding of premature neonate’s affects heart rate fluctuations and arterial oxygen saturation. López et al. [ 28 ] in their study showed that O 2 Sat was less than 85% after cup feeding. The authors emphasize that the probable fall of O 2 Sat may be related to the vigorous attempt to suck the milk from the cup. Araújo et al. [ 16 ] observed that oxygen saturation and heart rate variations observed before, during, and after feeding were within normal limits for both syringe and finger feeding methods. In addition, oxygen saturation increased between the moments before and after the syringe feeding. Among the neonate’s feeding options, the cup feeding may be an easy method with a protracted history and a semipermanent feeding solution for those that cannot breastfeed [ 29 ], which may be used to supplement breastfeeding and minimize gavage exposure. The theoretical advantages of cup feeding include avoiding any confusion between the breast and the bottle, increasing the neonate’s sucking ability, and facilitating the neonate’s ability in self‐regulation and feed demand [ 8 , 30 ]. Further, there are many benefits to cup feeding, including strengthened bonding, mother’s higher sense of control and confidence, the possibility to engage other family members in caring for the neonate, and freeing up the nursing staff when the mothers conduct health care [ 29 ]. The main and most important use of the cup feeding is to provide a safe artificial feeding method for preterm and low birth weight neonate’s until they become strong and grow up enough to exclusively breastfeed [ 31 ]. The finger probe method is emerged as an option to transfer nutrition, which is widely used in the various service routines as a suction training method or as a supplementary method. Finger probe method is used during feeding as an option when there is no good compatibility with the cup [ 8 , 12 , 13 , 32 ]. Finger feeding is a safe method for preterm neonate’s, which can be recommended to accelerate the transition to breastfeeding, increase the rate of weight gain, and shorten the hospitalization period [ 18 ]. The evidence revealed that the finger feeding method requires more time and costs compared to the cup feeding method. Nevertheless, finger feeding method provides oral stimuli to the neonate’s, which is beneficial for suction training, maintaining alertness, and coordination of suction, swallowing, and breathing. The weight gain of finger-fed neonate’s is more than that of syringe-fed neonate’s. Given the advantages of finger feeding method in terms of achieving oral feeding of preterm neonate’s, more convenience, and shorter hospitalization time, especially in the gestational age below 34 weeks, finger feeding is considered as a desirable method [ 13 , 17 , 18 , 33 ]. In the syringe feeding method, the milk was directed to the inner part of the neonate’s cheek and also the piston was ironed once only if when the preterm neonate was sucking and not when swallowing or breathing, and the rate was twenty cc per minute [ 16 ]. Although syringes are commonly used in neonatal wards, this method provides an anti-physiological stimulus regardless of the neonate’s desire to suck or reach [ 34 ]. In the present study, the level of mothers’ satisfaction with the intervention was slightly higher in the syringe feeding group. However, there was no statistically significant difference among the three groups. The same level of satisfaction indicates that all three feeding methods can be used for mothers in breastfeeding the preterm neonate’s. In the present study, 13, 11, and 14 cases of chocking occurred in the cup feeding, finger feeding, and syringe feeding groups, respectively, as there was no statistically significant difference among the three groups. However, chocking was slightly more in the syringe group and slightly less in the finger group compared to the other two groups. Given that, the milk flows continuously in the syringe feeding method and the neonate does not control the volume of milk entered in the oral cavity, more chocking probably occurred in the syringe feeding group for this reason. The randomized controlled trail study design is regarded as one of the strengths of this research. The birth weight recorded in the newborn’s cases was entered in the socio-demographic characteristic questionnaire. Given that the birth weight was not measured by the researcher, this is considered as one of the limitations of this research. The small sample size in each group is another limitation of the present study. Further, 80% power was considered in the calculation of the sample size. Based on the results of the present study, the cup, syringe, and finger feeding methods had no remarkable difference on reaching the time of full oral feeding and weight gain of preterm neonate’s, as well as heart rate and arterial oxygen saturation after feeding. The level of mothers’ satisfaction with the cup, syringe, and finger feeding methods was not different in the three groups, and suffocation on milk in the syringe feeding group was slightly higher than that in the other two groups, which is negligible. Therefore, one of the cup, syringe, and finger feeding methods can be considered in NICU based on the staff’s proficiency in feeding neonates. However, conclusions should be made with caution, due to the small sample size. Neonatal intensive care unit Analysis of variance test Analysis of covariance test Arterial oxygen saturation Iranian registry of clinical trials World health organization Nasogastric Continuous positive airway pressure The Intention to treat Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The present study was derived from the master’s thesis of midwifery education, and the research project was approved by Tabriz University of Medical Sciences (IR.TBZMED.REC.1399.819). The authors would like to thank the cooperation of the Vice Chancellor for Research of Tabriz University of Medical Sciences and the officials and staff of the Neonatal Intensive Care Unit and Neonatal ward of Al-Zahra Hospital. PA contributed to planning, manuscript draft and data collection. NSJ contributed in planning of research. MMG supervised in data collection and technical support. LAN contributed in writing manuscript. SH contributed to planning, statistical analysis and writing manuscript and interpreted analysis. All authors read and approved the final manuscript. This study is funded by research deputy of Tabriz University of Medical Sciences. There is no other funder for this research. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate this protocol have been approved by the Ethics Committee of Tabriz University of Medical Sciences, Tabriz, Iran (reference number: IR.TBZMED.REC.1399.819). And this trial has also been registered on IRCT and received the code IRCT20150424021917N11. Written informed consent was obtained from the parents, who agree to participate in the study. All methods were performed in accordance with the relevant guidelines as regulations. Not applicable. The authors declare that they have no competing interests. Effect of cup, syringe, and finger feeding on time of oral feeding of preterm neonate’s: a randomized controlled clinical trial Instruments for assessing readiness to commence suck feeds in preterm infants: effects on time to establish full oral feeding and duration of hospitalisation Nutrition for the extremely preterm infant Sucking and swallowing in infants and diagnostic tools Problemas de la alimentación en lactantes Oral and nonoral sensorimotor interventions facilitate suck–swallow–respiration functions and their coordination in preterm infants Cochrane review: non-nutritive sucking for promoting physiologic stability and nutrition in preterm infants Cup feeding versus other forms of supplemental enteral feeding for newborn infants unable to fully breastfeed Alternative feeding methods for premature newborn infants Comparison of the finger-feeding versus cup feeding methods in the transition from gastric to oral feeding in preterm infants Indicações e uso da técnica" sonda-dedo" Comparison of sucking pattern in premature infants with different feeding methods Significado do uso do copinho em unidade de terapia intensiva neonatal: a vivência materna [Meaning of cup feeding in a neonatal intensive care unit: the mother’s experience] Estimulação sensoriomotora intra e extra-oral em neonatos prematuros: revisão bibliográfica Preterm and late preterm infants: their differences and breastfeeding Efeitos da estimulação da sucção não nutritiva com dedo enluvado na transição alimentar em recém-nascido prematuro de muito baixo peso Comparison of the finger feeding method versus syringe feeding method in supporting sucking skills of preterm babies Evaluation of syringe feeding compared to bottle feeding for the transition from gavage feeding to oral feeding in preterm infants Effects of feeding nozzle and cup feeding on reaching the time of full oral feeding in the premature infants in the neonatal intensive care unit Investigating the effect of two feeding methods with cup and finger on feeding tolerance and gain weight in preterm infants admitted to the neonatal intensive care unit Clinicians guide for cue-based transition to oral feeding in preterm infants: an easy-to-use clinical guide Neonatal outcomes of moderately preterm infants compared to extremely preterm infants National and regional trends in gastrostomy in very low birth weight infants in the USA: 2000–2012 Delayed achievement of oral feedings is associated with adverse neurodevelopmental outcomes at 18 to 26 months follow-up in preterm infants The effects of oral feeding methods in preterm infants on transition to direct-breastfeeding and discharge time: a retrospective cohort design Cup feeding: an alternative method of infant feeding Effect of cup feeding and bottle feeding on breastfeeding in late preterm infants: a randomized controlled study A comparison of the safety of cupfeedings and bottlefeedings in premature infants whose mothers intend to breastfeed Effect of palady and cup feeding on premature neonates’ weight gain and reaching full oral feeding time interval Avaliação eletromiográfica dos músculos faciais durante o aleitamento natural e artificial de lactentes: identificação de diferenças entre aleitamento materno e aleitamento com uso de mamadeira ou copo Percepção da equipe de enfermagem sobre métodos alternativos de alimentação para recém-nascidos em alojamento conjunto |
Answer the following medical question. | What does research say about Heart rate ranges in premature neonates using high resolution physiologic data.? | Compliance with ethical standards Conflict of interest Randall Moorman, MD, is the Chief Medical Officer of Advanced Medical Predictive Devices, Diagnostics, and Displays. All other authors declare that they have no conflict of interest. There are limited evidence-based published heart rate ranges for premature neonates. We determined heart rate ranges in premature neonates based on gestational and post-menstrual age. Retrospective observational study of premature neonates admitted to the neonatal intensive care unit at the University of Virginia between January 2009 and October 2015. We included gestational ages between 23 0/7 weeks and 34 6/7 weeks. We stratified data by gestational and post-menstrual age groups. Over two billion heart rate values in 1703 neonates were included in our study. We established percentile-based reference ranges based on gestational and post-menstrual age. Our results demonstrate a slight increase in the initial weeks after birth, followed by a gradual decline with age. The baseline heart rate is lower with advancing gestational age. Knowing heart rate reference ranges in the premature neonatal population can be helpful in the bedside assessment of the neonate. Heart rate ranges in premature neonates using high resolution physiologic data |
Answer the following medical question. | What does research say about Cerebral oxygen monitoring with near infrared spectroscopy: clinical application to neonates.? | Near infrared spectroscopy is a new noninvasive optical method for bedside monitoring of cerebral oxygenation. It uses differential absorbance of near infrared light to assess relative changes in the oxidation-reduction state of cytochrome aa3, as well as changes in the amounts of oxyhemoglobin, deoxyhemoglobin, and blood volume in the monitored field. Although this technique is applicable to all ages and sizes of patients and to multiple clinical settings, the majority of clinical studies to date have focused on the neonate. These studies have demonstrated its potential for advancing neonatal care and in understanding how diseases and therapies affect cerebral oxygenation. This paper reviews the near infrared spectroscopy technique and summarizes its potential applications in the field of neonatal intensive care. |
Answer the following medical question. | What does research say about Iron supplementation for infants in the NICU: What preparation, how much, and how long is optimal?? | Infants born preterm or with other perinatal risk factors are at added risk for both iron deficiency and overload. Insufficient iron supplementation in the perinatal period is associated with long-term neurodevelopmental effects. Based on this, iron supplements must be targeted to infants' individual iron needs to avoid the adverse effects of both iron deficiency and overload. Enteral iron supplements have been the gold standard in iron supplementation of neonates for many years. However, emerging parenteral formulations may provide an alternative for some infants, such as those who are unable to tolerate oral supplements or who are refractory to enteral supplementation. Optimal dosing and timing of supplementation is an area of ongoing research. In this review, we will summarize available enteral and parenteral iron formulations, review iron measurement parameters, and identify outstanding questions and ongoing research. |
Answer the following medical question. | What does research say about Determinants of neonatal mortality in Nigeria: evidence from the 2008 demographic and health survey.? | Nigeria continues to have one of the highest rates of neonatal deaths in Africa. This study aimed to identify risk factors associated with neonatal death in Nigeria using the 2008 Nigeria Demographic and Health Survey (NDHS). Neonatal deaths of all singleton live-born infants between 2003 and 2008 were extracted from the 2008 NDHS. The 2008 NDHS was a multi-stage cluster sample survey of 36,298 households. Of these households, survival information of 27,147 singleton live-borns was obtained, including 996 cases of neonatal mortality. The risk of death was adjusted for confounders relating to individual, household, and community level factors using Cox regression. Multivariable analyses indicated that a higher birth order of newborns with a short birth interval ≤ 2 years (hazard ratio [HR] = 2.19, confidence interval [CI]: 1.68–2.84) and newborns with a higher birth order with a longer birth interval > 2 years (HR = 1.36, CI: 1.05–1.78) were significantly associated with neonatal mortality. Other significant factors that affected neonatal deaths included neonates born to mothers younger than 20 years (HR = 4.07, CI: 2.83–5.86), neonates born to mothers residing in rural areas compared with urban residents (HR = 1.26, CI: 1.03–1.55), male neonates (HR = 1.30, CI: 1.12–1.53), mothers who perceived their neonate’s body size to be smaller than the average size (HR = 2.10, CI: 1.77–2.50), and mothers who delivered their neonates by caesarean section (HR = 2.80, CI: 1.84–4.25). Our study suggests that the Nigerian government needs to invest more in the healthcare system to ensure quality care for women and newborns. Community-based intervention is also required and should focus on child spacing, childbearing at a younger age, and poverty eradication programs, particularly in rural areas, to reduce avoidable neonatal deaths in Nigeria. Neonatal mortality is still a significant public health problem worldwide, and accounts for more than 60% of newborn deaths before their first birthday [ 1 ]. Of the world’s 7.7 million deaths in those aged younger than 5 years, 3.1 million occurred after birth through to 1 month of life (neonatal deaths) [ 2 ]. Nearly 99% of these neonatal deaths occur in low- and middle-income countries, mostly in sub-Saharan Africa, including Nigeria [ 3 ]. The majority of these deaths are caused by preventable or treatable diseases, such as infectious diseases, which contribute to approximately 36% of these deaths [ 3 ]. Previous studies have shown that the global decline in neonatal mortality rates has been slower compared with infant and under-5 years of age mortality rates, especially in the sub-Sahara African region [ 1 , 2 , 4 ]. Globally, Nigeria ranks second to India with the highest number of neonatal deaths, with the highest reported number in Africa [ 5 ]. Each year in Nigeria, more than a quarter million neonates die, which translates to approximately 700 neonates every day [ 5 ]. Neonatal mortality remains disturbingly high in Nigeria, despite the significant decline in most parts of the developing world, including some sub-Sahara African countries, such as Ghana and Uganda [ 6 ]. A recent United Nations (UN) report on childhood mortality reported that over the last 2 decades, the Nigerian neonatal mortality rate (NMR) dropped by only 20.4%, from 49 deaths per 1000 live births in 1990 to 39 in 2011 [ 5 ]. Similarly, evidence from the Nigeria Demographic and Health Survey (NDHS) also indicated a marginal decline of 4.8% (42 deaths per 1000 live births in 1990 to 40 in 2008) [ 7 ]. The 39 and 40 neonatal deaths per 1000 live births reported by the UN and NDHS, respectively, can be interpreted as approximately one in every 25 neonates born in Nigeria died in the first month of life. Previous studies on neonatal mortality in Nigeria have indicated that low birth weight, lack of antenatal care, maternal illness, mother’s age, prematurity, and birth asphyxia are linked with neonatal mortality, but these studies were all hospital-based case–control and experimental studies [ 8 - 11 ]. Limitations of these hospital-based case–control and experimental studies are that neonates delivered at home were not included and that control groups were not population based, and may not be generalizable to the wider Nigerian population. Evidence from the NDHS showed that home delivery in Nigeria remains high. An example of this situation is in the 1999 NDHS, where approximately 58% of neonates were delivered at home [ 12 ], and this number rose to 66% in the 2003 NDHS [ 13 ], and was 62% in the 2008 NDHS [ 7 ]. Importantly, neonatal mortality rates play an increasingly important role in childhood mortality, and there are currently no effective community based intervention programs in Nigeria specifically targeting neonatal mortality. The main goal of this study was to determine factors associated with neonatal mortality using the 2008 NDHS. Findings from the study would be useful to public health researchers and policy makers in reviewing and designing new community based intervention strategies aimed at reducing neonatal mortality in Nigeria. Therefore, this study presents population-based data on risk factors associated with neonatal mortality in Nigeria. This study was based on a public domain dataset that is freely available online. The data were collected for the NDHS 2008 [ 7 ]. The survey was conducted by the National Population Commission in conjunction with the ICF Macro, Calverton, MD, USA, in 36 states and the federal capital territory [ 7 ]. The 2008 NDHS was a stratified two-stage cluster design. Each state was stratified into two distinct groups of urban and rural areas. The census enumeration areas of the 2006 population census were used as the clusters for the 2008 NDHS. In the first stage, clusters were selected based on probability proportionate to the population size among its urban and rural areas. In each of the selected clusters, a complete listing of households was obtained. The listed households then served as the sampling frame for the selection of households to be interviewed in the second stage. Thereafter, a systematic sampling with equal probability was used in the second stage in selecting the specified number of households in each cluster for interview [ 7 ]. A structured questionnaire was used for interviewing the selected households for the 2008 NDHS. The questionnaires that were administered to the respondent household members were the household questionnaire, the women’s questionnaire, and the men’s questionnaire. These questionnaires consisted of a series of questions on population and health issues. The household questionnaire recorded all of the usual residents of the selected household and their characteristics, such as age, sex, education, and their relationship with the head of the household, as well as information on amenities and features of the household’s dwelling unit. Additionally, the survey collected data on height and weight measurements for children aged younger than 5 years, and women aged 15–49 years. The women’s questionnaire consists of information included, but not limited to, birth history, childhood mortality, fertility preferences, knowledge and use of family planning methods, antenatal care, delivery, postnatal care, vaccinations, and childhood illnesses, as well as malaria prevention and treatment. The 2008 NDHS men’s questionnaire was the same as the women’s questionnaire, but did not contain a detailed reproductive history, maternal and child health, or nutrition. However, notably, gestational age, intrapartum-related complications, and birth asphyxia, which could potentially improve neonatal data, were not collected in the 2008 NDHS. A total of 888 clusters were selected for the 2008 NDHS sample survey. Of these clusters, a total of 36,298 households were selected for interview in the 2008 NDHS. At the time of the survey, nearly 5% of the households were not occupied. However, more than 98% of the occupied households were successfully interviewed. A total of 34,596 eligible women aged between 15 and 49 years were interviewed, yielding a response rate of 96.5%. The analysis was restricted to all singleton live births for a 5-year period preceding the 2008 NDHS to reduce recall bias about birth and death dates reported by mothers. A conceptual framework of child survival in developed and developing countries has been developed by other authors [ 14 - 17 ]. However, the model by Moseley [ 15 ] is regarded as the most elaborate and systematic conceptual framework [ 18 ], and is frequently referenced in other studies on childhood mortality [ 19 ]. As a result, our study used the Moseley [ 15 ] conceptual framework as the basis for identifying important risk factors for neonatal mortality in Nigeria. The outcome variable for this study was neonatal death as reported by the mothers who participated in the survey, and it was defined as the death of a neonate between birth and 1 month of life. This takes a binary form, such that neonatal death will be regarded as a success (1 = if death occurs in the specified age period) or failure (0 = if the newborn is alive in the specified age period). The outcome variable was examined against all confounding variables, and these variables were classified into three distinct groups: community level factors, household factors, and individual level factors consisting of socioeconomic factors (Table 1 ). These variables were used in the study to identify risk factors associated with neonatal mortality. Based on the adapted conceptual framework, all of the confounding variables influencing neonatal mortality along with their categorisations are shown in Table 1 . Definition and categorisation of potential variables used in identifying risk factors associated with neonatal mortality There were two community level factors used, residence type and geopolitical zone, while the wealth index variable measured the economic status of the household. The wealth index variable was constructed using household facilities and assets, which were weighted, using a principal components analysis [ 20 ]. The range of assets considered were a television, radio, and fridge, and ownership of a car, bicycle, and motorcycle. Household facilities were also included, such as the source of drinking water, type of toilet, electricity, and type of building materials used in the place of dwelling. Among the individual factors, there were 14 variables of maternal and child characteristics (Table 1 ). In this analysis, two perinatal healthcare variables, antenatal care and postnatal care, were not included because nearly one third of the information was missing. Additionally, we did not include birth weight of neonates because almost half of the neonates were not weighed at the time of birth. However, perceived newborn size at birth by mothers (small or very small, and average or large) was used instead of birth weight because a previous study showed that there is a close relationship between mean birth weight and perceived newborn size by the mother [ 21 ]. The NMR was calculated by using a similar method described by Rutstien and Rojas [ 22 ]. The crude hazard ratios (HRs) for factors associated with neonatal death were determined by univariate analyses, which were performed using a Cox proportional hazards regression model. In addition, multivariable analysis was used to examine the association between the potential independent variables and the study outcome. Analyses were performed using STATA/MP version 12.0 (StataCorp, College Station, TX, USA). Cox proportional hazards models were fitted using STATA survey commands to adjust for the cluster sampling design, weights, and the calculation of standard errors. The multivariable analysis models conducted used a stepwise backwards elimination procedure to identify independent variables that were significantly associated with the study outcome. To avoid any statistical bias, we double checked our backward elimination method by using the following procedures: (1) we entered only potential risk factors with a p value < 0.20 obtained in the univariable analysis for backward elimination process, (2) we tested the backward elimination by including all of the variables (all potential risk factors), and (3) we tested and reported any collinearity in the final model. HRs and 95% confidence intervals (CIs) were calculated to assess the adjusted risk factors that affect study outcome, and those with p < 0.05 were retained in the final model. Table 2 shows the number of live births, the number of neonatal deaths and NMR by community, the household wealth index, and individual level factors. A weighted total of 27,147 singleton live births of children aged younger than 5 years occurred within the 5-year period preceding the 2008 NDHS, of which the total neonatal deaths over this period was 996 (Table 2 ). Neonates born to mothers residing in rural residences had a higher NMR than those living in urban residences (NMR: 38.9 vs 31.3). The NMR for neonates born to mothers in poor households was higher than that in mothers in middle-class households (NMR: 39.3 vs 35.6). Neonates whose mothers perceived them as small or a smaller size, had a greater NMR than those of average or larger size (NMR: 57.0 vs 30.0). The majority of live-born neonates were not weighed at birth, and more than half of the neonatal deaths occurred at home. Neonatal mortality rates (NMR) with 95% confidence interval (CI) *Interval for 30–39 years and 40–49 years were merged. NMR not calculated for missing values. Neonates delivered by caesarean section had a higher NMR than those born vaginally (NMR: 89.9 vs 35.8). The NMR for male neonates was higher than that for female neonates (NMR: 41.4 vs 31.7). Newborns born to mothers residing in rural areas had a higher risk of neonatal mortality than those who lived in urban areas (HR = 1.26, 95% CI: 1.03–1.55, p = 0.026). Compared with neonates born to mothers aged between 30 and 39 years, neonates born to younger mothers (<20 years) (HR = 4.07, 95% CI: 2.83–5.86, p < 0.001) reported a significantly higher risk of neonatal deaths. When the place of residence was replaced by household wealth index in the final model, neonates born to mothers in poor households had a high risk of neonatal death, although this was not statistically significant (HR = 1.24, 95% CI: 0.93–1.65). Male neonates were more likely (HR = 1.30, 95% CI: 1.12–1.53, p = 0.001) to die than female neonates in the first month of life. Neonates delivered by caesarean section had a significantly higher risk of neonatal mortality (HR = 2.80, 95% CI: 1.84–4.25, p <0.001) compared with non-caesarean delivery. Neonates whose birth size were perceived by their mothers as small or smaller were also more likely to die than those of average or larger-sized neonates (HR = 2.10, 95% CI: 1.77–2.50, p < 0.001). As shown in Table 3 , there was a significantly higher risk of neonatal death for fourth or higher birth order neonates with a short birth interval ≤ 2 years (HR = 2.19, 95% CI: 1.68–2.84, p < 0.001), second or third birth order neonates with a short birth interval ≤2 years (HR = 1.75, 95% CI: 1.31–2.34, p < 0.001), and fourth or higher birth order with a longer birth interval > 2 years (HR = 1.36, 95% CI: 1.05–1.78, p = 0.022) compared with second or third birth order neonates with a longer birth interval > 2 years. Adjusted and unadjusted hazard ratios (95% confidence interval [CI]) for variables associated with neonatal mortality ‴Caesarean section is a combination of both elective and emergency caesarean. *Interval for 30–39 years and 40–49 years were merged. ^ 2,465 missing information were not included in the analysis. HR, hazard ratio; P-values based on Cox regression. The overall aim of this study was to identify risk factors associated with neonatal mortality in Nigeria using a nationally representative sample. This study showed several factors that were significantly associated with neonatal mortality after adjusting for confounding factors, and each of these factors are discussed below. We found that the NMR for singleton live-born infants between 2003 and 2008 was 36.7 (95% CI: 34.4–39.0). However, a preliminary report from the 2013 NDHS indicated that the NMR slightly fell by approximately 8% from 40 deaths per 1000 live births in 2008 to 37 in 2013 [ 23 ]. Despite this decline, Nigeria still has a long way to go in achieving the Millennium Development Goal 4 target for the under-5 years of age mortality rate. Our study showed that male neonates had a significantly higher risk of dying during the neonatal period compared with female neonates. This finding is consistent with a cross-sectional study conducted in Indonesia in 2008, which indicated that male neonates were more likely to die than female neonates [ 19 ]. Additionally, a cross-sectional study performed in Bangladesh in 2009 reported a lower relative risk for female neonates compared with male neonates [ 24 ]. An increased risk of dying in the first month of life among male neonates may be attributed to high vulnerability to infectious disease [ 25 ]. Another possible reason for the low rate of neonatal deaths among girls may be because of the development of early fetal lung maturity in the first week of life [ 26 ], resulting in a lower incidence of respiratory diseases in female neonates compared with male neonates. Globally, it is estimated that approximately 23% of newborn deaths are attributed to respiratory problems [ 27 ]. In our study, mothers who perceived the size of their newborns to be small or very small had a 2.26 times greater risk of dying in the first month of life than those mothers who perceived their neonates to be of average or larger size. Similarly, findings from a cross-sectional study conducted in five Asian countries (India, Indonesia, Nepal, Bangladesh, and the Philippines) in 2008 also showed that smaller than average neonates had an increased risk of neonatal deaths than average or larger sized neonates in four of the five countries with data on perceived newborn size [ 28 ]. Even though our finding on perceived size of newborns were significant, we need to exercise caution in interpreting this result because the rationale mothers used in estimating the size of their neonates is unclear. However, this measure is not an unreasonable proxy for birth weight because a previous study showed a correlation between perception of birth weight and actual birth weight [ 21 ]. Our study showed that neonates delivered by caesarean section had a higher relative risk of neonatal mortality compared with vaginal deliveries. This result contradicts previous reports, which indicated a statistically insignificant relationship between the mode of delivery and neonatal mortality [ 29 ]. A similar study conducted in Swaziland reported a higher risk of death for neonates delivered by caesarean section than vaginal delivery, but this was not significant [ 30 ]. The significantly high risk of caesarean section observed in our study may be attributed to negative perceptions, such as misconception, fear, and aversion to caesarean section among mothers in Nigeria [ 31 , 32 ]. This could explain why pregnant mothers are presented to health facilities after experiencing labor at home or elsewhere, with life-threatening complications for emergency caesarean section [ 33 ]. This is also supported by a recent study on caesarean section and perinatal mortality in South Western, Nigeria, which found that nearly 84% of early neonatal deaths occurred in pregnant mothers who delivered their newborns by emergency caesarean section [ 34 ]. The current study observed that neonates born to mothers aged younger than 20 years had a significantly higher risk of mortality than those born to mothers aged 20–29 years, 30–39 years, and 40–49 years. This finding is similar to that reported in previous studies [ 35 , 36 ]. However, our analysis is not consistent with cross-sectional studies conducted in Swaziland and Tanzania, which found no significant relationship between maternal age and neonatal mortality [ 30 , 37 ]. This significantly higher rate of death in Nigeria could be related to inadequate use of maternal health services, physical immaturity, poor nutritional status, inexperience regarding child rearing among younger mothers, and poor maternal health outcomes, such as pregnancy complications. These factors are more common in younger mothers, and are all possible factors that could lead to higher adverse effects of neonatal and child health outcome in young motherhood [ 35 ]. We found that children of birth order (2 through 4 or higher) born with a shorter birth interval (≤2 years) were at higher risk of dying than those with a longer birth interval (>2 years). This finding is similar to a cross-sectional study carried out in India, which showed that neonates of fourth or higher birth order with a shorter birth interval of < 2 years have an increased risk of death compared with those of second and third birth order with a longer birth interval of > 2 years [ 38 ]. Maternal depletion syndrome could be attributed to this finding. Short-interval births could have adverse effects on the mother’s biological well-being and there could be economic resource competition between infants, especially in poor households, as well as inadequate care given to infants compared with high-ranked infants [ 39 ]. The current study showed that neonates born to mothers residing in rural areas had a higher risk of neonatal mortality compared with those living in urban areas. This finding is consistent with previous studies [ 40 , 41 ], which attributed this finding to limited access to health facilities and maternal healthcare services, such as delivery assisted by a healthcare professional, and prenatal and postnatal care. This disproportionally hinders rural dwellers from receiving adequate healthcare services, resulting in a high probability of neonatal death. In Nigeria, as in many developing countries, the majority of well-equipped hospitals and health centers are typically located in urban areas. However, neonatal jaundice and sepsis, as well as gestational age, which were previously found to be significantly associated with neonatal morality in most hospital-based studies [ 42 , 43 ], were not examined in our study. These variables could potentially be determinants of neonatal mortality in Nigeria. The strengths and weaknesses of this study need to be considered when drawing specific inferences. This study was a nationally representative survey, with a stratified two-stage cluster sampling design, which achieved a 98.3% response rate. Additionally, recall errors arising from dates of birth and death given by women interviewed in the survey were minimized by restricting our analyses to births within the 5-year period preceding the survey. Third, the proportion of missing data was relatively small, such that it may not have influenced findings in our study. Despite these strengths, a number of weaknesses were also present in the study and they are as follows. (1) Only surviving women were interviewed, which may have led to under-reporting of the number of newborn deaths because of the association of neonatal death with maternal death [ 22 ]. (2) Gestational age, which may be an important risk factor for neonatal mortality, was not examined in this study. (3) Other factors previously found to be associated with neonatal mortality, such as antenatal care, postnatal care, and birth weight at birth, were lacking in information in the 2008 NDHS. (4) The Demographic and Health Surveys are the largest source of national data, but they are expensive and time consuming, and in Nigeria, this survey is usually conducted once in every 5 years. (5) Causal effects could not be measured because the study was based on a retrospective cross-sectional study. A community-based interventional study on reducing neonatal death in Nigeria should be performed to focus on using verbal autopsy and birth weight. To reduce the recall period of using these instruments, a verbal autopsy should be undertaken before the culturally prescribed mourning period [ 44 ]. In addition, traditional birth attendants should be provided training or refresher training on delivery, how to recognise signs of pregnancy complications, and how to measure the newborn’s weight at birth because approximately 62% of mothers in Nigeria deliver their newborns at home [ 7 ]. Our analysis of factors associated with neonatal mortality in Nigeria revealed that living in rural areas, child bearing at a younger age, birth order and birth interval, sex of the newborn (being male), caesarean delivery, and mothers who perceive their newborns as smaller than average at birth significantly increased the risk of neonatal death. Our findings indicate the need to implement community based newborn care interventions particularly, educating community health workers and traditional birth attendants about safe delivery practice, the benefits of Kangaroo mother care method on low birth weight newborns, child spacing and promote delay of first pregnancy will contribute to the improvement of neonatal mortality statistics in Nigeria. The authors declare that they have no competing interests. OKE and KEA were involved in the conception and design of this study. OKE carried out the analysis and drafted the manuscript. KEA, MJD, JH, and ANP gave advice on interpretation and revised and edited the manuscript. All authors read and approved the final manuscript. The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2458/14/521/prepub This study is part of the first author’s thesis for a doctoral dissertation with the School of Science and Health at the University of Western Sydney, Australia. We are grateful to Measure DHS, ORC Macro, Calverton, MD, USA for providing the 2008 NDHS data for this analysis. Determinants of neonatal mortality in Nigeria: evidence from the 2008 demographic and health survey The state of the world’s children 2008 Neonatal, postneonatal, childhood, and under-5 mortality for 187 countries,1970–2010: a systematic analysis of progress towards millennium development goal 4 Neonatal survival 1: 4 million neonatal deaths: when? where? where? why? neonatal survival series paper 1 Two million intrapartum-related stillbirths and neonatal deaths: where, why, and what can be done? 3.6 millions neonatal deaths- what is progressing and what is not Neonatal mortality in an urban population in Ibadan, Nigeria Determinants of neonatal mortality at Wesley guild hospital, llesa, Nigeria Determinants of perinatal mortality in Nigeria A comparison of kangaroo mother care and conventional incubator care for thermal regulation of infants < 2000 g in Nigeria using continuous ambulatory temperature monitoring Poverty and infant mortality in the United States An analytical framework for the study of child survival in developing countries Causal pathways to infant mortality: linking social variables to Infant mortality through intermediate variables Socio-economic determinants of infant and child mortality in Sri Lanka: an analysis of post-war experience What explains rural–urban differentials in child mortality in Brazil? Determinants of neonatal mortality in Indonesia Estimating wealth effects without expenditure data – or tears: an application to educational enrolments in states of India Iron and folic acid supplements and reduced early neonatal deaths in Indonesia Factors influencing infant and child mortality: a case study of Rajshashi district, Bangladesh Causes of neonatal mortality in Spain (1975–98): influence of sex, rural–urban residence and age at death Factors affecting the sex differential neonatal mortality: the role of respiratory distress syndrome The global burden of disease: 2004 update Association between maternal, birth, and newborn characteristics and neonatal mortality in five Asian countries Some determinants of neonatal mortality in a ruralarea, EL-Minia governorate, Egypt, 2008 Factors influencing neonatal mortality: an analysis using the Swaziland demographic and health survey, 2007 Beliefs and perceptions of pregnant women at llesa about caesarean section Optimizing caesarean section rates in West Africa Pregnant Nigeria women’s view of caesarean section Caesarean section and perinatal mortality in South Western Nigeria What Is the association between maternal age and neonatal mortality? An analysis of the 2007 bangladesh demographic and health survey Maternal-perinatal morbidity and mortality associated with adolescent pregnancy in latin America: cross-sectional study Impact of place ofdelivery on neonatal mortality in rural tanzania Neonatal mortality in the empowered action group States of India: trends and determinants Effects of preceding birth intervals on neonatal, infant and under-five years mortality and nutritional status in developing countries: evidence from the demographic and health surveys Perinatal mortality in Nigeria: do place of delivery and delivery assistants matter Associations between social and environmental factors and perinatal mortality in Jamaica A 4 year review of neonatal outcome at the University of Benin teaching hospital, Benin city, Nigeria A study of neonatal deaths at the Ogun state university teaching hospital, Sagamu, Nigeria The WHO verbal autopsy standard 2012 |
Answer the following medical question. | What does research say about Effect of massage therapy on preterm neonate's body temperature.? | Low-cost care strategies can be implemented to avert the morbidity and mortality associated with hypothermia in preterm neonates. To determine the effect of massage therapy on body temperature of preterm neonates. A quasi-experimental design was conducted among 72 preterm neonates at a level II special care nursery in Western Kenya. Neonates were recruited on the third day of life and followed up for 10 days. Neonates in the intervention group were massaged three times a day for 15 minutes. Body temperature was monitored and recorded before, during and after each therapy session. Neonates in the control group received routine care: temperature monitoring three times a day, feeding and diaper change. Neonates who received massage had higher mean body temperature than the control group during therapy on day 6 (p = .019) and after therapy on day 6 (p = .017) and day 8 (p = .005). A comparison within massage group (before/during, during/after, before/after) showed an increase in mean body temperature during therapy compared to before therapy (p <.001) and after therapy compared to before therapy (p <.001). Massage therapy increases body temperature in preterm neonates. Preterm neonates' ability to regulate body temperature is compromised owing to their large body surface area in relation to weight and relative lack of subcutaneous fat. Furthermore, the lack of facilities (e.g. incubators) compounds the preterm neonates' risk for hypothermia and cold stress 1 – 3 . Hypothermia results in variety of physiologic stresses including; increased oxygen consumption, metabolic acidosis, hypoglycemia, decreased cardiac output, and increased peripheral vascular resistance 3 . In order to avert these negative consequences of hypothermia, use of incubators has become a routine practice in neonatal units. Availability of the incubators is, however, a challenge in low-and middle-income countries (LMICs) such as Kenya. Consequently, preterm neonates in LMICs are at higher risk for developing complications attendant with hypothermia such as poor feeding, apnea, and consequent morbidity and mortality 2 .To avert the deleterious consequences of hypothermia, nurses have adopted ingenious strategies such as kangaroo care 4 , 5 . Studies in high-income countries have shown that other care strategies such as massage therapy, a moderate pressure stroking of preterm neonates, have the potential to increase preterm neonates' body temperature 6 . Researchers 7 – 9 have attributed the increase in body temperature during massage therapy to a) therapists hands transferring heat to the neonate, b) facilitation of neurological temperature regulation by containment during message and c) increased blood circulation as a result of vasodilatation. It is, however, unclear whether similar effects of massage therapy on preterm neonates' body temperature would be witnessed in resource-limited settings such as Kenya. Therefore, this study aimed at determining the effect of massage therapy on body temperature of preterm neonates in an academic hospital in Kenya. A quasi-experimental study was carried out among 72 (36 each in massage and control Nursery (SCN) in an academic hospital in the western region of Kenya. Neonates were recruited into the study if they a) were on breast milk or formula feeds via gavage or cup and spoon, b) were born at 28 to 37 weeks gestational age and c) weighed ≥1000grams based on significant neonatal mortality rate in neonates born before 28 weeks gestation and/or weighing <1000grams in MTRH 10 . Preterm neonates who were critically ill, those on ventilation support (continuous positive airway pressure [CPAP] or mechanical ventilation) and those with neonatal infections such as severe sepsis or necrotizing enterocolitis were excluded. Consecutive sampling was used to recruit study participants. Neonates were recruited on day 3 of life to allow period for the researcher to explain to the mothers about the study. The first participant was recruited to the control group with the next neonate being recruited to the massage group. The recruitment continued in similar manner until the desired number for each group was attained. A study tool developed by the authors after thorough review of related literature was used to collect data on baseline characteristics including gestational age, birth weight and temperature at birth. Body temperature was also recorded before, during and after therapy in the massage group and thrice in 15 minutes for control group, all recordings were done three times a day for ten days. The study tool was reviewed for content validity by five pediatric nursing experts and suggestions made incorporated into the tool. Inter-rater reliability using two observers (research assistant and staff nurse at SCN) was done for temperature recording. Notably, there was no variation in temperature recording between the two observers. In all the neonates, the massage therapy was performed by first author (EM). To be effective and not to cause harm (e.g. injury to internal organs) the first author was trained on the procedure by a specialized pediatric nurse with more than 10 years experience doing massage therapy. The training focused on the correct procedure of doing the massage with the main focus being ensuring that moderate pressure is applied on the body surface in a manner to cause effect and not harm the neonate. The training was conducted in three sessions each lasting two hours. The first and second session were conducted in the skills laboratory while the third session was carried out in a hospital setting. The first session comprised review of massage procedure and watching the video clips. The second session was return demonstration on a dummy. The third session was practice on preterm neonates to achieve competency. The study intervention involved three massage sessions per day; morning (6 a.m.), afternoon (12 noon), and evening (6 p. m.) for 10 days starting day 3 of life. After thorough hand scrubbing, the researcher placed her warmed hands on the preterm neonate's body. Access ports were used for neonates in the incubator and the neonates in the cots were exposed only on areas being massaged. The rest of the body remained covered with blanket to prevent hypothermia. The massage therapy was given 1–2 hours after feeding to avoid discomfort and vomiting. A small amount of sunflower oil was used to prevent injurious friction between surfaces (providers' palms and neonate's skin) and was removed with cotton after the therapy. The therapy was temporarily stopped if the neonate started crying or passed urine or stool then continued when the neonate regained stability. The 15-minutes therapy included three standardized 5 minutes phases. The phases were as follows: Phase 1: Preterm neonates were placed in prone position. Moderate pressure (sufficient to produce slight skin indentation or slight skin color change from pink to white) was used to provide 12 strokes with palms of the hands, each stroke lasting 5 seconds. The strokes were provided in each area as follows: (a) head- from forehead hairline over scalp down to neck with alternate hands; (b) neck - from midline outwards with both hands simultaneously; (c) shoulders- from midline outwards with both hands simultaneously, and (d) back - from nape of neck down to buttocks, long stroke with alternate hands. Phase 2: The preterm neonates were placed in supine position. Twelve moderate pressure strokes with palms of the hands, 5 seconds each, were provided in each area as follows: (a) forehead - from midline, outwards with both hands simultaneously; (b) cheeks - from side of nose, with both hands simultaneously in rotating and clockwise direction; (c) chest -'butterfly'stroking from midline upwards, outwards, downwards and inwards back to initiating point; (d) abdomen - from right iliac fossae, in a clock wise direction around abdomen avoiding the epigastrium and probes, with gentle strokes; (e) upper limbs (each separately) - from shoulders to wrist using alternate hands for stroking; (f) lower limbs (each separately) - from hips to ankles using alternate hands for stroking; (g) palms - from wrist to finger tips using alternate hands for stroking; and (h) soles - from heel to toe tips using alternate hands for stroking. Phase 3: Joint stimulation was done for 5 minutes. The intervention comprised five passive flexion and extension movements of each large joint (shoulder, elbow, wrist, hip, knee, and ankle) for two seconds. The massage therapy protocol was adopted from Mathai 2001 11 a modification of Field et al. (1986) protocol for medically stable preterm neonates. Neonates in the control group received the usual care which included routine body temperature monitoring three times daily, feeding and diaper change. The body temperature reading of the neonates were recorded in degree Celsius to one decimal point before (baseline), during (after the 12 strokes), and after the massage using a temperature probe connected to a cardiorespiratory monitor (CODEC patient monitor CMS6000) attached to the chest. Neonates in the control group also had their temperature monitored for 15 minutes three times a day. The temperature probe was disinfected with spirit swab before and after each use to prevent infection. The RA's recorded the temperature reading from monitor to paper sheet (study tool), notably the RA's were not blinded to the allocation of the study participants since temperature recordings were done in the course of the intervention and thus, he/she could see what was being done on the neonate. Data were coded and enterd into Statistical Package for the Social Sciences (SPSS)version 20 database. Student t-test was used to (a) compare demographic characteristics between groups and (b) examine differences in body temperature between the groups. Paired t-test was employed to compare mean temperature within groups for before/during, during/after, and before/after. The study was registered under Clinical Trials.gov trial registration number NCT04287322 and approved by the Institutional Research & Ethics Committee (IREC) of the study hospital (approval number FAN: IREC 1573). Out of the 72 singleton preterm neonates who were recruited, only 60 (30 in each group) completed the study; 10 participants (6 in treatment group and 4 in control group) were discharged before the 12 th day of life while 2 neonates in the control group died before completing the study. Neonates in both groups had similar body temperature at birth but the massage group had a lower gestational age (p = .032). ( Table 1 ). Demographic Characteristics t: Student t-test significant at p ≤ 0.05 The lowest and highest mean body temperature was 35.2 and 36.5 respectively across the two groups. The mean temperature before therapy was higher in the control group than the massage group on days 4 (35.2±0.9 & 35.9±0.7; p = .002), 7 (35.9±0.5 & 36.4±36.4±0.9; p = 017), 8 (35.9±0.7 & 36.3±0.8; p = 0.035), 9 (35.7±0.6 & 36.2±0.7; p = .005), 10 (35.7±0.6 & 36.4±0.9; p = .003), 11 (35±0.7 & 36.4±0.7; p = .007), and 12 (35.9±0.6 & 36.4±0.6; p = .003). The massage group had a higher mean body temperature than the control group during therapy on day 6 only (36.3±0.7 & 35.8±0.9; p = .019) and after therapy on days 6 (36.3±0.7 & 35.8±0.9; p = .017) and 8 (36.3±0.7 & 35.8±0.9; p = .005). ( Table 2 ). Mean body temperature between groups findings Student t-test significant at p ≤ 0.05 Mean body temperature of the neonates did not differ within the control group; however, the temperatures were higher during than before therapy (p < .001) and after than before therapy (p < .001) in the massage group for the entire study period. ( Table 3 ). Mean body temperature within group findings Paired t-test significant at p ≤ 0.05 -NA-: Not Applicable To the best of our knowledge, this is the first study exploring the effects of massage therapy on preterm neonates' body temperature in a resource-limited setting. The study is of significance considering that majority of the preterm neonates in LMCs are nursed in cots. Notably the control group had significantly higher temperature than massage group on certain days, possibly due to their relative higher GA with more mature physiological function capable of thermoregulation. Although the mean body temperature was significantly higher in the control than in the massage group at the beginning of therapy, it became significantly higher in massage than in the control group during and after therapy. The mean body temperature remained constant in the control group during the 15-minutes observation period which is inconsistent with what has been reported elsewhere 6 . Similar to previous studies 6 , 12 , 13 , we noted a significant increase in mean body temperature during massage therapy that remained elevated after therapy. Diego et al. 6 found that preterm neonates' body temperature increased from baseline, reaching a peak during the massage and remained elevated during the post-massage period. Inconsistent with current study findings, Mathai et al. 11 didn't find a difference in temperature during massage therapy from the baseline recordings. Although the study has shed some light on the potential benefits of massage therapy on preterm neonates in low income settings, the findings should be interpreted with caution. Firstly, the sample size was relatively small thus limiting the clinical significance of the findings. Furthermore, the broad definition of preterm neonates (28–37 weeks GA) in this study makes it impossible to tell weather the findings would apply to both very preterm (28–32 weeks) and moderate-to-late preterm (32–37 weeks) neonates. Additionally, although the researcher and the RA's strived to maintain fidelity to the study, the fact that it was impossible to blind both to group allocation may have resulted in exaggerated rating of effects particularly with regard to body temperature reading for the intervention group. Massage therapy, a non-invasive, low-cost care strategy promotes body temperature regulation in preterm neonates that is maintained even after stimulation. Considering the dishearteningly high hypothermia-related neonatal morbidity and mortality particularly in preterm neonates in LMICs, there is need to (a) incorporate massage therapy as part of standard neonatal care and (b) train nurses and other health care providers on how to safely perform massage therapy on preterm neonates. Future studies should focus on effects of maternal massage therapy on preterm neonates' outcomes as a way of involving mothers in care of preterm neonates. We wish to thank Evelyne and Collet for their assistance with data collection. We are indebted to Mona Shawki for her assistance with statistical analysis. None declared. Effect of massage therapy on preterm neonate's body temperature Effect of body weight on temperature control and energy expenditure in preterm infants “Late-preterm” infants: a population at risk Heat loss prevention in neonates Wong's essentials of pediatric nursing Temperature increases in preterm infants during massage therapy Effects of pulse-synchronized massage with air cuffs on peripheral blood flow and autonomic nervous system Massage therapy research The effect of skin-toskin contact (kangaroo care) shortly after birth on the neurobehavioral responses of the term newborn: a randomized, controlled trial An assessment of the overall mortality of low birth weight neonates at the new birth units of the Moi Teaching and Referral hospital in Eldoret, Kenya Effects of tactile-kinesthetic stimulation in preterms-A contolled trial Effect of applying massage therapy on physical, physiological and behavioral states of premature neonates Comparative Effect of Massage Therapy versus Kangaroo Mother Care on Physiological Responses, Chest Expansion and Body Weight in Low Birthweight Preterm Infants |
Answer the following medical question. | What does research say about Intra-arterial blood pressure monitoring in the neonate.? | The advent of intra-arterial pressure monitoring has had a significant impact on the nursing care given in the neonatal intensive care unit. The nurse working in these units must become technically competent in monitoring techniques as well as clinically acute to physiologic measurements and their significance. These skills can be incorporated into planning and providing effective, individualized patient care. Continuous intra-arterial pressure monitoring is an invaluable clinical tool when caring for critically ill neonates. With care, an intra-arterial monitoring system can be easily prepared. This procedure requires minimal nursing time for care and maintenance and is a very safe procedure if appropriate nursing precautions are followed. |
Answer the following medical question. | What does research say about Can neonatal lung ultrasound monitor fluid clearance and predict the need of respiratory support?? | At birth, lung fluid is rapidly cleared to allow gas exchange. As pulmonary sonography discriminates between liquid and air content, we have used it to monitor extrauterine fluid clearance and respiratory adaptation in term and late preterm neonates. Ultrasound data were also related to the need for respiratory support. Consecutive infants at 60 to 120 minutes after birth underwent lung echography. Images were classified using a standardized protocol of adult emergency medicine with minor modifications. Neonates were assigned to type 1 (white lung image), type 2 (prevalence of comet-tail artifacts or B-lines) or type 3 profiles (prevalence of horizontal or A lines). Scans were repeated at 12, 24 and 36 hours. The primary endpoint was the number of infants admitted to the neonatal ICU (NICU) by attending staff who were unaware of the ultrasound. Mode of respiratory support was also recorded. A total of 154 infants were enrolled in the study. Fourteen neonates were assigned to the type 1, 46 to the type 2 and 94 to the type 3 profile. Within 36 hours there was a gradual shift from types 1 and 2 to type 3. All 14 type 1 and 4 type 2 neonates were admitted to the NICU. Sensitivity was 77.7%, specificity was 100%, positive predictive value was 100%, negative predictive value was 97%. Four type 1 infants were mechanically ventilated. In the late preterm and term neonate, the lung ultrasound scan follows a reproducible pattern that parallels the respiratory status and can be used as a predictor of respiratory support. The fetal lung is filled with fluid actively secreted by the pulmonary epithelium on a chloride ion gradient [ 1 ]. At birth, the fluid is rapidly cleared to allow post-natal gas exchange through epithelial sodium channels [ 2 ]. Impairment of this transition has been linked to neonatal respiratory distress (RD), particularly after cesarean section [ 3 ]. A similar mechanism has also been postulated for the increased rate of RD in late preterm newborns [ 4 ]. At present, there are no good techniques to follow the gradual passage to an air filled lung of a newly born infant and much relies on clinical and radiological signs. In an experimental animal model, Jambrik et al. found a close correlation between the dry/wet ratio in the minipig lung and the number of ultrasound lung comets also known as B-lines [ 5 ]. In adult medicine, lung ultrasound scan has been successfully used to monitor the reverse change, that is, from a dry to a wet lung [ 6 ]. This standardized, non-invasive technique can diagnose pulmonary edema with high sensitivity and specificity and no radiation exposure [ 7 ]. The present study explores the potential of ultrasound as a monitoring tool of fluid to air passage in the neonatal lung. Ultrasound data suggesting a deranged changeover are also correlated with the need for respiratory support. Our approach, then, differs from previous studies performed mostly on preterm babies looking at the sonographic diagnosis of specific causes of respiratory distress [ 8 - 10 ]. Normal lung tissue scanned with ultrasound yields the superficial image of the pleural line rhythmically moving (the lung sliding sign) and horizontal repetition artifacts known as 'A lines'. Fluid accumulation in the alveolar interstitial space generates 'B lines', that is, comet-like, vertical artifacts [ 11 ]. Lichtenstein and Meziere have standardized the study of the adult lung interstitial syndrome describing the prevalence of B lines when scanning the anterior and lateral chest wall. In their series, this 'B profile' with present lung sliding diagnosed pulmonary edema with 97% sensitivity and 95% specificity [ 7 ]. In the present study, we have modified the previous classification into three profiles: Type 1 - full hyperechoic image of the lung fields or 'white lung' (Figure 1A ); Type 2 - prevalence of B lines, lung sliding sign present (Figure 1B ); Type 3 - A lines predominance, lung sliding sign present (Figure 1C ). Neonatal lung ultrasound profiles . A ) Type 1- full hyperechoic image of the lung fields or 'white lung'; B ) Type 2- prevalence of B lines, that is, vertical, comet-tail artifacts; C ) Type 3- predominance of A lines, that is, horizontal repetitions of the pleural line. The investigation was carried out at the well baby nursery and neonatal ICU (NICU) of the University "Federico II" of Naples, the largest regional delivery center with 2,400 live births/year. The study was approved by the local ethics committee (AOU "Federico II") and parental consent was obtained. As a general policy, newly born babies were brought to the Nursery. Infants were admitted to the NICU if signs and symptoms of RD (nasal flaring, expiratory grunting, tachypnea, shallow breathing, and so on) were present beyond the normal observation time of four hours; it was the responsibility of the attending physician, who was unaware of infants being scanned, to set the indication for respiratory support. The purpose of the study was to evaluate the relative distribution of the three profiles and document the eventual transition from types 1 and 2 to type 3 with serial scans; to correlate the persistence of significant fluid as assessed by ultrasound with clinical outcome expressed as NICU admission rate, use of supplemental oxygen, nasal continuous positive airways pressure (N-CPAP) and mechanical ventilation. Clinical decisions were taken by a separate team of attending physicians, blinded to the study, operating according to the local NICU protocols. All live neonates with gestational age ≥34 weeks were included in the study: 112 (72.8%) full-term neonates (range 37 to 42 weeks) and 42 (27.2%) pre-term neonates (range 34 + 1 to 36 + 6 weeks); 120 (55%) had a birth weight greater than 2,500 grams, while 34 (22%) weighed less; 106 (68.8%) infants were delivered by cesarean-section while 48 (31.1%) were born vaginally; 107 (69.5%) babies were not given antenatal steroids whereas 40 (26%) received the treatment. Newborns with major congenital malformations and/or intrauterine growth retardation (IUGR) were excluded. Scans on the anterior and lateral chest walls of both lungs in supine infants were acquired in the Nursery by a single neonatologist (AS or FM) who then sent the acquired image to the Radiology Department in a separate building. The pediatric radiologist (GV) reviewed and classified the scans according to the study protocol. After completion of the study, concordance was assessed between the evaluation of the initial operator, who could not avoid observing the infant, and the pediatric radiologist who was fully masked to the infants' clinical conditions. Any clinical decision (NICU admission and type of treatment for respiratory distress) was taken by a third party physician, unaware of the present study. In our hospital, the Nursery and the NICU are separate environments attended by different medical staff. The infants were scanned in the absence of the physician in charge, taking extra care not to report the results of our investigation. A broadband linear transducer (mod L12-5, Philips, Eindhoven, the Netherlands) which encompasses the superior and inferior lung fields in the same image was used. All infants had the first scan performed no sooner than one hour and no later than two hours after birth. Scans were then repeated at 12, 24 and 36 hours. The study was conducted in a level III hospital with 2,400 total births per year. The population of term and late preterm infants was 2,200 with 11% admitted to the NICU for RD in 2010. We calculated that a cohort of 150 neonates would be representative of the population given a sampling error <5% with a confidence interval of 95%. When lung ultrasound images had been classified by the neonatologists and by the pediatric radiologist who was blind to the infants' clinical conditions, we investigated the accuracy of the sonographic profile with maximal echodensity (type 1 or white lung) to predict admission to the NICU for respiratory support. We defined true positive (TP) as type 1 and admitted to the NICU; true negative (TN) as type 2 or 3 and not admitted; false positive (FP) as type 1 and not admitted; false negative (FN) as type 2 or 3 and admitted. The specificity of the test was defined TN/(TN + FP); sensitivity was TP/(TP + FN); positive predictive value (PPV) was TP/(TP + FP); negative predictive value (NPV) was TN/(TN + FN). Kappa coefficient was calculated to assess the interobserver variability. One hundred fifty nine neonates were enrolled in the study. Two were excluded for congenital malformations (cystic adenomatous malformation and Tetralogy of Fallot) and three for IUGR. Population characteristics are described in Table 1 . Based on the initial ultrasound scan, 14 neonates were assigned to type 1, 46 to type 2 and 94 to type 3 profiles. Review by the pediatric radiologist gave a full interobserver concordance (kappa = 1). Characteristics of the 154 subjects at the time of enrollment. Sequential scans in Table 2 show a gradual shift from type 1 and 2 to type 3 that was almost complete at 36 hours. As reported in Table 3 , all 14 neonates initially classified as type 1 were admitted to the NICU (average age at admission: 5 hours) with a clinical diagnosis of RD (tachypnea, shallow breathing, grunting, nasal flaring). Among these, four infants with a 'ground glass' chest X-ray picture suggestive of hyaline membrane disease (HMD) received surfactant and were mechanically ventilated. The remaining ten neonates had an unremarkable chest X-ray and were supported with N-CPAP and supplemental oxygen. Lung ultrasound findings at sequential scans. Lung ultrasound findings and clinical treatment. nCPAP, nasal continuous positive airways pressure; NICU, neonatal ICU; SIMV: synchronized intermittent mandatory ventilation. The four infants in the type 2 group (8.7%) who were admitted to the NICU with clinical RD and unremarkable chest X-ray received support with N-CPAP and supplemental oxygen. No baby in the type 3 group needed NICU admission or additional respiratory support. Given the above pattern distribution, we calculated the performance of the Type 1 profile in predicting NICU admission: sensitivity was 77.7%, specificity was 100%, PPV was 100% and NPV was 97%. Likewise, we calculated the accuracy of the Type 1 profile in identifying the four HMD/RDS cases (sensitivity = 100%; specificity = 93%; PPV = 28%; NPV = 100%). The remaining 14 infants admitted to the NICU were affected by transient tachypnea of the neonate (TTN) and the accuracy of the Type 1 profile was as follows: sensitivity = 71.4%; specificity = 97.1%; PPV = 71.4%; NPV = 97.1%. This study shows that in the term and late preterm infant the early lung ultrasound profile can be classified in distinct patterns correlated to the lung fluid content. We document an evolution to the least hyperechogenic profile that is consistent with a clinically stable baby. We found no previous approach using serial ultrasound scans to examine the extra-uterine respiratory adaptation in this neonatal population. Most other studies were focused on the preterm baby lung. In an unmasked investigation of 32 preterm infants, Copetti et al. described a specific sign of TTN comparing a single sonographic scan with the corresponding chest X-ray [ 8 ]. Using the same approach, they also studied the ultrasound appearance of surfactant deficiency in a group of 40 infants with a mean gestational age of 27 weeks compared to 15 significantly larger and more mature controls (mean gestational age: 30 weeks) [ 9 ]. In the very preterm population, respiratory distress syndrome is associated with a sonographic white lung image that remains unmodified after surfactant replacement [ 12 ]. Studying less immature neonates, we focused our attention on the clinical outcomes in our series and the practical implications for the clinical neonatologist regardless of nosologic classifications. When compared with neonates at 39 to 40 weeks of gestation, the risk of respiratory failure almost triples at 37 weeks and increases more than tenfold at 34 weeks. Similarly, there is a significant increase in the risk of developing symptomatic TTN (adjusted odds ratio 6.1 at 36 and 14.7 at 34 weeks, respectively) or hyaline membrane disease (adjusted odds ratio 9.1 at 36 and 40.1 at 34 weeks, respectively) [ 13 ]. As the regional organization of deliveries is often based on a 'hub and spoke' model, the timely identification of those infants in need of moderate to advanced respiratory support is crucial. Our results can help in this task. Likewise, an early type 3 profile (identical to the previously described normal lung image) was always confirmed at 12 hours and never associated with RD; this is also of clinical significance to those clinicians operating in birth centers where additional support equipment is not readily available. We acknowledge some limitations of the present study. First, although an early allocation in the Type 1 group was effective in predicting the need for respiratory support, it did not discriminate between a milder and a more severe condition requiring mechanical ventilation. Second, the neonatologists acquiring the scans could not avoid observing the infant. This, however, was not critical in classifying the images, as assessed by the full agreement with the pediatric radiologist who was masked to the clinical conditions of the neonates. In the late preterm and term neonate, lung ultrasound scan follows a reproducible pattern that parallels the respiratory status and can be used as a predictor of the need for respiratory support. Health care givers working in a low technology setting can use lung ultrasound for early screening of neonates in need of respiratory support. • At birth, lung fluid content can be assessed non-invasively by ultrasound. • Over the first 36 hours, pulmonary adaptation can be monitored with serial ultrasound scans. • Lung ultrasound permits the early and reliable identification of those newborns who fail to adapt and show signs and symptoms of respiratory distress. • Health care givers working in a low technology setting can use lung ultrasound for an early screening of neonates in need of respiratory support. HMD: hyaline membrane disease; IUGR: intrauterine growth retardation; NICU: neonatal intensive care unit; N-CPAP: nasal continuous positive airways pressure; NPV: negative predictive value; PPV: positive predictive value; RD: respiratory distress; TTN: transient tachypnea of the neonate. The authors declare that they have no competing interests. FR conceived the study design and wrote the manuscript. FM and AS performed the ultrasound scans while GV reviewed them as a third, masked observer. AU and AR helped with data management and statistics. LC critically reviewed the manuscript. All authors read and approved the final manuscript. The authors thank Eduardo H. Bancalari, MD, for critically revising the manuscript. We are also indebted to Ardelio Galletti, PhD, for his assistance with the statistics and to Roberto Paludetto, MD, for his constant supervision of the NICU clinical activity while the study was ongoing. Can neonatal lung ultrasound monitor fluid clearance and predict the need of respiratory support? Clinical implication of lung fluid balance in the perinatal period Pulmonary fluid balance in the human newborn infant Respiratory distress syndrome in near term babies after C-section Health issues of the late preterm infant B-Lines quantify the lung water content: a lung ultrasound versus lung gravimetry study in acute lung injury Should lung ultrasonography be more widely used in the assessment of acute respiratory disease? Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol The 'double lung point': an ultrasound sign diagnostic of transient tachypnea of the newborn Lung ultrasound in respiratory distress syndrome: a useful tool for early diagnosis Lung ultrasonography of pulmonary complications in preterm infants with respiratory distress syndrome A-lines and B-lines: lung ultrasound as a bedside tool for predicting pulmonary artery occlusion pressure in the critically ill Surfactant administration for neonatal respiratory distress does not improve lung interstitial fluid clearance: echographic and experimental evidence Respiratory morbidity in late preterm births |
Answer the following medical question. | What does research say about Hand-touch method for detection of neonatal hypothermia in Nepal.? | Neonatal hypothermia is the fourth leading causes of neonatal death in Nepal. Thus, it is the caregivers' responsibility to identify the hypothermia by using valid and less time consuming method like hand-touch method. Therefore, we examined the diagnostic validity of hand-touch method against low-reading mercury (LRM) thermometer for detecting neonatal hypothermia. We assessed neonate's temperature first by hand-touch method, then by LRM thermometer and tympanic thermometer among 100 full-term neonates, delivered within 24 h in Maternity Ward of Tribhuvan University Teaching Hospital, Nepal. We used World Health Organization (1997) criteria for classification of neonatal hypothermia. The sensitivity and specificity of the hand-touch method for detection of neonatal hypothermia were 95.6% and 70.1% against LRM thermometer and 76.6% and 83% against the tympanic thermometer, respectively. Touching method is practical and therefore has a good diagnostic validity; it can be introduced in essential newborn care package after giving adequate training to caregivers. |
Answer the following medical question. | What does research say about Postexchange transfusion-related acute lung injury in a term neonate.? | We report a successful case where a newborn with transfusion-related acute lung injury following an exchange transfusion was effectively treated using conservative methods, eliminating the need for surfactant therapy. Very few instances of this complication have been documented globally. A low birth weight, small for gestational age, term neonate, diagnosed with hyperbilirubinaemia due to Rh incompatibility, experienced sudden respiratory distress in the form of severe retractions, tachypnoea and cyanosis 3 hours after the procedure. Neonate required mechanical ventilation on the grounds of mixed acidosis and diffuse alveolar infiltrates on the chest radiograph. The medical team suspected and treated the baby for transfusion-related acute lung injury through conservative measures. Transfusion-related acute lung injury, an acute life-threatening complication of blood component transfusion, can exhibit symptoms in neonates that are frequently misinterpreted as sepsis. The baby was discharged in good health after successful management after 19 days. |
Answer the following medical question. | What does research say about Cerebral near-infrared spectroscopy for early recognition of impending cardiac tamponade in a preterm neonate.? | Cardiac tamponade is a rare but life-threatening complication of umbilical venous catheter (UVC) placement in neonates. Mortality rates are high; therefore, early diagnosis is important. We present a case of a preterm infant with a UVC in situ who underwent a laparotomy on the first day of life for pneumoperitoneum secondary to meconium ileus. The operation was uneventful; however, 2 hours after surgery, the patient developed cardiac tamponade, requiring resuscitation and pericardiocentesis. In retrospect, near-infrared spectroscopy (NIRS) showed a gradual decline in cerebral oxygenation (crSO2) in the 30 min prior to the cardiac arrest, while other vital signs were within normal ranges. Our case demonstrates that cerebral NIRS monitoring can serve as an additional clinical marker for early recognition of impending cardiac tamponade. |
Answer the following medical question. | What does research say about [Role of evoked potentials in neonatal hypoxic-ischemic encephalopathy: review of the literature].? | Results of the studies on evoked potentials (EP) in neonates with hypoxic-ischaemic encephalopathy and their technical feasibility support extensive application in neonatal intensive care units. The combined application of visual evoked potentials (VEP) and somestesic evoked potentials (SEP) is the method of choice for neurodevelopmental prognostication in full-term neonate; especially useful in cases with moderate encephalopathy; in preterm neonates EP are complementary to head ultrasound scans, particularly early on when the findings are in the process of evolution. Brainstem auditory evoked potentials (BAEP) are the technique of choice for early identification of sensorineural hearing loss necessitating intervention. Long term prognosis on vision and audition is based on VEP and BAEP. Studies devoted to definition of the role of EP in selection of babies and monitoring neuroprotective intervention are warranted. |
Answer the following medical question. | What does research say about Neutral temperature range in incubators: performance of equipment in current use and new developments.? | Low-birth-weight neonates should be nursed at thermoneutrality inside incubators. Thermoneutrality control is essential to enhance body growth and to reduce neonatal illnesses and mortality. Guidelines have been published to provide the thermoneutral range, but the recommendations did not always take into account all ambient and physiological parameters influencing thermoneutrality. In most marketed incubators, the heat supply is controlled through convective air flow (closed incubators) or through radiant power density (radiant warmer beds). The heating unit (on/off cycling or adjustable proportional control) is activated by an error signal calculated from the difference between a controlled temperature and a reference value preset by the clinician. The controlled variable can be either the incubator air or the skin temperature of the anterior abdominal region of the neonate. The neonate's size, thermal properties of the mattress and of incubator walls, air temperature and humidity, air velocity, incubator wall temperatures all influence the heat exchanges between the neonate and the surroundings, and, consequently, modify the obtention of thermoneutrality. Moreover, studies of the physiological mechanisms by which the neonate regulates body heat storage suggest that metabolic rate, behavior, vigilance level, nursing care, and heater control processes should also be taken into account. Little attention has been paid to these factors, and incubator performances are often disappointing. This article reviews the different factors that modify thermoneutral condition. An attempt is made to suggest new ways to design equipment incorporating these factors in algorithms controlling heater processes in order to reach the optimal thermal environment in which the neonate should be nursed. |
Answer the following medical question. | What does research say about Off-label use of inhaled nitric oxide after release of NIH consensus statement.? | Inhaled nitric oxide (iNO) therapy is an off-label medication in infants <34 weeks' gestational age. In 2011, the National Institutes of Health released a statement discouraging routine iNO use in premature infants. The objective of this study was to describe utilization patterns of iNO in American NICUs in the years surrounding the release of the National Institutes of Health statement. We hypothesized that iNO prescription rates in premature infants have remained unchanged since 2011. The Pediatrix Medical Group Clinical Data Warehouse was queried for the years 2009-2013 to describe first exposure iNO use among all admitted neonates stratified by gestational age. Between 2009 and 2013, the rate of iNO utilization in 23- to 29-week neonates increased from 5.03% to 6.19%, a relative increase of 23% (confidence interval: 8%-40%; P = .003). Of all neonates who received iNO therapy in 2013, nearly half were <34 weeks' gestation, with these infants accounting for more than half of all first exposure iNO days each year of the study period. The rates of off-label iNO use in preterm infants continue to rise despite evidence revealing no clear benefit in this population. This pattern of iNO prescription is not benign and comes with economic consequences. |
Answer the following medical question. | What does research say about Hypoglycemia screening of asymptomatic newborns on the 2nd day of life.? | Neonatal hypoglycemia management in the first 48 hours is guided by the American Academy of Pediatrics (AAP) and Pediatric Endocrine Society (PES) recommendations. Our aim was to determine the incidence of hypoglycemia via point of care test (POCT) on the 2nd day of life (DOL) among healthy, asymptomatic neonates regardless of risk factors. In this prospective observational study, preprandial point of care glucose concentration was measured on the 2nd DOL in 150 healthy, asymptomatic neonates in the newborn nursery. We used 50 mg/dl (2.8 mmol/L) as the hypoglycemia threshold based on PES recommendations. The incidence of hypoglycemia on the second DOL was 10% among asymptomatic neonates (no risk factors = 8%; late preterm birth (LPT) + small for gestational age (SGA) = 16%; large for gestational age (LGA) + infant of diabetic mother (IDM) = 6%). SGA + LPT neonates accounted for the majority of the hypoglycemic cases (53.3%) and exhibited a trend towards the lowest glucose concentration (p = 0.09). The incidence of hypoglycemia on DOL 2 among asymptomatic neonates is high and of unclear significance in the absence of dedicated neurodevelopmental follow-up. |
Answer the following medical question. | What does research say about Immunomodulation, Part V: probiotics.? | The five-part "Pointers in Practical Pharmacology" immunomodulation series has presented some of the agents researchers are investigating in hopes of finding the means to effectively prevent and treat infectious processes in neonates. The phosphodiesterase inhibitor pentoxifylline appears promising, but large, randomized, clinical trials are still lacking. So far, there is no clear evidence to support the use of G-CSF for either the prevention or the treatment of sepsis. The results of a large, randomized, clinical trial of G-CSF in the United Kingdom are pending. Although intravenous immunoglobulin (IVIG) therapy does not appear to be useful in the prevention of sepsis, its effectiveness in the treatment of sepsis is uncertain. It is hoped that the results of the International Neonatal Immunotherapy Study will provide definitive answers regarding treatment of sepsis with IVIG. The "conditionally essential" amino acid glutamine administered either enterally or parenterally does not make a difference in the rate of systemic infection or NEC in very low birth weight infants. Finally, probiotics appear promising as documented by at least two of the three randomized, clinical trials described here. As the search continues for agents to enhance the neonate's immune system and prevent and treat infectious diseases, remember that our best prevention tool is excellent and consistent hand hygiene. |
Answer the following medical question. | What does research say about Decreased survival in necrotizing enterocolitis is significantly associated with neonatal and maternal blood group: the AB isoagglutinin hypothesis.? | To determine the effect of neonatal and maternal blood group on the mortality risk from necrotizing enterocolitis (NEC). Retrospective chart review of all neonates admitted to the neonatal intensive care unit over 24 years. Data on birth date, gestational age, maternal/neonatal blood group, number of transfusions, and survival time (defined as date of birth to date of death/discharge) were collected on those with NEC. 276 neonates with Bell stage II-III NEC were analyzed. AB neonates had a significantly higher risk of mortality from NEC compared with other blood groups (HR 2.87; 95% CI 1.40 to 5.89; P=0.003). Multivariate analysis showed AB blood group to be an independent risk factor for mortality from NEC. Neonatal and maternal blood groups are significantly associated with a neonate's survival from NEC. The increased mortality of AB neonates may be related to factors such as neonatal blood group antigens and/or transplacental transfer of isoagglutinins. |
Answer the following medical question. | What does research say about The importance of quiet in the home: Teaching noise awareness to parents before the infant is discharged from the NICU.? | Research over several decades describes various adverse health effects of noise on the hospitalized neonate. Noise is a direct cause of long-lasting auditory problems and a significant cause of cardiovascular and respiratory problems and neurologic impairment. Many hospitals have turned the NICU into a quiet environment that promotes the neonate's health and well-being. But auditory pathways continue to develop during the neonatal period, reaching maturation at 12 months and beyond. Some of this development thus occurs after the neonate is discharged from the hospital. It is a responsibility of NICU professionals to teach families about the health benefits of noise modulation and planned quiet in the home environment. This teaching may make a world of difference to the continued healthy growth, development, and well-being of the infant. |
Answer the following medical question. | What does research say about Resuscitation of the Small Baby: A Team Approach.? | Recent advancements in medicine have improved the survival of extremely low gestational age neonates, or small babies (22-27 weeks' gestation). Once inconceivable that an infant born as early as 22 weeks' gestation could survive, infants born at periviable gestational ages are now increasingly surviving to discharge from the NICU. Subsequently, clinical focus is pivoting toward practices that decrease morbidity in this extremely vulnerable population. This article aims to discuss obstetrical and neonatal practices during delivery to improve outcomes of the small baby and emphasize the importance of collaboration among all disciplines involved in the pregnancy, delivery, and postnatal care of the small baby. Effective communication and teamwork are cornerstones to improving outcomes in this patient population. |
Answer the following medical question. | What does research say about Neonatal sepsis: confronting the challenge.? | The challenge of neonatal sepsis is reviewed and updated, and the incidence and importance of microbial pathogens are addressed. Important maternal, neonatal, and environmental risk factors responsible for increasing the incidence of neonatal sepsis are reviewed. Underlying the neonate's susceptibility to sepsis is the markedly limited immunologic defense of the neonate. The neonate's humoral, cellular, and barrier defense limitations are analyzed with respect to how each alters host susceptibility. The clinical manifestations and progression of sepsis in the neonate are reviewed and the status of new therapeutic approaches is examined. Ways that nurses can assist in the prevention and limitation of disability from neonatal sepsis are provided. |
Answer the following medical question. | What does research say about Nursing management of the infant with a congenital malignancy.? | Care of the newborn diagnosed with a congenital malignancy is a challenge for the neonatal intensive-care unit nurse. Malignancies found in infants differ from those found in older children. Nursing care of the neonate suspected or diagnosed with congenital malignancy includes standard practices and problem identification as well as interventions unique to the patient with cancer. This article reviews the incidence, diagnosis, treatment, and nursing management of neoplasms diagnosed in neonates. |
Answer the following medical question. | What does research say about Use of ultrasound in the haemodynamic assessment of the sick neonate.? | Clinician performed ultrasound (CPU) by the clinician caring for a sick patient is increasingly used in critical care specialties. The real-time haemodynamic information obtained helps the clinician to understand underlying physiology, target treatment and refine clinical decision-making. Neonatologists are increasingly using ultrasound to assess sick neonates with a range of clinical presentations and demand for training and accreditation programmes is increasing. This review discusses the current expanded uses for CPU in the haemodynamic assessment of the sick neonate. |
Answer the following medical question. | What does research say about Difficult intubation in a neonate: a diagnostic dilemma.? | Competing interests: None declared. Difficult intubation in neonates has innumerable aetiologies. It especially poses a formidable challenge to save a newborn baby immediately after birth where antenatal details are unavailable. A late preterm neonate was born limp and apnoeic. Several attempts to intubate the baby were unsuccessful. Possibility of subglottic obstruction was considered. The baby died of severe perinatal asphyxia. Autopsy showed a mass around the airway which turned out to be ectopic thymus on histopathology. Ectopic thymus can present as periglottic mass without externally visible cervical swelling and can cause difficult intubation which may lead to serious adverse outcome including death if not anticipated early and managed accordingly. Difficult intubation in a neonate: a diagnostic dilemma |
Answer the following medical question. | What does research say about Pressure ulcers in the hospitalized neonate: rates and risk factors.? | Pressure ulcers (PU) are serious, reportable events causing pain, infection and prolonged hospitalization, particularly among critically ill patients. The literature on PUs in neonates is limited. The objective was to determine the etiology, severity and influence of gestational age on PUs among hospitalized infants. A two-year prospective study was conducted among 741 neonatal intensive care patients over 31,643 patient-days. Risk factors were determined by comparing the characteristics of infants who developed PUs with those who did not. There were 1.5 PUs per 1000 patient days with 1.0 PU per 1000 days in premature infants and 2.7 per 1000 days in term infants. The number of PUs associated with devices was nearly 80% overall and over 90% in premature infants. Infants with PUs had longer hospitalizations and weighed more than those who did not. Infants with device-related PUs were younger, of lower gestational age and developed the PU earlier than patients with PUs due to conventional pressure. The time to PU development was longer in prematurely born versus term infants. Hospitalized neonates are susceptible to device-related injury and the rate of stage II injury is high. Strategies for early detection and mitigation of device-related injury are essential to prevent PUs. Hospitalized neonates are at risk for pressure ulcers (PUs) due to immature skin, compromised perfusion, decreased mobility, altered neurological responsiveness, fluid retention, moisture, and medical devices 1 . Premature infants have an underdeveloped epidermal barrier with only a few cornified layers. The dermis is deficient in structural proteins and easily torn 2 . They are at risk for increased permeability to exogenous materials, additional skin damage, and infection 3 4 . Skin barrier formation is rapid once very premature infants are exposed to a dry environment 5 6 7 , although one month later it is not fully competent 8 . The timeline to full functional maturity in premature infants is currently not well defined, although it may be as long as 9 weeks postnatal age 5 8 9 10 and longer for complete acid mantle formation 11 . Pressure ulcers (PUs) can develop from the surface or from below, at the level of muscle and dermal tissue interaction and compression 12 13 . Unrelieved pressure can lead to tissue injury particularly when ischemia/reperfusion cycles are repeated. PUs are classified by the depth and severity of tissue injury. Stage I is non-blanchable erythematous skin that may be painful, soft, warmer or cooler than adjacent tissue. Stage II has partial dermal loss, e.g. shallow open ulcer or an intact blister. Stage III has dermal loss wherein subdermal elements are visualized. Stage IV ulcers are full thickness tissue loss with exposed bone, tendon or muscle. Unstageable ulcers are full thickness wounds covered by slough and/or eschar. Deep tissue injuries (DTI) have grossly intact skin with obvious underlying tissue injury related to pressure 14 . Stage III and IV PUs are serious reportable events, considered ‘never events' by several national benchmarking organizations. The incidence is higher in critically ill patients 15 with increased pain, infection rate and prolonged hospitalization 16 . Over 70% of adult PUs are “conventional” ulcers from pressure over bony prominences, e.g. sacrum, shoulder and heels 17 18 . Up to 34% are associated with medical devices, e.g., nasal cannulas, facemasks 19 20 . PUs are relatively well studied in adults. The emphasis on preventing serious harm has prompted evaluation in pediatric patients. The incidence in the intensive care setting ranges from 7.3% 21 to 26.7% 22 23 24 25 when all stages are included. Pediatric studies report prevalence between 1.6% 26 and 13.4% 27 and there is variability in how PUs due to devices are counted. The literature in premature and term neonates is sparse, due to an incomplete understanding of neonatal skin physiology 28 29 30 . Both conventional and device-related PUs have been reported 21 22 31 32 . The objective of this research was to determine the incidence and severity of PUs and the influence of gestational age among neonatal intensive care patients. We identified risk factors for pressure ulcer (PU) development by comparing the demographic characteristics of patients who developed PUs to those who did not. We classified the PUs by cause as (1) conventional caused by pressure over bony prominences or (2) device-related cause by pressure on the tissue due to a medical device, e.g., face mask, line hub, pulse oximeter probe. The prospective study was conducted at Cincinnati Children's Hospital Medical Center, a 598-bed free standing quaternary care academic facility. The 59-bed level III neonatal intensive care unit (NICU) treats premature and term infants who require surgery, have complex conditions or require specific diagnostic procedures. Patients were evaluated from September 2007 – October 2009. The Institutional Review Board of Cincinnati Children's Hospital Medical Center approved the study and waived the requirements to obtain written parental permission. The study was conducted in accordance with international and institutional guidelines for research involving human subjects, in accordance with the Declaration of Helsinki. Designated nursing staff (skin champions) examined all inpatients from head to toe at admission and during hospitalization on one day every two weeks. They received training on PU physiology, skin evaluation and data collection. The skin, including areas under devices, was examined for evidence of PUs. PUs that occurred between evaluations were included in the count for the next period. PU stage was verified by a certified wound ostomy and continence nurse using the National Pressure Ulcer Advisory Panel staging system within 24 hours of discovery 14 . If necessary, the stage was changed at this verification. The cause was classified as conventional pressure or device-related, i.e., the PU could be directly attributed to pressure from use of a device. New PUs occurring after admission 33 were counted and reported as rate, i.e., number per 1000 patient days, calculated from the length of stay summed for all evaluated NICU patients, as used by the Institute for Healthcare Improvement 34 . This method accounts for varying lengths of stay. PUs were evaluated at least every 12 hours after discovery, treated and followed until resolution. The characteristics of patients with and without PUs were compared using univariate general linear models (GLM) with significance levels of p < 0.05 (SPSS, IBM Corporation, Somers, NY, USA). Patients were stratified as premature (< 37 weeks of gestation) or term (≥ 37 weeks of gestation) based on weeks of gestation. Statistical comparisons for PU severity, cause and demographic features were made by group (premature, term) using GLM procedures. No other independent factors were included in the model. Group comparison of PU rates were made using z-test procedures (p < 0.05). A total of 741 unique neonates over 31,643 patient days were evaluated ( Table 1 ). Twenty-eight patients developed one or more PUs. Neonates with PUs were hospitalized for longer than infants without PUs (p < 0.05) but the groups did not differ for weeks of gestation or birth weight. There were 49 PUs among 28 unique patients for 1.5 PUs per 1000 patient days. There were 12.2% stage I PUs, 65.3% stage II and 22.4% combined stage III, unstageable and deep tissue injury. There were no stage IV ulcers. Thirty nine PUs were due to pressure from medical devices (79.6%) and ten (20.4%) were due to conventional pressure. Infants with device-related injuries were younger when PUs developed than patients with conventional PUs ( Table 2 ). Although the differences did not reach significance, infants with device PUs tended to develop them earlier, weigh less at the time of PU and have a lower birth weight than infants with conventional PUs. There were 428 unique premature infants over 21,218 patient days and 313 unique term infants over 10,425 patient days. Of the unique premature infants, 232 were < 33 weeks of gestation and 196 were ≥ 33 - < 37 weeks of gestation. Compared to premature infants without PUs, those with PUs had longer stays and were younger and weighed less at birth (p < 0.05) ( Table 1 ). In contrast, the term infants with PUs and without PUs did not differ for any characteristics ( Table 1 ). Fourteen premature infants developed one or more for a total of 21 PUs. Of these, 11 were < 33 weeks of gestation and three were ≥ 33 - < 37 weeks of gestation. Nine premature infants had one PU, three had 2 and two had 3 PUs during their hospitalizations. Fourteen term infants developed 28 PUs. Eight infants had one PU, two had 2, two had 3, one had 4 and one had 6 PUs. The 21 PUs over 21,218 premature patient days yielded a rate 1.0 PU per 1000 patient days. There were 28 PUs over 10,425 term patient for 2.7 PUs per 1000 patient days. The rate was lower for premature infants (p < 0.05). The distribution by PU severity was 14%, 72% and 14% for stages I, II, and III, respectively, for premature infants and 11%, 61% and 28% for stages I, II and III, respectively, for term infants. Devices accounted for 90.5% of the PUs in premature infants and 71.4% in term infants. Conventional pressure caused 9.5% of PUs in premature infants and 28.6% in term infants. The frequencies of stage III and conventional PUs were each higher in term infants (p < 0.05). Premature infants with PUs had significantly longer time to PU development and length of hospitalization than term infants (p < 0.05) ( Table 3 , Figure 1 ). As expected, the premature infants weighed less at birth than the term infants (p < 0.05) ( Table 3 ). However, the two groups did not differ for age or for weight at the time of PU development ( Table 3 ). Of the 14 premature infants, only six were < 37 weeks of age (adjusted) when the PUs occurred. The times to PU development for the individual premature (n = 14) and term (n = 14) are shown in Figure 1 . The medical diagnoses, causes and locations for the 14 premature and 14 term infants with PUs are listed in Table 4 . The diagnoses and clinical courses varied with respiratory or gastrointestinal diagnoses the majority in premature infants. Neurological diagnoses, e.g., hydrocephalus and hypoxic ischemic encephalopathy, and congenital diaphragmatic hernia were the majority in term infants. The latter reflects patients referred to our Fetal Care Center. Pulse oximeters, tracheostomies and face masks were among the specific devices. In this study of 741 hospitalized neonates we identified 1) a relatively low rate of 1.5 PUs per 1000 patient days, 2) a predominance (80%) due to medical devices, 3) a high rate of stage II injuries, 4) differential characteristics for infants with device versus pressure PUs, and 5) a lower rate for premature versus term infants. Infants with device-related PUs were younger, of lower gestational age and developed the PU earlier in their stay than patients with PUs due to conventional pressure. To our knowledge, this study is the first to examine the severity, potential causes, and the impact of gestational age on PUs in a large population of hospitalized neonates. The time from birth to PU development was more variable in premature infants than term infants ( Figure 1 ) but on average was significantly longer. A longer hospitalization could perhaps increase the potential for injury. However, devices such as tracheostomies were a consequence of prematurity with PU development later in the hospital stay ( Table 4 ). Mothers of infants diagnosed prenatally with congenital diaphragmatic hernia are managed to deliver close to term, so the diagnosis in premature infants is uncommon. The infants are medically complex, immobile and may be cannulated for extracorporeal membrane oxygenation (ECMO). Repositioning to prevent occipital PUs is challenging. The rate of 1.5 PUs per 1000 patient days was lower than at other institutions 35 . Among 81 infants over 1723 days in seven NICUs, the rate was 8% 36 . The infants were housed in incubators, in contrast to our study where all infants were included. The utilization of noninvasive ventilation (e.g., continuous positive airway pressure) was higher than in our NICU. Use of this intervention in neonates is increasing, a factor which may increase PU occurrence. Five of the 21 PUs in our premature patients occurred within the first seven days of hospitalization compared to 6 or 14 PUs in the multicenter NICU trial 36 . The ongoing patient assessments during our two year study focused staff attention on PUs, the importance of early detection and strategies to prevent them. We began daily head to toe skin assessments examined skin under medical devices every 12 hours and rotated sites of pulse oximeter placement. These factors may account for the overall low PU rate. Our high rates of device related PUs differs from pediatric intensive care settings where 50–62% of patients had PUs from devices 23 37 . The rate is also in contrast to the adults where up to 34% are from devices (e.g., nasal cannulas, facemasks) and over 60% are from conventional pressure. Nearly a third of premature infants of 29–30 weeks of gestation using nasal prongs or nasal masks for continuous positive airway pressure (CPAP) treatment experienced nasal skin compromise 38 . Among neonates using CPAP, 42.5% developed nasal PUs 39 . Consistent with our findings, the neonates with PUs were of lower gestational age and birth weight, had longer hospitalizations and used CPAP for longer periods than neonates who did not develop PUs. The high device rate in the present study may indicate a susceptibility to iatrogenic injury in the infant population, perhaps resulting from physiologic differences between adult and neonatal skin. Skin characteristics such as stratum corneum integrity, permeability, hydration, and fully formed dermal architecture vary substantially for months after birth in premature infants 2 11 28 30 40 41 42 . Our 65% frequency of stage II PUs is higher than in previous reports, e.g., 88% stage I from face-masks 39 . This is concerning, given a Minnesota state wide data analysis that device-related stage II ulcers advanced to more serious stage III and IV ulcers than conventional PUs 20 . The authors hypothesized that this progression was due to lack of adipose tissue to deflect pressure from devices in the affected regions. Patients with excess moisture were associated with more frequent and more severe ulcers (stage II) 43 . Stage II PUs may arise from device-related occlusion in combination with mechanical stress. The applied pressure results in periods of ischemia and epidermal damage 44 . This is exacerbated by cycles of ischemia-reperfusion with formation of cytotoxic free radicals, but damage occurs after a single cycle with only two hours of ischemia 45 . Occlusion via continuous contact with the skin blocks normal transepidermal water loss. Increased moisture over time can cause maceration, disruption of the lipid bilayer structure, and increased permeability to exogenous agents 46 47 48 . Increased moisture results in a higher coefficient of friction 29 49 , an effect that may enhance the effects of mechanical trauma 50 . Reduction of stage II device-associated ulcers will require identification of interventions to effectively mitigate the causes. Some specific features of the present study are noteworthy as they address potential limitations of the results. Multiple statistical comparisons were made on the dataset in an attempt to discern population differences, perhaps resulting in an artificially high alpha error. The findings should be considered as exploratory. The higher number of PUs due to ECMO cannulas is likely due to the higher use of ECMO in term versus premature infants. The occurrence of PUs in patients with congenital diaphragmatic hernia reflects their high acuity, complex medical course, and the large number of patients treated through our comprehensive Fetal Care Center. While length of stay is a PU risk factor, the high variability limits its predictive value. Further study is needed to better identify neonates predisposed to PUs. We did not investigate patient-related factors that influence PU development including presence/extent of traumatic injury, blood loss anemia, hypoperfusion, hypovolemia, presence of sepsis, edema, fluid retention, length of immobolization, and hypermetabolism 51 52 53 . Examination of these factors, alone and in combination with others, is warranted to better predict PU risk in pediatrics. None the less, premature infants are at risk for PUs during hospitalization. Early detection and interventions to protect underdeveloped skin from trauma are essential for preventing serious harm in this population. Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose. The authors declare no competing financial interests. Author Contributions M.V. and T.T. designed the research, interpreted the data and wrote the main manuscript. M.V. analyzed the data and prepared the tables. M.V. and T.T. reviewed the manuscript and approved it for submission. The time to PU development is shown for the 14 premature (A) and 14 term (B) infants with PUs. The time was significantly longer for premature infants (p < 0.05) and may be related to the longer hospitalizations, particularly in extremely young patients who develop complications over time. The shorter time in term infants may reflect the acuity of these particular patients. *omphalocele-extrophy-imperforate anus-spinal defects. *omphalocele-extrophy-imperforate anus-spinal defects. Pressure Ulcers in the Hospitalized Neonate: Rates and Risk Factors Skin integrity in critically ill and injured children Neonatal dermatology Development of the epidermis in the newborn The epidermal barrier Barrier properties of the newborn infant's skin Surface electrical capacitance as a noninvasive bedside measure of epidermal barrier maturation in the newborn infant Ambient humidity influences the rate of skin barrier maturation in extremely preterm infants Transepidermal water loss in infants born at 24 and 25 weeks of gestation Transepidermal water loss in 24 and 25 weeks gestational age infants Development of skin barrier function in premature infants Skin care in the NICU patient: effects of wipes versus cloth and water on stratum corneum integrity The etiology of pressure ulcers: skin deep or muscle bound? Role of ischemia and deformation in the onset of compression-induced deep tissue injury: MRI-based studies in a rat model National Pressure Ulcer Advisory Panel's updated pressure ulcer staging system Incidence and risk factors for pressure ulcers in the intensive care unit Pressure ulcers in intensive care patients: a review of risks and prevention Incidence of pressure ulcers in intensive care unit patients at risk according to the Waterlow scale and factors influencing the development of pressure ulcers The 2003 national pediatric pressure ulcer and skin breakdown prevalence survey: a multisite study Medical device related pressure ulcers in hospitalized patients Preventing device-related pressure ulcers: using data to guide statewide change Pressure sores in children--the acute hospital perspective Pressure ulcers in pediatric intensive care: incidence and associated factors Predicting pressure ulcer risk in pediatric patients: the Braden Q Scale Frequency of pressure ulcers in the paediatric population: a literature review and new empirical data Altered skin integrity in children admitted to a pediatric intensive care unit Skin integrity in hospitalized infants and children: a prevalence survey The prevalence of pressure ulcers in a tertiary care pediatric and adult hospital Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life Biomedical assessment and instrumental evaluation of healthy infant skin Changes in diapered and nondiapered infant skin over the first month of life Pressure sore risk assessment in children Prevention of Tracheostomy-related Pressure Ulcers in Children Preventing Pressure Ulcer in Hospitals: A Toolkit for Improving Quality of Care. Vol IHI Innovation Series white paper. Cambridge, Massachusetts: Institute for Healthcare Improvement; 2007 Pressure ulcers in neonates and children: an NPUAP white paper Incidence and risk factors of pressure ulcers in seven neonatal intensive care units in Japan: a multisite prospective cohort study Identifying the characteristics of children with pressure ulcers Incidence of nasal trauma associated with nasal prong versus nasal mask during continuous positive airway pressure treatment in very low birthweight infants: a randomised control study Nasal trauma due to continuous positive airway pressure in neonates Effect of chlorhexidine gluconate on the skin integrity at PICC line sites Update on the use of topical agents in neonates Neonatal skin maturation--vernix caseosa and free amino acids Subepidermal moisture is associated with early pressure ulcer damage in nursing home residents with dark skin tones: pilot findings The transport profile of cytokines in epidermal equivalents subjected to mechanical loading Ischemia-reperfusion injury-induced histological changes affecting early stage pressure ulcer development in a rat model Hydration Injury to Human Skin Acute irritant contact dermatitis: recovery time in man Effect of water on experimentally irritated human skin Friction coefficient of skin in real-time The effects of wearing diapers on skin Pressure sores in the acute trauma patient: incidence and causes Correlation of pressure sores and nutritional status Association between pressure sores and immobilization in the immediate post-injury period |
Answer the following medical question. | What does research say about The feasibility of a Swiss complex interprofessional intervention to improve the management of procedural pain in neonates in the Finnish context: A qualitative study.? | To evaluate the feasibility of the Swiss complex interprofessional intervention, NEODOL© (NEOnato DOLore), for improving the management of procedural pain in neonates in the Finnish context. Interprofessional collaboration is important for all professionals involved in the care of neonates and for neonates' parents, to understand the appropriate use of non-pharmacological and/or pharmacological methods for each pain situation and how to assess pain in real-life situations. Appropriate methods of pain relief for neonates should be preferred as they protect the development of the neonate's brain. A descriptive qualitative design. Data were collected through semi-structured focus group discussions following the Medical Research Council's framework for evaluation of complex interventions, in this case NEODOL© which aims to improve the procedural pain management of neonates. A purposive sample (n = 13) included eleven professionals representing various professions within Finnish Neonatal Intensive Care Units and two parents of infants who have received care in a Neonatal Intensive Care Unit. Data were analysed using inductive content analysis, and the results were reported in accordance with the COREQ guidelines. Professionals' and parents' evaluations suggest that NEODOL© is feasible, because it is consistent and addresses a current need. They assessed its overall content to be relevant and accessible, and its components to be internally coherent. However, they emphasise the need for further evaluation and refinement of the intervention to achieve the desired outcomes and cost-effectiveness. While NEODOL© is considered feasible, it requires further evaluation and refinement in the local context of each hospital before implementation. |
Answer the following medical question. | What does research say about Heated and humidified high flow therapy (HHHFT) in extreme and very preterm neonates with respiratory distress syndrome (RDS): a retrospective cohort from a tertiary care setting in Pakistan.? | To determine the role of heated humidified high flow therapy (HHHFT) as primary respiratory support in spontaneously breathing moderate-late, very and extreme preterm neonates with respiratory distress syndrome (RDS) at a tertiary care hospital from a developing country. Retrospective cohort study. Neonatal intensive care unit of Indus Hospital and Health Network, Karachi, Pakistan. All preterm neonates with RDS and who received HHHFT as primary respiratory support were included retrospectively, while neonates with orofacial anomalies, congenital heart and lung diseases other than RDS, abdominal wall defects, encephalopathy, congenital pneumonia and received continuous positive airway pressure or invasive ventilation were excluded. HHHFT as primary respiratory support for RDS. Effectiveness, duration, failure rate and complications of HHHFT as a primary respiratory support in moderate-late, very and extremely preterm neonates were evaluated. The cohort included 138 neonates during a period of 12 months. The median gestational age was 32 weeks, and the median birth weight was 1607 g. Grade 1–2 RDS was seen in 97%, surfactant instillation was done in 10.8% and HHHFT was provided in all the neonates as primary respiratory support. The total duration of HHHFT support was <1 week in 94% of neonates. Bronchopulmonary dysplasia and pneumothorax until discharge or death were observed in one neonate, haemodynamically significant Patent Ductus Artriosus (HsPDA) in two neonates and intraventricular haemorrhage Grade ≥2 in five neonates, while only one neonate died. This study appears to show that HHHFT is a simple, safe, efficient and cheap mode of primary respiratory support that can be given to spontaneously breathing moderate-late, very and extremely preterm neonates with RDS, especially in low- or middle-income countries. Continuous positive airway pressure and invasive ventilation are recommended as primary respiratory support in preterm neonates less than 32 weeks of gestation. The safety and effectiveness of heated humidified high flow therapy (HHHFT) as the first line of respiratory support are not well proven in preterm neonates <32 weeks. HHHFT appears to be effective as primary respiratory support in preterm infants in low-income and middle-income countries. Chances of failure with HHHFT as primary respiratory support are low. Complications of HHHFT are uncommon. HHHFT should be considered globally as primary respiratory support in babies with low grades of RDS, especially in low-resource settings. Early weaning from respiratory support can be regarded in babies once the respiratory status is stable. Preterm neonates often develop respiratory distress syndrome (RDS) due to a surfactant deficiency. 1 Incidence of RDS is inversely proportional to gestational age. It affects approximately 98% of neonates born at or before 24 weeks, while only a quarter of Very Low Birth Weight (VLBW) neonates develop RDS. 2 With advancement in the field of neonatology and usage of maternal antenatal steroids for fetal lung maturation, the incidence and severity of RDS have decreased by 34%. 3 Despite this, RDS remains a leading complication among preterm neonates. RDS presents early with difficulty in breathing, grunting and desaturation, which may lead to type 1 and type 2 respiratory failure and ultimately developing multiorgan dysfunction if not treated optimally and timely. 1 Treatment strategies for RDS include surfactant administration and respiratory support, including invasive and non-invasive ventilation. These respiratory support strategies have led to improved neonatal survival and outcomes. 4 Invasive ventilation may cause significant complications like atelectasis, pneumothorax and ventilator-associated pneumonia compared with non-invasive ventilation. There is an increasing trend to initiate non-invasive ventilation. 5 6 This is particularly true for low- and middle-income countries (LMIC) due to the limited resources and expertise for invasive ventilation. 7 Non-invasive ventilation means giving respiratory support through a face mask, nasal mask or nasal cannula. Non-invasive ventilation is further classified into continuous positive airway pressure (CPAP), synchronised and non-synchronised nasal intermittent positive pressure ventilation (NIPPV), nasal high-frequency oscillatory ventilation, bi-level positive airway pressure and heated humidified high flow therapy (HHHFT). 8 Non- invasive ventilation is reported as safe, efficacious, economical, user-friendly and reduces the duration required for respiratory support than invasive ventilation. Non-invasive ventilation also decreases the risk of complications associated with endotracheal intubation including bronchopulmonary dysplasia (BPD), sepsis and trauma to the upper airways. 9 The current European consensus guidelines also favour non-invasive ventilation over mechanical ventilation. 9 According to our literature search, CPAP is considered the most common initial respiratory support strategy and is considered the gold standard. 10 However, as the use of CPAP has a high chance of nasal trauma abdominal distention, and requires greater nursing skill (which are short in LMICs), alternative respiratory support strategies, including HHHFT, are gaining popularity. 11 In a recent meta-analysis, it was suggested to use HHHFT as the first line of therapy in preterm neonates with RDS in set-ups where CPAP and NIPPV were both available. 12 HHHFT was non-inferior to CPAP, with a lesser chance of trauma. 5 9 Despite better safety, tolerance and outcome, HHHFT has not been universally adopted. Through this paper, we would like to share the experience of a tertiary care hospital in Pakistan in managing preterm neonates with varying degrees of RDS using HHHFT as primary respiratory support in moderate-late and very preterm neonates. To determine the role of HHHFT as primary respiratory support in spontaneously breathing moderate-late,very preterm neonates with RDS. This retrospective cohort study was conducted to assess the experience of HHHFT and its outcome as the primary respiratory support in the management of moderate-late and very preterm neonates with RDS from June 2021 to June 2022 in the neonatal intensive care unit (NICU) at Sheikh Saeed Memorial Campus (SSMC) of the Indus Hospital and Health Network (IHHN), Karachi Pakistan. This tertiary care facility has 20 incubators and an intensive care facility admitting around 1500–1800 sick neonates annually. The facility has the resources to provide all respiratory support except nitric oxide and Extra corporeal membranous oxygenation (ECMO). To Strengthening the Reporting of Observational Studies in Epidemiology cohort reporting guidelines were followed in writing this manuscript. 13 This study was conducted at a tertiary care neonatal unit in a developing country. Two doses of antenatal corticosteroids (dexamethasone) are provided to all mothers expected to give birth before 37 weeks of gestation. We do not use early prophylactic CPAP or sustained lung inflation in the labour and delivery unit. We use prophylactic caffeine, with a loading dose of 20 mg/kg, followed by a maintenance dose of 5–10 mg/day as a single dose in babies less than 32 weeks gestation and or birth weight <1500 g. Surfactant provision is usually administered within the first 2 hours of life if the neonate has a fractional inspired oxygen (FiO 2 ) requirement >0.4. We use HHHFT as primary respiratory support in spontaneously breathing neonates with a flow rate of 6–8 litres per minute. At the time of birth, an assessment is done for breathing effort and difficulty. Preterm neonates with RDS breathing spontaneously are provided with non-invasive ventilation. CPAP is considered in spontaneously breathing neonates with RDS at the discretion of the attending neonatologist. Neonates who have significant distress or poor breathing efforts are started on conventional invasive ventilation with synchronised intermittent mandatory ventilation with pressure support with or without sedation (morphine/fentanyl), depending on the synchronisation. Surfactant is given to babies requiring >40% oxygen to maintain O 2 saturation >92% and respiratory acidosis (PCO 2 )>55 mg/dL (in capillary blood gas) on any respiratory support type. Weaning is started by considering the rate of breathing (PCO 2 ), pH and ventilator pressures by checking tidal volumes and FiO 2 and SpO 2 kept between 90% and 95%. Babies are weaned onto HHHFT or CPAP. All preterm neonates who were diagnosed with RDS and had HHHFT as primary respiratory support were included retrospectively, while neonates with orofacial anomalies, congenital heart and lung diseases other than RDS, abdominal wall defects, encephalopathy, congenital pneumonia and received CPAP or invasive ventilation were excluded. Data collection was performed from June 2021 to June 2022 on predesigned proforma by reviewing patient flow charts and data from the Health Management Information System of the hospital for biodata, maternal comorbid, perinatal details, APGAR score, initial respiratory condition, oxygen requirement, radiological grade of RDS, respiratory support details, duration, complications and outcomes using SPSS V.26. One hundred and thirty-eight neonates were included by non-probability consecutive sampling. There were 70 (50.7%) female babies, 98 (71%) babies were inborn (born at SSMC) and 83 (60%) were delivered by caesarean section. Maternal comorbidities, gestational age, birth weight stratification, 5-minute Agar score and some independent variables are given in table 1 . Descriptive statistics The RDS radiological grade based on chest X-ray is given in table 2 , while gestation-specific respiratory support and outcome are shown in table 3 . Respiratory distress syndrome radiological grading, respiratory support strategies and duration Gestation-specific respiratory support and its outcomes *HsPDA: Hemodyanamically significant patent ductus artriosus †IVH: Intraventricular Hemorrhage Our study was conducted to assess the outcome related to HHHFT in RDS in moderate-late an extremely preterm infants. Most neonates in this study had mild-to-moderate RDS; surfactant therapy was required in 10.8% of the cohort. HHHFT was the primary mode of support used in this study. Respiratory support duration was less than 7 days in the majority of neonates, and complications, including pneumothorax, pulmonary haemorrhage, lung collapse and intraventricular haemorrhage related to respiratory support and mortality were almost the same as compared with previous studies involving HHHFT. 14 High Flow Nasal cannula as Primary respiratory Support inthe treatment of Early Respiratory distress (HIPSTER) trial assessed the safety of high-flow therapy versus CPAP in preterm neonates with RDS; they reported significant treatment failure of 25.5% in the high-flow group versus 13.3% in the CPAP group. 15 However, in the secondary analysis of data from the high-flow therapy group, they observed that there were a few factors that increased the risk of failures, like gestational age of <30 weeks and high FiO 2 requirement. 16 A single-centre study was published from China that supported the use of HHHFT in mild-to-moderate RDS and was reported as safe and effective with equal chances of failure in comparison with CPAP. 17 BPD is one of the common pulmonary complications, affecting almost one-fourth of preterm neonates with RDS requiring respiratory support. 18 At the same time, in our population, it was observed that only 01 (1.2%) baby (<32 weeks) developed features of BPD during the hospital stay, and no infant >32 weeks developed signs and symptoms of BPD. Pneumothorax was estimated to occur in more than 5% of preterm neonates, according to a survey done from 1991 to 1999, 19 though, in our cohort, the incidence was only 1.44%. An explanation for the lower rates of complications in our study may be the short duration of respiratory support required, non-invasive ventilation and the low severity of RDS. 20 It is recognised that the duration of respiratory support requirement varies in neonates of different gestation and different severity of RDS 21 ; however, in our study cohort that included babies from 24 weeks and above, 94% required primary respiratory support for less than a week. Our study has some limitations. It was a single-centre, retrospective study with a small sample size. Due to the small sample size, related complications like BPD, Intraventricular Hemorrhage (IVH), air leak, haemodynamically significant Patent Ductus Artriosus (HsPDA) and Necrotizing Enterocollitis (NEC), relative risk could not be established. Also, our NICU is HHHFT-oriented, making our staff and doctors more comfortable and experienced with HFFFT than other non-invasive modalities. This study adds that HHHFT appears to be effective as the primary mode of respiratory support in moderate-late and extremely preterm infants in LMICs. This study shows that HHHFT appears to be safe and effective and can be used in moderate-late and very preterm neonates with RDS as primary respiratory support. It is suggested that more extensive prospective randomised controlled trials be done to validate our results, leading to new recommendations for using HHHFT as primary respiratory support for preterm neonates with lower grades of RDS in LMIC. Contributors: Conception of idea: SRA, VKK, IA. Literature search: IA, VKK, FH, KNH. Proposal development: VKK, IA. Data collection: AS, RZ, IA. Data cleaning and analysis: VKK, AS, RZ, IA. Manuscript drafting: VKK, JKD, KNH, SRA, FH, SN. Manuscript revision: VKK, KNH, FH, SR, JKD, SN, Guarantor: VKK. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Provenance and peer review: Not commissioned; externally peer reviewed. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable. Institutional Review Board (IRB) approval was granted with approval number IHHN_IRB_2021_11_005. Heated and humidified high flow therapy (HHHFT) in extreme and very preterm neonates with respiratory distress syndrome (RDS): a retrospective cohort from a tertiary care setting in Pakistan Neonatal respiratory distress syndrome Respiratory distress syndrome management in resource-limited settings—current evidence and opportunities in 2022 Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth Current methods of non-invasive ventilatory support for neonates High-flow nasal cannula versus continuous positive airway pressure in primary respiratory support for preterm infants: a systematic review and meta-analysis High flow nasal Cannula for respiratory support in preterm infants Pulmonary complications of mechanical ventilation in neonates High-frequency ventilation as a mode of noninvasive respiratory support European consensus guidelines on the management of respiratory distress syndrome: 2022 update Continuous positive airway pressure (CPAP) for apnoea of prematurity Nasal Mask’In comparison with ‘nasal prongs’ or ‘rotation of nasal mask with nasal prongs’ reduce the incidence of nasal injury in preterm neonates supported on nasal continuous positive airway pressure (nCPAP): a randomized controlled trial Systematic review of high-flow nasal cannula versus continuous positive airway pressure for primary support in preterm infants The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies Efficacy and complications of humidified high-flow nasal cannula versus nasal continuous positive airway pressure in neonates with respiratory distress syndrome after surfactant therapy Nasal high-flow therapy for primary respiratory support in preterm infants Refining the use of nasal high-flow therapy as primary respiratory support for preterm infants The effect of the treatment with heated humidified high-flow nasal cannula on neonatal respiratory distress syndrome in China: a single-center experience Epidemiology of bronchopulmonary dysplasia Trends in mortality and morbidity for very low birth weight infants, 1991–1999 Neonatal respiratory distress syndrome in karachi: some epidemiological considerations Current respiratory support practices in premature infants: an observational study |
Answer the following medical question. | What does research say about A systematic approach to neonatal pathophysiology: understanding respiratory distress syndrome.? | The vast amount of growing and changing literature and knowledge available today regarding the pathophysiology and care of the critically ill neonate can provide a confusing and overwhelming picture to the neonatal nurse. Coupled with advanced technology and new clinical research, the comprehension of neonatal pathophysiology requires an organized scheme to understand a newborn's response to illness. The concept analysis approach is one way to master learning and nursing care. Concept analysis is an eight-step process for investigating and organizing a neonate's response to illness, which is the basis for planning and managing nursing care. This article explains the approach and uses the common illness response of RDS to show how to utilize it. This ultimately provides an essential and meaningful plan of care for the neonatal nurse. |
Answer the following medical question. | What does research say about Cardiac Tamponade - a Cause of Sudden Death in a Premature Newborn.? | Cardiac tamponade is a potential complication in neonates with central venous catheters (CVC). Cardiac tamponade may be due to infection, a CVC related complication, or parental nutrition (PN) effusion. This is a preterm (30 weeks gestational age), very low birth weight male, admitted to the Neonatal Intensive Care Unit, requiring nasal continuous positive airway pressure. PN was provided via an umbilical venous catheter. An unexpected cardiac arrest occurred on the third day of life with an unsuccessful resuscitation. Autopsy revealed pericardial effusion composed of PN fluid with cardiac tamponade as the cause of death. Cardiac tamponade due to total PN effusion in the premature neonate may be fatal. The mechanism of the epicardial/pericardial effusion is not known. |
Answer the following medical question. | What does research say about Clinical Validation of a Wearable Respiratory Rate Device for Neonatal Monitoring.? | Respiratory rate monitoring is of paramount importance in neonatal care. Manual counting of expansions and contractions of the abdomen or diaphragm of the neonate is still the widely accepted measure of respiratory rate in most clinical settings. A practical, affordable, easy-to-use technology to continuously measure respiratory rate in neonates is essential to recognize the signs and symptoms of respiratory disorders. Clinical validation of a system for continuous and long term respiratory rate monitoring of neonates, in a wearable form factor with the capability of remote monitoring is presented in this paper. The respiratory rate monitor was validated in clinical settings on 10 premature babies with various disease conditions and respiratory rates varying from 25 to 90 breaths per minute. Results show a high degree of correlation between the respiratory rate measured by the device and reference measurements. An intelligent algorithm which can remove motion corruption from the accelerometer data and provide reliable results is essential for large-scale adoption of the technology for both clinical as well as home monitoring. The technical details of implementation, results and analysis of the clinical study and observations made during clinical study regarding the feasibility of integrating the device in neonatal care are covered in this paper. |
Answer the following medical question. | What does research say about Implementierung eines neonatalen Schmerzassessmentinstruments auf einer neonatologischen Intensivstation - Ein Qualitätsentwicklungsprojekt.? | Implementation of a Neonatal Pain Assessment Instrument at a Neonatal Intensive Care Unit - A Quality Improvement Project |
Answer the following medical question. | What does research say about D or anti-D!!! Unblocking the dilemma of blocking-D phenomenon using acid elution.? | Maternal IgG antibodies directed against fetal red cells can cause hemolytic disease in fetus and newborn manifesting as anemia and jaundice. Sometimes, these antibodies are so strong that they encapsulate the antigens on neonatal red blood cells and result in erroneous laboratory findings when tested. A requisition for double volume exchange transfusion was received for a term,3.1 kg female baby with neonatal jaundice at day 2 of life, born to a multiparous woman. The neonate was typed as AB RhD negative and the mother as A Rh D negative. The maternal sample tested positive for Indirect antiglobulin testing showing presence of Anti-D with IgG titer of 128. The direct antiglobulin testing for baby was strongly (4 +) positive. The strong DAT result with negative RhD typing for the neonate indicated towards the Blocking-D phenomenon. We attempted to resolve the Blocked-D case using acid elution, which revealed the presence of D antigen on the eluted neonate's red cells. The report emphasizes the importance of appropriate blood typing for neonates to provide prompt adequate care as a team by the departments of Neonatology and Transfusion Medicine. |
Answer the following medical question. | What does research say about Elimination of public funding of prenatal care for undocumented immigrants in California: a cost/benefit analysis.? | We compared the perinatal outcomes and costs of undocumented women with and without prenatal care and inferred the impact of denial of prenatal benefits to undocumented immigrants in California. We retrospectively reviewed the delivery records of a cohort of 970 undocumented immigrants. The effects of prenatal care on low birth weight and prematurity were evaluated by means of logistic regression. The difference in the costs of postnatal care between neonates with and without prenatal care was compared with the cost of prenatal care. This ratio was extrapolated to calculate the net cost to the state. Long-term morbidity costs were also considered. Nearly 10% of undocumented women had no prenatal care. These women were nearly 4 times as likely to be delivered of low birth weight infants (relative risk, 3.8; 95% confidence interval, 2.03-7.05) and >7 times as likely to be delivered of premature infants (relative risk, 7.4; 95% confidence interval, 4.35-12.59) as were undocumented women who had prenatal care. The cost of postnatal care for a neonate without prenatal care was $2341 more initially and $3247 more when incremental long-term morbidity cost was added than that for a neonate with prenatal care. For every dollar cut from prenatal care we expect an increase of $3. 33 in the cost of postnatal care and $4.63 in incremental long-term cost. Elimination of publicly funded prenatal care for undocumented women could save the state $58 million in direct prenatal care costs but could cost taxpayers as much as $194 million more in postnatal care, resulting in a net cost of $136 million initially and $211 million in long-term costs. Elimination of public funding of prenatal care for undocumented immigrants in California could substantially increase low birth weight, prematurity, and postnatal costs. |
Answer the following medical question. | What does research say about Neurophysiological measures of nociceptive brain activity in the newborn infant--the next steps.? | Infants within neonatal intensive care units can receive multiple medically essential painful procedures per day. How they respond to these events, how best to alleviate the negative effects, and the long-term consequences for the infant are all significant questions that have yet to be fully answered. In recent years, several studies have examined cortical responses to noxious stimuli in the neonate through the use of near-infrared spectroscopy (NIRS) and electroencephalography (EEG). These investigations dispel any notion that the newborn infant does not process noxious stimuli at a cortical level and open the way for future research. In this Viewpoint Article, we review these studies and discuss key clinical challenges which may be elucidated with the use of these techniques. Simultaneously measuring the changes that are evoked in behaviour, physiology and the cortex following noxious events will provide the best approach to understanding the neonate's experience of pain. Pain is an emotional subjective response to a (potential or actual) tissue damaging procedure ( 1 ). As such, it is not possible to determine directly whether non-verbal patients are in pain, or whether they find certain stimuli more painful than others. This is a particular issue in the neonatal population where the nervous system is developing ( 2 ) and responses to nociceptive stimuli are known to differ from those observed in the adult ( 3 ). While scepticism towards the existence of infant pain, which dominated 20th century literature, is no longer a prevailing view, researchers and clinicians still struggle to measure pain effectively in infants ( 4 ). A large number of studies aim to quantify infants' responses to noxious procedures and aid clinicians in the treatment of pain [for reviews, see Ranger et al. ( 5 ) and Anand et al. ( 6 )]. In this Viewpoint Article, we will discuss the notion that human infant pain may be best understood by combining measures of neonatal brain activity with other well-characterised behavioural and physiological indicators of pain. This approach may provide the best composite measure of an infant's pain experience. In the past decade, several studies have used neurophysiological techniques to measure cortical responses to noxious stimuli. Studies using near-infrared spectroscopy (NIRS) have shown increases in haemoglobin concentration over central regions following acute noxious stimuli ( 7 , 8 ). Electroencephalography (EEG) recordings have demonstrated an increase in power in right frontal regions ( 9 ) and evoked responses over central regions ( 10 , 11 ). This evoked activity is noxious-specific in term infants ( 10 ), while non-specific delta brush activity is predominantly observed in response to both noxious and tactile stimulation before 35-weeks gestation ( 11 ). Cortical activation is a fundamental component of pain processing widely demonstrated in the adult literature ( 12 ). Thus, the observation that the youngest infants are able to manifest cortical responses to noxious stimuli is of clear importance and challenges any notion of the decorticate neonate, proposed by Sherman et al. in 1936 ( 13 ) and still common in the late 1960s ( 14 ). Additionally, as cortical processing is an important component of conscious awareness, it has been suggested that these observations give credence to consciousness in the newborn ( 15 ) and may reflect pain perception. However, to date, this work provides only the first steps in understanding how human neonates process noxious stimuli at a cortical level. The advantages and disadvantages of these techniques will be discussed in terms of their relevance to the study of neonatal pain and future directions are considered. Electroencephalography and NIRS are non-invasive techniques that can be used to monitor brain activity from short periods up to several days. Recordings can be carried out alongside clinical care with portable recording equipment, and for this reason, they are ideally suited to the environment of neonatal wards. Both techniques, however, require trained staff to conduct and interpret the recordings. Behavioural and physiological measures ( 5 ) are more easily and efficiently obtained and in this respect are advantageous to EEG and NIRS for clinical assessment of pain. So what can be gained in the clinical setting from neurophysiological studies? As with any complex process, our best understanding of infant pain can be achieved through the assessment and integration of multiple measures. However, as cortical processing is required for the perception of pain, recording cortical activity evoked by noxious events is perhaps the closest we can get to a physiological measure of pain. It is therefore beneficial that research studies are undertaken that aim to identify the physiological and behavioural measures that best correlate with nociceptive-specific changes in cortical brain activity. Indeed, while many studies have examined behavioural and physiological responses to noxious procedures, there is limited consensus within the literature as to the most appropriate measure (or measures) for quantifying neonatal pain ( 5 ). Measuring cortical activity concurrently with behavioural and physiological measures may help identify the best clinically practical measures of infant pain ( 16 ). Good agreement has been shown between premature infant pain profile (PIPP) scores, in particular facial expression, and cortical activity recorded using NIRS ( 17 ). However, it is important to note that some infants without a change in facial expression still demonstrated a localised change in haemoglobin concentration in the contralateral somatosensory cortex ( 17 ). This result highlights the advantages of analysing cortical activity compared with behavioural measures and the additional information that such analysis may yield. Correlations between evoked activity recorded using EEG and facial expression or other measures of behaviour have not been investigated [other than with sucrose administration ( 18 )]. We propose that future research studies should continue to examine behavioural indicators of pain – the way the infant interacts with their environment and communicates their experience with others is of clear importance – but that these measures should be combined with the analysis of nociceptive-specific brain and spinal cord activity (Fig. 1 ). While all these measures are necessarily surrogate indicators of pain, which by its nature is a subjective experience modulated by environmental and psychological factors ( 12 ), understanding the way that nociceptive inputs are processed at all levels of the nervous system and how this experience is manifest behaviourally will improve the treatment and understanding of infant pain. Thus, while it is neither feasible nor necessary to assess cortical or spinally mediated activity in all infants, we suggest that current research efforts should focus in this area to maximise the clinical potential that may come from these investigations. Methods for simultaneous recordings of neurophysiological, behavioural and physiological responses are described by Worley, Fabrizi and colleagues ( 19 , 20 ). Schematic of the range of recording measures [electroencephalography (EEG), near-infrared spectroscopy (NIRS), EMG, ECG, respiration, change in facial expression] that can be used to quantify nociceptive processing in the infant nervous system. Early-life pain may have long-term consequences on subsequent pain experience, with altered responses to nociceptive stimuli reported later in life ( 21 – 23 ). Relatively short-term alterations in nociceptive processing have also been identified using EEG: subjects born prematurely (who will have been subject to a number of medically essential noxious stimuli during the premature period) have an increased evoked response at term-corrected age compared with term-born controls ( 24 ). However, it is not known whether this change is related to the number of previous nociceptive events, or whether it is a direct consequence of receiving noxious procedures during a particular developmental period. Furthermore, children born very prematurely are more likely to have cognitive difficulties ( 25 ). It is plausible that these problems relate to abnormal exposure to stimuli in the ex utero environment at a critical phase of development. While this is speculative and the mechanisms that underlie these observations are not fully understood, there are some indications that pain experienced in early life may have adverse outcomes, such as poorer cognition or alterations in sensory processing. Indeed, neuroimaging techniques have begun to show evidence that corroborates this. Neonatal skin breaking ( 26 ) and stressful ( 27 ) procedures are associated with abnormal brain development within the neonatal period. Recently, Doesburg et al. ( 28 ) demonstrated a link between neonatal skin breaking procedures, functional brain activity and visual perceptual ability in school-age children born at extremely low gestational age. They found no association with older preterm and term-born children suggesting an early period of heightened vulnerability to neonatal pain-related stress. A key question is whether direct measurements of nociceptive brain activity in the neonatal period can improve our understanding of how these abnormal outcomes arise. Given the possible long-term consequences of neonatal pain, and the short-term distress associated with these procedures, it is important that we provide pain relief during noxious events. While studies have shown changes in behavioural and physiological measures in relation to pain management techniques, it is important to remember that these changes may not be correlated with the underlying nociceptive activity in the brain and spinal cord. Indeed, there was no difference in the cortical evoked response in a randomised controlled trial of neonates receiving oral sucrose compared with those who received sterile water ( 18 ). This was despite the usual reduction in facial expression scores ( 18 , 29 ) in the group who received sucrose. Methods of pain relief that result in a diminished behavioural response may imply that there is an altered experience of the noxious event; however, if the nociceptive input is still reaching the brain, then negative short-term effects and long-lasting consequences may still prevail. Indeed, Taddio and colleagues demonstrated that hyperalgesia caused by repeated blood tests performed in the first 2 days of life was not alleviated by the administration of sucrose ( 30 ). Conversely, if a particular analgesic is found to alter cortical activity but does not change the observed physiological or behavioural measures (compared with controls), then the reflexive and/or autonomic responses, which can have important health consequences for the infant, still need to be addressed. The sickest infants may be unable to mount a behavioural response to a painful procedure (due to medication, obstructive procedures such as ventilators or lack of energy). They may also have neurological complications leading to altered neuronal responses to noxious stimuli. In postasphyxic and very preterm infants, somatosensory evoked potentials have been shown to have prognostic value for neurological sequelae and future cerebral palsy ( 31 , 32 ). It has therefore been suggested that EEG and evoked potentials be used routinely as a clinical assessment tool in the neonatal period ( 32 ). However, neonates with specific pathologies have yet to be examined using neurophysiological techniques in relation to noxious processing. This is important for the treatment of these infants, who are likely to require the largest number of noxious procedures during their time in neonatal intensive care. The neurophysiological studies to date have in the most part focused on acute noxious stimuli (heel lances and venopuncture). However, a study conducted by Limperopoulos et al. ( 33 ) showed an increased haemodynamic response to a variety of clinically required procedures, with the greatest response during endotracheal tube repositioning and ‘complex caregiving events’. Due to the prolonged nature of some procedures, it is possible that they present more of a ‘risk’ to the developing infant brain than many of the acute procedures that have been most well studied. Future investigations examining longer clinical procedures would be of great benefit to our understanding of the cortical processing of noxious stimuli. Moreover, prolonged pain, for example, postoperative pain, also presents a problem on the neonatal ward. Future work should examine whether prolonged pain alters the response to acute noxious stimuli, as well as the neurological signatures associated with prolonged pain. EEG and NIRS provide objective quantitative approaches for investigating these questions. When combined with simultaneous recordings of behavioural and physiological measures, such research would lead to a better understanding of ongoing pain in neonates. Electroencephalography and NIRS provide a non-invasive ‘window into the brain’, of key importance for understanding the rapidly developing human infant nervous system. These techniques can be used to examine cortical activity in response to noxious stimuli, and we suggest that future research examining the processing of noxious stimuli in infants incorporate these measures in combination with physiological and behavioural indicators of pain. Simultaneous recordings of multiple measures will provide a more complete picture of the response to a procedure and how this response may be affected by analgesics. Future work should also investigate prolonged painful experiences, noxious processing in pathological states and the network of brain regions involved in processing noxious stimuli at different developmental stages. The studies conducted thus far provide a significant starting point in our understanding of cortical pain processing in the newborn infant. As quantitative measures of cortical activity are perhaps the closest we can get to understanding pain in non-verbal populations, these techniques have strong potential for future research. While it may be unfeasible to use these techniques directly within clinical protocols, the studies we have suggested here should lead to improved pain management strategies for newborn infants. The authors would like to thank Ravi Poorun for data collection (Neonatal Unit, John Radcliffe Hospital, Oxford) and production of Figure 1 . Neurophysiological measures of nociceptive brain activity in the newborn infant – the next steps Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain The development of nociceptive circuits The infancy of infant pain research: the experimental origins of infant pain denial Current controversies regarding pain assessment in neonates Pain activates cortical areas in the preterm newborn brain Cortical pain responses in human infants Sucrose attenuates a negative electroencephalographic response to an aversive stimulus for newborns Evoked potentials generated by noxious stimulation in the human infant brain A shift in sensory processing that enables the developing human brain to discriminate touch from pain The cerebral signature for pain perception and its modulation Infant behavior Pain relief in the pediatric patient Basic consciousness of the newborn Assessing pain in preterm infants in the neonatal intensive care unit: moving to a ‘brain-oriented’ approach How well do clinical pain assessment tools reflect pain in infants? Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial Multi-modal pain measurements in infants Electrophysiological measurements and analysis of nociception in human infants Effect of neonatal circumcision on pain response during subsequent routine vaccination Infant pain management: a developmental neurobiological approach Long-term alteration of pain sensitivity in school-aged children with early pain experiences Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants Neurodevelopmental outcomes of preterm infants Procedural pain and brain development in premature newborns Neonatal intensive care unit stress is associated with brain development in preterm infants Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age Sucrose for analgesia in newborn infants undergoing painful procedures Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants Prognostic significance of multimodality evoked response testing in high-risk newborns Neonatal SEP – back to bedside with basic science Cerebral hemodynamic changes during intensive care of preterm infants |
Answer the following medical question. | What does research say about Placental chorioangioma associated with polyhydramnios and hydrops fetalis.? | Competing interests: None declared. A 27-year-old multigravida woman was noted on routine growth scan at 27 weeks gestation to have a central placental hypoechoic area measuring 6.7×6.0×4.4 cm. A subsequent magnetic resonance scan confirmed a solid mass in the placenta lying anteriorly; therefore, a preliminary diagnosis of giant placental chorioangioma was made. A repeat ultrasound scan at 30 weeks gestation indicated that the mass had increased, with the presence of polyhydramnios. The patient experienced reduced fetal movements at 31 weeks gestation. There was persistent fetal tachycardia at 33 weeks gestation, and consequently the neonate was delivered by emergency caesarean section. The placenta revealed a large chorioangioma. The neonate’s birth weight was 2.85 kg and non-immune hydrops fetalis was diagnosed. The neonate improved significantly in the neonatal intensive care unit and is currently well with no medical problems. Placental chorioangioma associated with polyhydramnios and hydrops fetalis |
Answer the following medical question. | What does research say about Administration of breast milk cell fractions to neonates with birthweight equal to or less than 1800 g: a randomized controlled trial.? | Most premature and very low birthweight infants cannot tolerate breast milk feeding in the first few days of life and are deprived of its benefits. This study evaluates the clinical outcomes of administering breast milk cell fractions to neonates with a birthweight of ≤1800 g. We conducted a randomized controlled trial on 156 infants in the neonatal intensive care unit of Mahdieh Maternity Hospital in Tehran, Iran, from May 2019 to April 2020. All neonates with a birthweight ≤1800 g were enrolled and divided into intervention and control groups using stratified block randomization. Neonates in the intervention group received the extracted breast milk cell fractions (BMCFs) of their own mother’s milk after being centrifuged in the first 6 to 12 h after birth. The control group received routine care, and breastfeeding was started as soon as tolerated in both groups. Study outcomes were necrotizing enterocolitis (NEC), death, and in-hospital complications. We divided participants into two groups: 75 neonates in the intervention group and 81 neonates in the control group. The mean birthweight of neonates was 1390.1 ± 314.4 g, and 19 (12.2%) neonates deceased during their in-hospital stay. The incidence of NEC was similar in both groups. After adjustment for possible confounders in the multivariable model, receiving BMCFs were independently associated with lower in-hospital mortality (5 [26.3%] vs. 70 (51.1%]; odds ratio (OR): 0.24; 95% confidence interval [CI] 0.07, 0.86). Also, in a subgroup analysis of neonates with birthweight less than 1500 g, in-hospital mortality was significantly lower in the intervention group (4 [9.5%] vs. 13 [30.2%]; OR: 0.24; 95% CI 0.07, 0.82). There were no differences in major complications such as bronchopulmonary dysplasia and retinopathy of prematurity between the two groups. No adverse effects occurred. Our research demonstrated a significantly lower mortality rate in neonates (with a birthweight of ≤1800 g) who received breast milk cell fractions on the first day of life. Since this is a novel method with minimal intervention, we are looking forward to developing and evaluating this method in larger studies. IIranian Registry of Clinical Trials. Registered 25 May 2019, IRCT20190228042868N1 . Breast milk is the best source of nutrition for all babies, including premature infants. It plays a notable and sensitive role in improving the function of the immune system [ 1 ]. It contains lipids, proteins, carbohydrates, and bioactive molecules, such as vitamins, immunomodulatory factors, and several different types of mediators [ 2 , 3 ]. The immunological properties of breast milk differ during breastfeeding periods. Thus, breast milk’s nutritional content is compatible with neonatal requirements. According to recent studies, breast milk components can change in response to neonatal infection, and some proved that breast milk fractions might enhance the transepithelial absorption of extrinsic iron (non-milk iron) and its bioavailability [ 4 – 6 ]. Breast milk prevents diseases related to free oxygen radicals due to its potent antioxidant property; some examples are necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD) [ 7 – 9 ]. We cannot initiate feeding in some preterm (gestational age < 37 weeks) and very low birthweight (birthweight < 1500 g) babies in the first few days of life due to limitations like respiratory distress, poor sucking, swallowing, low gastrointestinal motility, and lack of digestive enzymes [ 10 – 12 ]. Despite the strong recommendation on early feeding and minimal enteral nutrition in the first days of life, it is postponed in some sick preterm neonates for several days or weeks after birth, and these infants are deprived of this optimum source of nutrition. We can reduce the outcomes of delayed-onset breastfeeding by starting early enteral feeding with a minimum tolerable amount of breast milk in preterm infants and reach full breast milk feeding earlier [ 10 , 11 ]. A study by Maffei et al. [ 13 ] investigated early oral colostrum administration in preterm neonates and infants who received the oral colostrum by syringe had significantly higher urinary secreted immunoglobulin A and lactoferrin comparing to application with a swab. Many studies have suggested early breastfeeding initiation (< 24 h) leads to a decrease in neonatal mortality [ 13 , 14 ]. However, there are few controlled trials about the early progressive feeding regarding preterm infants. Breast milk has different fractions after centrifugation at 4 °C; it consists of an upper-fat fraction, and the rest is skimmed milk, a combination of casein, whey, and cellular strains with numerous types of cells that precipitate [ 6 ]. Recent studies have discovered mesenchymal cells, including progenitor cells, stem cells, and myoepithelial cells, as well as different bioactive factors during the first 6 months of breastfeeding in widespread concentration ranges. Yet, we still do not know or understand the relationship between these bioactive factors, mesenchymal stem cell content, and their health implications. Some studies suggest an essential role in organogenesis, anti-viral protection, and not only short-term effects but also long-term benefits for these components in breast milk cell fractions [ 4 , 15 – 19 ]. In this trial, we separated the creamy layer from the expressed breast milk, and the neonates received cellular and immune fractions of breast milk during the first 6–12 h after birth, and compared them to other babies who received routine care in the ward. This randomized controlled trial was conducted at Mahdieh maternity Hospital affiliated with Shahid Beheshti University of Medical Sciences in Tehran, Iran, from May 2019 to April 2020. The inclusion criteria were all inborn neonates with a birthweight of ≤1800 g. The exclusion criteria were significant congenital anomalies, severe birth asphyxia (APGAR score < 3 at the first minute), other lethal diseases during the follow-up period (such as severe metabolic diseases, massive intracranial hemorrhage, etc.), and mothers with conditions that contraindicated breast milk feeding. The primary outcome was infants diagnosed with NEC during the hospital course, and we also followed up all infants who incurred death and in-hospital complications. All mothers were asked to express their breast milk within the first 6 hours after birth. A refrigerated centrifuge was used to separate the fresh expressed break milk components at a speed of 600 rounds per minute for 5 minutes at 4 °C temperature (Fig. 1 ). During the preparation procedure, after centrifuging 10–12 ml of breast milk in the refrigerated centrifuge “Universal 320 R Hettich Zentrifugen” a creamy layer starts to form on top of the sample tube while the cold helps it to stick together (Fig. 2 ). Then a large part of this material was removed using one or two sterile cotton swaps so the Pasteur pipette or insulin syringe (without needle) could easily reach the inside the tube. At that time, 0.1–0.2 ml of the lower semi-solid (watery) part and cream-colored strings at the bottom of the tube were dropped in the oral cavity of the neonates who participated in the intervention group during the first 6–12 h after birth. Hygiene protocols were considered in all steps of milk preparation. Both groups received all neonatal intensive care unit routine care, and breast milk initiation was based on the neonates’ general condition. Blinding was not possible due to the nature of the intervention. Nevertheless, the participants were unaware of the randomization list but not blinded to the study group. The potential risk of aspiration was considered as an adverse event for this intervention, while we did not record any adverse effects during this trial. Fig. 1 Refrigerated centrifuge“ Universal 320R Hettich Zentrifugen” Fig. 2 Centrifuged breast milk sample. A creamy layer on the top, followed by a watery phase with cream-colored strings at the bottom of the sample that contains most of the cells Refrigerated centrifuge“ Universal 320R Hettich Zentrifugen” Centrifuged breast milk sample. A creamy layer on the top, followed by a watery phase with cream-colored strings at the bottom of the sample that contains most of the cells Data were collected from hospital medical records. Demographics and clinical outcomes were recorded using a pre-prepared checklist. All participants were observed for infants diagnosed with NEC, BPD, ROP, early-onset sepsis (positive blood culture), hospital length of stay, and in-hospital mortality. NEC, BPD, and ROP were defined using Bell’s criteria, the National Institute of Health consensus definition, and international classification of retinopathy of prematurity consecutively [ 20 – 22 ]. The sample size was calculated to detect a 20% difference in NEC morbidity rate after using breast milk cell fractions, assuming an 11% NEC morbidity rate [ 23 ]. We used the sample size calculation for comparing proportions [ 24 ], considering a 5% alpha-type error rate and a statistical power of 80%. After correcting the 15% sample volume loss in each group, a sample size of 80 participants was needed for each group. Neonates were 1:1 randomly assigned to the case and control group using a computer-generated block randomization sequence of variable block-sized [ 25 ], stratified for birthweight of 1800 g. According to the stratified block randomization method, patients were divided into two equal groups: a) neonates with birthweight less than 1500 g and b) neonates with birthweight 1500–1800 g. \documentclass[12pt]{minimal}
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\begin{document}$$ N={\left({\mathrm{Z}}_{\upalpha /2}+{\mathrm{Z}}_{\upbeta}\right)}^2\ast \left({\mathrm{P}}_1\left(1-{\mathrm{P}}_1\right)+{\mathrm{P}}_2\left(1-{\mathrm{P}}_2\right)\right)/{\left({\mathrm{P}}_1-{\mathrm{P}}_2\right)}^2 $$\end{document} N = Z α / 2 + Z β 2 ∗ P 1 1 − P 1 + P 2 1 − P 2 / P 1 − P 2 2 Where for the sample size N, Z α/2 was the critical value of the normal distribution at α/2 (considering a 5% alpha-type error rate, the critical value is 1.96), Z β was the critical value of the normal distribution at β (considering a statistical power of 80%, the critical value is 0.84) and p 1 and p 2 were the expected sample proportions of the two groups [ 24 ]. Categorical variables were presented as numbers (percentage) and compared using chi-square and Fisher exact test. Numerical variables are reported as mean ± standard deviation, and the Kolmogorov-Smirnov test was used to evaluate the distribution. Means of numerical variables were compared using an independent group T-test if the data were normally distributed; otherwise, the Mann–Whitney U-test was used. We fitted binary logistic regression analysis to evaluate risk factors associated with in-hospital mortality. In this study, all numerical variables had non-normal distribution. Variables with P -value < 0.1 in the univariate model (including gestational age, birthweight, and 1-min APGAR score) were considered as possible confounders and entered the multivariable model. We employed a standard entry method to adjust these models for possible confounders. The Hosmer–Lemeshow’s test was used to evaluate the goodness of fit for logistic regression models. Data were analyzed using SPSS version 23, and P -value < 0.05 is considered statistically significant. Based on the study protocol, 170 neonates were eligible for enrollment into the study. We excluded eight neonates who did not meet the inclusion criteria, and six infants in the intervention group were excluded during the follow-up due to lack of cooperation. Eventually, 156 neonates with a birthweight of ≤1800 g entered the final analysis, including 75 neonates in the intervention group who received breast milk cell fractions (BMCFs) and 81 neonates who received routine care as the control group (Fig. 3 ). The birthweight mean was 1390.1 ± 314.4 g. Also, 69 (44%) infants were female, and mode of delivery births was normal vaginal delivery in 33 (21.2%). The incidence rate of NEC was 7.1% (11 out of 156), with an overall mortality rate of 12.2%. Fig. 3 CONSORT study flow chart CONSORT study flow chart The baseline characteristics, in-hospital outcomes, and neonatal complications between intervention and control groups are presented in (Table. 1 ). Demographics and baseline characteristics were similar between two groups except for higher C/S birth in the intervention group (65 [86.7%] vs. 58 [71.6%]; OR: 2.58; 95% CI 1.13, 5.87; P -value: 0.02). During this study, one infant fed only with infant formula milk, and 19 infants used formula milk as a supplement and then switched to breast milk feeding. The infant formula milk consumption during hospitalization was lower in the intervention group (6 [8.0%] vs. 14 [17.3%]; OR: 0.42; 95% CI 0.15, 1.15; P -value: 0.08), but the difference was not significant. No infant with formula milk consumption was deceased during the in-hospital course. There was a weak evidence for lower incidence of NEC (4 [5.3%] vs. 7 [8.8%]; OR: 0.59; 95% confidence interval [CI] 0.16, 2.09; P -value: 0.41) in the intervention group, but the difference was not significant. In-hospital mortality was significantly lower in the intervention group compared to the control group (5 [6.7%] vs. 14 [17.3%]; Odds ratio [OR]: 0.34; 95% CI 0.12, 1.00; P -value: 0.04). We observed weak evidence for less positive blood cultures (4 [5.4%] vs. 6 [7.6%]; OR: 0.69; 95% CI 0.19, 2.57; P -value: 0.58), and shorter intubation period (3.2 ± 7.1 days vs. 4.0 ± 6.6 days; Degree of freedom (Df): 152; P -value: 0.17) in neonates in the intervention group, but the difference was not significant. The in-hospital complications were similar in both groups. Infants in the control group who deceased were younger than those in the BMCFs group (12.9 ± 8.9 days vs. 21.4 ± 32.8 days; Df: 4.21; P -value: 0.60), but the difference was not significant. Table 1 Baseline characteristics and clinical outcomes in neonates who received BMCFs and the control group Characteristic* Total ( = 156) N Received BMCFs ( = 75) N Control ( = 81) N OR (95% CI)‡ Df ‡ P † Gestational age (week) 30.79 ± 2.47 31.00 ± 2.61 30.59 ± 2.34 151 0.18 Birthweight (grams) 1390.1 ± 314.4 1392.0 ± 325.6 1388.3 ± 305.7 154 0.85 Sex Female 69 (44.2%) 34 (45.3%) 35 (43.2%) 1.09 (0.58, 2.05) 0.79 Male 87 (55.8%) 41 (54.7%) 46 (56.8%) Delivery mode NVD 33 (21.2%) 10 (13.3%) 23 (28.4%) 2.58 (1.13, 5.87) 0.02 C-Section 123 (78.8%) 65 (86.7%) 58 (71.6%) 1-min Apgar 8.0 [6.0–8.0] 9.0 [8.0–10.0] 9.0 [8.0–9.0] 154 0.53 5-min Apgar 9.0 [8.0–9.75] 9.0 [8.0–10.0] 9.0 [8.0–9.0] 154 0.42 Gravidity 2.0 [1.0–3.0] 2.0 [1.0–3.0] 2.0 [1.0–3.0] 154 0.91 Parity 1.0 [1.0–2.0] 1.0 [1.0–2.0] 1.0 [1.0–2.0] 154 0.52 Use of infant formula Formula milk consumption 20 (12.8%) 6 (8.0%) 14 (17.3%) 0.42 (0.15, 1.15) 0.08 Formula milk consumption duration (day) 17.4 ± 12.7 14.8 ± 11.4 18.5 ± 13.4 18 0.57 In-hospital outcomes Hospital length of stay (day) 28.0 ± 22.9 29.8 ± 23.8 26.3 ± 21.9 154 0.48 Discharge weight (grams) 1694.6 ± 212.6 1679.1 ± 195.2 1710.8 ± 229.7 135 0.60 Mortality 19 (12.2%) 5 (6.7%) 14 (17.3%) 0.34 (0.12, 1.00) 0.04 Intubation period (day) 3.6 ± 6.9 3.2 ± 7.1 4.0 ± 6.6 152 0.17 NIV period (day) 8.1 ± 10.9 9.4 ± 11.9 6.9 ± 9.7 153 0.21 NEC 11 (7.1%) 4 (5.3%) 7 (8.8%) 0.59 (0.16, 2.09) 0.41 BPD 24 (15.4%) 14 (18.7%) 10 (12.3%) 1.63 (0.67, 3.93) 0.27 ROP 41 (26.3%) 21 (28.4%) 20 (24.7%) 1.21 (0.59, 2.47) 0.60 Positive blood culture 10 (6.4%) 4 (5.4%) 6 (7.6%) 0.69 (0.19, 2.57) 0.58 * Data are presented as mean ± standard deviation, number (%), or median [interquartile range] † Statistically significant P -values are bolded. Categorical variables were compared using the chi-square test and numerical variables were compared using the Mann–Whitney U-test ‡ Odds ratio (OR) and 95% confidence interval (95% CI) are presented for categorical variables, and the degree of freedom (df) is presented for numerical variables BMCFs breast milk cell fractions, BPD bronchopulmonary dysplasia, C-Section Cesarean section, DF degree of freedom, NEC necrotizing enterocolitis, NIV non-invasive ventilation, NVD normal vaginal delivery, OR odds ratio, ROP retinopathy of prematurity Baseline characteristics and clinical outcomes in neonates who received BMCFs and the control group * Data are presented as mean ± standard deviation, number (%), or median [interquartile range] † Statistically significant P -values are bolded. Categorical variables were compared using the chi-square test and numerical variables were compared using the Mann–Whitney U-test ‡ Odds ratio (OR) and 95% confidence interval (95% CI) are presented for categorical variables, and the degree of freedom (df) is presented for numerical variables BMCFs breast milk cell fractions, BPD bronchopulmonary dysplasia, C-Section Cesarean section, DF degree of freedom, NEC necrotizing enterocolitis, NIV non-invasive ventilation, NVD normal vaginal delivery, OR odds ratio, ROP retinopathy of prematurity In a subgroup analysis, we separately compared the in-hospital outcomes of both intervention and control groups in two categories: a) neonates with a birthweight of less than 1500 g and b) neonates with a birthweight of 1500–1800 g (Table 2 ). The incidence of NEC was similar between the intervention and control in both subgroups. About neonates with a birthweight < 1500 g, there was a significantly lower mortality rate in the intervention group compared to the control group (4 [9.5%] vs. 13 [30.2%]; OR: 0.24; 95% CI 0.07, 0.82; P -value: 0.02). However, in neonates with a 1500–1800 g birthweight, the mortality rate was similar between the two groups ( P -value: 0.92). In terms of in-hospital complications, there was no statistically significant difference between the two groups. Nevertheless, there was weak evidence for the lower incidence of less positive blood cultures and shorter intubation periods in the intervention group in both subgroups, which is in line with our prior results. Table 2 In-hospital outcomes according to the birthweight in neonates who received BMCFs and the control group In-hospital outcomes* Birthweight 1500-1800 g OR (95% CI)‡ DF‡ P † Birthweight < 1500 g OR (95% CI)‡ DF ‡ P † Received BMCFs ( = 33) N Control ( = 38) N Received BMCFs ( = 42) N Control ( = 43) N Hospital length of stay (day) 14.7 ± 7.1 18.3 ± 13.6 69 0.35 41.6 ± 25.7 33.4 ± 25.4 83 0.09 Discharge weight (grams) 1683.7 ± 113.6 1683.6 ± 166.5 67 0.38 1675.1 ± 245.4 1744.3 ± 289.1 66 0.15 Mortality 1 (3.0%) 1 (2.6%) 1.16 (0.07, 19.24) 0.92 4 (9.5%) 13 (30.2%) 0.24 (0.07, 0.82) 0.02 Intubation period (day) 1.2 ± 1.5 1.5 ± 2.8 67 0.82 4.7 ± 9.0 6.2 ± 8.2 83 0.07 NIV period (day) 3.5 ± 2.7 4.2 ± 4.0 69 0.64 14.1 ± 14.3 9.3 ± 12.4 82 0.06 NEC 1 (3.0%) 2 (5.3%) 0.56 (0.05, 6.50) 0.64 3 (7.1%) 5 (11.9%) 0.57 (0.13, 2.55) 0.46 BPD 0 2 (5.3%) – 0.18 14 (33.3%) 8 (18.6%) 2.19 (0.80, 5.95) 0.12 ROP 1 (3.0%) 3 (7.9%) 0.36 (0.04, 3.68) 0.37 20 (48.8%) 17(39.5%) 1.46 (0.61, 3.46) 0.39 Positive blood culture 1 (3.0%) 1 (2.7%) 1.12 (0.07, 18.73) 0.93 3 (7.3%) 5 (11.9%) 0.58 (0.13, 2.62) 0.48 * Data are presented as mean ± standard deviation, number (%) † Statistically significant P -values are bolded. Categorical variables were compared using the chi-square test and numerical variables were compared using the Mann–Whitney U-test ‡ Odds ratio (OR) and 95% confidence interval (95% CI) are presented for categorical variables, and the degree of freedom (DF) is presented for numerical variables BMCFs breast milk cell fractions, BPD bronchopulmonary dysplasia, DF degree of freedom, NEC necrotizing enterocolitis, NIV non-invasive ventilation, OR odds ratio, ROP retinopathy of prematurity In-hospital outcomes according to the birthweight in neonates who received BMCFs and the control group * Data are presented as mean ± standard deviation, number (%) † Statistically significant P -values are bolded. Categorical variables were compared using the chi-square test and numerical variables were compared using the Mann–Whitney U-test ‡ Odds ratio (OR) and 95% confidence interval (95% CI) are presented for categorical variables, and the degree of freedom (DF) is presented for numerical variables BMCFs breast milk cell fractions, BPD bronchopulmonary dysplasia, DF degree of freedom, NEC necrotizing enterocolitis, NIV non-invasive ventilation, OR odds ratio, ROP retinopathy of prematurity We used binary logistic regression analysis to evaluate the predisposing factors associated with NEC and in-hospital mortality (Table. 3 ). In univariate regression model, administration of BMCFs did not decrease the incidence of NEC (OR: 0.59; 95% CI 0.16, 2.09; P -value: 0.41). On the other hand, higher gestational age, higher birthweight, higher 1-min APGAR score, and receiving BMCFs were significantly associated with lower in-hospital mortality based on the univariate model. In multivariate model, after adjustment with these variables, only higher birthweight (OR:0.99; 95% CI 0.99, 1.00; P -value < 0.01) and receiving BMCFs (OR: 0.24; 95% CI 0.07, 0.86; P -value: 0.03) were independently associated with lower in-hospital mortality. Hosmer and Lemeshow’s test demonstrate that the model fits the data well ( P -value: 0.56). Table 3 In-hospital mortality logistic regression models Characteristic* Deceased ( = 19) N Survived ( = 137) N Univariate model Multivariate model ‡ OR (95% CI) † P OR (95% CI) † P Demographics Gestational age (week) 28.70 ± 2.62 31.08 ± 2.31 0.95 (0.92, 0.97) < 0.01 0.99 (0.95, 1.03) 0.59 Birthweight (grams) 1045.8 ± 269.9 1437.8 ± 290.1 0.99 (0.99, 1.00) < 0.01 0.99 (0.99, 1.00) < 0.01 Sex Female 11 (57.9%) 58 (42.3%) 1.87 (0.71, 4.95) 0.21 Male 8 (42.1%) 79 (57.7%) Delivery parameters Delivery mode NVD 5 (26.3%) 28 (20.4%) 0.72 (0.24, 2.17) 0.56 C-Section 14 (73.7%) 109 (79.6%) 1-min Apgar 7.0 [5.0–8.0] 8.0 [6.0–8.0] 0.73 (0.54, 0.98) 0.04 1.08 (0.71, 1.64) 0.72 5-min Apgar 9.0 [8.0–9.0] 9.0 [8.0–10.0] 0.68 (0.46, 1.02) 0.06 Gravidity 2.0 [1.0–3.0] 2.0 [1.0–3.0] 1.06 (0.74, 1.52) 0.75 Parity 2.0 [1.0–2.0] 1.0 [1.0–2.0] 1.16 (0.74, 1.80) 0.52 Intervention Received BMCFs 5 (26.3%) 70 (51.1%) 0.34 (0.12, 1.00) 0.05 0.24 (0.07, 0.86) 0.03 * Data are presented as mean ± standard deviation, number (%), or median [interquartile range] † Statistically significant P -values are bolded ‡ Multivariate binary logistic regression adjusted with gestational age, birthweight, 1-min APGAR, and received BMCFs (Hosmer and Lemeshow test P -value: 0.56) BMCFs breast milk cell fractions, C-Section Cesarean-section, NVD normal vaginal delivery, OR odds ratio In-hospital mortality logistic regression models * Data are presented as mean ± standard deviation, number (%), or median [interquartile range] † Statistically significant P -values are bolded ‡ Multivariate binary logistic regression adjusted with gestational age, birthweight, 1-min APGAR, and received BMCFs (Hosmer and Lemeshow test P -value: 0.56) BMCFs breast milk cell fractions, C-Section Cesarean-section, NVD normal vaginal delivery, OR odds ratio This randomized controlled trial has shown a significantly lower mortality rate in neonates with a birthweight of ≤1800 g who received BMCFs on the first day of life (OR: 0.24; 95% CI 0.07, 0.86) after adjustment with possible confounders. In subgroup analysis in neonates with a birthweight of < 1500 g, the mortality rate was more than three times lower in the BMCFs group (4 [9.5%] vs. 13 [30.2%]; OR: 0.24; 95% CI 0.07, 0.82). In addition, there was a trend for a lower incidence rate of NEC, less positive blood cultures, and shorter intubation periods in neonates in the intervention group. However, the difference was not significant in any major complications. Despite the increased survival rate of premature neonates in recent years, some complications are the most leading causes of death [ 26 ]. As one of the most severe complications in preterm infants, NEC has a mortality rate ranging from 15 to 30%, followed by an increased risk of low long-term growth and neurodevelopmental impairment in survived infants [ 27 ]. In recent decades, many discoveries have been made about breast milk cell fractions. Breast milk contains a myriad of cell types, including leukocytes, epithelial cells, stem cells, and probiotic bacteria [ 4 , 16 ]. In a study by Indumathi et al. [ 28 ], after identifying the cell surface markers in human breast milk, myoepithelial progenitors, immune cells, growth factors, and cell adhesion molecules were demonstrated the major constitutes of breast milk cell fractions. Some studies have presented mesenchymal stem cells as the most multipotent stem cells in breast milk [ 17 , 29 ]. These cells can potentially differentiate into chondrogenic, osteogenic, adipogenic cells and can differentiate into astrocytes and oligodendrocytes as well as neurons [ 17 – 19 ]. Our study demonstrated that early use of extracted BMCFs during the first 6–12 h after birth independently reduced the risk of in-hospital mortality in neonates with a birthweight of ≤1800 g (OR: 0.03; 95% CI 0.07, 0.86), while other major complications including NEC, BPD, and positive blood culture were similar between groups. In a study by Modi et al. [ 10 ], 131 neonates with a birthweight of 750–1250 g were evaluated for early enteral feeding. All-cause mortality was lower in infants with early aggressive feeding regimes than routine regimes (33.3% vs. 43.1%; P -value: 0.25), but there was no significant difference in mortality or major morbidities. They have found that neonates with early aggressive feeding regimes reached full enteral feeding 3 days earlier ( P -value < 0.01). In another study by Salas et al. [ 12 ], they investigated early feeding in 60 preterm infants (< 28 weeks). Early progressive feeding reduced the need for parenteral feeding, while in-hospital outcomes, including mortality or NEC, were similar between groups. These differences may be explained by; a) we exclusively used their own mothers’ breast milk rather than any formula. b) in this new method, precipitated BMCFs and 0.1–0.2 mm of lower semi-solid (watery) part and cellular strings were extracted and used. In comparison, other studies used the whole components of breast milk. c) different inclusion criteria regarding gestational age and birthweight can potentially affect these studies’ results. We found a lower hospital length of stay in the control group (26.3 ± 21.9 days vs. 29.8 ± 23.8 days) which can be explained by a higher mortality rate in this group. The discharge weight was higher in the control group compared to the intervention group (1710.8 ± 229.7 g vs. 1679.1 ± 195.2 g), which can be attributed to a higher rate of formula milk consumption (14 [17.3%] vs. 6 [8.0%]; OR: 0.42; 95% CI 0.15, 1.15) and duration (18.5 ± 13.4 days vs. 14.8 ± 11.4 days) during the hospitalization in the control group while gestational age, birthweight, and sex were similar between the two groups. We observed no association between infant formula consumption and in-hospital mortality since all deceased infants were only fed with their own mother’s breast milk during their hospital course. We would like to emphasize that our study has some limitations. First, the low sample size and lack of double-blinding may have influenced the study results. Second, the prescription of only a single dose of BMCFs in the intervention group is another limitation of this study. The repetitive use of BMCFs on the first days of life may change these research results, especially in infants who are not allowed to start enteral feeding due to an underlying disease. Third, lacking information regarding cause-specific deaths in each group is another limitation of this trial. Fourth, since it is a single-center study on the Iranian population, further multicenter studies on different ethnicities are needed. Nevertheless, according to our knowledge, this is the first randomized clinical trial that prescribes BMCFs to neonates with a birthweight of ≤1800 g. We hope this new method is followed by further researches with a larger sample size and repetitive use of BMCFs on very-low-birthweight infants. Our research demonstrated a significantly lower mortality rate in neonates with a birthweight of ≤1800 g who received breast milk cells on the first day of life. Since this is a novel method with minimal intervention, we are looking forward to developing and evaluating this method in larger studies with more frequent use of breast milk cell fractions. Breast milk cell fractions Bronchopulmonary dysplasia Cesarean section Necrotizing enterocolitis Retinopathy of prematurity Normal vaginal delivery Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We gratefully acknowledge the Neonatal Health Research Center of the Shahid Beheshti University of Medical Sciences for financially supporting this research. The authors appreciated the efforts and assistance of Mrs. Zahra Aziz khanee in implementing the project. We used Hettich refrigerated centrifuge “Model: Universal 320 R Hettich Zentrifugen; reference number: 1406; serial number: 0006459-09” (Fig. 1 ) to prepare the samples. Concept and design: MF, SMS, MK. Acquisition, analysis, or interpretation of data: SMS, NTT, MKS, SN, FP, SK. Statistical analysis: SK, MH, MK. Drafting of the manuscript: MF, SMS, SK, MK. Critical revision of the manuscript: MK, MF, NTT, SN, SK. Supervision: MK. All authors have read and approved the manuscript and are responsible for its content. Shahid Beheshti University of Medical Sciences supported this study. The funding source had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript, or submission decision. Data are available upon a reasonable request to the corresponding author. The study protocol was approved by the ethics committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.RETECH.REC.1397.1287) and the Iranian clinical trial ethical committee (IRCT20190228042868N1) on 25 May 2019. All participants were informed about the purpose of the study, the right to withdraw from the study at any stage without being penalized. Also, we obtained informed consent from all the parents who agreed to participate in the study. Not applicable. All authors declare that they have no competing interests. Administration of breast milk cell fractions to neonates with birthweight equal to or less than 1800 g: a randomized controlled trial Hormones in breast milk and effect on infants' growth: a systematic review Nutritional and physiologic significance of human milk proteins Long-term effects of breastfeeding on children's hospitalization for respiratory tract infections and diarrhea in early childhood in Japan Cells of human breast milk Maternal and infant infections stimulate a rapid leukocyte response in breastmilk Breast milk fractions solubilize Fe(III) and enhance iron flux across Caco-2 cells Evaluation of antioxidant capacity and aroma quality of breast milk Breast milk provides better antioxidant power than does formula Total antioxidant concentrations of breastmilk--an eye-opener to the negligent Early aggressive enteral feeding in neonates weighing 750-1250 grams: a randomized controlled trial Effects of early intervention on feeding behavior in preterm infants: a randomized controlled trial Early progressive feeding in extremely preterm infants: a randomized trial Early oral colostrum administration in preterm infants Early enteral feeding in preterm infants Distribution of bioactive factors in human milk samples At the dawn of a new discovery: the potential of breast milk stem cells Human breast milk is a rich source of multipotent mesenchymal stem cells Differentiation of human breast-milk stem cells to neural stem cells and neurons From breast milk to brains: the potential of stem cells in human milk Necrotizing enterocolitis in the premature infant: neonatal nursing assessment, disease pathogenesis, and clinical presentation Bronchopulmonary dysplasia: comparison between the two most used diagnostic criteria Neonatal outcomes of extremely preterm infants from the NICHD neonatal research network Blocked randomization with randomly selected block sizes Trends in premature mortality in the USA by sex, race, and ethnicity from 1999 to 2014: an analysis of death certificate data Prevalence and factors associated with anaemia among children aged 6 to 59 months in Namutumba district, Uganda: a cross- sectional study Exploring the stem cell and non-stem cell constituents of human breast milk Breast milk MSCs: an explanation of tissue growth and maturation of offspring |
Answer the following medical question. | What does research say about The neonatal piglet as a model for human neonatal carnitine metabolism.? | Investigations concerning carnitine metabolism and possible requirements for exogenous carnitine in human preterm neonates are limited by ethical considerations. The neonatal piglet is a potential animal model for these investigations. Tissue carnitine concentrations were determined in fetuses from cross-bred domestic gilts at stages of gestation corresponding to those of neonates found in neonatal intensive care units. Fetal piglet plasma and red blood cell carnitine levels decreased from approximately 90 d to term. Skeletal muscle carnitine increased from 60 d to term. Temporal changes in fetal carnitine concentrations in plasma, red blood cells and skeletal muscle throughout gestation are similar to the pattern reported by our laboratory for the human neonate. Cardiac muscle carnitine increased earlier than skeletal muscle but also continued to increase to term. Carnitine concentrations in fetal liver, kidney and intestine were maximal at 90 d and decreased until term. Similarities in physiology, metabolism and profiles of tissue carnitine concentration between the newborn piglet and the human neonate indicate that the neonatal piglet is an appropriate animal model for investigations concerning neonatal carnitine metabolism. |
Answer the following medical question. | What does research say about Self-reinforcement: Coping strategies of Iranian mothers with preterm neonate during maternal role attainment in NICU; A qualitative study.? | Having a preterm neonate in the neonatal intensive care unit (NICU) is one of the most stressful experience for parents. In facing these stressors, mothers need to find ways to adapt and control resources to maintain stability. The aim of this paper is to report coping strategies of mothers with preterm neonate during maternal role attainment in NICU. This paper reports a part of the findings of a grounded theory study that investigated how the mothers of preterm neonates go through maternal role attainment. The data were collected through in-depth semi-structured interviews with 12 mothers with preterm neonate admitted to the NICU and 5 nurses working in NICU. Data were analyzed according to Corbin and Strauss's (2015) approach using constant comparative analysis technique. Four themes, emerged from experiences of the participants, formed the concept of "Self-reinforcement" as the prominent strategy of mothers: "support seeking", "Spiritual getting in the mood", "Hope creation" and "Getting energy from the baby". These findings showed that mothers use strategies to calm and support themselves and their neonates, and recognize that their lives had changed and need to adjust to their new circumstances. |
Answer the following medical question. | What does research say about Discharge criteria for the term newborn.? | The birthing process represents a traumatic eviction from the warm, quiet womb with a constant supply of food to the cold, bright world with nothing to eat. Tremendous physiologic strains are suddenly placed on the newborn infant. In a time frame of a few days, the neonate must transition successfully to extrauterine life, and the family must be prepared for the care of their newborn at home. This article reviews the physiologic and social issues that face the newborn and mother, discusses the specific issues created by early discharge, and provides suggested criteria for the timing of discharge of the well term neonate. |
Answer the following medical question. | What does research say about Serum glial fibrillary acidic protein as a biomarker of brain injury in premature neonates.? | Neonatal brain injury (NBI) is a serious adverse outcome of prematurity. Early detection of high risk premature neonates to develop NBI is not currently feasible. The predictive value of many biomarkers has been tested, but none is used in clinical practice. The purpose of this study was to determine the levels and predictive value of serum glial fibrillary acidic protein (GFAP) in a prospective longitudinal case–control study during the first 3 days of life in premature neonates (<34 weeks of gestation) that later developed either intraventricular hemorrhage or periventricular leukomalacia. Each case (n=29) was matched according to birth weight and gestational age to one neonate with normal head ultrasound scans. No significant differences in GFAP levels were observed between the groups. Nevertheless, neonates with brain injury presented more frequently with GFAP levels above the lowest detection limit (0.056 ng/ml) and this trend was significantly different during all 3 days. Thus, the effectiveness of GFAP as an early biomarker of NBI in premature neonates seems to be limited. Preterm birth (<37 weeks of gestation) is a significant worldwide public health issue with an estimated global rate of 10.6% for the year 2014 with identified data points from 107 countries [ 1 ]. Consequences of prematurity are numerous, with the neonatal brain injury (NBI) being one of the most severe ones [ 2 ]. The underlying mechanisms of NBI involve an initial insult to the vulnerable fetal brain that is usually either hypoxic–ischemic, hemorrhagic, or infectious in nature. Intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and hypoxic-ischemic encephalopathy (HIE) are the most common subtypes of NBI, which can affect neonates born at any gestational age (GA). However, neonates born <32 weeks of gestation are more prone to IVH and PVL, while neonates born >35 weeks to HIE [ 3 ]. As a consequence, the initial injury activates a cascade of events leading to further brain damage which increases the risk for serious long-term neurodevelopmental impairment, including motor, cognitive, neurologic, and sensory disability [ 2 ]. Although noteworthy progress has been made in the management of preterm neonates, the rates of neonatal morbidity and adverse neurodevelopmental outcomes remain high, underlining the need for early, and individualized therapeutic intervention to prevent severe brain injury [ 3 ]. Despite the ongoing research, there is currently no available effective prognostic model used in clinical practice, which may provide early detection of neonates at high risk to develop NBI [ 3 , 4 ]. At present, the identification of high risk premature neonates is based mainly on general clinical characteristics such as birth weight <1500 g, GA <28 weeks and perinatal factors associated with brain injury, such as fetal growth restriction or chorioamnionitis [ 2 , 4 ]. In an effort to provide early therapeutic interventions, on the one hand, and prognostic data on survival or density of residual deficits, on the other hand, a number of brain injury biomarkers are under evaluation since clinical but mostly radiological signs remain silent during the first days of life [ 4 , 5 ]. Of the biomarkers associated with brain injury, preliminary research on glial fibrillary acidic protein (GFAP) appears to be promising in the early recognition of NBI in premature neonates [ 5 , 6 ]. GFAP is a brain-specific cytoskeletal intermediate filament protein with a molecular mass between 40 and 53 kDA, which is localized predominantly in astroglial cells and is released as a consequence of brain injury and astrogliosis [ 6 ]. Stewart et al. [ 6 ] demonstrated that levels of circulating GFAP on days 1-4 of life are significantly elevated in preterm neonates that later on developed PVL and that even among neonates with IVH, GFAP could identify which ones were at higher risk for the later development of PVL. Serum GFAP has also been reported by Ennen et al. [ 7 ]. to be significantly elevated in neonates with GA between 36 and 41 weeks with HIE receiving hypothermia therapy when compared with controls. Thus, identification of premature neonates who are at risk of developing NBI in the early neonatal period with the use of one or more biomarkers could provide the clinicians with the potential for early intervention. For instance, therapeutic hypothermia in late preterm neonates and brain-focused care, as well as neuroprotective medication in early preterm neonates could probably improve the neurodevelopmental outcomes [ 8 - 12 ]. Yet, there is limited data available regarding the use of GFAP as a biomarker for the early detection of NBI and long-term neurologic outcome, especially in preterm neonates [ 6 ]. Furthermore, there is no available study in premature neonates that provides evidence on serum GFAP levels and its predictive value comparing GFAP with the levels and predictive value of other biomarkers, such as S100B, in the same study population and this makes our study of great interest [ 13 ]. The purpose of this study was to determine whether serum GFAP levels measured within the first 3 days of life differ between premature neonates (<34 weeks) (a) with and without NBI, (b) with IVH and those with PVL, and (c) with different grades of NBI as well as (d) to evaluate the predictive value of serum GFAP during the first 3 days of life to early identify high-risk premature neonates that will either develop NBI or will be complicated with a severe adverse neonatal outcome such as death or seizures/hypertonia. IVH typically initiates in the periventricular germinal matrix, which is particularly vulnerable to hemorrhage in premature neonates mostly in the first 48 h of life [ 14 ]. The classic grading system of IVH was initially described by Papile et al. [ 15 ]. Findings are graded on a scale from I to IV [ 16 ] and it is estimated that it affects 15-20% of the neonates born <32 weeks [ 2 , 15 - 17 ]. PVL is defined as injury to the deep cerebral white matter that can be seen in two characteristic patterns: (a) Focal necrosis with loss of all cellular elements in periventricular white matter and (b) diffuse lesion in cerebral white matter [ 18 ]. It is the most common type of brain injury in premature neonates, often associated with or considered as a direct consequence of IVH, but also seen in the absence of IVH. Developmental outcomes for neonates with PVL are related to the grade and location of parenchymal involvement [ 19 ]. According to Romero-Guzman et al. [ 18 ], prevalence is estimated under 28 weeks at 39.6%, under 32 weeks at 27.4%, and under 37 weeks at 7.3% and it is classified on a scale from I to IV [ 20 ]. This is an Institutional Review Board (IRB) approved prospective longitudinal case–control study of live born premature (<34 weeks) neonates, born at a single tertiary hospital, who were admitted to the Neonatal Intensive Care Unit (NICU) between November 2016 and March 2018 (“Aretaieio” University Hospital - IRB R.No: B-216/13-10-2016/APPROVAL NUMBER-ID: KM140657 ). The study is part of a wider research protocol on the levels and predictive value of brain injury biomarkers in premature neonates with and without NBI and was carried out according to “ICMJE Recommendations for the Protection of Research Participants” [ 13 ]. All procedures were in accordance with the Declaration of Helsinki. Inclusion criteria were (a) prematurity (<34 weeks) and (b) NBI in the form of either PVL or IVH for the case group. Neonates with major congenital, genetic, or chromosomal abnormalities as well as other types of NBI, such as HIE, were excluded from the study. Only neonates whose parents gave their written informed consent were included in the study. All neonates were admitted to NICU right after delivery. According to the NICU’s protocol, on admission routine laboratory investigation included complete blood count (CBC), blood culture, and C-reactive protein (CRP). CBC and CRP should be additionally assessed in all premature neonates on the 2 nd and 3 rd day of life. Any unused quantity of serum was then used for the measurement of GFAP. Blood was collected from peripheral or umbilical vessels and the residual serum was aliquoted and stored at −35°C until assayed. NBI was classified at discharge taking into account head ultrasound scans (HUS) and the neonates were allocated in the case or control group. HUS followed the European Standards of Care for Newborn Health (ESCNH) [ 21 ] and were all performed in the NICU and evaluated by the Consultant Paediatric Radiologist of the Hospital. HUS through the cranial fontanels is considered as the gold standard for the diagnosis of NBI, allowing rapid bedside evaluation of the neonatal brain [ 22 - 24 ]. Until now, there is no universally accepted protocol for HUS screening in preterm neonates [ 21 , 24 ]. According to the protocol of ESCNH [ 21 ], a HUS should be performed in preterm neonates on days 1, 3, 7, 14, 21, and 28 at 6 weeks and at term equivalent age (TEA) if GA is >28 weeks. If GA is <28 weeks, a HUS should be performed on days 1, 3, 7, 14, 21, and 28 then for every 2 weeks until the 34 th week GA and at TEA. Finally, a HUS should be intensified in case of abnormalities or after episodes of clinical deterioration (e.g., unexplained anemia, neurological symptoms, surgery, HIE, central nervous system infection, and metabolic disease). Medical records were reviewed by the study personnel to identify relevant maternal and neonatal data regarding clinical and laboratory perinatal factors that could be of interest to either influence or predict NBI. Before any statistical analysis accuracy of data collection was double checked by the study personnel. Coding of all participants (mothers and neonates) was automatically created by the database used, to preserve anonymization/deidentification. High-risk pregnancy was defined according to international standards and guidelines including preeclampsia [ 25 ], oligohydramnios [ 26 ], hypothyroidism [ 27 ], gestational diabetes mellitus [ 28 ], chorioamnionitis [ 29 ], fetal growth restriction [ 30 ], and pathological Doppler [ 31 ]. Determination of GFAP concentrations was performed with one of the most sensitive commercially available kits (GFAP - MBS2701011, GFAP, ELISA) from MyBioSource, USA. According to the kit’s inserts, the lowest detection limit was 0.056 ng/ml and the precision, as estimated by the total CV (%), was <10%. Values <0.056 ng/mL were reported as zero. Statistical analysis was crosschecked and performed by the research team with the use of the commercially available software package: IBM SPSS statistics version 23 (IBM Corporation, Somers, NY 10589, USA). As there were no available studies on the levels of serum GFAP in the general population of premature neonates complicated with the development of NBI, sample size calculation for this wider research protocol was based on the levels of S100B, which is considered as the “gold standard” of NBI biomarkers [ 13 ]. Clinical characteristics and laboratory findings of women and neonates included in the study were compared in an effort to assure the success of the matching and to specify dissimilarities between the two groups. Pearson’s Chi-square test ( X 2 ) was performed for comparisons of qualitative data. One-Sample Kolmogorov–Smirnov test was done to control the normality of the distribution of GFAP and the rest of the quantitative parameters. Based on this analysis, either parametric t-test or Mann–Whitney U-test was used to compare GFAP concentration and the other quantitative parameters between the groups. Kruskal–Wallis test was applied to compare levels of GFAP within groups. Control and neonates with either PVL or IVH were included in a subgroup analysis, so as to investigate if GFAP levels varied in different types of NBI. Further subgroup analysis was made to compare GFAP levels in the five deceased neonates of the case group with the levels of control neonates and the rest of the cases, on purpose to identify if GFAP’s levels are altered in case of imminent death during the early neonatal period. Finally, the value of serum GFAP to predict NBI in the first 3 days of life was examined through multivariate logistic regression analysis setting as dependent variable either (a) the development or not of NBI during hospitalization in NICU or (b) the presence or not of Grade II-IV IVH complicated by seizures/hypertonia or death, and as independent variables the levels of serum GFAP and S100B [ 13 ] in the same study population during the first 3 days of life. A probability level of less or equal to 0.05 was considered significant. In this wide research protocol ninety-six (n=96) neonates fulfilled the inclusion criteria and were finally included in the study [ 13 ]. Sixty-five (n=65) of these neonates did not develop NBI while the rest thirty-one (n=31) were complicated with a type of NBI. From the latter, seventeen neonates developed PVL (n=17), twelve IVH (n=12), and two HIE which were excluded from the study. Consequently, the case group consisted of twenty-nine (29) neonates. Sixteen (n=16) neonates from the PVL group were diagnosed with Grade I unilateral or bilateral PVL and one with Grade II unilateral PVL. From the IVH group (n=12), four (n=4) neonates were diagnosed with Grade I unilateral or bilateral IVH and eight (n=8) with Grade II-IV unilateral or bilateral IVH. Six (n=6) neonates of the IVH group had seizures during hospitalization and three (n=3) finally died. The rest three (n=3), apart from seizures, also developed hypertonia. Totally, five (n=5) neonates died, all of which were diagnosed with IVH. From the sixty-five neonates with normal HUS, twenty-nine were selected to constitute the control group. Matching between cases (n=29) and controls (n=29) was conducted manually in a 1:1 fashion, taking into account closeness of GA (within 1 week) and birth weight. The mean and standard deviation (SD) GA for control neonates and cases were 29.8 ± 2.5 weeks and 29.6 ± 3.0 weeks while birth weight at admission was 1302 ± 429 gr and 1225 ± 475 gr, respectively (Tables 1 and 2 ). Maternal demographic and clinical characteristics of control and cases neonates Neonatal demographic - clinical characteristics and laboratory findings of control and cases neonates Comparison between cases and control neonates for maternal demographic and clinical characteristics identified no differences except for the antenatal use of corticosteroids between women whose neonates developed IVH and those that developed PVL ( Table 1 ). Neonatal demographic – clinical characteristics and laboratory findings between the case and control group are presented in Table 2 . Neonates in the case group had significantly lower admission pH and white blood cells count when compared to control neonates while admission base deficit and concentration of lactic acid were higher in neonates in the case group. Moreover, no difference was observed on therapeutic interventions in neonates between the two groups ( Table 3 ). Finally, regarding neonatal outcomes ( Table 4 ), necrotizing enterocolitis was more frequent in control neonates while seizures and death were more frequent in the case group. Therapeutic interventions of control and cases neonates Neonatal outcomes of control and cases neonates Serum GFAP levels were available for comparison at 85/87 (97.7%) of the desired time points for both case and control group. Missing data were due to insufficient serum after routine investigation had been performed. Mean ± SD and Median – Interquartile Range of GFAP levels are presented in Table 5 . No difference was observed within groups during the first 3 days of life. Moreover, GFAP levels did not differ significantly between control neonates with and without necrotizing enterocolitis. Although mean GFAP concentration (ng/ml) was higher in the case group in all days, this difference was not significant ( Table 5 , Figure 1 ). Mean ± Standard Deviation (SD), Median (Interquartile Range, IQR) and frequency of concentrations of Glial Fibrillary Acidic Protein (ng/ml) below the lowest detection limit in neonates with and without brain injury during the first 3 days of life Concentration of serum Glial Fibrillary Acidic Protein (ng/mL) in neonates with and without brain injury during the first 3 days of life. Box plots (horizontal line: median; box: 25-75% percentiles; whiskers: min–max; asterisk: outliers). It is worth mentioning though, that neonates in the case group presented more frequently GFAP levels above the kit’s lowest detection limit (0.056 ng/ml) and these percentages were significantly different during the first 3 days of life (p<0.05, Pearson’s Chi-square test) ( Table 5 ). Moreover, as shown in Figure 1 , neonates in the case group presented more frequently very high levels of GFAP (outliers) but these measurements were not necessarily associated with neonates that died. Further subgroup analysis among control neonates and neonates with either IVH or PVL revealed no significant difference on the levels of GFAP (results not shown). Notably, when the five neonates that died in the case group were compared to either control or the rest of the neonates with NBI, no significant difference was observed during the first 3 days of life (results not shown). Interestingly, additional subgroup analysis between neonates with PVL and IVH showed that neonates whose mothers received antenatal corticosteroids ( Table 1 ) developed more frequently PVL instead of IVH and had significantly lower probability of neonatal death during hospitalization ( Table 4 ). Finally, the multivariable logistic regression analysis including as independent variables serum GFAP and S100B levels during the first 3 days of life confirmed that the predictive value of serum GFAP, regarding either the development of NBI or a severe adverse neonatal outcome such as II-IV grade IVH complicated by seizures/hypertonia or death, is limited, as it did not reach statistical significance (results not shown). At present, there is no model or biomarker that can detect premature neonates at high risk for developing NBI [ 32 - 34 ]. Head ultrasound imaging is considered as the gold standard for the diagnosis but not the prediction of NBI in neonates, especially premature ones that will develop either PVL or IVH [ 22 - 24 ]. Moreover, MRI has been shown to identify moderate-to-severe cerebral white matter injury that can predict adverse neurodevelopmental outcome but again its predictive value regarding NBI in the first days of life is limited [ 21 , 35 , 36 ]. Early detection of premature neonates that will later on in life develop NBI is crucial, as early therapeutic interventions might moderate neurodevelopmental defects. Numerous biomarkers have been investigated regarding their prognostic value for NBI, but data on the efficacy of GFAP in preterm neonates remain limited. In the present study, we demonstrate that levels of serum GFAP on days 1-3 of life are elevated in preterm neonates which will later develop NBI. While elevated the difference was not statistically significant. Our findings differ to these by Stewart et al. [ 6 ] who detected a significant difference between normal and neonates with NBI. However, the case group in Stewart’s study consisted of either very low birth weight (VLBW) (<1500 g) or LBW neonates (1500-2500 g) “with suspected neurologic morbidity at birth, which included prolonged hypotonia or seizures,” while the case group in our study was more representative of the general population of premature neonates as no weight limit or neurologic morbidity was set as inclusion criteria. Furthermore, many neonates in Stewart’s study developed both PVL and IVH and as mentioned in the same study “GFAP was significantly increased in neonates with both IVH and PVL on days 2-4 of life” when compared to neonates with IVH only. Consequently, when combined, PVL and IVH can elevate cumulatively the levels of GFAP contributing to higher levels in the case group. Contrarily, in our study, the case group consisted of neonates with either PVL or IVH, but not both, representing a well separated study population in terms of subsequent pathology. Nevertheless, as in the study by Stewart et al., we identified a clear trend as GFAP was detected more frequently below the lowest detection limit (0.056 ng/ml) in the control group compared to neonates with NBI. Our findings are also consistent with the observation that neither neonates that died (n=5) nor those with II-IV grade IVH showed significantly higher GFAP concentrations when compared to neonates of either the control or case group during the first 3 days of life (results not shown). Although the levels of GFAP were more elevated in these neonates when compared to controls, it seems that GFAP is either of limited value in the prognosis of NBI in the general population of premature neonates or not as powerful as other biomarkers, such as S100B [ 37 , 38 ]. The latter is considered as one of the most effective biomarkers to predict severe types of NBI in premature neonates according to a number of previous studies, including ours [ 13 ]. More specifically, in our previous study for a cutoff value of 10.51 ng/ml, serum S100B on the 1 st day of life performed an excellent sensitivity of 100% and specificity of 93.9% to predict severe adverse neonatal outcome such as death or IVH of II-V grade complicated with seizures and/or hypertonia. The fact that we have investigated both GFAP and S100B in the same study population is an important strength of our study as no previous study provides evidence on the prognostic value of GFAP when directly compared to the most well studied biomarker of NBI in premature neonates. Another strength of our study is the prospective longitudinal methodology, which allows the repetitive evaluation of GFAP levels. Following that methodology, the absence of significant difference between control and case neonates was confirmed during the first 3 days of life which is the most important period for the early detection of premature neonates at risk to develop NBI. While not a primary aim of this study, we observed that antenatal corticosteroids, specifically betamethasone, have a neuroprotective effect. In both our study and the study by Stewart et al. [ 6 ] neonates whose mothers received antenatal steroids were less likely to develop IVH and had significantly lower rates of mortality. Finally, our study has some limitations as well. A main limitation is the low number of neonates in both groups which could explain the fact that differences on serum GFAP between the two studied groups did not reach statistical significance. Nonetheless, in our previous study with the same study population, differences on serum S100B levels were significant already from the 1 st day of life, indicating that differences on GFAP levels are limited [ 13 ]. Moreover, even though we used one of the most sensitive commercial kits for serum GFAP, many neonates in the control group presented GFAP levels below the lowest detection limit, which indicates that future studies should consider using a more sensitive method to measure serum GFAP levels, and consequently determine its predictive value regarding NBI in premature neonates more accurately. We report that serum GFAP levels in premature neonates (<34 weeks) that develop NBI do not differ significantly to the levels of neonates without NBI during the first 3 days of life. Consequently, its effectiveness as an early predictive biomarker of NBI in the general population of premature neonates is probably limited. However, premature neonates without NBI had more often GFAP levels below the lowest detection limit. Therefore, a more sensitive detection method for serum GFAP in the future might highlight its predictive role in the early identification of NBI in the general population of premature neonates. The authors would like to thank the laboratory staff members Kapetanaki Antigoni, Zisi Georgia and Vrachnou Nota-Maria for data documentation and skillful technical assistance. Conflict of interest: The authors declare no conflicts of interest. Funding: The author(s) received no specific funding for this work. Serum glial fibrillary acidic protein as a biomarker of brain injury in premature neonates Global regional and national estimates of levels of preterm birth in 2014:A systematic review and modelling analysis Perinatal brain injury:Mechanisms, prevention, and outcomes Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study):A longitudinal cohort study Early predictors of perinatal brain damage:The role of neurobiomarkers Biomarkers of brain injury in the premature infant Glial fibrillary acidic protein as a biomarker for periventricular white matter injury Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole body cooling Impaired oligodendrocyte maturation in preterm infants:Potential therapeutic targets Neuroprotective strategies in neonatal brain injury Pharmacologic neuroprotective strategies in neonatal brain injury Neonatal neurocritical care:Providing brain-focused care for all at risk neonates Neuroprotective care of extremely preterm infants in the first 72 hours after birth S100B as a biomarker of brain injury in premature neonates. A prospective case-control longitudinal study Intraventricular hemorrhage in premature infants:Mechanism of disease Incidence and evolution of subependymal and intraventricular hemorrhage:A study of infants with birth weights less than 1,500 gm Intraventricular hemorrhage in neonates born before 32 weeks of gestation-retrospective analysis of risk factors Prevalence and risk factors for periventricular leukomalacia in preterm infants. A systematic review Incidence of brain injuries in premature infants with gestational age ≤34 weeks in ten urban hospitals in China Neonatal periventricular leukomalacia:Current perspectives Neurological Monitoring in the High-risk Infant:Ultrasound and MRI Scanning Neonatal brain injury and aberrant connectivity Clinical neuroimaging in the preterm infant:Diagnosis and prognosis Practice parameter:Neuroimaging of the neonate:Report of the quality standards subcommittee of the American academy of neurology and the practice committee of the child neurology society Clinical presentation of preeclampsia and the diagnostic value of proteins and their methylation products as biomarkers in pregnant women with preeclampsia and their newborns Perinatal outcome in patients with isolated oligohydramnios at term:A prospective study Reporting thyroid function tests in pregnancy International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy Clinical chorioamnionitis at term III:How well do clinical criteria perform in the identification of proven intra-amniotic infection? Racial/ethnic standards for fetal growth:The NICHD fetal growth studies Fetal medicine foundation reference ranges for umbilical artery and middle cerebral artery pulsatility index and cerebroplacental ratio Inflammatory biomarkers of birth asphyxia Biochemical markers of perinatal brain damage Serum biomarkers to evaluate the integrity of the neurovascular unit Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study Neuroimaging for neurodevelopmental prognostication in high-risk neonates Relation between prognosis and changes of MBP and S100B in premature infants with periventricular leukomalacia Elevation of serum S100 protein concentration as a marker of ischemic brain damage in extremely preterm infants |
Answer the following medical question. | What does research say about Joint observation in NICU (JOIN): study protocol of a clinical randomised controlled trial examining an early intervention during preterm care.? | Preterm birth may generate significant distress among the parents, who often present with difficulties in appropriating their parental role. Parental stress and low perceived parental self-efficacy may interfere with the infant’s socioemotional and cognitive development, particularly through disrupted parent–infant interactions. Perceived parental self-efficacy represents the belief of efficacy in caring for one’s own infant and successful incarnation of the parental role, as well as the perception of one’s own abilities to complete a specified task. Interventions to support parental role, as well as infant development, are needed, and parental self-efficacy represents a useful indicator to measure the effects of such early interventions. This study protocol describes a randomised controlled trial that will test an early intervention in the neonatal intensive care unit (NICU) (JOIN: Joint Observation In Neonatology) carried out by an interdisciplinary staff team. Mothers of preterm neonates born between 28 and 32 6/7 weeks of gestational age are eligible for the study. The intervention consists of a videotaped observation by a clinical child psychologist or child psychiatrist and a study nurse of a period of care delivered to the neonate by the mother and a NICU nurse. The care procedure is followed by an interactive video guidance intended to demonstrate the neonate’s abilities and resources to his parents. The primary outcome will be the difference in the perceived maternal self-efficacy between the intervention and control groups assessed by self-report questionnaires. Secondary outcomes will be maternal mental health, the perception of the parent– infant relationship, maternal responsiveness and the neurodevelopment of the infant at 6 months corrected age. Ethical approval was granted by the Human Research Ethics Committee of the Canton de Vaud (study number 496/12). Results from this study will be disseminated at national and international conferences, and in peer-reviewed journals. NCT02736136 , Pre-results. The study will test the effects of an early intervention carried out by an interdisciplinary partnership between neonatal intensive care unit nurses and clinical child psychologists/child psychiatrists. Among other objectives, the intervention aims at increasing perceived parental self-efficacy in mothers of very preterm infants. The intervention draws on theories of neonatal and infant development, as well as interactive video guidance. Methodological rigour, including concealment of random allocation and prospective trial registration and publication, limits risk of bias. Unblinded participants and clinicians, as well as contamination due to improvement of usual care by healthcare providers, may increase the risk of bias. Improvement of prenatal and postnatal care over the past decades has led to increased survival of very preterm neonates born less than 32 weeks’ gestation. 1 Among others, protective measures to promote health and subsequent neurodevelopment have been developed, including optimisation of nutritional support, better characterisation of neonatal stress and improved pain management. In the same perspective, developmental care was introduced in the neonatal intensive care units (NICU) since the 1990s with the intention of minimising the adverse consequences of prematurity on the developing brain. During a critical period of development, the preterm brain is highly vulnerable to injury, represented by cerebral haemorrhage and insult to the white matter. Additionally, beyond the injury, preterm neonates are prone to alteration of brain maturation with disruption of normal developmental trajectory of both grey and white matters. 2–4 Over the last two decades, a growing body of research focused on the impact of excessive stimuli such as sound, light, touch or pain on the preterm neonate, hypothesising that an unfavourable and stressful environment may add to the adverse effects of neonatal morbidity. 5 These concerns led progressively to the introduction of developmental care, which consists of individualised strategies mainly based on the neonate’s skills and/or difficulties, 6 and supporting the neonate’s regulation and development. The first aim of the developmental care is to limit exposure to deleterious environmental stimulations. Management of sensorial dystimulation, as well as of pain and stress during invasive care procedures, represents a central target of developmental care. 7 8 The second main objective focuses on the child’s well-being through the adaptation of the sensorial environment in order to provide more physiological external stimuli (tactile, auditory, visual, vestibular), that will help to promote behaviours and postures fostering comfort and regulation. The third objective of the developmental care aims to support parents in their role and to strengthen the relationship they are developing with their child. 7 9 10 Although studies have found contradictory results, 11–13 some evidence shows a positive impact of developmental care on short-term and long-term neonatal and neurodevelopmental outcomes. 14–19 Taken together, the different aspects of developmental care aim to build support around the neonate and the family, leading to the development of ‘family-centred care’, with specific recommendations for its implementation in the NICU. 20–22 Preterm birth and caring for a preterm infant may be distressing for parents, who often feel vulnerable and incompetent in the high-tech NICU environment. 23–25 Parents may present with difficulties in understanding and capturing subtle cues from their infant. 26 Parents show important signs of stress, 27 and require more support during the first year after the preterm birth compared with parents of term infants. 28 They may also experience mental health symptoms, including post-traumatic stress disorder (PTSD), 29–35 anxiety and depression. 25 36 Although the hospitalisation of a preterm neonate may affect both parents equally, 36 most of the studies examining parental emotional distress so far focused on mothers’ experience and needs. 24 37 38 After birth, the mother normally initiates specific behaviours towards her newborn, aimed at supporting the neonate who experiences high levels of stress during hospitalisation in the NICU, 39 and at fostering the infant’s socioemotional development. 40 41 However, mothers of preterm infants may present difficulties in developing these protective behaviours. 42 Thus, parental stress may interfere with the infant’s socioemotional and cognitive development, and is associated with more difficulties in building positive parent–infant relationships due to disrupted interactions. 40 43 44 However, a recent meta-analysis showed that mothers of preterm children were not less sensitive or responsive toward their children than mothers of full-term children. 45 Perceived parental self-efficacy is defined as ‘beliefs or judgements a parent holds of their capabilities to organise and execute a set of tasks related to parenting a child’. 46 Self-efficacy includes two separate notions: first, the belief of efficacy in caring for one’s own child across several varied domains of functioning and successful incarnation of the parental role (general self-efficacy), 47–49 and second, the perception of one’s own abilities to complete a specified task within a specific domain (specific self-efficacy). 50 The present study will focus on the specific self-efficacy, which appears to drive actions and predicts parents’ behaviours. 48 51 As demonstrated in previous studies, perceived parental self-efficacy appears to mediate the relationship between psychosocial risk factors and maternal competences. 52 53 Thus, a perception of low self-efficacy is associated with parental depression, 52 54–57 high levels of parenting stress, 58 59 low family support, 60 poor infant health 59 61 and demanding infant temperament. 62 63 In contrast, a perception of high self-efficacy is associated with sensitive and receptive parental behaviour, and is related to improved infant socioemotional development. 56 64 Parents of preterm neonates face a complex challenge. While they might be responsive to their infant cues, preterm neonates might not be capable of engaging in sustained and responsive interaction, as they tend to be less attentive and reactive due to immaturity, and to show more negative behaviours and emotions, as well as less rewarding interactions than their term-born peers. 56 65–67 In parallel, mothers of preterm neonates, who are at risk of experiencing depression, anxiety or post-traumatic disorder, 25 35 may not be able to interact as adequately with their child, and could be less sensitive than mothers without mental health symptoms. Mothers of preterm infants may be at a higher risk of decreased maternal confidence, 68 although the limited evidence available so far is mixed. 57 69 The quality of care provided by parents is strongly influenced by the maternal perception of self-efficacy, and interventions promoting this may therefore help to increase parenting quality. 49 70 To date, only few early interventions have focused on enhancing perceived parental self-efficacy. The interventions that are currently available in the early neonatal period mainly aim to decrease parental trauma and stress-related symptoms, and to improve parental responsiveness within the parent–`infant interaction. 10 23 71–73 Thus, a recent meta-analysis identified only two interventions intended to increase perceived maternal self-efficacy. 74–76 These two interventions concentrated on different techniques of parenting education, and one of the two demonstrated improved cognitive child development at 4 months of age. 76 The present study focuses on the joint observation, which is an interdisciplinary intervention performed in the NICU soon after birth. The main aim of the study is to examine whether this early intervention increases perceived parental self-efficacy. The joint observation (JOIN: Joint Observation In Neonatology 77 ) was developed in line with the three objectives of the developmental care model. This early intervention programme in the NICU is carried out by an interdisciplinary partnership of professionals, thereafter called observers, including NICU nurses, paediatricians, clinical child psychologists or child psychiatrists. They all received a 20-hour training, delivered by the same experienced clinical child psychologist (AB) for consistency, and participate in regular supervision sessions during the study period. The intervention combines elements issued from four distinct theories of neonatal and infant development. First, the evaluation of neonatal behaviour developed by Brazelton and Nugent 78 underlines the importance of parents detecting the neonate’s competences and fragilities, and interpreting stress cues to adjust to the infant’s regulation needs. Second, the synactive model of Als 79 proposes a programme of individualised care avoiding overstimulation in the NICU and supporting the neonate’s self-regulation and competences. Third, the sensorimotor approach elaborated by Bullinger 80 consists mainly of the assessment of sensory dystimulations provided to the neonate, and the management of subsequent tonico-postural disturbances observed during the NICU stay with the long-term perspective of optimising the infant’s development. This approach builds a framework to adjust the care procedures to the neonate’s capacity to treat multisensory information, and to reach a sensoritonic balance that allows and supports interactive behaviours. Fourth, the interactive guidance is a model based on the observation and analysis of parent–infant interactions through the therapeutic use of video feedback. 81–83 This approach aims to allow parents to become aware of their competences and resources, as well as the skills and needs of their infant. Video feedback has recently been studied as an intervention in the NICU. 84 85 The authors postulated that the interactive guidance through video feedback reduces the negative impact of preterm birth on the parent–infant relationship, and the behavioural withdrawal of the parent. The results of this previous work have revealed increased parental sensitivity and positive effects on the developing relationship. 84 A randomised clinical study implementing video feedback not only during the NICU stay but also during the first year of life specifically demonstrated positive effects on parents of preterm infants with a lowering of mothers’ post-traumatic stress symptoms and enhancement in maternal sensitivity and quality of mother–infant interactions. 86 In order to address the main objective, the present intervention is focusing on following areas: (1) The neonate’s adaptive capacity and competences are highlighted, as well as interactive signals, in order to promote parents’ emotional involvement, awareness of the infant’s perspective, resources and needs. For instance, the neonate’s interactive initiatives, as well as the responses to parental touch and/or voice, such as eye opening or head turning, will be highlighted. (2) To reinforce parental responsiveness, the parent’s behaviours that are supporting the neonate’s signals are pointed out during the video extracts, highlighting the parental relational competences frequently unidentified by the parents themselves. For example, positive emotional interactions between the mother and her neonate will be emphasised, such as adapting the voice and facial expression in order to support the neonate’s alertness. (3) With the aim of developing individualised care, measures can be suggested acknowledging the specificities of each neonate (sensorial irritability, tonico-postural disturbances or withdrawal for instance), and adjusting the care to reinforce the neonate’s own capacity of autoregulation and to support sensoritonic balance development in a long-term perspective. For instance, the parent’s gestures of support according to the baby’s tonico-postural needs will be identified, such as supporting the baby’s neck or pelvis during the interaction or adjusting the rhythm to help the neonate developing autoregulation competencies. The joint observation pragmatically consists of two phases. First, a video-recorded period of routine care for the preterm neonate (such as a nappy change) is carried out by both the parent (mostly the mother) and a NICU nurse for a duration of approximately 30 min. There is no intervention by the observers during the videotaping. Second, before gathering with the mother, several short extracts of the period of care are carefully selected by the observers in order to reach the objectives of the intervention. During the discussion and for illustration purpose, the observers will play back 4–6 short extracts of 10–30 s each to the parents, showing short specific moments of interactive behaviours that usually escape awareness. This video feedback, which lasts about 60 min, is conducted in order to point out the quality of the relational and emotional parent–infant interactions, and highlights moments of attunement, adjustment, synchrony, reciprocity and mutuality. The objectives of the present study are to measure the effects of the joint observation as an early intervention performed in the NICU on outcomes relative to parental perception and mental health, as well as to indices of the parent–infant relationship quality and of child development. The primary outcome measure will be the perceived maternal self-efficacy. Secondary objectives will be to measure the impact of this intervention on maternal mental health (including perceived stress, post-traumatic stress, anxiety, depression), on maternal perception of the parent–infant relationship, on maternal responsiveness and on the neurodevelopment of the infant at 6 months corrected age (CA). In addition, acceptability of the intervention and maternal satisfaction will be assessed. We will conduct a monocentric randomised controlled trial testing an intervention compared with treatment-as-usual, in the level III NICU of a Swiss University Hospital. All mothers of preterm neonates born between 28 and 32 6/7 weeks of gestational age (GA), admitted to the NICU and aged less than 8 weeks of life are eligible to participate. Exclusion criteria were set for ethical considerations and in order to avoid approaching mothers needing acute treatment, and include the following: maternal age <18 years; established intellectual disability or psychotic illness; insufficient French-speaking level to complete questionnaires due to impossibility to obtain valid translations to multiple languages for financial reasons; and cardiorespiratory instability of the preterm neonate (severe brady-apnoea syndrome, oxygen requirement >30%) to ensure survival during the study period. Regarding twins or triplets, only the first-born neonate or the one being more stable will be included in the study. Recruitment will be performed by the study nurses, who approach the eligible mothers once their infants are stable enough, that is, after the critical period of the first week of life when cardiorespiratory stability is established, usually on non-invasive ventilation and with oxygen requirement <30%, which would also permit more active participation of the parents in the neonate’s care. The allocation ratio of randomisation is 1:1, using a computer-generated list of random blocks ( https://www.sealedenvelope.com/simple-randomiser ). The allocation sequence will be concealed from the principal investigator in sequentially numbered, opaque, sealed envelopes. Envelopes will be opened only after the enrolled participants gave signed consent and completed all baseline assessments. The principal investigator and the statistician will be blind to group allocation. All participant data will be coded to ensure confidentiality. Participants in the control group will receive treatment-as-usual. They will be asked to complete questionnaires at the same time points as the participants in the intervention group: at recruitment, at 1 month after enrolment and at 6 months of their infant’s CA. At 6 months CA, a neurodevelopmental assessment of the infant and a 10 min filmed mother– infant interaction will take place. Mothers assigned to the intervention group will be asked to complete self-report questionnaires at the three time points described above. The intervention in the form of the joint observation will be planned after enrolment depending on the infant’s clinical state and stability. The intervention is twofold: first, the observers are jointly observing a period of care administered to the neonate jointly by her mother and a NICU nurse. The care procedure is video-taped and an observation grid 87 is completed by the observers. Second, the mother and the NICU nurse participate in a video feedback session with the two observers. The discussion is based on the principles of interactive guidance, 84 as described above. At the end of the intervention, the mother will also be asked to complete a questionnaire regarding her satisfaction with the intervention. At 6 months CA, a neurodevelopmental assessment of the infant and a 10 min filmed mother–infant interaction will be carried out. The primary outcome is the difference in perceived maternal self-efficacy between the control and intervention groups measured with the Perceived Maternal Parenting Self-Efficacy questionnaire 1 month after study enrolment. Using validated self-reported questionnaires described below, various aspects of maternal well-being will be compared between the two groups at baseline and at the 1-month and 6-month follow-up, including symptoms of PTSD (Posttraumatic Diagnostic Scale), parental stress (Parental Stressor Scale: Neonatal Intensive Care Unit and Parenting Stress Index-Short form), anxiety (Hospital Anxiety and Depression Scale) and depression (Edinburgh Postnatal Depression Scale). Other measures will include maternal perception of the parent–infant relationship (Mother-to-Infant Bonding Scale) and of her infant’s temperament (Infant Behaviour Questionnaire–Revised), perceived social support (Modified Medical Outcomes Study Social Support Survey) and maternal sensitivity or responsiveness (Emotional Availability Scales and Care Index). In addition, acceptability and maternal satisfaction of the intervention will be assessed in the intervention group. The neurodevelopmental outcome of the preterm neonates will be measured at 6 months CA (Bayley Scales of Infant Development, third edition [BSID-III]). After enrolment, mothers will be asked to complete several questionnaires described below, and again 1 month after study enrolment and at 6 months CA. Infants will return at 6 months CA to the neonatal follow-up clinic for the neurodevelopmental assessment and the 10 min filmed mother–infant interaction. The study measures and timings are summarised in table 1 and figure 1 . Flow chart of the study. CA, corrected age. The measures at the three different time points BSID-III, Bayley Scales of Infant Development, third edition; CA, corrected age; CRIB, Clinical Risk Index for Babies; EPDS, Edinburgh Postnatal Depression Scale; F-PSS NICU, Parental Stressor Scale Neonatal Intensive Care Unit; HADS, Hospital Anxiety and Depression Scale; IBQ-R, Infant Behavior Questionnaire-Revised; MIBS, Mother-to-Infant Bonding Scale; mMOS-SS, Modified Medical Outcomes Study Social Support Survey; PDS-F, Posttraumatic Diagnosis Scale; PMP-SE, Perceived Maternal Self-Efficacy; PSI, Parental Stress Index. This questionnaire, including 20 items, which represent four subscales (care taking procedures, evoking behaviour(s), reading behaviours or signalling and situational beliefs), was specifically developed for mothers of preterm neonates, and has good psychometric properties. 50 Responses to each item are recorded on a four-point Likert scale (from ‘strongly disagree’, score 1, to ‘strongly agree’, score 4). To obtain a French version of the questionnaire, a translation and cultural adaptation were performed with the forward-backward method. 88 Maternal PTSD is measured using this 17-item scale based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria. Mothers will rate frequency and severity of symptoms, such as re-experiencing, avoidance and hyperarousal, experienced over the last month and graded on a four-point Likert scale. The Posttraumatic Diagnosis Scale displays good psychometric properties, 89 and a French version has been validated. 90 This questionnaire was translated into French and assesses parental stress with 31 items focusing on their perception of stress factors during the NICU stay of their neonate and explores three domains: impact of the visual and auditory environment, behaviour and aspect of the neonate and parental role. 91 Good psychometric properties have been reported. 91 This 36-item questionnaire is a shortened version of the Parental Stress Index, 92 which measures the stress related to parenthood, and is intended for parents of children 0 to 3 years. The three subscales investigate parental distress, dysfunctional interactions between the parents and the child and child difficulties. Its validity has been demonstrated in studies of parents of preterm neonates. 93 In this study, the validated French version will be used. 94 Anxiety and depression symptoms are assessed using the French version of the Hospital Anxiety and Depression Scale, which includes 14 items, and measures the severity of symptoms. 95 This questionnaire has good psychometric properties. 96 Maternal depression symptoms will also be assessed with the Edinburgh Postnatal Depression Scale, which focuses on the symptoms experienced over the last 7 days. 97 The French version displays good psychometric characteristics. 98 In this questionnaire, the mother rates (from 0 to 5) eight adjectives describing her feelings toward her infant, which is indicative of mother–infant bonding 99 100 and was translated into French with good psychometric properties. 101 Infant temperament is assessed through the French version of this questionnaire (total of 191 items). The parent reports on a seven-point Likert scale the frequency of his infant’s behaviours during the previous 2 weeks. 102 Good psychometric properties have been reported. 102 This validated self-reported evaluation consisting of eight items measuring different aspects of social support 103 is based on the 19-item questionnaire assessing the dimensionality of four functional support scales (emotional/informative, tangible, affectionate and positive social interaction). 104 A French translation and cultural adaptation was performed using the forward-back method. 88 This questionnaire comprises a general question on maternal satisfaction with the intervention and six questions on its setting, value and usefulness, which will provide a qualitative evaluation. In addition, three questions focus on the acceptability of the intervention by the mothers. Mothers will also report demographic information, including socioeconomic status, level of education 105 and previous psychiatric disorder. Neonatal characteristics will be collected from the medical record on severity of morbidity (GA and weight at birth, Apgar score, complications—need for mechanical ventilation and respiratory morbidity, sepsis and cerebral lesions), as well as the Clinical Risk Index for Babies, 106 which represents neonatal morbidity severity. Maternal sensitivity will be assessed at 6 months CA by coding a session of free play between the mother and her infant with the Emotional Availability Scales. 107 Six domains are evaluated, of which four relate to the mother’s behaviour (sensitivity, structuration, intrusion and hostility toward the infant), and two to the infant’s behaviour (reactivity to the mother and maternal involvement). Patterns of interaction and emotional availability can therefore be measured on separate scales. 108 A second tool, the Care Index, 109 will measure maternal sensitivity, by assessing the interactive behaviour within the mother–infant dyad according to seven scales (facial expressions, vocalisations, posture, expressed affection, turn-taking, control and activity). Three maternal (sensitive, controlling, passive) and four infant (cooperative, compulsive-compliant, demanding, passive) characteristic behaviours are coded on each scale. A standardised neurodevelopmental assessment will be conducted at 6 months CA by a developmental paediatrician, using the BSID-III, 110 which entails three subscales (cognitive, language and motor) with a normative mean score of 100±15 SD. Power calculation (G*Power) 111 based on published means and SD 50 55 related to perceived parental self-efficacy in a sample of preterm (M=58.51, SD=12.57) and of term-born (M=65.9, SD=8.2) neonates showed that 68 participants would need to be recruited (α=0.05, 1-β=0.80, unilateral hypothesis). This is based on the assumption that parental self-efficacy in mothers of preterm babies in the intervention group who benefited from the intervention would be comparable to that in mothers of term babies. Therefore, it is planned that 80 mothers will be enrolled to anticipate possible participant withdrawal. For the primary outcome regarding the difference in the perceived maternal self-efficacy between the intervention and control groups, linear regression analysis will be employed, with maternal self-efficacy at 1 month as the dependent variable and group as the explanatory variable, with adjustment for baseline maternal self-efficacy. For secondary analyses, linear mixed model regressions will be conducted, with maternal self-efficacy at 1 and 6 months as dependent variables and group, time and the interaction group x time as independent variables, adjusted for baseline maternal self-efficacy. The sample principle will be applied to all other secondary outcomes. W e will include potential confounding variables, if necessary. These include maternal age, sex of the children and socioeconomic status where applicable. For confirmatory analyses, a Bonferroni correction for multiple analyses will be applied. For initial exploratory analyses, no such correction will be used. 112 Differences between groups will be adjusted for the respective baseline values in case they differ using potential confounding variables, if necessary. These include maternal age, sex of children and socioeconomic status where applicable. Variables will be transformed if residuals are not normally distributed. In the early 2000s, the joint observation was introduced in our NICU by two professionals as part of the care of the parent–infant dyads. 77 Due to positive feedback from the parents, the intervention was more routinely performed and systematised to the point that a randomised controlled trial was needed to examine its validity. Although patients and caregivers’ feedback was considered in designing and adapting the intervention, they were not directly involved in the design or recruitment of this study. However, results will be disseminated in written form to the participants and distributed to the public via social media and public events. Expected and unexpected adverse events will be recorded during the study period. As the intervention does not involve medical or pharmaceutical treatment, the risk that an adverse event would occur is low. A child psychiatrist will be available for clinical assessment and follow-up if needed, particularly if significant psychological distress or psychiatric illness of the mother or her infant is detected during study participation. All study data will be coded and entered by research staff (psychology assistant). The database will be regularly updated by the IT Service of the Lausanne University Hospital. Double data entry will be done for the primary outcomes. For the rest of the data, a random 5% will be double-checked. The principal investigator, the coinvestigators and the statistician will have access to the final trial data set. Individual participant data collected during the trial (after deidentification) on which publications from JOIN consortium are based will be available on reasonable request. The local ethical committee approved the study protocol. Little to no risk is expected by participation of the mothers and their neonates in the trial. Signed informed consent will be obtained from all participating mothers. Participation in the study will not interfere with the typical care patients receive after childbirth and during NICU stay. Results from the study will be disseminated at national and international conferences, and in peer-reviewed journals. This randomised controlled trial is registered in clinicaltrials.gov ( NCT02736136 , Pre-results stage). This study might result in an evidence-based early intervention aimed at reinforcing parental competences, in particular at increasing perceived parental self-efficacy. It would represent a brief, easily accessible and safe early intervention, which could be implemented in the routine care in the NICU, thus leading to significant changes in clinical practice. It will also help to characterise the relationships between perceived parental self-efficacy, maternal mental health, maternal perception of their relationship with their infant and their infant’s temperament and maternal sensitivity. Due to its interdisciplinary nature, this research is of interest for clinicians, educators and researchers in the field of paediatrics and development, psychology, child psychiatry and public health. We would like to thank Lyne Jaunin, Geneviève Métrailler Dizi and Manon Macherel for contributing to the writing of the ethics proposal. We acknowledge the contribution of Carole Muller-Nix and Margot Forcada-Guex to the development of the intervention. We are also grateful to Priska Udriot, Joanne Horisberger, Cassie Pernet and Vania Sandoz for help with data collection. Finally, we would like to acknowledge the Clinic of Neonatology, and Carole Richard, in particular for her support. Contributors: All coauthors substantially contributed to the manuscript and approved the final version as submitted. AH and NF designed the study with input from all other members of the consortium. AB and MMH designed the intervention with input from members of the consortium. JS and AH drafted the manuscript and contributed equally to the present version. AB, MMH, NF, CT, ALB and J-FT significantly contributed to the establishment and refinement of study procedures and critically revised the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Ethics approval: Commission d’Ethique du Canton de Vaud, Switzerland, study number: 496/12 Provenance and peer review: Not commissioned; externally peer reviewed. Collaborators: Cindy Boche (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Ayala Borghini (Department of Child and Adolescent Psychiatry, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Josée Despars (Department of Child and Adolescent Psychiatry, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Alice Manser Chenaux (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Noémie Faure (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Valérie Goyer (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Antje Horsch (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Aurélie Le Berre (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Maryline Monnier (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Mathilde Morisod Harari (Department of Child and Adolescent Psychiatry, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Roxane Romon (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Juliane Schneider (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Catherine Sperandio (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Chloé Tenthorey (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), Jean-François Tolsa (Department of Woman-Mother-Child, Clinic of Neonatology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland), and Aline Yersin (Department of Child and Adolescent Psychiatry, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland). Patient consent for publication: Not required. Joint observation in NICU (JOIN): study protocol of a clinical randomised controlled trial examining an early intervention during preterm care Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009 Brain Injury in the preterm infant: new horizons for pathogenesis and prevention Brain injury in premature neonates: a primary cerebral dysmaturation disorder? Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances Noise and light exposures for extremely low birth weight newborns during their stay in the neonatal intensive care unit [Research, developmental care and NIDCAP: specific methodological issues] Effectiveness of individualized neurodevelopmental care in the newborn intensive care unit (NICU) Neonatal individualized care in practice: a Swedish experience Individualized developmental care for high risk newborns in the NICU: a practice guideline Family nurture intervention improves the quality of maternal caregiving in the neonatal intensive care unit: evidence from a randomized controlled trial Developmental care for promoting development and preventing morbidity in preterm infants Systematic review of developmental care interventions in the neonatal intensive care unit since 2006 NIDCAP: a systematic review and meta-analyses of randomized controlled trials Level of NICU quality of developmental care and neurobehavioral performance in very preterm infants A randomized, controlled trial to evaluate the effects of the newborn individualized developmental care and assessment program in a Swedish setting Early intervention improves cognitive outcomes for preterm infants: randomized controlled trial The stockholm neonatal family centered care study: effects on length of stay and infant morbidity Family nurture intervention in the neonatal intensive care unit improves social-relatedness, attention, and neurodevelopment of preterm infants at 18 months in a randomized controlled trial Depression and anxiety symptoms of mothers of preterm infants are decreased at 4 months corrected age with Family Nurture Intervention in the NICU Psychosocial program standards for NICU parents Recommendations for involving the family in developmental care of the NICU baby NICU discharge planning and beyond: recommendations for parent psychosocial support Helping parents cope with the trauma of premature birth: an evaluation of a trauma-preventive psychological intervention Posttraumatic stress symptoms in mothers of premature infants Scoping review of the mental health of parents of infants in the NICU Using knowledge to cope with stress in the NICU: how parents integrate learning to read the physiologic and behavioral cues of the infant Stress experiences of parents with premature infants in a special care nursery Effect of newborn hospitalization on family and child behavior: a 12-year follow-up study Posttraumatic stress among mothers of very low birthweight infants at 6 months after discharge from the neonatal intensive care unit Maternal posttraumatic stress response after the birth of a very low-birth-weight infant Parental post-traumatic reactions after premature birth: implications for sleeping and eating problems in the infant Acute posttraumatic stress symptoms among urban mothers with newborns in the neonatal intensive care unit: a preliminary study Perinatal stressors as predictors of symptoms of posttraumatic stress in mothers of infants at high risk Improving maternal mental health following preterm birth using an expressive writing intervention: a randomized controlled trial A comparative prospective cohort study of women following childbirth: mothers of low birthweight infants at risk for elevated PTSD symptoms Infants in a neonatal intensive care unit: parental response Mothers' experiences of having a preterm infant in the neonatal care unit: a meta-synthesis Effectiveness of a parent "buddy" program for mothers of very preterm infants in a neonatal intensive care unit Maternal postpartum behavior and the emergence of infant-mother and infant-father synchrony in preterm and full-term infants: the role of neonatal vagal tone Early dyadic patterns of mother-infant interactions and outcomes of prematurity at 18 months Very preterm birth: maternal experiences of the neonatal intensive care environment Premature birth: complexities and difficulties in building the mother–child relationship Prematurity, maternal posttraumatic stress and consequences on the mother–infant relationship Perinatal assessment of infant, parents, and parent-infant relationship: prematurity as an example Maternal sensitivity in parenting preterm children: a meta-analysis Perceived parental efficacy: concept analysis Self-efficacy and parenting of high-risk infants: the moderating role of parent knowledge of infant development Self-efficacy and parenting quality: findings and future applications Perceived Maternal Parenting Self-Efficacy (PMP S-E) tool: development and validation with mothers of hospitalized preterm neonates Toward a psychology of human agency Behavioral competence among mothers of infants in the first year: the mediational role of maternal self-efficacy Maternal parental self-efficacy in the postpartum period Parenting self-efficacy: links with maternal depression, infant behaviour and adult attachment First-time mothers: social support, maternal parental self-efficacy and postnatal depression Prematurity and parental self-efficacy: the preterm parenting & self-efficacy checklist Development of control-of-outcome scales and self-efficacy scales for women in four life roles Parenting self-efficacy after childbirth Social support and postpartum depressive symptomatology: the mediating role of maternal self-efficacy Maternal self-esteem as affected by infant health infant behavior and family support Social support, infant temperament, and parenting self-efficacy: a mediational model of postpartum depression First-time mothers' perceptions of efficacy during the transition to motherhood: links to infant temperament Mother and father interactions over the first year with term and preterm infants Mother-infant interaction assessment at discharge and at 6 months in a French cohort of infants born very preterm: The OLIMPE study The effects of denial of early mother-infant interaction on maternal self-confidence Postpartal anxiety and depression in mothers of term and preterm infants Mothers' and fathers' personality and parenting: the mediating role of sense of competence Effectiveness of therapeutic behavioral interventions for parents of low birth weight premature infants: a review Parenting stress in mothers after very preterm birth and the effect of the infant behavioural assessment and intervention program NICU-based interventions to reduce maternal depressive and anxiety symptoms: a meta-analysis Key components of early intervention programs for preterm infants and their parents: a systematic review and meta-analysis Effect of an early intervention programme on low birthweight infants with cerebral injuries Intervention With African American Premature Infants: Four-Month Results of an Early Intervention Program L’observation du bébé prématuré: un travail conjoint parents-spécialistes A synactive model of neonatal behavioral organization: framework for the assessment of neurobehavioral development in the premature infant and for support of infants and parents in the neonatal intensive care environment Le bébé prématuré, acteur de son développement. Video feedback in parent-infant treatments How does video interaction guidance contribute to infant and parental mental health and well-being? Effectiveness of hospital-based video interaction guidance on parental interactive behavior, bonding, and stress after preterm birth: a randomized controlled trial The effectiveness of video interaction guidance in parents of premature infants: a multicenter randomised controlled trial Effects of an early intervention on maternal post-traumatic stress symptoms and the quality of mother-infant interaction: the case of preterm birth Development and assessment of a sensory-motor scale for the neonate: a clinical tool at the bedside Principles of good practice for the translation and cultural adaptation Process for Patient-Reported Outcomes (PRO) Measures: report of the ISPOR Task force for translation and cultural adaptation The validation of a self-report measure of posttraumatic stress disorder: the posttraumatic diagnostic scale A French adaptation of the posttraumatic diagnostic scale Parental stressor scale: neonatal intensive care unit Maternal psychological distress and parenting stress after the birth of a very low-birth-weight infant The hospital anxiety and depression scale A validation study of the Hospital Anxiety and Depression Scale (HADS) in a large sample of French employees Detection of postnatal depression. Development of the 10-item edinburgh postnatal depression scale Validation study of the French version of the Edinburgh Postnatal Depression Scale (EPDS): new results about use and psychometric properties A new Mother-to-Infant Bonding Scale: links with early maternal mood Three self-report questionnaires of the early mother-to-infant bond: reliability and validity of the dutch version of the MPAS, PBQ and MIBS Impact of perinatal asphyxia on parental mental health and bonding with the infant: a questionnaire survey of Swiss parents Development and assessment of short and very short forms of the infant behavior questionnaire-revised The eight-item modified medical outcomes study social support survey: psychometric evaluation showed excellent performance The MOS social support survey Significance of prenatal, perinatal and postnatal factors in the development of AGA preterm infants at five to seven years CRIB II: an update of the clinical risk index for babies score Appendix A: the emotional availability scales (2nd ed.; an abridged infancy/Early Childhood version) Emotional availability in mother-child interactions: a reconceptualization for research G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences No adjustments are needed for multiple comparisons |
Answer the following medical question. | What does research say about Response to Therapeutic Interventions in the NICU: Role of Sex as a Biological Variable.? | Sex as a biological variable plays a critical role in the pathophysiology of specific diseases and can have a potential impact on the response to therapies and disease outcomes. Sex-specific differences have been reported in prematurity-related outcomes, suggesting that preterm infants exhibit differences in biological predisposition or resilience to disease. Furthermore, striking differences in response to common neonatal therapies such as antenatal and postnatal steroids, indomethacin, and other nonpharmacologic agents raise the critical need to assess therapeutic responses stratified by biological sex. Very few clinical and translational studies in neonates report outcomes by sex, even though most account for biological sex at enrollment. Sex-specific differences in the newborn may arise from baseline or adaptive differences in male and female preterm neonates. In the current era of precision medicine and the increasing interest in tailoring risk-based therapy to patients, data from neonatal clinical studies should be disaggregated by sex and reported for informing studies with a larger sample size or meta-analyses. Response to Therapeutic Interventions in the NICU: Role of Sex as a Biological Variable |
Answer the following medical question. | What does research say about Myocardial performance imaging for the early identification of cardiac dysfunction in neonates with sepsis.? | The assessment of cardiac performance in septic new-borns is crucial for detecting hemodynamic instability and predicting outcome. The aim of the study is to assess myocardial performance in neonates with sepsis for the early identification of cardiac dysfunction. A case control study was carried out from September 2022 to May 2023 at the Neonatal Intensive care unit, Kasturba Medical College, Manipal. A total of 68 neonates were included in the study, with 33 females and 35 males. The study population was further subdivided into 3 groups namely preterm septic neonates ( n = 21), term septic neonates ( n = 10) and non-septic healthy controls ( n = 37). The cardiac structure and function were assessed using conventional method, Tissue Doppler imaging (Sm) and speckle tracking echocardiography (GLS). The study was approved by the Institutional Ethics Committee at Kasturba Medical College, Manipal (approval number IEC: 90/2022). The CTRI registration number for the study is CTRI/2022/09/045437 and was approved on September 12, 2022. Prior to the neonate’s enrolment, informed consent was obtained from their mothers or legal guardians. Out of the total 68 neonates, 31 were cases and 37 were controls which included 33 females and 35 males. LV systolic function was not statistically significant between cases and controls. E/A ratio of the mitral valve was significantly lower in septic newborns than in healthy neonates. (1.01 ± 0.35 vs 1.18 ± 0.31, p < 0.05) preterm neonates showed significantly lower Lateral E’ and RV E’ velocities than term neonates. TAPSE was significantly lower in septic preterm neonates. (8.61 ± 1.28 vs. 10.7 ± 2.11, p < 0.05) No significant difference was noted in the Myocardial Performance Index between septic neonates and healthy neonates. LV Global Longitudinal Strain was slightly lower in preterm septic neonates than in term neonates with sepsis. Septic newborns are associated with LV diastolic dysfunction, RV systolic dysfunction and substantially higher pulmonary systolic pressures. Open access funding provided by Manipal Academy of Higher Education, Manipal “Neonatal sepsis is a clinical syndrome characterized by signs and symptoms of infection with or without accompanying bacteremia in the first month of life. It encompasses various systemic infections of the new born such as septicemia, meningitis, pneumonia, arthritis, osteomyelitis, and urinary tract infections.” [ 1 ]. Globally, sepsis affects 4 to 22 new-borns per 1,000 live births, with frequencies changing inversely with the gestational age at birth [ 2 ]. Furthermore, clinical sepsis is most common in India with a prevalence of 17,000 per 1,00,000 live births and has a fatality rate ranging between 25 and 65% [ 3 ]. Neonatal sepsis is classified as early and late onset sepsis on the basis of time and age of onset [ 4 ]. The effects of neonatal sepsis in neonates include cardiovascular problems, myocyte destruction, and changes in cardiac blood flow caused by inflammatory mediators [ 5 ]. Tissue Doppler imaging is more sensitive in assessing diastolic function and is less dependent on preload and afterload than conventional Doppler methods [ 6 ]. Myocardial strain and strain rate analyse cardiac deformational changes with the advantage of detecting preclinical cardiac dysfunction. Strain is a measure of myocardial deformation. Whereas Strain rate is the speed at which the deformation occurs and is expressed as per second [ 7 ]. Speckle tracking echocardiography imaging technique outlines the limitations imposed by traditional methods like M mode, volumetric methods and Doppler imaging technique which are routinely used to assess cardiac function. Neonates with sepsis showed subclinical diastolic and systolic dysfunction when assessed using tissue Doppler imaging [ 8 ]. Strain imaging has been proved as a sensitive method in detecting sub- clinical myocardial dysfunction. However only a few studies have been done on the assessment of cardiac function in preterm and term neonates with sepsis using speckle tracking echocardiography. Thus, in this present study we aimed to assess cardiac function in septic neonates by using various non-invasive assessment methods such as Tissue Doppler Imaging, Speckle Tracking Echocardiography which would assist in detecting subclinical LV dysfunction and in determining the optimal timing for management strategies. A case control study was carried out from September 2022 to May 2023 at the Neonatal Intensive Care Unit (NICU), Kasturba Medical College, Manipal. A total of 68 neonates were included in the study. The study population was further subdivided into 3 groups namely preterm septic neonates (Gestational age < 37weeks, n = 21), term septic neonates (Gestational age > 37weeks, n = 10) and non-septic healthy controls ( n = 37). Neonates admitted to Neonatal Intensive care unit (NICU), Kasturba Medical College, Manipal with diagnosis of culture positive sepsis, Intra Uterine Growth Restriction, and Babies on ventilators and Non Invasive Ventilation were included in the study. Whereas Infants with congenital malformations, Hypoxic ischemic encephalopathy, genetic syndromes, critical CHDs were excluded. Enrolled control subjects were the ones admitted to Neonatal Intensive care unit, Manipal without culture proven sepsis. The study was approved by the Institutional Ethics Committee, Kasturba Medical College, Manipal, (approval number IEC: 90/2022). The CTRI registration number for the study is CTRI/2022/09/045437 and was approved on September 12, 2022. Informed consent was obtained from the mothers or guardians of the neonates before their enrolment. For the neonates fulfilling the inclusion criteria, initial Echocardiographic examination was performed within 48 h of diagnosis using Vivid IQ echo machine from GE with 5 MHz transducer. The cardiac structure and function were assessed using conventional, Tissue Doppler imaging and speckle tracking echocardiography with ECG. LV internal dimensions, Interventricular septum (IVS), Posterior wall (PW) thickness, Ejection Fraction (EF), and Fractional Shortening (FS) were obtained from M mode by placing the cursor perpendicular to mitral leaflets. Mitral (E, E/A ratio) and aortic flow velocities was acquired from apical views (4 &5 chamber) respectively using pulse wave doppler by placing sample volume at tips (Fig. 1 ). Fig. 1 Bar graph representation of group wise gender distribution Bar graph representation of group wise gender distribution Tricuspid annular plane systolic excursion (TAPSE) and Inferior vena cava (IVC) values were obtained from M mode at tricuspid valve annulus and IVC respectively [ 7 ]. The TEI-index for the left and right ventricles were determined by analysing the Doppler tracings of the respective AV valves and semilunar valves and was measured using the formula (IVRT + IVCT)/ET [ 7 ]. [IVRT: Isovolumetric relaxation time, IVCT: Isovolumetric contraction time, ET: Ejection time]. RV systolic pressure was obtained through continuous wave Doppler analysis with the sample volume across the TR jet. The obtained TR jet velocity provides an estimation of the pressure difference between the right heart chambers. To quantify pulmonary hypertension, systolic pulmonary artery pressure (PAP) was estimated by calculating the fraction of systemic systolic blood pressure (BP). A ratio of less than one-third was considered normal, while ratios ranging from one-third to two-thirds indicated mild pulmonary hypertension. Ratios between two-thirds and one signified moderate pulmonary hypertension and ratios exceeding one indicated severe pulmonary hypertension [ 9 ]. TDI targets the tissue motion and has 3 phases which are denoted by early diastolic tissue annular velocity (Ea), late diastolic annular velocity (Aa), and systolic annular velocity (Sa), respectively. Tissue Doppler velocities were obtained by placing the cursor across respective walls and by applying Pulse wave Doppler [ 7 ] (Fig. 2 ). Fig. 2 LV diastolic function by conventional doppler LV diastolic function by conventional doppler Longitudinal strain and strain rate analysis were performed offline using the ECHOPAC software system. Displacement of each myocardial speckles was tracked and analyzed frame to frame. Three consecutive cardiac cycles were recorded in the apical 4,3,2 chamber views. The LV myocardium was traced in its entirety (Fig. 3 ). Fig. 3 LV diastolic function by TDI LV diastolic function by TDI The software automatically generates a Bull’s eye visualization of 17 myocardial segments, along with strain and strain rate curve patterns for each segment. Strain rates were measured at peak systole, early diastole, and late diastole, and Global Longitudinal Strain (GLS) was obtained [ 10 ] (Fig. 4 ). Fig. 4 Deformation imaging of LV in apical 4ch view Deformation imaging of LV in apical 4ch view All the data was entered in an Excel sheet, and analysis was performed using SPSS version 16. Continuous variables were expressed as mean ± SD. Comparison between cases and controls was done using an independent T test. Non-parametric Kruskal wallis test was used for skewed data and the variables were presented in Median (IQR). Within group comparison was carried out using ANOVA and Post hoc analysis by Bonferroni test. P < 0.05 was considered statistically significant. A total of 68 neonates were enrolled, of whom 31 were cases and 37 were controls. Among the case subjects, 21 (30.8%) were preterm neonates, while 10 (14.7%) were term neonates. The mean gestational age at birth of the study participants was 35.5 ± 3.6 weeks and the mean age of enrolled neonates was 7.3 ± 5.4 days. Of the 68 neonates, 33 (48.5%) were females and 35 (51.5%) were male. Group-wise gender analysis revealed that among the preterm neonates, 14 (66.7%) were male and 7 (33.3%) were female. Among the term neonates, 4 (40%) were male and 6 (60%) were female. Among the control group, 17 (45.9%) were male and 20 (54.1%) were female (Fig. 5 ). Fig. 5 Global longitudinal assessment using STE with bull’s eye model Global longitudinal assessment using STE with bull’s eye model Other demographic variables and clinical characteristics are mentioned in (Table 1 ). Table 1 Demographic variables and clinical characteristics of the subjects Variable Preterm N = 21 [Mean ± SD] OR [Median (IQR)] Term N = 10 [Mean ± SD] OR [Median (IQR)] Control N = 37 [Mean ± SD] OR [Median (IQR)] P Value Age in days 9 (6.5, 14.5) 9 (5,19) 4(2, 6) < 0.001* Length (cm) 40 ± 3.6 47.7 ± 2.9 46.3 ± 3.6 < 0.001* Birth weight (g) 1481 ± 433 2674 ± 305.7 2674 ± 486.5 < 0.001* Gestational age (weeks) 31.6 ± 2.9 39 ± 0.78 37.0 ± 2.0 < 0.001* Invasive ventilation n (%) 6(28%) 3 (30%) - - Non-invasive ventilation n (%) 13(61%) 3 (30%) - - No respiratory support n (%) 2(9%) 4 (40%) - - Demographic variables and clinical characteristics of the subjects Among the 31-culture positive septic neonates in our study, Klebsiella pseudomonas was the predominant pathogen 12 (38.7%) followed by Acinetobacter baumanii (25.8%) and Escherichia coli (16.1%) (Table 2 ). Table 2 Pathogens involved in sepsis among the study population Organism N = 31 Klebsiella pseudomonas 12(38.7%) Acinetobacter baumanii 8 (25.8%) Escherichia coli 5 (16.1%) Enterococcus faecium 2 (6.45%) Streptococcus agalactiae 1 (3.22%) Herbaspirullum 1 (3.22%) Streptococcus gallolyticus 1 (3.22%) Chryobacterium sepsis 1 (3.22%) Pathogens involved in sepsis among the study population Preterm neonates needed more ventilator and non-invasive ventilation (NIV) support than term neonates during hospital stay, with dopamine being the most frequently used inotropic agent. It was observed that C-reactive protein(CRP) is substantially high in preterm neonates than in term and control neonates with a p value < 0.05 (Table 3 ). Table 3 Comparison of laboratory parameters among controls and sub group of cases Lab parameters Preterm N = 21 [Mean ± SD] OR [Median (IQR)] Term N = 10 [Mean ± SD] OR [Median (IQR)] Control N = 37 [Mean ± SD] OR [Median (IQR)] P Value Hb (g/dl) 15.2 ± 3.6* 15.8 ± 3.1 17.7 ± 2.9* 0.025* Hct (%) 45.8 ± 8.8* 47.5 ± 9.8 53.7 ± 9.2* 0.009* TLC (×10 3 /µL) Median (IQR) 8.6 (4.75, 15.6) 10 (5.702, 13.455) 12.68 (9.57, 16.82) 0.084 Neutrophil (%) 51.6 ± 14.5 55.6 ± 19.7 58.7 ± 19.1 0.364 Lymphocyte (%) Median (IQR) 29 (19.5, 38.55) 24.5 (11.52, 44.075) 21.25(13.22, 38.37) 0.518 Monocyte (%) Median (IQR) 8 (5.5, 12.6) 11.15 (8.75, 12.35) 9.5 (7.05, 12.12) 0.407 Eosinophil (%) Median (IQR) 2 (1.0, 5.5) 3.6 (1, 9) 1.5 (0.90, 3.025) 0.140 PLT (×10 3 /µL) Median (IQR) 189 (90.5, 271) 109 (69, 220) 251 (214, 294.5) 0.003* CRP (mg/L) Median (IQR) 25.15 (0.745, 77.33) 27.34 (2.31, 49.885) 0.6 (0.6, 2.61) 0.001* Hb: Hemoglobin, HCT: hematocrit, TLC: Total leukocyte count, PLT: Platelet count CRP: C reactive protein Comparison of laboratory parameters among controls and sub group of cases TLC (×10 3 /µL) Median (IQR) Lymphocyte (%) Median (IQR) Monocyte (%) Median (IQR) Eosinophil (%) Median (IQR) PLT (×10 3 /µL) Median (IQR) CRP (mg/L) Median (IQR) Hb: Hemoglobin, HCT: hematocrit, TLC: Total leukocyte count, PLT: Platelet count CRP: C reactive protein The echocardiographic parameters of septic new-borns and control group are summarized in Tables 4 and 5 . Table 4 Comparison of echocardiographic parameters between cases and controls Parameters Case N = 31 Control N = 37 P value IVSd (mm) 3.35 ± 0.79 3.54 ± 0.60 0.279 IVSs (mm) 3.54 ± 0.92 4.05 ± 0.8 0.022* LVPWd (mm) 3.09 ± 0.78 3.02 ± 0.49 0.660 LVPWs (mm) 4.67 ± 1.04 4.59 ± 0.76 0.707 Mitral E (m/s) 0.50 ± 0.11 0.48 ± 0.12 0.519 Mitral A(m/s) 0.52 ± 0.14 0.42 ± 0.10 0.001* Mitral E/A ratio 1.01 ± 0.35 1.18 ± 0.31 0.048* Tricuspid E (m/s) 0.43 ± 0.13 0.43 ± 0.11 0.921 Tricuspid A(m/s) 0.51 ± 0.12 0.470 ± 0.11 0.123 Tricuspid E/A ratio 0.88 ± 0.32 0.95 ± 0.28 0.327 LV EDD (mm) 14.8 ± 2.77 16.54 ± 2.14 0.007* LV ESD (mm) 9.64 ± 1.74 10.70 ± 1.43 0.008* LV EF (%) 67.7 ± 5.67 67.83 ± 4.44 0.959 LV FS (%) 34.6 ± 4.16 34.89 ± 3.35 0.788 TAPSE (mm) 9.2 ± 1.84 9.51 ± 1.21 0.553 PASP (mmHg) 21.83 ± 12.06 15.24 ± 3.78 0.002* LV IVCT (ms) 43.29 ± 6.43 44.18 ± 6.73 0.578 LV IVRT (ms) 46.74 ± 7.65 48.54 ± 8.01 0.350 LV ET (ms) 165.58 ± 24.37 181 ± 23.97 0.011* LV MPI 0.54 ± 0.09 0.51 ± 0.1 0.221 LV DT (ms) 85.58 ± 29.95 103.62 ± 33.51 0.023* RV IVCT (ms) 40.51 ± 8.78 42.29 ± 8.53 0.401 RV IVRT (ms) 40.83 ± 8.05 43.02 ± 8.42 0.280 RV ET (ms) 163.8 ± 53.67 187.73 ± 40.71 0.041* RV MPI 0.54 ± 0.21 0.47 ± 0.14 0.103 RV DT (ms) 90.5 ± 30.68 106.13 ± 38.39 0.073 Septal E’ (m/s) 0.053 ± 0.013 0.051 ± 0.013 0.449 Septal A’ (m/s) 0.054 ± 0.013 0.047 ± 0.012 0.031* Septal S’ (m/s) 0.04 ± 0.008 0.04 ± 0.007 0.113 Lateral E’ (m/s) 0.062 ± 0.018 0.066 ± 0.016 0.299 Lateral A’ (m/s) 0.067 ± 0.017 0.06 ± 0.013 0.069 Lateral S’ (m/s) 0.055 ± 0.013 0.054 ± 0.008 0.522 RV E’ (m/s) 0.07 ± 0.02 0.07 ± 0.01 0.508 RV A’ (m/s) 0.09 ± 0.017 0.09 ± 0.013 0.668 RV S’ (m/s) 0.07 ± 0.016 0.06 ± 0.01 0.013* LV STRAIN (%) -18.8 ± 3.29 -19.58 ± 2.14 0.245 LV SSR (%) -2.21 ± 0.36 -1.96 ± 0.26 0.002* LV EDSR 2.87 ± 0.75 3.02 ± 0.61 0.388 LV LDSR 2.59 ± 0.53 1.96 ± 0.47 < 0.001* RV STRAIN (%) -23.02 ± 5.38 -21.9 ± 4.26 0.342 RV SSR (%) -2.57 ± 0.58 -2.09 ± 0.42 < 0.001* RV EDSR 3.37 ± 1.3 2.63 ± 1.00 0.010 RV LDSR 3.1 ± 1.19 2.55 ± 1.09 0.035 LVEDD-LV internal dimension in diastole, LVESD-LV internal dimension in systole, EF-Ejection fraction FS- Fractional shortening IVSd- septal thickness diastole IVSs- septal thickness systole PWd- posterior wall thickness diastole PWs- posterior wall thickness systole TAPSE-Tricuspid annular plane septal excursion. PASP- pulmonary artery systolic pressure IVCT- Isovolumic contraction time IVRT- Isovolumic relaxation time ET- Ejection time MPI: Myocardial performance index DT- Deceleration time SSR- strain rate EDSR- Early diastolic strain rate LDSR- Late diastolic strain rate Comparison of echocardiographic parameters between cases and controls LVEDD-LV internal dimension in diastole, LVESD-LV internal dimension in systole, EF-Ejection fraction FS- Fractional shortening IVSd- septal thickness diastole IVSs- septal thickness systole PWd- posterior wall thickness diastole PWs- posterior wall thickness systole TAPSE-Tricuspid annular plane septal excursion. PASP- pulmonary artery systolic pressure IVCT- Isovolumic contraction time IVRT- Isovolumic relaxation time ET- Ejection time MPI: Myocardial performance index DT- Deceleration time SSR- strain rate EDSR- Early diastolic strain rate LDSR- Late diastolic strain rate Table 5 Comparison of echocardiographic parameters between sub group of cases and controls Parameters Preterm n = 21 Term N = 10 Control N = 37 P value IVSd (mm) 3.04 ± 0.58*$ 4 ± 0.81* 3.54 ± 0.6$ 0.001* IVSs (mm) 3.14 ± 0.65*$ 4.4 ± 0.84* 4.05 ± 0.84$ < 0.001* LVPWd (mm) 2.81 ± 0.6* 3.7 ± 0.82*$ 3.02 ± 0.49$ 0.001* LVPWs (mm) 4.42 ± 0.97 5.2 ± 1.03 4.59 ± 0.76 0.074 Mitral E (m/s) 0.46 ± 0.1* 0.58 ± 0.1* 0.48 ± 0.12 0.042* Mitral A(m/s) 0.52 ± 0.14* 0.53 ± 0.14$ 0.42 ± 0.1*$ 0.004* Mitral E/A ratio 0.94 ± 0.25* 1.18 ± 0.47 1.18 ± 0.31* 0.023* Tricuspid E(m/s) 0.42 ± 0.11 0.45 ± 0.18 0.43 ± 0.11 0.904 Tricuspid A(m/s) 0.51 ± 0.12 0.53 ± 0.13 0.47 ± 0.11 0.279 Tricuspid E/A ratio 0.87 ± 0.26 0.9 ± 0.42 0.95 ± 0.28 0.602 LV EDD (mm) 13.9 ± 2.66*$ 16.9 ± 1.79$ 16.54 ± 2.14* < 0.001* LV ESD (mm) 9 ± 1.61*$ 11 ± 1.15$ 10.7 ± 1.43* < 0.001* LV EF (%) 67.95 ± 5.8 67.4 ± 5.69 67.83 ± 4.44 0.959 LV FS (%) 34.61 ± 4.27 34.7 ± 4.16 34.89 ± 3.35 0.963 TAPSE (mm) 8.61 ± 1.28* 10.7 ± 2.11* 9.51 ± 1.21 0.001* PASP (mmHg) 21 ± 12.33 23.6 ± 11.89* 15.24 ± 3.78* 0.008* LV IVCT (ms) 42.85 ± 6.58 44.2 ± 6.33 44.18 ± 6.73 0.747 LV IVRT (ms) 46.52 ± 7.92 47.2 ± 7.42 48.54 ± 8.01 0.633 LV ET (ms) 163.61 ± 27.21* 169.7 ± 17.51 181 ± 23.97* 0.032* LV MPI 0.55 ± 0.1 0.53 ± 0.08 0.51 ± 0.1 0.446 LV DT (ms) 79.52 ± 26.78* 98.3 ± 33.64 103.62 ± 33.51* 0.024* RV IVCT (ms) 40.81 ± 9.45 39.9 ± 7.6 42.29 ± 8.53 0.679 RV IVRT (ms) 40.76 ± 8.39 41 ± 7.71 43.02 ± 8.42 0.559 RV ET (ms) 162.66 ± 54.97 166.2 ± 53.62 187.73 ± 40.71 0.123 RV MPI 0.54 ± 0.20 0.54 ± 0.25 0.47 ± 0.14 0.268 RV DT (ms) 84.09 ± 30.11 104.1 ± 28.66 106.13 ± 38.39 0.067 Septal E’ (m/s) 0.05 ± 0.012 0.06 ± 0.014 0.051 ± 0.013 0.130 Septal A’ (m/s) 0.051 ± 0.014 0.060 ± 0.012* 0.047 ± 0.012* 0.026* Septal S’ (m/s) 0.044 ± 0.008 0.05 ± 0.009 0.043 ± 0.007 0.052 Lateral E’ (m/s) 0.054 ± 0.013*$ 0.078 ± 0.018* 0.066 ± 0.016$ 0.001* Lateral A’ (m/s) 0.065 ± 0.018 0.072 ± 0.013 0.060 ± 0.013 0.110 Lateral S’ (m/s) 0.054 ± 0.015 0.058 ± 0.009 0.054 ± 0.008 0.616 RV E’ (m/s) 0.066 ± 0.021* 0.088 ± 0.025* 0.070 ± 0.015 0.016* RV A’ (m/s) 0.09 ± 0.013 0.09 ± 0.024 0.09 ± 0.013 0.766 RV S’ (m/s) 0.07 ± 0.013$ 0.08 ± 0.018*$ 0.06 ± 0.010* 0.001* LV STRAIN (%) -18.29 ± 3.64 -19.88 ± 2.17 -19.58 ± 2.14 0.161 LV SSR -2.19 ± 0.31* -2.26 ± 0.47$ -1.96 ± 0.26*$ 0.007 LV EDSR 2.71 ± 0.8 3.21 ± 0.52 3.02 ± 0.61 0.114 LV LDSR 2.55 ± 0.43* 2.67 ± 0.72$ 1.96 ± 0.47*$ < 0.001 RV STRAIN (%) -22.16 ± 5.6 -24.82 ± 4.65 -21.9 ± 4.26 0.226 RV SSR -2.59 ± 0.65* -2.52 ± 0.44 -2.09 ± 0.42* 0.001 RV EDSR 3.3 ± 1.08 3.52 ± 1.73 2.63 ± 1.00 0.32 RV LDSR 3.04 ± 1.11 3.38 ± 1.4 2.55 ± 1.09 0.082 LVEDD-LV internal dimension in diastole, LVESD-LV internal dimension in systole, EF-Ejection fraction FS- Fractional shortening IVSd- septal thickness diastole IVSs- septal thickness systole PWd- posterior wall thickness diastole PWs- posterior wall thickness systole TAPSE-Tricuspid annular plane septal excursion. PASP- pulmonary artery systolic pressure IVCT- Isovolumic contraction time IVRT- Isovolumic relaxation time ET- Ejection time MPI: Myocardial performance index DT- Deceleration time SSR- strain rate EDSR- Early diastolic strain rate LDSR- Late diastolic strain rate * and $ indicate that the observed differences between groups are statistically significant ( p < 0.05) Comparison of echocardiographic parameters between sub group of cases and controls LVEDD-LV internal dimension in diastole, LVESD-LV internal dimension in systole, EF-Ejection fraction FS- Fractional shortening IVSd- septal thickness diastole IVSs- septal thickness systole PWd- posterior wall thickness diastole PWs- posterior wall thickness systole TAPSE-Tricuspid annular plane septal excursion. PASP- pulmonary artery systolic pressure IVCT- Isovolumic contraction time IVRT- Isovolumic relaxation time ET- Ejection time MPI: Myocardial performance index DT- Deceleration time SSR- strain rate EDSR- Early diastolic strain rate LDSR- Late diastolic strain rate * and $ indicate that the observed differences between groups are statistically significant ( p < 0.05) The Ejection Fraction and fractional Shortening determining LV systolic function showed no significant difference between septic preterm, term and control groups. LV internal dimensions are higher in term neonates than preterm neonates which was statistically significant ( p < 0.05). Mitral E/A ratio is lower in septic newborns than controls. Inexplicably, non-septic control newborns had lower mitral E (0.48 ± 0.12 vs. 0.58 ± 0.1) and A wave (0.42 ± 0.1 vs. 0.53 ± 0.14, p < 0.05) velocities when compared with septic term neonates. TAPSE is significantly lower in preterm neonates indicating impaired RV systolic function while substantially high Pulmonary artery systolic pressure (PASP) was noted in two preterm and one term septic newborns. A positive correlation was noted between CRP and PASP, however, other echocardiographic parameters did not show any correlation. LV and RV ejection time, LV deceleration time were significantly lower in neonates with sepsis than in non-septic neonates with a p value < 0.05. However, the Myocardial Performance Index (MPI) showed no difference between septic neonates and control group. The septal A’ velocity and RV S’ velocity was higher in neonates with sepsis than in controls, which was statistically significant (p value < 0.05). Other parameters, however, displayed no significant variation between groups. In comparison to controls, the LV myocardial contractility is slightly reduced in septic neonates. However, LV systolic strain rate (SSR), LV late diastolic strain rate (LDSR), RV Systolic Strain Rate were significantly higher in septic newborns than in controls ( p < 0.05). In our investigation comprising 31 neonates with sepsis, we observed a mortality rate of 12.9%, with 4 neonates succumbing to death. Septic shock emerged as the predominant cause of mortality among the affected neonates. Increased neonatal vulnerability to sepsis is primarily due to an immature immune system. During the period of sepsis in neonates, the cytokine production, as well as the concomitant acidosis and hypoxia, may be responsible for the myocardial dysfunction [ 11 – 13 ]. In the present study a total of 68 neonates which included [33 female and 35 males], with a mean age of 7.3 ± 5.4 days were enrolled. In the present study, CRP is markedly higher in neonates with sepsis than in the control group. Moreover, preterm neonates exhibited higher levels of CRP than term babies. According to the literature, CRP can be deemed a dependable adjunctive tool for suspecting sepsis, despite its nonspecific nature [ 14 ] [Table 3 ]. As a measure of systolic function, LV fractional shortening is commonly applied to neonates. However, it is highly sensitive to variations in heart rate and ventricular burden [ 15 ]. As a measure of global left ventricular systolic function, Systolic velocity wave (Sm) of mitral annulus is preferred as it is less sensitive to loading conditions [ 16 ]. The results of our study revealed no statistically significant distinction in LV systolic function and Sm of the mitral annulus when comparing the septic group to the control group, as well as between preterm and term neonates. These findings align with a previous study conducted by Tomerak RH et al. [ 17 ] and differ from those of the earlier study conducted by Abdel- Hady et al. who demonstrated that septic neonates showed significantly lower Sm values compared to controls suggesting LV systolic dysfunction [ 18 ]. Diastolic dysfunction is characterized by impaired ventricular filling and relaxation during diastole. The findings of our study revealed that the E/A ratio of the mitral valve was significantly lower in septic newborns than in healthy neonates, suggesting left ventricular diastolic dysfunction which is in accordance with the findings of Tomerak et al. [ 17 ] On the contrary, Abdel-Hady et al. found no statistically significant difference in mitral E/A ratio among septic and healthy neonates [ 8 ]. On comparison of diastolic parameters among preterm and term neonates with sepsis, mitral E wave velocity and E/A ratio are lower in preterm neonates. It’s because of poor cardiac compliance and alleviated diastolic performance. Preterm newborns have lower trans-mitral early filling flow phase (E- wave) than active flow (A-wave). As a result, the E/A ratio is less than 1.0. This is in contrast to the term neonate, in which the passive flow phase predominates and the E/A > 1 [ 18 ]. These findings are in contrast with those of Tomerak et al who reported no significant difference in mitral E and E/A ratio between term and preterm septic neonates. The results of our study suggest that preterm neonates showed significantly lower lateral E’ and RV E’ velocities than term neonates may be indicating an early impaired LV and RV diastolic dysfunction respectively. The current study revealed that pulmonary artery systolic pressure was substantially higher in septic newborns than in controls (Table 5 ). This is in support of the previous findings by Mohsen and Amin, who disclosed that neonatal sepsis is the second most prevalent cause of pulmonary hypertension, accounting for 43.7% of all cases [ 19 ]. We found no significant variations in the E/A ratio of the tricuspid valve among septic and healthy newborns, which is in accordance with the findings of [ 8 ]. A study conducted by Abdel-Hadey et al., 2012 aimed at analysing myocardial performance using tissue doppler imaging reported a significant increase in Myocardial Performance Index in neonates with sepsis. However, in the present study the Myocardial Performance Index showed no significant difference between the septic neonates and controls, which was partially consistent with the findings of Tomerak et al. The differences in findings may be due to unequal sample distribution. Abdel hadey et al., also stated that septic newborns had significantly lower RV S’ velocity when compared to healthy controls, indicating right ventricular systolic dysfunction [ 8 ]. TAPSE is a simple method that is confirmed to be relevant for assessing right ventricular function, and in our study, when TAPSE was compared among term and preterm septic neonates, it was significantly lower in septic preterm neonates, suggesting impaired RV systolic function (Table 5 ). Speckle tracking echocardiography is superior to Tissue Doppler Imaging in providing an angle-independent evaluation of regional myocardial deformation [ 20 ]. In our study, the LV global longitudinal strain was slightly lower in preterm septic neonates than in term neonates with sepsis, may be indicating subclinical myocardial dysfunction which is in line with the study conducted by Hirose A et al [ 21 ]. On the contrary, Mostafa Awany et al., reported significant reductions in LV and RV Global Longitudinal Strain values among septic neonates than healthy neonates indicating sub clinical systolic dysfunction [ 22 ]. According to a study conducted by Hirose et al., preterm newborns had lower baseline circumferential early diastolic strain rate and greater late diastolic strain rate than healthy neonates. And also, there were no statistically significant differences between preterm infants and controls in terms of Ejection fraction, Fractional Shortening, longitudinal or circumferential strain, or strain rate [ 21 ]. In our study we found that LV Systolic strain rate and RV Systolic strain rate showed statistically significant difference between cases and controls with higher values in septic neonates however strain rate values cannot clinically detect cardiac dysfunction in neonates with sepsis [Table 4 ]. Further studies are needed to determine the optimal approach to strain imaging in neonates with sepsis, and to validate its use in this population. Unequal sample distribution among preterm and term neonates with sepsis is the major limitation of our study. Due to technical issues, time frame and challenging echo windows in extremely preterm, very low birth weight neonates the sample size could not be achieved. And parents of premature or critically sick infants did not give their consent for this study. Upon the assessment of cardiac function by conventional, Tissue Doppler Imaging and speckle tracking echocardiography, it is found that septic newborns are associated with LV diastolic dysfunction, RV systolic dysfunction, and substantially higher pulmonary systolic pressures. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Not applicable. Ms. Sudheshna Lalitha Sumbaraju collected the data, analysis and excel sheet entry.Dr Leslie Edward Lewis and Dr Krishnananda Nayak supervised the entire study.Ms. Sridevi Prabhu and Ms. Vidya Nayak prepared the manuscript.Ms. K Prathiksha Prabhu did the statistical analysis. Not applicable. Open access funding provided by Manipal Academy of Higher Education, Manipal Master sheet with individual patient data will be submitted if requested. Institutional ethical committee clearance was obtained. Mothers or guardians of neonates gave informed written consent. Mothers or guardians of enrolled neonates gave their written informed consent for publication of data. Not applicable. Myocardial performance imaging for the early identification of cardiac dysfunction in neonates with sepsis Risk factors of neonatal sepsis in India: a systematic review and meta-analysis Assessment of neonatal Sepsis on myocardial function by tissue Doppler Imaging Echocardiographic assessment of pulmonary arterial hypertension for pediatricians and neonatologists American College of Critical Care Medicine task force committee members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock Left ventricular end-systolic wall stress- velocity of fiber shortening relation: a load-independent index of myocardial contractility Neonatologist-performed functional echocardiography in the neonatal intensive care unit Risk factors and outcomes of persistent pulmonary hypertension of the newborn in neonatal intensive care unit of Al-Minya University hospital in Egypt Evolution of left ventricular function in the preterm infant Cardiac functions by tissue doppler and speckle Tracking Echocardiography in neonatal Sepsis and its correlation with Sepsis markers and Cardiac Troponin-T |
Answer the following medical question. | What does research say about Restrictive guideline for red blood cell transfusions in preterm neonates: effect of a protocol change.? | To evaluate red blood cell ( RBC ) transfusion practices in preterm neonates before and after protocol change. All preterm neonates (<32 weeks of gestation) admitted between 2008 and 2017 at our neonatal intensive care unit were included in this retrospective study. Since 2014, a more restrictive transfusion guideline was implemented in our unit. We compared transfusion practices before and after this guideline change. Primary outcome was the number of transfusions per neonate and the percentage of neonates receiving a blood transfusion. Secondary outcomes were neonatal morbidities and mortality during admission. The percentage of preterm neonates requiring a blood transfusion was 37·5% (405/1079) before and 32·7% (165/505) after the protocol change ( P = 0·040). The mean number of transfusions given to each transfused neonate decreased from 2·93 (standard deviation ( SD ) ± 2·26) to 2·20 ( SD ±1·29) ( P = 0·007). We observed no association between changes in transfusion practices and neonatal outcome. The use of a more restrictive transfusion guideline leads to a reduction in red blood cell transfusions in preterm neonates, without evidence of an increase in mortality or short‐term morbidity. Blood products, in particular red blood cell (RBC) transfusions, are frequently administered in preterm neonates during their stay in the neonatal intensive care unit (NICU). Up to 90% of extreme preterm neonates receive one or more transfusions in the first few weeks of life 1 , 2 . RBC transfusions in neonates are mostly administered prophylactically, when haemoglobin (Hb) levels drop below a certain level (transfusion trigger). However, the optimal transfusion trigger in neonates is not known and wide variance in Hb triggers and transfusion guidelines is used internationally 1 . In the past decade, studies comparing liberal vs. restrictive transfusion guidelines in neonates showed conflicting results, in terms of short‐term outcome as well as long‐term neurodevelopmental outcome 3 , 4 , 5 , 6 . Various studies, both in adults and in children admitted to intensive care units, reported that restrictive RBC transfusion guidelines decrease transfusion requirements and the intrinsically associated patient burden, costs and labour. Importantly, the restrictive transfusion strategies were not associated with an increase in adverse outcomes 7 . On the contrary, several studies suggest that less RBC transfusions should also reduce possible transfusion‐related immunomodulation 8 , 9 . Therefore, the lack of evidence for inferiority, together with the default advantages of restriction, led to ditto recommendations in the national transfusion guideline in 2014. We accordingly adapted our local transfusion protocol from a liberal to a more restrictive transfusion strategy. The objective of this study was to evaluate the effect of the protocol change on the RBC transfusion practices and investigate the effect on neonatal morbidity and mortality. This retrospective observational cohort study was conducted at the Leiden University Medical Centre (LUMC), a tertiary care centre in the Netherlands. We included all consecutive preterm neonates admitted to our NICU between 01‐01‐2008 and 31‐12‐2016, with gestational age at birth between 24 + 0 and 31 + 6 weeks. The neonates were divided into two cohorts based on their year of birth, before and after the protocol change made in 2014. The study was approved by the Leiden Medical Ethics Committee (institutional review board) in July 2017 (G17·045). Before 2014, the guidelines used in the LUMC for RBC transfusions in neonates were based on the Dutch national guidelines from 2004 10 . Since 2014, our local guideline was changed, based on a Cochrane systematic review 11 . The transfusion guidelines before 2014 were mainly based on specific Hb triggers (arterial or venous blood samples) and the need and type of respiratory support. The transfusion guidelines after 2014 were based on lower Hb triggers (also arterial or venous blood samples) in association with both the need of respiratory support and postnatal age in weeks (Table 1 ). The transfusion dosage, velocity of infusion and irradiation requirements remained the same during the two study periods. Routine transfusion dosage was 15 ml/kg administered in 3 h, using irradiated and leucocyte‐depleted product. (a) Haemoglobin transfusion triggers before guideline change in 2014. (b) Haemoglobin transfusion triggers after guideline change in 2014 Respiratory support g/dl No respiratory support g/dl CPAP, continuous positive airway pressure. After postnatal age ≥ 28 days, the recommended transfusion trigger was <7 g/dl (4·5 mmol/l). The primary outcome was the number of neonates requiring a RBC transfusion and the number of RBC transfusions per neonate. The secondary outcomes were changes in neonatal morbidities and mortality during admission. Data were furthermore analysed according to gestational age at birth and week of life. We recorded the following neonatal variables, including respiratory distress syndrome (RDS) defined as respiratory failure requiring ventilator support and surfactant treatment, severe intraventricular haemorrhage (IVH grade 3 or 4), cystic periventricular leukomalacia (PVL grade 2 or 3), symptomatic patent ductus arteriosus (PDA) requiring medical treatment (indomethacin or ibuprofen) or surgical closure, necrotizing enterocolitis (NEC) ≥ stage 2 12 , proven neonatal sepsis defined as a clinically ill neonate with a positive bacterial blood culture and neonatal mortality and length of stay at our NICU. The recorded short‐term morbidities were not indications for transfusions, but used as secondary outcomes for this study. In order to detect 10% difference in transfusions before and after the protocol change (assuming 40% in the cohort before and 30% in the cohort after 2014), with a power of 80% and type one error of 5%, the sample size was estimated to be at least 354 neonates per cohort. Results are expressed as percentages, mean (standard deviation (SD)) for normally distributed values (as calculated for with the Shapiro–Wilk test) or median (interquartile range (IQR)) for nonnormally distributed values. Results of categorical variables were compared using the chi‐squared test, whereas the independent Student's t ‐test and Mann–Whitney U‐test were used for normally and nonnormally distributed continuous variables, as appropriate. A P ‐value <0·05 was considered to indicate statistical significance. All statistical analyses were performed using spss version 23·0 (IBM, Chicago, IL, USA). A total of 1584 preterm neonates delivered before 32 weeks of gestation were admitted to our NICU between 1 January 2008 and 31 December 2016, of which 1079 in the first study period (01/01/2008‐31/12/2013) and 505 in the second study period (01/01/2014‐31/12/2016). The baseline characteristics of all included neonates from both cohorts are presented in Table 2 . In the second period, significantly more children were born by caesarean section. Baseline characteristics Values given as mean (SD), median (range) or n (%). Inborn: born in the LUMC. SGA: small for gestational age (birthweight below the 10th centile according to Dutch neonatal birthweight curves 28 ). The percentage of neonates receiving a RBC transfusion decreased significantly from 37·5% (405/1079) in the first period and 32·7% (165/505) in the second period ( P = 0·040). The mean number of transfusions given to each transfused neonate decreased from 2·93 (± 2·26) transfusions per neonate in the first study period to 2·20 (± 1·29) in the second period ( P = 0·007). In both cohorts, gestational age at birth was related to the need for RBC transfusions (Figs. 1 and 2 ). We found no difference in percentage of neonates requiring a transfusion nor in number of transfusions per neonate before and after protocol changes, when analysed by gestational age at birth. Percentage of neonates receiving RBC transfusion ( Y ‐axis) per gestational age at birth in weeks ( X ‐axis), before and after guideline change. Mean number of transfusions per neonate ( Y ‐axis) per gestational age at birth in weeks ( X ‐axis), before and after guideline change. RBC transfusions are mostly administered in the first week of life (Fig. 3 ). In the second study period, the need for RBC transfusion was significantly lower in the third week ( P < 0·001) and fourth week of life ( P = 0·036), but not in the first 2 weeks. Percentage of neonates requiring a blood transfusion in the first 4 weeks of life and thereafter. Table 3 shows the incidence of neonatal morbidity and mortality in both cohorts, both in the overall group of included neonates and in the subgroup receiving at least one RBC transfusion. When comparing the study periods, a significant decrease in incidence of severe IVH was found. In the second study period, the length of hospitalization was significantly higher compared to the first period. Transfusion requirement and neonatal outcomes before and after transfusion guideline changes Therefore, we calculated the number of transfusions per 100 admission days. The number of RBC transfusions per 100 days of hospitalization was 5·3 (SD ± 12·4) in the first period and 2·7 (SD ± 7·4) per 100 days in the second period ( P < 0·001). For the neonates who received at least one RBC transfusion, the number of transfusions per 100 days of hospitalization was 13·9 (SD ±16·9) in the first period and 8·2 (SD ±11·0) in the second period ( P < 0·001). In this large retrospective single centre study in more than 1500 very preterm neonates, we found a significant decrease in the rate of RBC transfusions. Since the introduction in 2014 of a more restrictive RBC transfusion guideline, the rate of neonates requiring a RBC transfusion dropped from 37·5 to 32·7% and the mean number of transfusions per transfused neonates was reduced from 2·93 to 2·20. The reduction in RBC transfusions using a more restrictive guideline did not result in an increase in mortality or morbidity. Recently, a possible association has been reported between red blood cell transfusions and NEC (transfusion‐associated NEC: TANEC 13 , 14 , 15 ). However, the causative relation is controversial and has not been proven yet. In this study, we found no significant changes in the incidence of NEC despite reduction in blood transfusions. Importantly, our study was not powered to detect changes in the incidence of NEC. Various factors, besides the protocol changes, could have contributed to this decrease. Increased awareness of the possible adverse effects of RBC transfusions in the latter years may have increased the adherence to transfusion guidelines and reduced the rate of protocol violation (both effects were not measured in this study). Several studies have shown that strict adherence to transfusion protocols reduces the number of RBC transfusions in preterm neonates 16 , 17 . Also, the reduced transfusion rate in the latter period could be related to an increased awareness on the deleterious impact of repeated blood testing on anaemia of prematurity 18 , 19 . Reducing the amount of blood drawn for laboratory testing in very preterm neonates reduces the risk of iatrogenic blood loss and the number of RBC transfusion 20 , 21 . Another crucial factor on the Hb level at birth and the need for RBC transfusions is the timing of cord clamping at birth. Various studies have shown that delaying cord clamping will result in a higher Hb level at birth and reduce the initial need for RBC transfusions 22 . Although our local guideline underscores the importance of delayed cord clamping, the timing of cord clamping is left to the discretion of the attending obstetrician, and the timing of cord clamping was unfortunately not routinely registered during the study period. As reported here above, it is conceivable that also other factors, besides the protocol change, may have contributed to the reduction in RBC transfusion. The baseline characteristics of the two cohorts were almost similar, except for a decrease in severe IVH and a longer period of hospitalization after the protocol change. The reduced incidence of severe IVH can be attributed to multiple factors. The longer stay in the more recent period may have led to an underestimation of the effects of restrictive transfusion guidelines since one could argue that the longer a neonate is admitted to a NICU, the sicker the neonate could be and the more at risk a neonate is for receiving a transfusion. We therefore calculated the rate of RBC transfusions per 100 hospitalization days and showed a stronger impact of restrictive transfusion guidelines on the reduction in transfusions. This study also confirmed the positive correlation between extreme prematurity and need for RBC transfusions. The blood sparing effect of a more restrictive transfusion protocol was particularly pronounced in week 3 and 4 after birth, and not so much in the first 2 weeks of life. This difference in effect is probably due to the differences in triggers for blood transfusion between the two guidelines. The trigger for blood transfusion in week 3 and 4 was much lower compared to the initial guideline. We found no difference in the need of transfusions when analysed by gestational age at birth between the two periods. The lack of association between gestational age and transfusions could be due to a limited sample size since our study was not powered to detect differences related to gestational age at birth. To date, international consensus on the optimal guideline for RBC transfusion in neonates is lacking and different protocol and transfusion triggers are being used around the world. The lack of consensus is partly due to contradicting results of various studies. Bell et al . 12 suggested that liberal RBC transfusions improved the short‐term neonatal outcome, but these findings were not confirmed in a larger study by Kirpalani et al . 3 (PINT study). Chen et al . 17 found an significant decrease in chronic lung disease due to restrictive transfusion threshold, without other significant changes in morbidity. Importantly, only one study assessed the effect of restrictive vs. liberal transfusions on the long‐term neurodevelopmental outcome. Although no major differences were found, a borderline statistical significant difference in cognitive delay favouring the liberal strategy was reported 4 . In addition, Nopoulos et al . 23 showed that RBC transfusions affected the long‐term outcome of premature infants, inflicting reduced brain volumes especially in those who were transfused with a liberal strategy. In the Cochrane systematic review, Whyte and Kirpalani 11 concluded that the use of restrictive as compared to liberal transfusion guidelines resulted in modest reductions in exposure to transfusion, without a significant impact on death or major morbidities. In 2014, Ibrahim et al . 24 performed a meta‐analysis which reflects the results of the Cochrane review. These partly contradicting results highlight the need for more studies and clearer evidence to reach global consensus on transfusion thresholds and improve neonatal care 2 , 25 . Two large prospective studies (ETTNO study 26 and TOP study 27 ) comparing liberal vs. restrictive RBC transfusion strategies are currently being conducted. These studies also compare neurological outcomes up to 2 years of age. The results of these studies are eagerly awaited and will hopefully provide more information on the impact of different transfusion thresholds, contributing to an international consensus. In conclusion, our study shows that the use of a more restrictive transfusion protocol has led to a reduction in RBC transfusions without an increase in morbidity or mortality. In addition to optimizing neonatal care, reducing the amount of transfusions also reduces the costs of neonatal medical care. Restrictive guideline for red blood cell transfusions in preterm neonates: effect of a protocol change Management and prevention of neonatal anemia: current evidence and guidelines Anaemia of prematurity: pathophysiology and treatment The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants Neurodevelopmental outcome of extremely low birth weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion The safety and efficacy of red cell transfusions in neonates: a systematic review of randomized controlled trials Neurocognitive profiles of preterm infants randomly assigned to lower or higher hematocrit thresholds for transfusion Transfusion strategies for patients in pediatric intensive care units Respiratory dysfunction associated with RBC transfusion in critically ill children: a prospective cohort study Transfusion‐related immunomodulation: review of the literature and implications for pediatric critical illness Low versus high haemoglobin concentration threshold for blood transfusion for preventing morbidity and mortality in very low birth weight infants Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants Anemia, red blood cell transfusions, and necrotizing enterocolitis Transfusion associated necrotizing enterocolitis: a meta‐analysis of observational data Increased odds of necrotizing enterocolitis after transfusion of red blood cells in premature infants Impact of transfusion guidelines on neonatal transfusions Effect of blood transfusions on the outcome of very low body weight preterm infants under two different transfusion criteria Phlebotomy overdraw in the neonatal intensive care nursery Evidence‐based advances in transfusion practice in neonatal intensive care units Management of anemia in the newborn Anemia, blood loss, and blood transfusions in North American children in the intensive care unit A systematic review and meta‐analysis of a brief delay in clamping the umbilical cord of preterm infants Long‐term outcome of brain structure in premature infants: effects of liberal vs restricted red blood cell transfusions Restrictive versus liberal red blood cell transfusion thresholds in very low birth weight infants: a systematic review and meta‐analysis Guidelines on transfusion for fetuses, neonates and older children Effects of Transfusion Thresholds on Neurocognitive Outcome of Extremely Low Birth Weight Infants (ETTNO) Transfusion of Prematures Trial (TOP) Intrauterine growth and intrauterine growth curves |
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