<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04478487</url>
  </required_header>
  <id_info>
    <org_study_id>MC-2018-01</org_study_id>
    <nct_id>NCT04478487</nct_id>
  </id_info>
  <brief_title>Novel Human Milk Based Human Milk Fortifier</brief_title>
  <acronym>MHMHMF</acronym>
  <official_title>TITLE OF STUDY: Safety and Efficacy of a Novel Human Milk-based Human Milk Fortifier in Very Low Birth Weight Infants</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwest Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Neolac Inc dba Medolac Laboratories</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Northwest Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective is to assess weight gain of VLBW infants fed human milk supplemented&#xD;
      with a novel human milk-based fortifier, in comparison to use of other fortifiers (historic&#xD;
      controls).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background Once feeding low birthweight (LBW) or very low birthweight (VLBW) infants was&#xD;
      primarily by commercial specialty formulas. As public health emphasis on breastfeeding&#xD;
      increased awareness and prevalence of breastfeeding, the use of human milk in the Neonatal&#xD;
      Intensive Care unit (NICU) became more common. However, despite the fact that milk from&#xD;
      mothers delivering prematurely has higher nutritional content than milk from mothers&#xD;
      delivering at term, mainly in protein and fat, thus calories, nutrient intake from human milk&#xD;
      alone is not sufficient to satisfy the nutrition of the LBW or VLBW infants and support&#xD;
      intrauterine growth rates. Low birth weight infants have faster growth when fed preterm&#xD;
      formula compared to when they are breastfed. Consequently, human milk fortifiers (HMF) with&#xD;
      an emphasis on protein and caloric density (to accommodate small gastric volume among these&#xD;
      babies) but with major minerals and selected micronutrients were developed as supplements to&#xD;
      admix with human milk for feeding preterm infants. HM fortifiers were initially based on cows&#xD;
      milk proteins and were manufactured as either powders or liquids, the latter having the&#xD;
      benefit of being sterile, avoiding the risk of contamination by bacterial contaminants in&#xD;
      powders, eg, cronobacter sakazakii. Attention to early life nutrition has reduced the&#xD;
      prevalence of growth restricted infants at discharge.&#xD;
&#xD;
      Protein Increased protein in fortifiers in LBW feeds directly improves weight gain, and early&#xD;
      introduction of fortifiers may mitigate typical protein intake shortfall that is seen during&#xD;
      the transition from parenteral to enteral feeding. The highest useful protein level may have&#xD;
      been determined.Growth of VLBW infants fed primarily breast milk supplemented with bovine&#xD;
      milk fortifier to obtain 4.3 g protein/kg/d was not improved over infants whose milk&#xD;
      fortification was 3.7 g/kg/d; both groups nearly achieved intrauterine growth rates. Breast&#xD;
      milk comprised 92 and 94% of total food intake and average daily weight gains were 16.3 g/kg&#xD;
      and 16.0 g/kg in the lower and higher protein groups, respectively. Length and head&#xD;
      circumference gains were similar between groups. In one study bovine based fortifier&#xD;
      providing total protein at a yet higher level of 4.6- 5.4 g/kg/d reported improved length&#xD;
      gain, but not weight gain.&#xD;
&#xD;
      Other variations of protein presentation also have been reported. Liquid HMF made with&#xD;
      extensively hydrolyzed protein at 3.6g/100 kcal gave slightly better weight gain than&#xD;
      powdered intact protein containing 3 g protein/100 kcal. A new powdered presentation using&#xD;
      partially hydrolysed whey protein at 16% higher total protein content than the commercial&#xD;
      product with intact protein gave improved weight gain. In addition to the protein content,&#xD;
      processing is important. Acidified liquid fortifier-fed infants fared poorer than infants fed&#xD;
      neutral pH sterilized HMF even though the acidified formula had higher protein intake (4.2&#xD;
      g/kg) than the sterilized (3.7 g/kg).&#xD;
&#xD;
      None of these studies assessed the effects of different levels of human milk protein, but&#xD;
      they suggest attention be paid to achieving protein targets; that liquids may be preferred&#xD;
      over powders, and that sterilized neutral pH products are preferable to acidified products.&#xD;
&#xD;
      Necrotizing enterocolitis (NEC) One study created awareness about the value of feeding&#xD;
      exclusive human milk in the NICU and reported that there was no difference in growth between&#xD;
      VLBW infants fed mothers own milk supplemented with a fortifier derived from donor human milk&#xD;
      or when a fortifier based on bovine milk was used, though the exclusively human milk diet&#xD;
      resulted in fewer cases of NEC and NEC requiring surgical intervention. Subsequently, another&#xD;
      study reported feeding with a fortifier based on human milk reduced days of parenteral&#xD;
      nutrition (p=0.04), trend toward all NEC (p= 0.08) and reduced surgical NEC (p=0.04) when&#xD;
      compared to fortification with preterm bovine milk based formula. Others report the timing of&#xD;
      onset of NEC was delayed and incidence of late onset NEC (after 7 feeding days) and incidence&#xD;
      of sepsis was significantly reduced among infants fed exclusive human milk diets compared to&#xD;
      an earlier cohort of infants supplemented with bovine products; however, respiratory distress&#xD;
      syndrome and use of surfactants was more common among the exclusive human milk cohort, and&#xD;
      infants fed bovine products were more commonly discharged to home. A 2014 Cochrane review of&#xD;
      9 studies found an increased risk of NEC among infants fed preterm formulas. This conclusion&#xD;
      has been supported by recent retrospective studies, and extending benefit of exclusive human&#xD;
      milk diets to reduced risk of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity&#xD;
      (ROP) in addition to NEC .&#xD;
&#xD;
      The value of exclusive human milk feeding also has been explored regarding growth. Questions&#xD;
      of the relative value of mother's own milk compared to donor human milk, the form of&#xD;
      fortifier (powder v liquid, v acidified liquid), the level of protein, and the source of&#xD;
      protein (bovine or human) have been explored. A study reported that infants fed &gt;75% donor&#xD;
      milk had higher risk of small for gestational age (SGA) compared to those fed their own&#xD;
      mothers milk. Donor milk fed infants had lower weight gain than infants fed either moms own&#xD;
      milk or preterm formula possibly because of lower nutrient content of donor milk. In&#xD;
      contrast, VLBW infants fed their own mother's milk fortified alternatively with donor milk or&#xD;
      preterm formula grew better (weight gain from birth to discharge) as the proportion of diet&#xD;
      as breast milk increased from &lt;25%, 25-50%, to &gt; 75% of total intake. A retrospective&#xD;
      analysis among extremely low birthweight infants (ELBW) exclusively human milk diets reported&#xD;
      a comparable growth and neurodevelopment as infants fed bovine milk based fortifiers.&#xD;
&#xD;
      Consequently, there is good evidence that fortification of human milk is needed to support&#xD;
      growth of LBW and VLBW infants, that higher protein up to about 4.3 g/kg/d supports more&#xD;
      rapid growth, and that risk of NEC and other diseases affecting LBW infants is less when LBW&#xD;
      infants are fed exclusive human milk diets. The difficulties have been to obtain liquid&#xD;
      fortifier derived from human milk, and evaluate its use at the protein concentrations that&#xD;
      have been evaluated using bovine-based products. This study addresses these two needs: a&#xD;
      sterile liquid fortifier derived from human milk is evaluated at protein intakes recommended&#xD;
      by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN),&#xD;
      4.0-4.5 g/kg/d for infants less than 1000g, and 3.5-4.0 g/kg for infants 1000-1800g.&#xD;
&#xD;
      Summary of Nonclinical Experience with MHMHMF The preclinical experience with this particular&#xD;
      fortifier is limited to analytical evaluation. There are no suitable animal models sensitive&#xD;
      to testing the biological source of the protein, and no alternative method for assessing&#xD;
      growth of infants fed a human protein-based fortifier than clinical study. The protein&#xD;
      quality of the processed protein has been established by amino acid analysis to be close to&#xD;
      the native protein, with up to a 15% decrease in available lysine, probably due to Maillard&#xD;
      reaction with lactose. The fortifier, even at its lowest recommended use rate represents more&#xD;
      than a 2-fold increase in all amino acids when compared to raw breast milk, we are not&#xD;
      concerned about protein quality with our manufacturing process. Additionally, the composition&#xD;
      of the blended fortifier exceeds Codex reference for protein quality for infant formula and&#xD;
      formulas for special medical purposes intended for infants.&#xD;
&#xD;
      Summary of Clinical Experience Medolac has processed donor whole human milk for feeding LBW&#xD;
      infants for some years. More recently Medolac has applied standard dairy processes to&#xD;
      partition milk into milk fat and skim fractions, and to enrich the protein content. The&#xD;
      processes have allowed the development of high protein human milk fortifier. Supplementation&#xD;
      of the high protein fraction with vitamins and minerals has resulted in a novel human milk&#xD;
      based human milk fortifier for fortification of human milk-fed VLBW infants. This is the&#xD;
      first clinical evaluation of the MHMHMF fortifier. Only one other fortifier derived from&#xD;
      human milk is available commercially (Prolacta). Reports on its use have been published&#xD;
      showing reduced days of parenteral nutrition (p=0.04), trend toward all NEC (p= 0.08) and&#xD;
      reduced surgical NEC (p=0.04) and rescue from failure after use of bovine based fortifiers.&#xD;
&#xD;
      Description of Investigational Product The investigational product is manufactured from whole&#xD;
      human breast milk with the addition of selected vitamins and minerals. The source of human&#xD;
      milk is full lactation, full term donor milk from Mothers Milk Cooperative (Boulder City,&#xD;
      NV), collected according to stringent blood screening criteria and quality control&#xD;
      procedures, including microbiological evaluation, nutritional composition and chemical&#xD;
      analyses. A fractionated, concentrated product is created by first delipidating then&#xD;
      filtering through ultrafiltration (UF) membranes to selectively concentrate protein with loss&#xD;
      of low molecular weight components such as lactose and minerals. Fat, selected minerals, and&#xD;
      vitamins are added to the protein enriched fluid to reach a standard ratio. It is then&#xD;
      packaged and processed by heat to achieve commercial sterility, granting room temperature&#xD;
      storage with extensive shelf-life.&#xD;
&#xD;
      Various blending ratios of the fortifier with either the mother's expressed milk or donor&#xD;
      milk can be used to deliver varying concentrations of vitamins, minerals, and macronutrients&#xD;
      enabling nutrient delivery to be adjusted according to the infant's tolerance for volume and&#xD;
      calories.&#xD;
&#xD;
      Blending ratios are illustrated in the table below. Simple blending of 50:50 results in a&#xD;
      high protein, fat enriched fortifier having a caloric density of 27 kcal/ounce with protein&#xD;
      provided at 3.0g/100 milliliters (mL). When this fortifier is mixed in a 1:2 ratio, the&#xD;
      resulting caloric density is 25 kcal/oz and protein is provided at 2.4 g/100 ml; when this&#xD;
      fortifier is mixed in a 1:3 ratio, the resulting caloric density is 23.6 kcal/oz and protein&#xD;
      is provided at 2.07 g/100 ml; Similarly, other nutrients are delivered as a function of the&#xD;
      ratio of MHMHMF to human milk.&#xD;
&#xD;
      The primary objective for growth with this fortifier is the delivery of protein and calories,&#xD;
      however we recognize that some vitamins are cofactors of enzymes involved in protein and&#xD;
      energy metabolism. Some minerals such as zinc is variable in human milk, so was selected for&#xD;
      addition. Other vitamins and minerals such as iron are generally monitored while others such&#xD;
      as copper, vitamin A, and niacin are not considered limiting in human milk. In addition, heat&#xD;
      processing used to achieve commercial sterility degrades some vitamins, making separate&#xD;
      administration desirable. For these reasons the MHMHMF is not comprehensive in its delivery&#xD;
      of vitamins and minerals which have been shown to be essential for nutrition. Infants should&#xD;
      be monitored for adequate nutrition and additional fortification given as needed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">September 1, 2019</start_date>
  <completion_date type="Anticipated">September 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This is a non-controlled observational trial using objective measures (body weight) to assess the support of growth and tolerance of a new fortifier based on human milk, thereby enabling an exclusive human milk diet for VLBW infants in the NICU.</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>weight gain (gm/kg/day)</measure>
    <time_frame>Daily from first day of enrollment until 36 weeks post menstrual age or discharge</time_frame>
    <description>Weights.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>length increment (cm/kg/day)</measure>
    <time_frame>Weekly until 36 weeks post menstrual age or discharge</time_frame>
    <description>length</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Head Circumference increment (cm/kg/day)</measure>
    <time_frame>Weekly until 36 weeks post menstrual age or discharge</time_frame>
    <description>Head circumference</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of Fortifier</measure>
    <time_frame>Daily until 36 weeks post menstrual age or discharge</time_frame>
    <description>Total intake of formula and fortifier</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Morbidity</measure>
    <time_frame>weekly until 36 weeks post menstrual age or discharge</time_frame>
    <description>Adverse Events-necrotizing enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Infant, Premature, Diseases</condition>
  <arm_group>
    <arm_group_label>Study Participants</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>all preterm infants ≤ 32 weeks and 0 days gestational age (GA) with a birth weight 700 g to 1500 g at the hospital, who are enterally fed human milk in the neonatal intensive care unit (NICU) for at least 7 days. Various blending ratios of the fortifier with either the mother's expressed milk or donor milk will be used to deliver macro and micronutrients based on established guidelines to be adjusted according to the infant's tolerance for volume and calories. The estimated time for each subject's participation is approximately from 1 week through 8 weeks, depending on the weight and age at enrollment. Historic control cases treated by another human milk based human milk fortifier will be obtained from medical records, matched on birth weight and gender, with sample size twice (n=80) that of the study population.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Medolac human milk based human milk fortifier (MHMHMF)</intervention_name>
    <description>MHMHMF is admixed with expressed or donor human milk in graded doses according to tolerated feed volume according to established guidelines and maintain adequate micronutrient levels.</description>
    <arm_group_label>Study Participants</arm_group_label>
    <other_name>exclusive human milk diet for VLBW infants</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Birth weight between 750 g-1500 g.&#xD;
&#xD;
          -  ≤ 32 weeks gestational age at birth. GA will be determined by an ultrasound scan or&#xD;
             the neonatologist's estimate, with consideration to maternal date.&#xD;
&#xD;
          -  Subject has been classified as appropriate for GA (AGA).&#xD;
&#xD;
          -  Enteral feeding of human milk must be initiated by 21 days of life for infants with a&#xD;
             birthweight of 750-1000 g (birth date is day of life 0) and initiated by 14 days of&#xD;
             life for infants with a birthweight of 1.0 - 1.5 kg birthweight.&#xD;
&#xD;
          -  Mother agrees to feed the infant human milk as the exclusive feeding during the study&#xD;
             period. Human milk may be mothers own or donor milk, plus MHMHMF.&#xD;
&#xD;
          -  Singleton or twin births only.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Serious congenital abnormalities or underlying disease that may affect growth and&#xD;
             development.&#xD;
&#xD;
          -  5 minute APGAR: 5 4.&#xD;
&#xD;
          -  Steroids used within the past 5 days&#xD;
&#xD;
          -  Grade Ill or IV periventricular/ intraventricular hemorrhage (PVH/IVH).&#xD;
&#xD;
          -  Maternal cocaine, alcohol or opioid abuse during pregnancy or currently or if the&#xD;
             mother or infant is currently receiving treatment for HIV infection.&#xD;
&#xD;
          -  Infant major surgery (intra-thoracic or intra-abdominal procedures or other surgery&#xD;
             requiring general anesthesia).&#xD;
&#xD;
          -  Asphyxia defined as progressive hypoxemia and hypercapnia with significant metabolic&#xD;
             acidemia characterized by APGAR score &lt;3 at 10 minutes, seizures within the first 12&#xD;
             hours of life, or a cord blood gas &lt; 7.0 and seizures and/or severe tonic&#xD;
             abnormalities in the first 12 hours of life.&#xD;
&#xD;
          -  Infant has any other condition that, in the opinion of the investigator, compromises&#xD;
             the ability to draw inference about the ability of the MHMHMF to support growth.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>23 Weeks</minimum_age>
    <maximum_age>32 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sean Fels</last_name>
    <role>Study Director</role>
    <affiliation>Medolac Laboratories</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Willow Creek Women's Hospital</name>
      <address>
        <city>Johnson</city>
        <state>Arkansas</state>
        <zip>72741</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.medolac.com</url>
    <description>Medolac Laboratories</description>
  </link>
  <reference>
    <citation>Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, Domellof M, Embleton ND, Fusch C, Genzel-Boroviczeny O, Goulet O, Kalhan SC, Kolacek S, Koletzko B, Lapillonne A, Mihatsch W, Moreno L, Neu J, Poindexter B, Puntis J, Putet G, Rigo J, Riskin A, Salle B, Sauer P, Shamir R, Szajewska H, Thureen P, Turck D, van Goudoever JB, Ziegler EE; ESPGHAN Committee on Nutrition. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010 Jan;50(1):85-91. doi: 10.1097/MPG.0b013e3181adaee0.</citation>
    <PMID>19881390</PMID>
  </reference>
  <reference>
    <citation>Cacho NT, Parker LA, Neu J. Necrotizing Enterocolitis and Human Milk Feeding: A Systematic Review. Clin Perinatol. 2017 Mar;44(1):49-67. doi: 10.1016/j.clp.2016.11.009. Epub 2016 Dec 24.</citation>
    <PMID>28159209</PMID>
  </reference>
  <reference>
    <citation>Chowning R, Radmacher P, Lewis S, Serke L, Pettit N, Adamkin DH. A retrospective analysis of the effect of human milk on prevention of necrotizing enterocolitis and postnatal growth. J Perinatol. 2016 Mar;36(3):221-4. doi: 10.1038/jp.2015.179. Epub 2015 Dec 3.</citation>
    <PMID>26633147</PMID>
  </reference>
  <reference>
    <citation>Colacci M, Murthy K, DeRegnier RO, Khan JY, Robinson DT. Growth and Development in Extremely Low Birth Weight Infants After the Introduction of Exclusive Human Milk Feedings. Am J Perinatol. 2017 Jan;34(2):130-137. doi: 10.1055/s-0036-1584520. Epub 2016 Jun 20.</citation>
    <PMID>27322667</PMID>
  </reference>
  <reference>
    <citation>Colaizy TT, Carlson S, Saftlas AF, Morriss FH Jr. Growth in VLBW infants fed predominantly fortified maternal and donor human milk diets: a retrospective cohort study. BMC Pediatr. 2012 Aug 17;12:124. doi: 10.1186/1471-2431-12-124.</citation>
    <PMID>22900590</PMID>
  </reference>
  <reference>
    <citation>Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, Dudell G, Rechtman DJ, Lee ML, Lucas A, Abrams S. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013 Dec;163(6):1592-1595.e1. doi: 10.1016/j.jpeds.2013.07.011. Epub 2013 Aug 20.</citation>
    <PMID>23968744</PMID>
  </reference>
  <reference>
    <citation>Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 2013 Apr 20;13:59. doi: 10.1186/1471-2431-13-59.</citation>
    <PMID>23601190</PMID>
  </reference>
  <reference>
    <citation>Gidrewicz DA, Fenton TR. A systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr. 2014 Aug 30;14:216. doi: 10.1186/1471-2431-14-216.</citation>
    <PMID>25174435</PMID>
  </reference>
  <reference>
    <citation>Hair AB, Peluso AM, Hawthorne KM, Perez J, Smith DP, Khan JY, O'Donnell A, Powers RJ, Lee ML, Abrams SA. Beyond Necrotizing Enterocolitis Prevention: Improving Outcomes with an Exclusive Human Milk-Based Diet. Breastfeed Med. 2016 Mar;11(2):70-4. doi: 10.1089/bfm.2015.0134. Epub 2016 Jan 20. Erratum In: Breastfeed Med. 2017 Dec;12 (10 ):663.</citation>
    <PMID>26789484</PMID>
  </reference>
  <reference>
    <citation>Hay WW, Ziegler EE. Growth failure among preterm infants due to insufficient protein is not innocuous and must be prevented. J Perinatol. 2016 Jul;36(7):500-2. doi: 10.1038/jp.2016.85. No abstract available.</citation>
    <PMID>27339826</PMID>
  </reference>
  <reference>
    <citation>Herrmann K, Carroll K. An exclusively human milk diet reduces necrotizing enterocolitis. Breastfeed Med. 2014 May;9(4):184-90. doi: 10.1089/bfm.2013.0121. Epub 2014 Mar 3.</citation>
    <PMID>24588561</PMID>
  </reference>
  <reference>
    <citation>Horbar JD, Ehrenkranz RA, Badger GJ, Edwards EM, Morrow KA, Soll RF, Buzas JS, Bertino E, Gagliardi L, Bellu R. Weight Growth Velocity and Postnatal Growth Failure in Infants 501 to 1500 Grams: 2000-2013. Pediatrics. 2015 Jul;136(1):e84-92. doi: 10.1542/peds.2015-0129.</citation>
    <PMID>26101360</PMID>
  </reference>
  <reference>
    <citation>Kim JH, Chan G, Schanler R, Groh-Wargo S, Bloom B, Dimmit R, Williams L, Baggs G, Barrett-Reis B. Growth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk Fortifier. J Pediatr Gastroenterol Nutr. 2015 Dec;61(6):665-71. doi: 10.1097/MPG.0000000000001010. Erratum In: J Pediatr Gastroenterol Nutr. 2016 Jan;62(1):188-9.</citation>
    <PMID>26488118</PMID>
  </reference>
  <reference>
    <citation>Kim EJ, Lee NM, Chung SH. A retrospective study on the effects of exclusive donor human milk feeding in a short period after birth on morbidity and growth of preterm infants during hospitalization. Medicine (Baltimore). 2017 Sep;96(35):e7970. doi: 10.1097/MD.0000000000007970.</citation>
    <PMID>28858132</PMID>
  </reference>
  <reference>
    <citation>Kumar N, Monga R, Sampath V, Ehrhart B. Prospective Comparison of Enfamil and Similac Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants. Am J Perinatol. 2017 Dec;34(14):1411-1416. doi: 10.1055/s-0037-1603940. Epub 2017 Jun 21. No abstract available.</citation>
    <PMID>28637062</PMID>
  </reference>
  <reference>
    <citation>Liu TT, Dang D, Lv XM, Wang TF, Du JF, Wu H. Human milk fortifier with high versus standard protein content for promoting growth of preterm infants: A meta-analysis. J Int Med Res. 2015 Jun;43(3):279-89. doi: 10.1177/0300060515579115. Epub 2015 May 8.</citation>
    <PMID>25956156</PMID>
  </reference>
  <reference>
    <citation>Maas C, Mathes M, Bleeker C, Vek J, Bernhard W, Wiechers C, Peter A, Poets CF, Franz AR. Effect of Increased Enteral Protein Intake on Growth in Human Milk-Fed Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2017 Jan 1;171(1):16-22. doi: 10.1001/jamapediatrics.2016.2681.</citation>
    <PMID>27893064</PMID>
  </reference>
  <reference>
    <citation>Madore LS, Bora S, Erdei C, Jumani T, Dengos AR, Sen S. Effects of Donor Breastmilk Feeding on Growth and Early Neurodevelopmental Outcomes in Preterm Infants: An Observational Study. Clin Ther. 2017 Jun;39(6):1210-1220. doi: 10.1016/j.clinthera.2017.05.341. Epub 2017 May 30.</citation>
    <PMID>28576299</PMID>
  </reference>
  <reference>
    <citation>McGuire W, Anthony MY. Formula milk versus preterm human milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2001;(3):CD002972. doi: 10.1002/14651858.CD002972.</citation>
    <PMID>11687034</PMID>
  </reference>
  <reference>
    <citation>Olsen IE, Harris CL, Lawson ML, Berseth CL. Higher protein intake improves length, not weight, z scores in preterm infants. J Pediatr Gastroenterol Nutr. 2014 Apr;58(4):409-16. doi: 10.1097/MPG.0000000000000237.</citation>
    <PMID>24231639</PMID>
  </reference>
  <reference>
    <citation>Rigo J, Hascoet JM, Billeaud C, Picaud JC, Mosca F, Rubio A, Saliba E, Radke M, Simeoni U, Guillois B, de Halleux V, Jaeger J, Ameye L, Hays NP, Spalinger J. Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial. J Pediatr Gastroenterol Nutr. 2017 Oct;65(4):e83-e93. doi: 10.1097/MPG.0000000000001686.</citation>
    <PMID>28727654</PMID>
  </reference>
  <reference>
    <citation>Sandhu A, Fast S, Bonnar K, Baier RJ, Narvey M. Human-Based Human Milk Fortifier as Rescue Therapy in Very Low Birth Weight Infants Demonstrating Intolerance to Bovine-Based Human Milk Fortifier. Breastfeed Med. 2017 Nov;12(9):570-573. doi: 10.1089/bfm.2017.0017. Epub 2017 Aug 4.</citation>
    <PMID>28777664</PMID>
  </reference>
  <reference>
    <citation>Shah SD, Dereddy N, Jones TL, Dhanireddy R, Talati AJ. Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants-A Randomized Controlled Trial. J Pediatr. 2016 Jul;174:126-131.e1. doi: 10.1016/j.jpeds.2016.03.056. Epub 2016 Apr 23.</citation>
    <PMID>27112041</PMID>
  </reference>
  <reference>
    <citation>Sisk PM, Lovelady CA, Dillard RG, Gruber KJ, O'Shea TM. Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol. 2007 Jul;27(7):428-33. doi: 10.1038/sj.jp.7211758. Epub 2007 Apr 19. Erratum In: J Perinatol. 2007 Dec;27(12):808.</citation>
    <PMID>17443195</PMID>
  </reference>
  <reference>
    <citation>Spiegler J, Preuss M, Gebauer C, Bendiks M, Herting E, Gopel W; German Neonatal Network (GNN); German Neonatal Network GNN. Does Breastmilk Influence the Development of Bronchopulmonary Dysplasia? J Pediatr. 2016 Feb;169:76-80.e4. doi: 10.1016/j.jpeds.2015.10.080. Epub 2015 Nov 25.</citation>
    <PMID>26621048</PMID>
  </reference>
  <reference>
    <citation>Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kiechl-Kohlendorfer U, Chan GM, Blanco CL, Abrams S, Cotten CM, Laroia N, Ehrenkranz RA, Dudell G, Cristofalo EA, Meier P, Lee ML, Rechtman DJ, Lucas A. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010 Apr;156(4):562-7.e1. doi: 10.1016/j.jpeds.2009.10.040. Epub 2009 Dec 29.</citation>
    <PMID>20036378</PMID>
  </reference>
  <reference>
    <citation>Taylor C. Health Professionals Letter on Enterobacter sakazakii Infections Associated With the Use of Powdered (Dry) Infant Formulas in Neonatal Intensive Care Units. Bethesda, MD: US Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling and Dietary Supplements; 2002.</citation>
  </reference>
  <reference>
    <citation>Thoene M, Lyden E, Weishaar K, Elliott E, Wu R, White K, Timm H, Anderson-Berry A. Comparison of a Powdered, Acidified Liquid, and Non-Acidified Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants. Nutrients. 2016 Jul 26;8(8):451. doi: 10.3390/nu8080451.</citation>
    <PMID>27472359</PMID>
  </reference>
  <reference>
    <citation>Valentine CJ, Morrow G, Reisinger A, Dingess KA, Morrow AL, Rogers LK. Lactational Stage of Pasteurized Human Donor Milk Contributes to Nutrient Limitations for Infants. Nutrients. 2017 Mar 18;9(3):302. doi: 10.3390/nu9030302.</citation>
    <PMID>28335478</PMID>
  </reference>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>July 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>September 27, 2022</last_update_submitted>
  <last_update_submitted_qc>September 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwest Health</investigator_affiliation>
    <investigator_full_name>Sameer Wagle, MD</investigator_full_name>
    <investigator_title>Medical Director, NICU</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infant, Premature, Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04478487
org study id: MC-2018-01
nct id: NCT04478487
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The primary objective is to assess weight gain of VLBW infants fed human milk supplemented
      with a novel human milk-based fortifier, in comparison to use of other fortifiers (historic
      controls).
Background Once feeding low birthweight (LBW) or very low birthweight (VLBW) infants was
      primarily by commercial specialty formulas. As public health emphasis on breastfeeding
      increased awareness and prevalence of breastfeeding, the use of human milk in the Neonatal
      Intensive Care unit (NICU) became more common. However, despite the fact that milk from
      mothers delivering prematurely has higher nutritional content than milk from mothers
      delivering at term, mainly in protein and fat, thus calories, nutrient intake from human milk
      alone is not sufficient to satisfy the nutrition of the LBW or VLBW infants and support
      intrauterine growth rates. Low birth weight infants have faster growth when fed preterm
      formula compared to when they are breastfed. Consequently, human milk fortifiers (HMF) with
      an emphasis on protein and caloric density (to accommodate small gastric volume among these
      babies) but with major minerals and selected micronutrients were developed as supplements to
      admix with human milk for feeding preterm infants. HM fortifiers were initially based on cows
      milk proteins and were manufactured as either powders or liquids, the latter having the
      benefit of being sterile, avoiding the risk of contamination by bacterial contaminants in
      powders, eg, cronobacter sakazakii. Attention to early life nutrition has reduced the
      prevalence of growth restricted infants at discharge.

      Protein Increased protein in fortifiers in LBW feeds directly improves weight gain, and early
      introduction of fortifiers may mitigate typical protein intake shortfall that is seen during
      the transition from parenteral to enteral feeding. The highest useful protein level may have
      been determined.Growth of VLBW infants fed primarily breast milk supplemented with bovine
      milk fortifier to obtain 4.3 g protein/kg/d was not improved over infants whose milk
      fortification was 3.7 g/kg/d; both groups nearly achieved intrauterine growth rates. Breast
      milk comprised 92 and 94% of total food intake and average daily weight gains were 16.3 g/kg
      and 16.0 g/kg in the lower and higher protein groups, respectively. Length and head
      circumference gains were similar between groups. In one study bovine based fortifier
      providing total protein at a yet higher level of 4.6- 5.4 g/kg/d reported improved length
      gain, but not weight gain.

      Other variations of protein presentation also have been reported. Liquid HMF made with
      extensively hydrolyzed protein at 3.6g/100 kcal gave slightly better weight gain than
      powdered intact protein containing 3 g protein/100 kcal. A new powdered presentation using
      partially hydrolysed whey protein at 16% higher total protein content than the commercial
      product with intact protein gave improved weight gain. In addition to the protein content,
      processing is important. Acidified liquid fortifier-fed infants fared poorer than infants fed
      neutral pH sterilized HMF even though the acidified formula had higher protein intake (4.2
      g/kg) than the sterilized (3.7 g/kg).

      None of these studies assessed the effects of different levels of human milk protein, but
      they suggest attention be paid to achieving protein targets; that liquids may be preferred
      over powders, and that sterilized neutral pH products are preferable to acidified products.

      Necrotizing enterocolitis (NEC) One study created awareness about the value of feeding
      exclusive human milk in the NICU and reported that there was no difference in growth between
      VLBW infants fed mothers own milk supplemented with a fortifier derived from donor human milk
      or when a fortifier based on bovine milk was used, though the exclusively human milk diet
      resulted in fewer cases of NEC and NEC requiring surgical intervention. Subsequently, another
      study reported feeding with a fortifier based on human milk reduced days of parenteral
      nutrition (p=0.04), trend toward all NEC (p= 0.08) and reduced surgical NEC (p=0.04) when
      compared to fortification with preterm bovine milk based formula. Others report the timing of
      onset of NEC was delayed and incidence of late onset NEC (after 7 feeding days) and incidence
      of sepsis was significantly reduced among infants fed exclusive human milk diets compared to
      an earlier cohort of infants supplemented with bovine products; however, respiratory distress
      syndrome and use of surfactants was more common among the exclusive human milk cohort, and
      infants fed bovine products were more commonly discharged to home. A 2014 Cochrane review of
      9 studies found an increased risk of NEC among infants fed preterm formulas. This conclusion
      has been supported by recent retrospective studies, and extending benefit of exclusive human
      milk diets to reduced risk of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity
      (ROP) in addition to NEC .

      The value of exclusive human milk feeding also has been explored regarding growth. Questions
      of the relative value of mother's own milk compared to donor human milk, the form of
      fortifier (powder v liquid, v acidified liquid), the level of protein, and the source of
      protein (bovine or human) have been explored. A study reported that infants fed >75% donor
      milk had higher risk of small for gestational age (SGA) compared to those fed their own
      mothers milk. Donor milk fed infants had lower weight gain than infants fed either moms own
      milk or preterm formula possibly because of lower nutrient content of donor milk. In
      contrast, VLBW infants fed their own mother's milk fortified alternatively with donor milk or
      preterm formula grew better (weight gain from birth to discharge) as the proportion of diet
      as breast milk increased from <25%, 25-50%, to > 75% of total intake. A retrospective
      analysis among extremely low birthweight infants (ELBW) exclusively human milk diets reported
      a comparable growth and neurodevelopment as infants fed bovine milk based fortifiers.

      Consequently, there is good evidence that fortification of human milk is needed to support
      growth of LBW and VLBW infants, that higher protein up to about 4.3 g/kg/d supports more
      rapid growth, and that risk of NEC and other diseases affecting LBW infants is less when LBW
      infants are fed exclusive human milk diets. The difficulties have been to obtain liquid
      fortifier derived from human milk, and evaluate its use at the protein concentrations that
      have been evaluated using bovine-based products. This study addresses these two needs: a
      sterile liquid fortifier derived from human milk is evaluated at protein intakes recommended
      by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN),
      4.0-4.5 g/kg/d for infants less than 1000g, and 3.5-4.0 g/kg for infants 1000-1800g.

      Summary of Nonclinical Experience with MHMHMF The preclinical experience with this particular
      fortifier is limited to analytical evaluation. There are no suitable animal models sensitive
      to testing the biological source of the protein, and no alternative method for assessing
      growth of infants fed a human protein-based fortifier than clinical study. The protein
      quality of the processed protein has been established by amino acid analysis to be close to
      the native protein, with up to a 15% decrease in available lysine, probably due to Maillard
      reaction with lactose. The fortifier, even at its lowest recommended use rate represents more
      than a 2-fold increase in all amino acids when compared to raw breast milk, we are not
      concerned about protein quality with our manufacturing process. Additionally, the composition
      of the blended fortifier exceeds Codex reference for protein quality for infant formula and
      formulas for special medical purposes intended for infants.

      Summary of Clinical Experience Medolac has processed donor whole human milk for feeding LBW
      infants for some years. More recently Medolac has applied standard dairy processes to
      partition milk into milk fat and skim fractions, and to enrich the protein content. The
      processes have allowed the development of high protein human milk fortifier. Supplementation
      of the high protein fraction with vitamins and minerals has resulted in a novel human milk
      based human milk fortifier for fortification of human milk-fed VLBW infants. This is the
      first clinical evaluation of the MHMHMF fortifier. Only one other fortifier derived from
      human milk is available commercially (Prolacta). Reports on its use have been published
      showing reduced days of parenteral nutrition (p=0.04), trend toward all NEC (p= 0.08) and
      reduced surgical NEC (p=0.04) and rescue from failure after use of bovine based fortifiers.

      Description of Investigational Product The investigational product is manufactured from whole
      human breast milk with the addition of selected vitamins and minerals. The source of human
      milk is full lactation, full term donor milk from Mothers Milk Cooperative (Boulder City,
      NV), collected according to stringent blood screening criteria and quality control
      procedures, including microbiological evaluation, nutritional composition and chemical
      analyses. A fractionated, concentrated product is created by first delipidating then
      filtering through ultrafiltration (UF) membranes to selectively concentrate protein with loss
      of low molecular weight components such as lactose and minerals. Fat, selected minerals, and
      vitamins are added to the protein enriched fluid to reach a standard ratio. It is then
      packaged and processed by heat to achieve commercial sterility, granting room temperature
      storage with extensive shelf-life.

      Various blending ratios of the fortifier with either the mother's expressed milk or donor
      milk can be used to deliver varying concentrations of vitamins, minerals, and macronutrients
      enabling nutrient delivery to be adjusted according to the infant's tolerance for volume and
      calories.

      Blending ratios are illustrated in the table below. Simple blending of 50:50 results in a
      high protein, fat enriched fortifier having a caloric density of 27 kcal/ounce with protein
      provided at 3.0g/100 milliliters (mL). When this fortifier is mixed in a 1:2 ratio, the
      resulting caloric density is 25 kcal/oz and protein is provided at 2.4 g/100 ml; when this
      fortifier is mixed in a 1:3 ratio, the resulting caloric density is 23.6 kcal/oz and protein
      is provided at 2.07 g/100 ml; Similarly, other nutrients are delivered as a function of the
      ratio of MHMHMF to human milk.

      The primary objective for growth with this fortifier is the delivery of protein and calories,
      however we recognize that some vitamins are cofactors of enzymes involved in protein and
      energy metabolism. Some minerals such as zinc is variable in human milk, so was selected for
      addition. Other vitamins and minerals such as iron are generally monitored while others such
      as copper, vitamin A, and niacin are not considered limiting in human milk. In addition, heat
      processing used to achieve commercial sterility degrades some vitamins, making separate
      administration desirable. For these reasons the MHMHMF is not comprehensive in its delivery
      of vitamins and minerals which have been shown to be essential for nutrition. Infants should
      be monitored for adequate nutrition and additional fortification given as needed.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a non-controlled observational trial using objective measures (body weight) to assess the support of growth and tolerance of a new fortifier based on human milk, thereby enabling an exclusive human milk diet for VLBW infants in the NICU.
primary purpose: Supportive Care
masking: None (Open Label)
measure: weight gain (gm/kg/day)
time frame: Daily from first day of enrollment until 36 weeks post menstrual age or discharge
description: Weights.
measure: length increment (cm/kg/day)
time frame: Weekly until 36 weeks post menstrual age or discharge
description: length
measure: Head Circumference increment (cm/kg/day)
time frame: Weekly until 36 weeks post menstrual age or discharge
description: Head circumference
measure: Volume of Fortifier
time frame: Daily until 36 weeks post menstrual age or discharge
description: Total intake of formula and fortifier
measure: Morbidity
time frame: weekly until 36 weeks post menstrual age or discharge
description: Adverse Events-necrotizing enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia.
arm group label: Study Participants
arm group type: Experimental
description: all preterm infants ≤ 32 weeks and 0 days gestational age (GA) with a birth weight 700 g to 1500 g at the hospital, who are enterally fed human milk in the neonatal intensive care unit (NICU) for at least 7 days. Various blending ratios of the fortifier with either the mother's expressed milk or donor milk will be used to deliver macro and micronutrients based on established guidelines to be adjusted according to the infant's tolerance for volume and calories. The estimated time for each subject's participation is approximately from 1 week through 8 weeks, depending on the weight and age at enrollment. Historic control cases treated by another human milk based human milk fortifier will be obtained from medical records, matched on birth weight and gender, with sample size twice (n=80) that of the study population.
intervention type: Dietary Supplement
intervention name: Medolac human milk based human milk fortifier (MHMHMF)
description: MHMHMF is admixed with expressed or donor human milk in graded doses according to tolerated feed volume according to established guidelines and maintain adequate micronutrient levels.
arm group label: Study Participants
other name: exclusive human milk diet for VLBW infants
criteria: 
gender: All
minimum age: 23 Weeks
maximum age: 32 Weeks
healthy volunteers: No
last name: Sean Fels
role: Study Director
affiliation: Medolac Laboratories
facility: 
country: United States
url: http://www.medolac.com
description: Medolac Laboratories
citation: Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, Domellof M, Embleton ND, Fusch C, Genzel-Boroviczeny O, Goulet O, Kalhan SC, Kolacek S, Koletzko B, Lapillonne A, Mihatsch W, Moreno L, Neu J, Poindexter B, Puntis J, Putet G, Rigo J, Riskin A, Salle B, Sauer P, Shamir R, Szajewska H, Thureen P, Turck D, van Goudoever JB, Ziegler EE; ESPGHAN Committee on Nutrition. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010 Jan;50(1):85-91. doi: 10.1097/MPG.0b013e3181adaee0.
PMID: 19881390
citation: Cacho NT, Parker LA, Neu J. Necrotizing Enterocolitis and Human Milk Feeding: A Systematic Review. Clin Perinatol. 2017 Mar;44(1):49-67. doi: 10.1016/j.clp.2016.11.009. Epub 2016 Dec 24.
PMID: 28159209
citation: Chowning R, Radmacher P, Lewis S, Serke L, Pettit N, Adamkin DH. A retrospective analysis of the effect of human milk on prevention of necrotizing enterocolitis and postnatal growth. J Perinatol. 2016 Mar;36(3):221-4. doi: 10.1038/jp.2015.179. Epub 2015 Dec 3.
PMID: 26633147
citation: Colacci M, Murthy K, DeRegnier RO, Khan JY, Robinson DT. Growth and Development in Extremely Low Birth Weight Infants After the Introduction of Exclusive Human Milk Feedings. Am J Perinatol. 2017 Jan;34(2):130-137. doi: 10.1055/s-0036-1584520. Epub 2016 Jun 20.
PMID: 27322667
citation: Colaizy TT, Carlson S, Saftlas AF, Morriss FH Jr. Growth in VLBW infants fed predominantly fortified maternal and donor human milk diets: a retrospective cohort study. BMC Pediatr. 2012 Aug 17;12:124. doi: 10.1186/1471-2431-12-124.
PMID: 22900590
citation: Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, Dudell G, Rechtman DJ, Lee ML, Lucas A, Abrams S. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013 Dec;163(6):1592-1595.e1. doi: 10.1016/j.jpeds.2013.07.011. Epub 2013 Aug 20.
PMID: 23968744
citation: Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 2013 Apr 20;13:59. doi: 10.1186/1471-2431-13-59.
PMID: 23601190
citation: Gidrewicz DA, Fenton TR. A systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr. 2014 Aug 30;14:216. doi: 10.1186/1471-2431-14-216.
PMID: 25174435
citation: Hair AB, Peluso AM, Hawthorne KM, Perez J, Smith DP, Khan JY, O'Donnell A, Powers RJ, Lee ML, Abrams SA. Beyond Necrotizing Enterocolitis Prevention: Improving Outcomes with an Exclusive Human Milk-Based Diet. Breastfeed Med. 2016 Mar;11(2):70-4. doi: 10.1089/bfm.2015.0134. Epub 2016 Jan 20. Erratum In: Breastfeed Med. 2017 Dec;12 (10 ):663.
PMID: 26789484
citation: Hay WW, Ziegler EE. Growth failure among preterm infants due to insufficient protein is not innocuous and must be prevented. J Perinatol. 2016 Jul;36(7):500-2. doi: 10.1038/jp.2016.85. No abstract available.
PMID: 27339826
citation: Herrmann K, Carroll K. An exclusively human milk diet reduces necrotizing enterocolitis. Breastfeed Med. 2014 May;9(4):184-90. doi: 10.1089/bfm.2013.0121. Epub 2014 Mar 3.
PMID: 24588561
citation: Horbar JD, Ehrenkranz RA, Badger GJ, Edwards EM, Morrow KA, Soll RF, Buzas JS, Bertino E, Gagliardi L, Bellu R. Weight Growth Velocity and Postnatal Growth Failure in Infants 501 to 1500 Grams: 2000-2013. Pediatrics. 2015 Jul;136(1):e84-92. doi: 10.1542/peds.2015-0129.
PMID: 26101360
citation: Kim JH, Chan G, Schanler R, Groh-Wargo S, Bloom B, Dimmit R, Williams L, Baggs G, Barrett-Reis B. Growth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk Fortifier. J Pediatr Gastroenterol Nutr. 2015 Dec;61(6):665-71. doi: 10.1097/MPG.0000000000001010. Erratum In: J Pediatr Gastroenterol Nutr. 2016 Jan;62(1):188-9.
PMID: 26488118
citation: Kim EJ, Lee NM, Chung SH. A retrospective study on the effects of exclusive donor human milk feeding in a short period after birth on morbidity and growth of preterm infants during hospitalization. Medicine (Baltimore). 2017 Sep;96(35):e7970. doi: 10.1097/MD.0000000000007970.
PMID: 28858132
citation: Kumar N, Monga R, Sampath V, Ehrhart B. Prospective Comparison of Enfamil and Similac Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants. Am J Perinatol. 2017 Dec;34(14):1411-1416. doi: 10.1055/s-0037-1603940. Epub 2017 Jun 21. No abstract available.
PMID: 28637062
citation: Liu TT, Dang D, Lv XM, Wang TF, Du JF, Wu H. Human milk fortifier with high versus standard protein content for promoting growth of preterm infants: A meta-analysis. J Int Med Res. 2015 Jun;43(3):279-89. doi: 10.1177/0300060515579115. Epub 2015 May 8.
PMID: 25956156
citation: Maas C, Mathes M, Bleeker C, Vek J, Bernhard W, Wiechers C, Peter A, Poets CF, Franz AR. Effect of Increased Enteral Protein Intake on Growth in Human Milk-Fed Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2017 Jan 1;171(1):16-22. doi: 10.1001/jamapediatrics.2016.2681.
PMID: 27893064
citation: Madore LS, Bora S, Erdei C, Jumani T, Dengos AR, Sen S. Effects of Donor Breastmilk Feeding on Growth and Early Neurodevelopmental Outcomes in Preterm Infants: An Observational Study. Clin Ther. 2017 Jun;39(6):1210-1220. doi: 10.1016/j.clinthera.2017.05.341. Epub 2017 May 30.
PMID: 28576299
citation: McGuire W, Anthony MY. Formula milk versus preterm human milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2001;(3):CD002972. doi: 10.1002/14651858.CD002972.
PMID: 11687034
citation: Olsen IE, Harris CL, Lawson ML, Berseth CL. Higher protein intake improves length, not weight, z scores in preterm infants. J Pediatr Gastroenterol Nutr. 2014 Apr;58(4):409-16. doi: 10.1097/MPG.0000000000000237.
PMID: 24231639
citation: Rigo J, Hascoet JM, Billeaud C, Picaud JC, Mosca F, Rubio A, Saliba E, Radke M, Simeoni U, Guillois B, de Halleux V, Jaeger J, Ameye L, Hays NP, Spalinger J. Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial. J Pediatr Gastroenterol Nutr. 2017 Oct;65(4):e83-e93. doi: 10.1097/MPG.0000000000001686.
PMID: 28727654
citation: Sandhu A, Fast S, Bonnar K, Baier RJ, Narvey M. Human-Based Human Milk Fortifier as Rescue Therapy in Very Low Birth Weight Infants Demonstrating Intolerance to Bovine-Based Human Milk Fortifier. Breastfeed Med. 2017 Nov;12(9):570-573. doi: 10.1089/bfm.2017.0017. Epub 2017 Aug 4.
PMID: 28777664
citation: Shah SD, Dereddy N, Jones TL, Dhanireddy R, Talati AJ. Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants-A Randomized Controlled Trial. J Pediatr. 2016 Jul;174:126-131.e1. doi: 10.1016/j.jpeds.2016.03.056. Epub 2016 Apr 23.
PMID: 27112041
citation: Sisk PM, Lovelady CA, Dillard RG, Gruber KJ, O'Shea TM. Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol. 2007 Jul;27(7):428-33. doi: 10.1038/sj.jp.7211758. Epub 2007 Apr 19. Erratum In: J Perinatol. 2007 Dec;27(12):808.
PMID: 17443195
citation: Spiegler J, Preuss M, Gebauer C, Bendiks M, Herting E, Gopel W; German Neonatal Network (GNN); German Neonatal Network GNN. Does Breastmilk Influence the Development of Bronchopulmonary Dysplasia? J Pediatr. 2016 Feb;169:76-80.e4. doi: 10.1016/j.jpeds.2015.10.080. Epub 2015 Nov 25.
PMID: 26621048
citation: Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kiechl-Kohlendorfer U, Chan GM, Blanco CL, Abrams S, Cotten CM, Laroia N, Ehrenkranz RA, Dudell G, Cristofalo EA, Meier P, Lee ML, Rechtman DJ, Lucas A. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010 Apr;156(4):562-7.e1. doi: 10.1016/j.jpeds.2009.10.040. Epub 2009 Dec 29.
PMID: 20036378
citation: Taylor C. Health Professionals Letter on Enterobacter sakazakii Infections Associated With the Use of Powdered (Dry) Infant Formulas in Neonatal Intensive Care Units. Bethesda, MD: US Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling and Dietary Supplements; 2002.
citation: Thoene M, Lyden E, Weishaar K, Elliott E, Wu R, White K, Timm H, Anderson-Berry A. Comparison of a Powdered, Acidified Liquid, and Non-Acidified Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants. Nutrients. 2016 Jul 26;8(8):451. doi: 10.3390/nu8080451.
PMID: 27472359
citation: Valentine CJ, Morrow G, Reisinger A, Dingess KA, Morrow AL, Rogers LK. Lactational Stage of Pasteurized Human Donor Milk Contributes to Nutrient Limitations for Infants. Nutrients. 2017 Mar 18;9(3):302. doi: 10.3390/nu9030302.
PMID: 28335478
responsible party type: Principal Investigator
investigator affiliation: Northwest Health
investigator full name: Sameer Wagle, MD
investigator title: Medical Director, NICU
mesh term: Infant, Premature, Diseases
sharing ipd: No