The Use of Early Fortification in Preterm Infants
Early Fortification to Shorten Birth Weight Recovery Time in Very Preterm or Very Low Birth Weight Infants
Very premature or very low birth weight (VLBW) infants are at risk of suboptimal growth after birth, making adequate nutrition essential. Breast milk alone is insufficient to meet the nutritional needs of premature infants, so fortification is added to breast milk to support catch-up growth. Standard human milk fortification (HMF) is typically started when the feeding volume reaches 100 ml/kg/day, but research suggests that early HMF administration can increase protein intake sooner without negative effects on the infant. Early HMF administration didn't increase the incidence of food intolerance and necrotizing enterocolitis (NEC). Other studies have shown that early fortification increases the rate of early weight gain without increasing the incidence of complications. There is no research in Indonesia comparing the duration of regaining birth weight between early HMF and standard HMF. This study aims to determine the difference in the duration of regaining birth weight in very premature or VLBW infants given early HMF versus standard HMF. The research method is a prospective, randomized, double-blind preliminary study comparing early HMF administration (when feeding volume reached 30 ml/kg/day) with standard HMF (when feeding volume reached 100 ml/kg/day).
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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DKI Jakarta
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Jakarta Pusat, DKI Jakarta, Indonesia, 10430
- Cipto Mangunkusumo Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Very preterm infants (gestational age 28 to <32 weeks) or very low birth weight infants (birth weight 1000 to <1500 grams)
- Infants receiving at least 50% of their daily enteral needs from breast milk
- Infants whose parents provided written informed consent to participate in the study
Exclusion Criteria:
- Infants with major congenital abnormalities
- Infants with grade 2 or grade 3 NEC or spontaneous intestinal perforation (SIP) before the intervention
- Infants who had already achieved return to birth weight (RTBW) before initiation of the intervention
- Infants with insufficient breast milk availability to provide ≥50% of their daily enteral requirements before enrollment
- Infants born to mothers with medical conditions that precluded breastfeeding
- Infants with known cow's milk protein allergy before initiation of the intervention
- Infants who died before initiation of the intervention
- Parents who withdrew informed consent
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Supportive Care
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Experimental: Early Fortification Group
Participants were given early fortification when the feeding volume reached 30 ml/kg/day |
In the early fortification group, 1 sachet of HMF was added to 30 ml of breast milk for the first 24 hours. If the feeding tolerance was good, 1 sachet of HMF was then mixed into 25 ml of breast milk. |
|
Experimental: Standard Fortification Group
Participants were given standard fortification when the feeding volume reached 100 ml/kg/day |
In the standard fortification group, 1 sachet of HMF was mixed into 25 ml of breast milk starting from the first day of HMF administration. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Return to birth weight
Time Frame: Body weight will be measured daily from birth until the day the infant first reaches their birth weight. The assessment period is expected to last up to 3 weeks after birth.
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The first day the infants reached their birth weight again |
Body weight will be measured daily from birth until the day the infant first reaches their birth weight. The assessment period is expected to last up to 3 weeks after birth.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Number of Participants with Feeding Intolerance
Time Frame: Feeding intolerance will be monitored from the initiation of HMF administration until the day the infant first reaches their birth weight. The monitoring period is expected to last up to 3 weeks after birth.
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Feeding intolerance was defined as inability to tolerate enteral feeding, characterized by a gastric residual volume greater than 50% (with or without regurgitation), vomiting, abdominal distension, decreased frequency of bowel movements, and disruption of the feeding plan. |
Feeding intolerance will be monitored from the initiation of HMF administration until the day the infant first reaches their birth weight. The monitoring period is expected to last up to 3 weeks after birth.
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Number of Participants with Electrolyte Imbalances
Time Frame: Electrolytes will be assessed once during intervention. Blood sampling will be scheduled by the attending physician. The intervention period starts with HMF administration and ends when birth weight is regained, expected within 3 weeks after birth.
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Electrolyte imbalance was identified when serum levels fell below institutional laboratory reference ranges, with assessments performed for all study subjects. |
Electrolytes will be assessed once during intervention. Blood sampling will be scheduled by the attending physician. The intervention period starts with HMF administration and ends when birth weight is regained, expected within 3 weeks after birth.
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Number of Participants with Necrotizing Enterocolitis
Time Frame: Necrotizing enterocolitis will be monitored from the initiation of HMF administration until the day the infant first reaches their birth weight. The monitoring period is expected to last up to 3 weeks after birth.
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Necrotizing enterocolitis was defined as a disorder of the intestinal mucosa, clinically manifested by feeding intolerance, bloody stools, and possibly accompanied by changes in abdominal skin color, supported by abdominal X-ray findings consistent with necrotizing enterocolitis. |
Necrotizing enterocolitis will be monitored from the initiation of HMF administration until the day the infant first reaches their birth weight. The monitoring period is expected to last up to 3 weeks after birth.
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Putri MT Marsubrin, MD, PhD, FKUI RSCM
Publications and helpful links
General Publications
- 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.
- Calkins K, Devaskar SU. Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care. 2011 Jul;41(6):158-76. doi: 10.1016/j.cppeds.2011.01.001.
- 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.
- Chawanpaiboon S, Vogel JP, Moller AB, Lumbiganon P, Petzold M, Hogan D, Landoulsi S, Jampathong N, Kongwattanakul K, Laopaiboon M, Lewis C, Rattanakanokchai S, Teng DN, Thinkhamrop J, Watananirun K, Zhang J, Zhou W, Gulmezoglu AM. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health. 2019 Jan;7(1):e37-e46. doi: 10.1016/S2214-109X(18)30451-0. Epub 2018 Oct 30.
- Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, Okwaraji YB, Mahanani WR, Johansson EW, Lavin T, Fernandez DE, Dominguez GG, de Costa A, Cresswell JA, Krasevec J, Lawn JE, Blencowe H, Requejo J, Moran AC. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023 Oct 7;402(10409):1261-1271. doi: 10.1016/S0140-6736(23)00878-4.
- Thanigainathan S, Abiramalatha T. Early fortification of human milk versus late fortification to promote growth in preterm infants. Cochrane Database Syst Rev. 2020 Jul 29;7(7):CD013392. doi: 10.1002/14651858.CD013392.pub2.
- Joosten K, Vermeulen M. Principles of feeding the preterm infant. Clin Nutr ESPEN. 2024 Feb;59:320-327. doi: 10.1016/j.clnesp.2023.12.016. Epub 2023 Dec 20. No abstract available.
- Fenton TR, Merlino Barr S, Elmrayed S, Alshaikh B. Expected and Desirable Preterm and Small Infant Growth Patterns. Adv Nutr. 2024 Jun;15(6):100220. doi: 10.1016/j.advnut.2024.100220. Epub 2024 Apr 24.
- Alizadeh Taheri P, Sajjadian N, Asgharyan Fargi M, Shariat M. Is early breast milk fortification more effective in preterm infants?: a clinical trial. J Perinat Med. 2017 Nov 27;45(8):953-957. doi: 10.1515/jpm-2015-0375.
- Gupta G, Murugesan A, Thanigainathan S, Adhisivam B. Does Early Fortification of Human Milk Decrease Time to Regain Birth Weight as Compared to Late Fortification Among Preterm Infants? - A Randomized Controlled Trial. Indian J Pediatr. 2025 Jun;92(6):592-597. doi: 10.1007/s12098-024-05066-5. Epub 2024 Feb 28.
- Marsubrin PMT, Rohsiswatmo R, Sjarif DR. Preterm human milk composition and dietary intake of breastfeeding mothers in the Indonesian population. Paediatr Indones. 2021;61:20-24.
- Gidi NW, Goldenberg RL, Nigussie AK, McClure E, Mekasha A, Worku B, Siebeck M, Genzel-Boroviczeny O, Muhe LM. Comparison of neonatal outcomes of small for gestational age and appropriate for gestational age preterm infants born at 28-36 weeks of gestation: a multicentre study in Ethiopia. BMJ Paediatr Open. 2020 Sep 15;4(1):e000740. doi: 10.1136/bmjpo-2020-000740. eCollection 2020.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Other Study ID Numbers
- 24-06-0986
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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