Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2020

01-12-2020 | Care | Study protocol

A randomized controlled trial protocol comparing the feeds of fresh versus frozen mother’s own milk for preterm infants in the NICU

Authors: Huiqing Sun, Yun Cao, Shuping Han, Rui Cheng, Ling Liu, Jiangqin Liu, Shiwen Xia, Jiajie Zhang, Zhankui Li, Xiuyong Cheng, Chuanzhong Yang, Xinnian Pan, Long Li, Xin Ding, Rensheng Wang, Mingyuan Wu, Xiaoying Li, Liping Shi, Falin Xu, Fengqin Yu, Jiahua Pan, Xiaolan Zhang, Li Li, Jie Yang, Mingxia Li, Changhong Yan, Qi Zhou, Jiao Lu, Mou Wei, Laishuan Wang, Ling Yang, Xiang Y. Ye, Sharon Unger, Foteini Kakulas, Shoo K. Lee

Published in: Trials | Issue 1/2020

Login to get access

Abstract

Background

Necrotizing enterocolitis (NEC) is the leading cause of death among preterm infants born at < 30 weeks’ gestation. The incidence of NEC is reduced when infants are fed human milk. However, in many neonatal intensive care units (NICUs), it is standard practice to freeze and/or pasteurize human milk, which deactivates bioactive components that may offer additional protective benefits. Indeed, our pilot study showed that one feed of fresh mother’s own milk per day was safe, feasible, and can reduce morbidity in preterm infants. To further evaluate the benefits of fresh human milk in the NICU, a randomized controlled trial is needed.

Methods

Our prospective multicenter, double-blinded, randomized, controlled trial will include infants born at < 30 weeks’ gestation and admitted to one of 29 tertiary NICUs in China. Infants in the intervention (fresh human milk) group (n = 1549) will receive at least two feeds of fresh human milk (i.e., within 4 h of expression) per day from the time of enrollment until 32 weeks’ corrected age or discharge to home. Infants in the control group (n = 1549) will receive previously frozen human milk following the current standard protocols. Following informed consent, enrolled infants will be randomly allocated to the control or fresh human milk groups. The primary outcome is the composite outcome mortality or NEC ≥ stage 2 at 32 weeks’ corrected age, and the secondary outcomes are mortality, NEC ≥ stage 2, NEC needing surgery, late-onset sepsis, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), weight gain, change in weight, increase in length, increase in head circumference, time to full enteral feeds, and finally, the number and type of critical incident reports, including feeding errors.

Discussion

Our double-blinded, randomized, controlled trial aims to examine whether fresh human milk can improve infant outcomes. The results of this study will impact both Chinese and international medical practice and feeding policy for preterm infants. In addition, data from our study will inform changes in health policy in NICUs across China, such that mothers are encouraged to enter the NICU and express fresh milk for their infants.

Trial registration

Chinese Clinical Trial Registry; #ChiCTR1900020577; registered January 1, 2019; http://​www.​chictr.​org.​cn/​showprojen.​aspx?​proj=​34276
Appendix
Available only for authorised users
Literature
1.
Berman L, Moss RL. Necrotizing enterocolitis: an update. Semin Fetal Neonatal Med. 2011;16:145–50.PubMedCrossRef
2.
3.
4.
Patel AL, Panagos PG, Silvestri JM. Reducing incidence of necrotizing enterocolitis. Clin Perinatol. 2017;44:683–700.PubMedCrossRef
5.
Talavera MM, Bixler G, Cozzi C, Dail J, Miller RR, McClead R Jr, Reber K. Quality improvement initiative to reduce the necrotizing enterocolitis rate in premature infants. Pediatrics. 2016;137(5):e20151119.PubMedCrossRef
6.
Ballard O, Morrow AL. Human milk composition: nutrients and bioactive factors. Pediatr Clin N Am. 2013;60:49–74.CrossRef
7.
Underwood MA. Human milk for the premature infant. Pediatr Clin N Am. 2013;60:189–207.CrossRef
8.
Hassiotou F, Geddes DT, Hartmann PE. Cells in human milk: state of the science. J Hum Lact. 2013;29:171–82.PubMedCrossRef
9.
Moles JP, Tuaillon E, Kankasa C, Bedin AS, Nagot N, Marchant A, McDermid JM, Van de Perre P. Breastmilk cell trafficking induces microchimerism-mediated immune system maturation in the infant. Pediatr Allergy Immunol. 2018;29:133–43.PubMedCrossRef
10.
11.
Garcia-Lara NR, Escuder-Vieco D, Garcia-Algar O, De la Cruz J, Lora D, Pallas-Alonso C. Effect of freezing time on macronutrients and energy content of breastmilk. Breastfeed Med. 2012;7:295–301.PubMedPubMedCentralCrossRef
12.
Lev HM, Ovental A, Mandel D, Mimouni FB, Marom R, Lubetzky R. Major losses of fat, carbohydrates and energy content of preterm human milk frozen at −80 degrees C. J Perinatol. 2014;34:396–8.PubMedCrossRef
13.
Akinbi H, Meinzen-Derr J, Auer C, Ma Y, Pullum D, Kusano R, Reszka KJ, Zimmerly K. Alterations in the host defense properties of human milk following prolonged storage or pasteurization. J Pediatr Gastroenterol Nutr. 2010;51:347–52.PubMed
14.
Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hrobjartsson A, Schulz KF, Parulekar WR, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.PubMedPubMedCentralCrossRef
15.
Chang JC, Chen CH, Fang LJ, Tsai CR, Chang YC, Wang TM. Influence of prolonged storage process, pasteurization, and heat treatment on biologically-active human milk proteins. Pediatr Neonatol. 2013;54:360–6.PubMedCrossRef
16.
Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2012;10:28–55.PubMedCrossRef
17.
Sari FN, Akdag A, Dizdar EA, Uras N, Erdeve O, Erel O, Dilmen U. Antioxidant capacity of fresh and stored breast milk: is −80 degrees C optimal temperature for freeze storage? J Matern Fetal Neonatal Med. 2012;25:777–82.PubMedCrossRef
18.
Silvestre D, Miranda M, Muriach M, Almansa I, Jareno E, Romero FJ. Frozen breast milk at −20 degrees C and −80 degrees C: a longitudinal study of glutathione peroxidase activity and malondialdehyde concentration. J Hum Lact. 2010;26:35–41.PubMedCrossRef
19.
Sun H, Han S, Cheng R, Hei M, Kakulas F, Lee SK. Testing the feasibility and safety of feeding preterm infants fresh mother’s own milk in the NICU: A pilot study. Sci Rep. 2019;9:941.PubMedPubMedCentralCrossRef
20.
Josephson CD, Caliendo AM, Easley KA, Knezevic A, Shenvi N, Hinkes MT, Patel RM, Hillyer CD, Roback JD. Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study. JAMA Pediatr. 2014;168:1054–62.PubMedPubMedCentralCrossRef
21.
Yoo HS, Sung SI, Jung YJ, Lee MS, Han YM, Ahn SY, Chang YS, Park WS. Prevention of Cytomegalovirus Transmission via Breast Milk in Extremely Low Birth Weight Infants. Yonsei Med J. 2015;56:998–1006.PubMedPubMedCentralCrossRef
22.
Lanzieri TM, Dollard SC, Josephson CD, Schmid DS, Bialek SR. Breast milk-acquired cytomegalovirus infection and disease in VLBW and premature infants. Pediatrics. 2013;131:e1937–45.PubMedCrossRef
23.
24.
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7.PubMedPubMedCentralCrossRef
25.
The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123:991–9 (Chicago, Ill : 1960).
26.
27.
Dicky O, Ehlinger V, Montjaux N, Gremmo-Feger G, Sizun J, Roze JC, Arnaud C, Casper C. Policy of feeding very preterm infants with their mother’s own fresh expressed milk was associated with a reduced risk of bronchopulmonary dysplasia. Acta paediatrica. 2017;106:755–62.PubMedCrossRef
28.
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. 2017;96:e7970.PubMedPubMedCentralCrossRef
29.
Autran CA, Kellman BP, Kim JH, Asztalos E, Blood AB, Spence ECH, Patel AL, Hou J, Lewis NE, Bode L. Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants. Gut. 2018;67:1064–70.PubMedCrossRef
30.
Haschke F, Haiden N, Thakkar SK. Nutritive and bioactive proteins in breastmilk. Ann Nutr Metab. 2016;69(Suppl 2):17–26.PubMedCrossRef
31.
Chatterton DE, Nguyen DN, Bering SB, Sangild PT. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Int J Biochem Cell. Biol. 2013;45:1730–47.PubMedCrossRef
32.
Grote V, Verduci E, Scaglioni S, Vecchi F, Contarini G, Giovannini M, Koletzko B, Agostoni C, European Childhood Obesity P. Breast milk composition and infant nutrient intakes during the first 12 months of life. Eur J Clin Nutr. 2016;70:250–6.PubMedCrossRef
33.
Uauy R, Mena P, Rojas C. Essential fatty acids in early life: structural and functional role. Proc Nutr Soc. 2000;59:3–15.PubMedCrossRef
34.
Isaacs CE, Litov RE, Thormar H. Antimicrobial activity of lipids added to human milk, infant formula, and bovine milk. J Nutr Biochem. 1995;6:362–6.PubMedCrossRef
35.
Alsaweed M, Lai CT, Hartmann PE, Geddes DT, Kakulas F. Human Milk Cells and Lipids Conserve Numerous Known and Novel miRNAs, Some of Which Are Differentially Expressed during Lactation. PLoS One. 2016;11:e0152610.PubMedPubMedCentralCrossRef
36.
Alsaweed M, Hartmann PE, Geddes DT, Kakulas F. MicroRNAs in breastmilk and the lactating breast: potential immunoprotectors and developmental regulators for the infant and the mother. Int J Environ Res Public Health. 2015;12:13981–4020.PubMedPubMedCentralCrossRef
37.
Bode L, McGuire M, Rodriguez JM, Geddes DT, Hassiotou F, Hartmann PE, McGuire MK. It's alive: microbes and cells in human milk and their potential benefits to mother and infant. Adv Nutr. 2014;5:571–3.PubMedPubMedCentralCrossRef
38.
39.
Hassiotou F, Beltran A, Chetwynd E, Stuebe AM, Twigger AJ, Metzger P, Trengove N, Lai CT, Filgueira L, Blancafort P, et al. Breastmilk is a novel source of stem cells with multilineage differentiation potential. Stem Cells. 2012;30:2164–74.PubMedPubMedCentralCrossRef
40.
41.
Li S, Zhang L, Zhou Q, Jiang S, Yang Y, Cao Y. Characterization of stem cells and immune cells in preterm and term mother's milk. Journal of human lactation: official journal of International Lactation Consultant Association. 2019;35:528-34.PubMedCrossRef
42.
Bertino E, Coppa GV, Giuliani F, Coscia A, Gabrielli O, Sabatino G, Sgarrella M, Testa T, Zampini L, Fabris C. Effects of holder pasteurization on human milk oligosaccharides. Int J Immunopathol Pharmacol. 2008;21:381–5.PubMedCrossRef
43.
Ewaschuk JB, Unger S, Harvey S, O'Connor DL, Field CJ. Effect of pasteurization on immune components of milk: implications for feeding preterm infants. Appl Physiol Nutr Metab. 2011;36:175–82.PubMedCrossRef
44.
Henderson TR, Fay TN, Hamosh M. Effect of pasteurization on long chain polyunsaturated fatty acid levels and enzyme activities of human milk. J Pediatr. 1998;132:876–8.PubMedCrossRef
45.
Paduraru L, Dimitriu DC, Avasiloaiei AL, Moscalu M, Zonda GI, Stamatin M. Total antioxidant status in fresh and stored human milk from mothers of term and preterm neonates. Pediatr Neonatol. 2018;59:600–5.PubMedCrossRef
46.
Oveisi MR, Sadeghi N, Jannat B, Hajimahmoodi M, Behfar AO, Jannat F, Mokhtarinasab F. Human breast milk provides better antioxidant capacity than infant formula. Iran J Pharm Res. 2010;9:445–9.PubMedPubMedCentral
47.
Lawrence RA. Milk banking: the influence of storage procedures and subsequent processing on immunologic components of human milk. Adv Nutr Res. 2001;10:389–404.PubMed
48.
Sam SS, Ingersoll J, Racsa LD, Caliendo AM, Racsa PN, Igwe D, Abdul-Ali D, Josephson C, Kraft CS. Long-term stability of CMV DNA in human breast milk. J Clin Virol. 2018;102:39–41.PubMedCrossRef
49.
Hamprecht K, Goelz R. Postnatal Cytomegalovirus Infection Through Human Milk in Preterm Infants: Transmission, Clinical Presentation, and Prevention. Clin Perinatol. 2017;44:121–30.PubMedCrossRef
50.
Thibeault DW. The precarious antioxidant defenses of the preterm infant. Am J Perinatol. 2000;17:167–81.PubMedCrossRef
Metadata
Title
A randomized controlled trial protocol comparing the feeds of fresh versus frozen mother’s own milk for preterm infants in the NICU
Authors
Huiqing Sun
Yun Cao
Shuping Han
Rui Cheng
Ling Liu
Jiangqin Liu
Shiwen Xia
Jiajie Zhang
Zhankui Li
Xiuyong Cheng
Chuanzhong Yang
Xinnian Pan
Long Li
Xin Ding
Rensheng Wang
Mingyuan Wu
Xiaoying Li
Liping Shi
Falin Xu
Fengqin Yu
Jiahua Pan
Xiaolan Zhang
Li Li
Jie Yang
Mingxia Li
Changhong Yan
Qi Zhou
Jiao Lu
Mou Wei
Laishuan Wang
Ling Yang
Xiang Y. Ye
Sharon Unger
Foteini Kakulas
Shoo K. Lee
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Care
Published in
Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-019-3981-4

Other articles of this Issue 1/2020

Trials 1/2020 Go to the issue

Study protocol

Protocol for the process evaluation of a cluster randomised controlled trial to determine the effectiveness and cost-effectiveness of independent pharmacist prescribing in care home: the CHIPPS study

Research

Two-by-two factorial randomised study within a trial (SWAT) to evaluate strategies for follow-up in a randomised prevention trial

Research

Using digital tools in the recruitment and retention in randomised controlled trials: survey of UK Clinical Trial Units and a qualitative study

Research

Identifying treatment effects of an informal caregiver education intervention to increase days in the community and decrease caregiver distress: a machine-learning secondary analysis of subgroup effects in the HI-FIVES randomized clinical trial

Study protocol

Effect of Daesiho-tang on obesity with non-alcoholic fatty liver disease: a study protocol for a randomised, double-blind, placebo-controlled pilot trial

Study protocol

Comparison of patient-led, fibromyalgia-orientated physical activity and a non-specific, standardised 6-month physical activity program on quality of life in individuals with fibromyalgia: a protocol for a randomised controlled trial