Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants
TL;DR: In extremely preterm infants given exclusive diets of pre term formula vs human milk, there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula.
About: This article is published in The Journal of Pediatrics.The article was published on 2013-12-01. It has received 385 citations till now. The article focuses on the topics: Necrotizing enterocolitis & Parenteral nutrition.
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TL;DR: In preterm and low birth weight infants, feeding with formula compared with donor breast milk results in a higher rate of short-term growth but also a higher risk of developing necrotising enterocolitis.
Abstract: BACKGROUND: When sufficient maternal breast milk is not available, alternative forms of enteral nutrition for preterm or low birth weight (LBW) infants are donor breast milk or artificial formula. Donor breast milk may retain some of the non-nutritive benefits of maternal breast milk for preterm or LBW infants. However, feeding with artificial formula may ensure more consistent delivery of greater amounts of nutrients. Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or LBW infants. OBJECTIVES: To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or low birth weight (LBW) infants. SEARCH METHODS: We used the Cochrane Neonatal search strategy, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 5), Ovid MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (3 May 2019), as well as conference proceedings, previous reviews, and clinical trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials (RCTs) comparing feeding with formula versus donor breast milk in preterm or LBW infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in subgroup analyses. We assessed the certainty of evidence for the main comparison at the outcome level using GRADE methods. MAIN RESULTS: Twelve trials with a total of 1879 infants fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and eight compared nutrient-enriched preterm formula versus donor breast milk. Only the five most recent trials used nutrient-fortified donor breast milk. The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in four trials and lack of blinding in most of the trials. Most of the included trials were funded by companies that made the study formula.Formula-fed infants had higher in-hospital rates of weight gain (mean difference (MD) 2.51, 95% confidence interval (CI) 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95% CI 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95% CI 0.47 to 1.23 mm/week). These meta-analyses contained high levels of heterogeneity. We did not find evidence of an effect on long-term growth or neurodevelopment. Formula feeding increased the risk of necrotising enterocolitis (typical risk ratio (RR) 1.87, 95% CI 1.23 to 2.85; risk difference (RD) 0.03, 95% CI 0.01 to 0.05; number needed to treat for an additional harmful outcome (NNTH) 33, 95% CI 20 to 100; 9 studies, 1675 infants).The GRADE certainty of evidence was moderate for rates of weight gain, linear growth, and head growth (downgraded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all-cause mortality, and necrotising enterocolitis (downgraded for imprecision). AUTHORS' CONCLUSIONS: In preterm and LBW infants, moderate-certainty evidence indicates that feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, results in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotising enterocolitis. The trial data do not show an effect on all-cause mortality, or on long-term growth or neurodevelopment.
624 citations
TL;DR: The current approach to the diagnosis and treatment of NEC is examined, an overview of the current knowledge regarding its molecular underpinnings is provided and advances made within the past decade towards the development of specific preventive and treatment strategies for this devastating disease are highlighted.
Abstract: Necrotizing enterocolitis is the most frequent and lethal gastrointestinal disease in premature infants. This Review outlines current approaches for the treatment and diagnosis of necrotizing enterocolitis and examines the progress made in our understanding of the molecular mechanisms of this disease as well as potential avenues for future treatment development. Necrotizing enterocolitis (NEC) is the most frequent and lethal disease of the gastrointestinal tract of preterm infants. At present, NEC is thought to develop in the premature host in the setting of bacterial colonization, often after administration of non-breast milk feeds, and disease onset is thought to be due in part to a baseline increased reactivity of the premature intestinal mucosa to microbial ligands as compared with the full-term intestinal mucosa. The increased reactivity leads to mucosal destruction and impaired mesenteric perfusion and partly reflects an increased expression of the bacterial receptor Toll-like receptor 4 (TLR4) in the premature gut, as well as other factors that predispose the intestine to a hyper-reactive state in response to colonizing microorganisms. The increased expression of TLR4 in the premature gut reflects a surprising role for this molecule in the regulation of normal intestinal development through its effects on the Notch signalling pathway. This Review will examine the current approach to the diagnosis and treatment of NEC, provide an overview of our current knowledge regarding its molecular underpinnings and highlight advances made within the past decade towards the development of specific preventive and treatment strategies for this devastating disease.
358 citations
TL;DR: HM provided a clear protective effect against NEC, with an approximate 4% reduction in incidence, and any volume of HM is better than EPTF, and the higher the dose the greater the protection.
Abstract: This systematic review and meta-analysis synthesised the post-1990 literature examining the effect of human milk on morbidity, specifically necrotising enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD) and neurodevelopment in infants born ≤28 weeks’ gestation and/or publications with reported infant mean birth weight of ≤1500 g. Online databases including Medline, PubMed, CINAHL, Scopus, and the Cochrane Central Register of Controlled Trials were searched, and comparisons were grouped as follows: exclusive human milk (EHM) versus exclusive preterm formula (EPTF), any human milk (HM) versus EPTF, higher versus lower dose HM, and unpasteurised versus pasteurised HM. Experimental and observational studies were pooled separately in meta-analyses. Risk of bias was assessed for each individual study and the GRADE system used to judge the certainty of the findings. Forty-nine studies (with 56 reports) were included, of which 44 could be included in meta-analyses. HM provided a clear protective effect against NEC, with an approximate 4% reduction in incidence. HM also provided a possible reduction in LOS, severe ROP and severe NEC. Particularly for NEC, any volume of HM is better than EPTF, and the higher the dose the greater the protection. Evidence regarding pasteurisation is inconclusive, but it appears to have no effect on some outcomes. Improving the intake of mother’s own milk (MOM) and/or donor HM results in small improvements in morbidity in this population.
219 citations
Cites background or methods from "Randomized Trial of Exclusive Human..."
...The International Classification of Retinopathy of Prematurity [84] was used to define ROP in most studies, with five studies providing no definition [21,22,34,37,51]....
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...Randomised Trials: One small RT [34] (Table 1) reported the effect of EHM, including a human milk derived fortifier, versus EPTF, on the risk of NEC (any and severe) and did not detect a difference (any NEC RR 0....
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...Sequence generation was not reported in three [34,36,37], blinding was not possible in one [37] and blinding of physicians but not nursing staff occurred in another [33]....
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...Randomised trials: One RT [34] reported the effect of EHM feeding (including a human milk derived fortifier) compared with EPTF feeding on the incidence of LOS (Table 1) and indicating a possible reduction in LOS (RR 0....
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...Cristofalo (2013) [34] USA and Austria RT 53 infants Gp1: 996 ± 152; 27....
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TL;DR: It is important that health care providers counsel families considering milk sharing about the risks of bacterial or viral contamination of nonpasteurized human milk and about the possibilities of exposure to medications, drugs, or herbs in human milk.
Abstract: The use of donor human milk is increasing for high-risk infants, primarily for infants born weighing <1500 g or those who have severe intestinal disorders. Pasteurized donor milk may be considered in situations in which the supply of maternal milk is insufficient. The use of pasteurized donor milk is safe when appropriate measures are used to screen donors and collect, store, and pasteurize the milk and then distribute it through established human milk banks. The use of nonpasteurized donor milk and other forms of direct, Internet-based, or informal human milk sharing does not involve this level of safety and is not recommended. It is important that health care providers counsel families considering milk sharing about the risks of bacterial or viral contamination of nonpasteurized human milk and about the possibilities of exposure to medications, drugs, or herbs in human milk. Currently, the use of pasteurized donor milk is limited by its availability and affordability. The development of public policy to improve and expand access to pasteurized donor milk, including policies that support improved governmental and private financial support for donor milk banks and the use of donor milk, is important.
205 citations
TL;DR: Understanding outcomes of extremely preterm infants can help better counsel families regarding antenatal and postnatal care and guide strategies to improve survival without morbidity.
Abstract: Prematurity is the leading cause of infant mortality worldwide. In developed countries, extremely preterm infants contribute disproportionately to both neonatal and infant mortality. Survival of this high-risk population has incrementally improved in recent years. Despite these improvements, approximately one in four extremely preterm infants dies during the birth hospitalization. Among those who survive, respiratory and other morbidities are common, although their effect on quality of life is variable. In addition, long-term neurodevelopmental impairment is a large concern for patients, clinicians, and families. However, the interplay of multiple factors contributes to neurodevelopmental impairment, with measures that change over time and outcomes that can be difficult to define and predict. Understanding outcomes of extremely preterm infants can help better counsel families regarding antenatal and postnatal care and guide strategies to improve survival without morbidity. This review summarizes recent evidence to provide an overview into the short- and long-term outcomes for extremely preterm infants.
205 citations
References
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TL;DR: In this article, the product-limit (PL) estimator was proposed to estimate the proportion of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t).
Abstract: In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed. For random samples of size N the product-limit (PL) estimate can be defined as follows: L...
52,450 citations
University of Florida1, Yeshiva University2, University of California, San Diego3, Rush University Medical Center4, Innsbruck Medical University5, University of Utah6, University of Texas Health Science Center at San Antonio7, Baylor College of Medicine8, Duke University9, University of Rochester10, Yale University11, Children's Hospital Oakland Research Institute12, Johns Hopkins University13, University College London14
TL;DR: For extremely premature infants, an exclusively human milk-based diet is associated with significantly lower rates of NEC and surgical NEC when compared with a mother's milk- based diet that also includes bovine Milk-based products.
791 citations
"Randomized Trial of Exclusive Human..." refers background or methods or result in this paper
...Nearly 80% of the milk fed to study infants was their mothers’ own milk so that benefits attributed only to donor human milk could not be ascertained fully.(8)...
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...These data support those reported in our previous study of pasteurized donor human milk vs preterm formula used as supplements to a mother’s own milk diet.(8) The processing and preparation of an exclusive human milk diet require extensive technology for pasteurization and ultrafiltration to enable concentration of components to produce a human milk fortifier....
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...We previously reported the beneficial effects of an exclusive human milk diet (mother’s own milk plus human milk–based human milk fortifier and supplementation only with pasteurized donor milk if needed) compared with a diet of mother’s own milk plus bovine milk–based human milk fortifier and supplementation with bovine milk–based products.(8) That multicenter randomized trial reported significantly less NEC and surgery for NEC in infants receiving the exclusive human milk diet....
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...On the other hand, the 3% rate in the group exclusively fed human milk is in close agreement with that reported in the study by Sullivan et al.(8) Thus, the data from these 2 randomized trials contribute significant knowledge to enable guidelines for the feeding of premature infants....
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...Sample size was based on the primary outcome, duration of parenteral nutrition, an objective, quantifiable surrogate of feeding tolerance and neonatal morbidity.(8) The mean duration of parenteral nutrition in extremely premature infants in a study of formula-fed infants was 35 days with an SD of 22 days (Paula Meier, MD and Cynthia Blanco, MD, personal communication, February 2007)....
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TL;DR: Although the study does not allow a comparison of FHM with unfortified human milk, the data suggest that the unique properties of human milk promote an improved host defense and gastrointestinal function compared with the feeding of formula.
Abstract: Background. In a large-scale study of feeding strategies in premature infants (early vs later initiation of enteral feeding, continuous vs bolus tube-feeding, and human milk vs formula), the feeding of human milk had more effect on the outcomes measured than any other strategy studied. Therefore, this report describes the growth, nutritional status, feeding tolerance, and health of participating premature infants who were fed fortified human milk (FHM) in comparison with those who were fed exclusively preterm formula (PF). Methods. Premature infants were assigned randomly in a balanced two-way design to early (gastrointestinal priming for 10 days) versus late initiation of feeding (total parenteral nutrition only) and continuous infusion versus intermittent bolus tube-feeding groups. The type of milk was determined by parental choice and infants to receive their mother9s milk were randomized separately from those to receive formula. The duration of the study spanned the entire hospitalization of the infant. To evaluate human milk versus formula feeding, we compared outcomes of infants fed >50 mL · kg−1 · day−1 of any human milk (averaged throughout the hospitalization) with those of infants fed exclusively PF. Growth, feeding tolerance, and health status were measured daily. Serum indices of nutritional status were measured serially, and 72-hour nutrient balance studies were conducted at 6 and 9 weeks postnatally. Results. A total of 108 infants were fed either >50 mL · kg−1 · day−1 human milk (FHM,n = 62) or exclusively PF (n = 46). Gestational age (28 ± 1 weeks each), birth weight (1.07 ± 0.17 vs 1.04 ± 0.19 kg), birth length and head circumference, and distribution among feeding strategies were similar between groups. Infants fed FHM were discharged earlier (73 ± 19 vs 88 ± 47 days) despite significantly slower rates of weight gain (22 ± 7 vs 26 ± 6 g · kg−1 · day−1), length increment (0.8 ± 0.3 vs 1.0 ± 0.3 cm · week−1), and increment in the sum of five skinfold measurements (0.86 ± 0.40 vs 1.23 ± 0.42 mm · week−1) than infants fed PF. The incidence of necrotizing enterocolitis and late-onset sepsis was less in the FHM group. Overall, there were no differences in any measure of feeding tolerance between groups. Milk intakes of infants fed FHM were significantly greater than those fed PF (180 ± 13 vs 157 ± 10 mL · kg−1 · day−1). The intakes of nitrogen and copper were higher and magnesium and zinc were lower in group FHM versus PF. Fat and energy absorption were lower and phosphorus, zinc, and copper absorption were higher in group FHM versus PF. The postnatal retention (balance) surpassed the intrauterine accretion rate of nitrogen, phosphorus, magnesium, zinc, and copper in the FHM group, and of nitrogen, magnesium, and copper in the PF group. Conclusions. Although the study does not allow a comparison of FHM with unfortified human milk, the data suggest that the unique properties of human milk promote an improved host defense and gastrointestinal function compared with the feeding of formula. The benefits of improved health (less sepsis and necrotizing enterocolitis) associated with the feeding of FHM outweighed the slower rate of growth observed, suggesting that the feeding of FHM should be promoted actively in premature infants.
639 citations
"Randomized Trial of Exclusive Human..." refers background in this paper
...Premature infants receiving their ownmother’s milk have better feeding tolerance and a lower incidence of necrotizing enterocolitis (NEC) than those fed preterm formula.(3) Because not all mothers of premature infants produce sufficient milk to meet their infants’ needs and some have medical contraindications, pasteurized donor human milk has emerged as an alternative for mother’s own milk....
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TL;DR: This document describes the call to action with 20 actions in the categories of mothers and their families, communities, health care, employment, research and surveillance, and public health infrastructure and summarizes the background literature around the importance of breastfeeding.
Abstract: Nancy K. Lowe Editor I n January 2011, U.S. Surgeon General Regina M. Benjamin released the landmark document The Surgeon General’s Call to Action to Support Breastfeeding. Prepared by three agencies of the U.S. Department of Health and Human Services (USDHHS; Centers for Disease Control and Prevention [CDC], the O⁄ce on Women’s Health [OWH], and the O⁄ce of the Surgeon General), this document summarizes the background literature around the importance of breastfeeding, rates of breastfeeding, barriers to breastfeeding in the United States, and breastfeeding from the public health perspective. It details the call to action with 20 speci¢c actions in the categories of mothers and their families, communities, health care, employment, research and surveillance, and public health infrastructure (Table 1). The full document is freely available as a download at http://surgeongeneral.gov/ topics / breastfeeding /calltoactiontosupportbreast feeding.pdf
624 citations
"Randomized Trial of Exclusive Human..." refers result in this paper
...Furthermore, the US Surgeon General’s Call to Action to Support Breastfeeding directly states that more research is needed and that the use of donor human milk should be increased.(14) In conclusion, the results of this study and other recent studies,(2,8) as well as the US national recommendations, mandate a greater need for enhanced lactation support in the neonatal intensive care unit as well as an imperative to establish more human milk banks....
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TL;DR: It is found that, as a substitute for MM, DM offered little observed short-term advantage over PF for feeding extremely premature infants, butvantages to an exclusive diet of MM were observed in terms of fewer infection-related events and shorter hospital stays.
Abstract: Objective. Compared with preterm formula (PF), mother9s milk (MM) is associated with lower rates of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) among premature infants. Because not all mothers of premature infants produce sufficient milk to supply their infants throughout hospitalization, we reasoned that pasteurized donor human milk (DM) would be a suitable alternative. Methods. Extremely premature infants ( Results. Of 243 infants, 70 (29%) received only MM; group DM included 81 infants and group PF included 92 infants. Because of poor weight gain, 17 infants (21%), all in group DM, were switched to PF. There were no differences in birth weight, gestational age, multiple births, and age at attainment of feeding of 50 mL/kg among groups. There were no differences between group DM and group PF in LOS and/or NEC, other infection-related events, hospital stay, or number of deaths. Group DM received a greater intake of milk and more nutritional supplements but had a slower rate of weight gain, compared with group PF. Compared with groups DM and PF, group MM had fewer episodes of LOS and/or NEC and total infection-related events and a shorter duration of hospital stay. Group MM also had fewer Gram-negative organisms isolated from blood cultures than did the other groups. Conclusions. In this randomized, blinded trial of feeding of extremely premature infants, we found that, as a substitute for MM, DM offered little observed short-term advantage over PF for feeding extremely premature infants. Advantages to an exclusive diet of MM were observed in terms of fewer infection-related events and shorter hospital stays.
558 citations
"Randomized Trial of Exclusive Human..." refers methods in this paper
...A randomized trial was conducted in extremely premature infants fed either pasteurized donor human milk or preterm formula as supplements if their ownmother’s milk supply was inadequate.(7) The results of this trial found that infants who received their own mother’s milk had 50% less NEC and/or late-onset sepsis compared with infants fed either donor human milk or preterm formula....
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