Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants

BackgroundHuman milk–based human milk fortifier (HMB-HMF) makes it possible to provide an exclusive human milk diet (EHMD) to very low birth weight (VLBW) infants in neonatal intensive care units (NICUs). Before the introduction of HMB-HMF in 2006, NICUs relied on bovine milk–based human milk fortifiers (BMB-HMFs) when mother's own milk (MOM) or pasteurized donor human milk (PDHM) could not provide adequate nutrition. Despite evidence supporting the clinical benefits of an EHMD (such as reducing the frequency of morbidities), barriers prevent its widespread adoption, including limited health economics and outcomes data, cost concerns, and lack of standardized feeding guidelines.MethodsNine experts from seven institutions gathered for a virtual roundtable discussion in October 2020 to discuss the benefits and challenges to implementing an EHMD program in the NICU environment. Each center provided a review of the process of starting their program and also presented data on various neonatal and financial metrics associated with the program. Data gathered were either from their own Vermont Oxford Network outcomes or an institutional clinical database. As each center utilizes their EHMD program in slightly different populations and over different time periods, data presented was center-specific. After all presentations, the experts discussed issues within the field of neonatology that need to be addressed with regards to the utilization of an EHMD in the NICU population.ResultsImplementation of an EHMD program faces many barriers, no matter the NICU size, patient population or geographic location. Successful implementation requires a team approach (including finance and IT support) with a NICU champion. Having pre-specified target populations as well as data tracking is also helpful. Real-world experiences of NICUs with established EHMD programs show reductions in comorbidities, regardless of the institution’s size or level of care. EHMD programs also proved to be cost effective. For the NICUs that had necrotizing enterocolitis (NEC) data available, EHMD programs resulted in either a decrease or change in total (medical + surgical) NEC rate and reductions in surgical NEC. Institutions that provided cost and complications data all reported a substantial cost avoidance after EHMD implementation, ranging between $515,113 and $3,369,515 annually per institution.ConclusionsThe data provided support the initiation of EHMD programs in NICUs for very preterm infants, but there are still methodologic issues to be addressed so that guidelines can be created and all NICUs, regardless of size, can provide standardized care that benefits VLBW infants.

Human milk is the best form of nutrition for preterm infants and has been associated with a lower incidence of necrotizing enterocolitis (NEC). Infants that develop NEC have a higher incidence of feeding intolerance and longer hospitalizations. The combination of a donor milk bank and donor milk-derived fortifier has changed feeding practices in neonatal intensive care units (NICU). The purpose of this study is to assess the benefits and cost of an exclusive human milk (EHM) diet in very low birth weight (VLBW) infants in a community level III NICU. This is a retrospective study including preterm infants ⩽28 weeks and/or VLBW (⩽1500 g) who were enrolled from March 2009 until March 2014. Infants were grouped as follows: group H (entirely human milk based, born March 2012 to 2014), group B (bovine-based fortifier and maternal milk, born March 2009 to 2012), group M (mixed combination of maternal milk, bovine-based fortifier and formula, born March 2009 to 2012) and group F (formula fed infants, born March 2009 to 2012). Baseline characteristics among the four groups were similar. The study included 293 infants between gestational ages 23 to 34 weeks and birth weights between 490 and 1700 g. Feeding intolerance occurred less often (P<0.0001), number of days to full feeds was lower (P<0.001), incidence of NEC was lower (P<0.011), and total hospitalization costs were lower by up to $106,968 per infant (P<0.004) in those fed an EHM diet compared with the other groups. Average weight gain per day was similar among the four groups (18.5 to 20.6 g per day). Implementing an EHM diet in our VLBW infants has led to a significant decrease in the incidence of NEC. Other benefits of this diet include: decreased feeding intolerance, shorter time to full feeds, shorter length of stay, and lower hospital and physician charges for extremely premature and VLBW infants.

An exclusive human milk diet (EHM) fortified with human milk-based fortifier decreases necrotizing enterocolitis (NEC) compared to maternal milk supplemented with preterm formula and bovine fortifier (PTF). Growth has been less with EHM and also maternal milk supplemented with donor human milk and bovine fortifier (HMBF). The objective was to evaluate the effect of a standardized feeding protocol on the growth of infants ≤1250 g birth weight supported with EHM and HMBF. The effect on the incidence of NEC was also evaluated. A retrospective study of growth before and after implementation of a feeding protocol for infants who received either EHM or HMBF. Primary outcomes were weight, length, and head circumference gain velocities from birth to discharge. The incidence of NEC was also recorded. Analysis of covariance for 379 total infants showed that earlier day of life for fortification to 24 Kcal/oz was associated with increased weight gain (p = 0.0166) and length gain (p = 0.0064). Implementation of the feeding protocol was associated with increased head circumference gain (p = 0.006). EHM was associated with decreased incidence of NEC (p = 0.0302). Implementation of a standardized feeding protocol including earlier fortification of maternal milk was associated with improved growth for infants receiving human milk feedings. EHM significantly decreased NEC. Earlier fortification had no effect on NEC.

Provision of human milk has important implications for the health and outcomes of extremely preterm (EP) infants. This study evaluated the effects of an exclusive human milk diet on the health of EP infants during their stay in the neonatal intensive care unit. EP infants <1,250 g birth weight received a diet consisting of either human milk fortified with a human milk protein-based fortifier (HM) (n=167) or a diet containing variable amounts of milk containing cow milk-based protein (CM) (n=93). Principal outcomes were mortality, necrotizing enterocolitis (NEC), growth, and duration of parenteral nutrition (PN). Mortality (2% versus 8%, p=0.004) and NEC (5% versus 17%, p=0.002) differed significantly between the HM and CM groups, respectively. For every 10% increase in the volume of milk containing CM, the risk of sepsis increased by 17.9% (p<0.001). Growth rates were similar between groups. The duration of PN was 8 days less in the subgroup of infants receiving a diet containing <10% CM versus ≥10% CM (p<0.02). An exclusive human milk diet, devoid of CM-containing products, was associated with lower mortality and morbidity in EP infants without compromising growth and should be considered as an approach to nutritional care of these infants.

Human Milk Use in the Preoperative Period Is Associated with a Lower Risk for Necrotizing Enterocolitis in Neonates with Complex Congenital Heart Disease

The University of Virginia neonatal intensive care unit is a 51-bed unit with approximately 600 to 700 admissions per year. Despite evidenced-based clinical care, necrotizing enterocolitis (NEC) and feeding intolerance remained problematic. In September 2016, the neonatal intensive care unit implemented an exclusive human milk diet (EHMD) for infants born 1250 g or less with the goal of reducing NEC, feeding intolerance, parenteral nutrition use, and late-onset sepsis. Length of stay, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity were also evaluated. A work group developed systems for charging and documenting products used in an EHMD. Outcomes were compared with a control group of similar infants born prior to the availability of the EHMD. Infants who received an EHMD had significantly fewer late-onset sepsis evaluations (P = .0027) and less BPD (P = .018). While not statistically significant, less surgical NEC was also demonstrated (4 cases vs 1 case, which was 57% of total NEC cases vs 14.3%) while maintaining desirable weight gain and meeting financial goals. A multidisciplinary team that implements financial and documentation systems can provide a sustainable clinical practice that improves patient outcomes. Ongoing evaluations of clinical and financial data provide valuable information to guide future clinical practices related to the EHMD. Future research on the anti-inflammatory effect of an EHMD is needed to provide direction regarding a potential dose-dependent response for reduced BPD rates and severity. The role of human milk and prevention or mitigation of sepsis is not fully understood, but the reduction of the number of late-onset sepsis evaluations may support the relationship between an EHMD and infection protection. Exploring clinical and financial outcomes for implementing the EHMD in infants born more than 1250 g remains a key area for research.

Background: Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in very low birthweight (VLBW) infants. Human milk feeding and standardized feeding protocols are protective, but clinical practice varies, particularly in fortifier choice. Whether human milk-derived fortifiers reduce NEC risk compared with cow milk-derived fortifiers remains unclear. Methods: We conducted a systematic state-of-evidence review and meta-analysis, searching PubMed, Web of Science, and Scopus through July 2025. Eligible studies included RCTs and observational cohorts of VLBW infants comparing an exclusive human milk diet (EHMD) including human milk-derived fortifiers to cow milk-derived diets. Two reviewers independently screened and extracted data. Both RCTs and observational studies were included to evaluate consistency of effect estimates across designs and to account for heterogeneity in control group feeding practices. Pooled odds ratios (ORs) with 95% CIs were calculated using a Sidik–Jonkman random-effects model. Sensitivity analyses by study design and exclusion of infant formula from controls were performed. Results: Twenty studies (five RCTs, 15 observational; n = 6794 infants) met inclusion criteria, most enrolling infants born ≤1250 g. Compared with cow milk-containing diets, EHMD was associated with lower odds of Bell Stage ≥ 2 NEC (OR: 0.59; 95% CI: 0.42, 0.81; p < 0.001; n = 4625) and surgical NEC (OR: 0.43; 95% CI: 0.32, 0.58; p < 0.0001; n = 4754). In direct comparisons of fortifier type with a base diet of human milk, estimates suggested lower odds of Bell Stage ≥ 2 NEC by 35% (OR: 0.65; 95% CI: 0.44, 0.97; p = 0.03, n = 2102) and surgical NEC by 49% (OR: 0.51; 95% CI: 0.26, 0.98; p = 0.04; n = 1659) with human milk-derived fortifiers. Effect estimates were generally consistent across study designs, although precision and statistical significance varied. Conclusions: EHMD with human milk-derived fortifiers was associated with lower odds of medical and surgical NEC in VLBW infants, with most evidence from infants born ≤1250 g, reflecting current clinical use in the highest-risk population. Although the number and sample sizes of RCTs remain limited, the consistency of effect estimates across both RCTs and observational studies, together with significance of pooled analyses, strengthens confidence in these findings. Pragmatic and registry-based studies using standardized fortification protocols may provide the most efficient pathway to strengthen the evidence base.

Background: An exclusive human milk (EHM) diet has numerous benefits. Formula supplementation may be recommended for former preterm infants at the time of neonatal intensive care unit (NICU) discharge to meet perceived metabolic demands and caloric goals. Recommendations addressing postdischarge nutrition for very preterm infants (VPTIs) are controversial, as the benefits of human milk supplementation regarding long-term growth, neurodevelopment, and chronic conditions are mixed. Objective: To compare growth and neurodevelopment of former VPTI fed an EHM diet to a supplemented/formula diet at NICU discharge. Materials and Methods: A retrospective cohort study of VPTI was followed at the Regional Neonatal Follow-up Program. Patients were categorized by diet at NICU discharge: EHM diet; mixed diet (EHM and formula); and exclusive formula diet. Growth percentile ranks at the first neonatal follow-up visit and 3 years of age were compared by diet type at NICU discharge. Neurodevelopmental outcomes as measured by the Bayley Scales of Infant Development 3rd Edition at 3 years of age were also compared. Results: Among 835 VPTIs, weight percentiles at the first neonatal follow-up visit were similar between the three NICU discharge diet types. One hundred fifty-eight subjects received neurodevelopmental evaluations at 3 years of age; anthropometrics and neurodevelopment were similar irrespective of diet at NICU discharge. Conclusion: An EHM diet at NICU discharge is appropriate to support growth in infancy as well as growth and neurodevelopment through 3 years of age. Thus, this raises the question of whether routine nutritional supplementation is necessary for VPTIs at NICU discharge.

Abstracts fromThe Academy of Breastfeeding Medicine 18th Annual International MeetingPhiladelphia, PennsylvaniaNovember 21–24, 2013

A Call to Action to Fight for Equity and End Necrotizing Enterocolitis Disparities.

Background: Hundred percent human milk diet plays a vital part in the nutritional management of preterm infants in the Neonatal Intensive Care Unit (NICU). NICU nurses play an important role in the management of nutrition and growth of preterm infants, who will also oversee the implementation of an exclusive human milk diet (EHMD) in the NICU. Objective: To understand the NICU nurses' perspectives on the benefits of 100% human milk diet through human milk-derived nutritional products in preterm infants. Material and Methods: Online survey was conducted through Google Forms which had nine questions on the benefits of human milk-based nutrition finalized by expert neonatologists. An online survey link was shared with the NICU nurses through emails and text messages. A request was made to the neonatologists and head nurses to disseminate the survey link with their counterparts and colleagues. Results: All the participants rated that exclusive breastfeeding or using 100% Human Milk Diet is very important for preterm babies in NICU [n=152 (100%)]. 46.7% (n=71) participants reported that seventy calories pasteurized human breast milk, (PHBM – 70 Cal) is the best option for preterm infants when the mother’s own milk (MOM) is unavailable. 84.9% (n=129) of the participants stated that the Human milk-based fortifier (HMDF) – Mother’s Milk Fortifier (MMF) is the best option for fortification. 96% (n=146) participants were satisfied with the safety and tolerance of 100% human milk-based products like PHBM - 70 calories and MMF. Conclusion: The majority of the NICU nurses in India are aware of the benefits of human milk and 100% human milk diet in preterm infants. Human milk-derived nutritional products; HMDF (MMF) and 70 Calories are reported to be having good tolerance and safety in preterm infants by most of the NICU nurses. Having regular training sessions about EHMD for NICU nurses would be impactful.

BackgroundAn infant's Own Mother's Milk (OMM) is the mainstay of very preterm nutrition. When a supplement is required, preterm formula and pasteurised human donor milk (pHDM), are options. Which is optimal is unknown. Aims and outcome measuresComparison of “survival to 34 weeks postmenstrual age (PMA) without surgery for necrotising enterocolitis (NEC)” and other outcomes, in infants receiving OMM supplemented with pHDM without bovine macronutrient fortification (exclusive human milk diet), and infants receiving OMM supplemented with preterm formula. DesignCohort analysis of observational data from the National Neonatal Research Database; data-adaptive Super Learner approach with Targeted Maximum Likelihood Estimation to calculate Adjusted Risk Differences (ARD) between the groups. ParticipantsInfants born below 32 weeks gestation admitted to neonatal units in England and Wales between 01 and 06-2017 and 31-05-2022. ResultsCompared to the formula supplemented group (n = 7133), infants receiving an exclusive human milk diet (n = 1007), had lower survival to 34 weeks PMA without NEC surgery (ARD -9.8 %, 95%CI -11.4 to −8.2), higher all-cause (10.7 %, 9.1 to 12.2) and NEC-related mortality (1.0 %, 0.4 to 1.5), and lower rates of treated retinopathy of prematurity (−2.8 %, −3.4 to −2.3) and bronchopulmonary dysplasia (−12.1 %, −14.0 to −10.1). ConclusionsThe lower survival to 34 weeks PMA without NEC surgery in infants receiving an exclusive human milk diet is unexpected. We adjusted for factors that influence outcomes but cannot exclude the possibility of confounding, hence our data justify a randomised controlled trial to identify optimal supplementary feeds for very preterm infants.

Necrotizing enterocolitis (NEC) is an important contributor towardmortality in extremely premature infants and Very Low Birth Weight(VLBW) infants. The incidence of NEC was 9% in VLBW infants(birth weight 401 to 1,500 grams) in the Vermont Oxford Network(VON, 2006 to 2010, n = 188,703).1 The incidence of NEC was 7%in 1993, increased to 13% in 2008, and decreased to 9% in extremelypreterm infants (22 to 28 weeks gestation) in the Neonatal ResearchNetwork Centers (1993 to 2012).2 The incidence of surgically treatedNEC varies from 28 to 50% in all infants who develop NEC.3 SurgicalNEC occurred in 52% in the VON cohort.1 In this cohort, the odds ofsurgery decreased by 5% for each 100 gram increase in birth.The incidence of surgical NEC has not decreased in the pastdecade.4 The mortality from NEC is significantly higher in infantswho need surgery compared to those who did not (35% versus 21%).1The case fatality rate among patients with NEC is higher in thosesurgically treated (23 to 36%) compared to those medically treated (5to 24%).3 In addition to surgery, NEC mortality rates are influencedby gestational age, birth weight,1,2,5 assisted ventilation on the day ofdiagnosis of NEC, treatment with vasopressors at diagnosis of NEC,and black race.6,7Extremely preterm infants who survive NEC are at risk for severeneurodevelopmental disability and those with surgical NEC have asignificantly higher risk of such delays (38% surgical NEC versus 24%medical NEC).8 Diagnosis of necrotizing enterocolitis is challengingand it is usually suspected based on non-specific clinical signs. Bell’scriteria and Vermont-Oxford Network criteria help in the diagnosisof NEC.Bell’s criteria, commonly used for diagnosis, staging, and planningtreatment of NEC, were described in 1978 and modified in 1986.9,10Bell’s stage I signs are non-specific: temperature instability, lethargy,decreased perfusion, emesis or regurgitation of food, abdominal distension,recurrent apnea, and on occasion, increased support withmechanical ventilation. Abdominal distension and emesis are morecommon than bloody stools in very preterm infants compared to terminfants.7 Abdominal radiographic findings are an integral part of Bell’scriteria. Identification of Bell’s stage I NEC (early NEC) with abdominalradiograph is challenging, as the features on abdominal radiograph(normal gas pattern or mild ileus) are non-specific. With progressionof NEC to Bell Stage IIA, the symptoms (grossly bloody stools,prominent abdominal distension, absent bowel sounds) and featureson abdominal radiographs (one or more dilated loops and focal pneumatosis)are more specific.On the other hand, the Vermont Oxford Network criteria for NECconsist of at least one physical finding (bilious gastric aspirate oremesis, abdominal distension or occult/gross blood in the stool inthe absence of anal fissure) and at least one feature on abdominalradiograph (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum).1 These features correspond to Bell Stage IIA or StageIIB and are not features of early NEC. Thus relying solely on abdominalradiograph for diagnosis of early NEC, as is practiced currently,has significant drawbacks especially in extremely premature infants.7Ultrasound has been suggested to improve the percentage of infantsdiagnosed with early NEC.11 However, this imaging modality is notused routinely in the diagnosis or management of NEC.As the incidence of surgical NEC and mortality from NEC continuesto be high, the literature to demonstrate the shortcomings ofabdominal radiographs and promise of abdominal ultrasound in diagnosisof NEC is reviewed.

This study evaluated the cost-effectiveness of a 100% human milk-based diet composed of mother's milk fortified with a donor human milk-based human milk fortifier (HMF) versus mother's milk fortified with bovine milk-based HMF to initiate enteral nutrition among extremely premature infants in the neonatal intensive care unit (NICU). A net expected costs calculator was developed to compare the total NICU costs among extremely premature infants who were fed either a bovine milk-based HMF-fortified diet or a 100% human milk-based diet, based on the previously observed risks of overall necrotizing enterocolitis (NEC) and surgical NEC in a randomized controlled study that compared outcomes of these two feeding strategies among 207 very low birth weight infants. The average NICU costs for an extremely premature infant without NEC and the incremental costs due to medical and surgical NEC were derived from a separate analysis of hospital discharges in the state of California in 2007. The sensitivity of cost-effectiveness results to the risks and costs of NEC and to prices of milk supplements was studied. The adjusted incremental costs of medical NEC and surgical NEC over and above the average costs incurred for extremely premature infants without NEC, in 2011 US$, were $74,004 (95% confidence interval, $47,051-$100,957) and $198,040 (95% confidence interval, $159,261-$236,819) per infant, respectively. Extremely premature infants fed with 100% human-milk based products had lower expected NICU length of stay and total expected costs of hospitalization, resulting in net direct savings of 3.9 NICU days and $8,167.17 (95% confidence interval, $4,405-$11,930) per extremely premature infant (p < 0.0001). Costs savings from the donor HMF strategy were sensitive to price and quantity of donor HMF, percentage reduction in risk of overall NEC and surgical NEC achieved, and incremental costs of surgical NEC. Compared with feeding extremely premature infants with mother's milk fortified with bovine milk-based supplements, a 100% human milk-based diet that includes mother's milk fortified with donor human milk-based HMF may result in potential net savings on medical care resources by preventing NEC.

Compared with preterm formula (PF), mother's 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. Extremely premature infants (<30 weeks of gestation) whose mothers intended to breastfeed were assigned randomly to receive either pasteurized DM or PF if the supply of their own MM became insufficient during the study (birth to 90 days of age or hospital discharge). Infection-related events (LOS, NEC, meningitis, presumed sepsis, or urinary tract infection) that occurred after the attainment of a milk intake of 50 mL/kg, dietary intake, growth, skin-to-skin contact, and duration of hospital stay were compared. The primary analysis compared groups DM and PF on an intent-to-treat basis. If no differences were noted, then these groups were combined and compared with the reference group, group MM. If differences were noted, then the subsequent analyses compared each group with group MM. 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. 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.