Differences in Neonatal Outcomes Among Premature Infants Exposed to Mother's Own Milk Versus Donor Human Milk : Advances in Neonatal Care

Secondary Logo

Journal Logo

Original Research

Differences in Neonatal Outcomes Among Premature Infants Exposed to Mother's Own Milk Versus Donor Human Milk

Cartagena, Diana PhD, RN, CPNP; Penny, Frances PhD, RN, MSN, IBCLC; McGrath, Jacqueline M. PhD, RN, FNAP, FAAN; Reyna, Barbara PhD, RN, NNP-BC; Parker, Leslie A. PhD, RN, NNP-BC, FAAN; McInnis, Joleen MS, LIS, MFA

Editor(s): Dowling, Donna PhD, RN, Section Editors; Newberry, Desi M. DNP, NNP-BC, Section Editors; Parker, Leslie PhD, APRN, FAAN, Section Editors

Author Information
doi: 10.1097/ANC.0000000000001002

Abstract

In the United States, more than 500,000 infants are born preterm (<37 weeks' gestation) each year, with 16% (∼80,000) of these infants born between 23 and 32 weeks' gestation and classified as very low birth weight (VLBW; birth weight <1500 g).1 VLBW infants are generally at considerable risk of developing prematurity-related morbidities, including late-onset sepsis (LOS), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), slower growth velocity, and feeding intolerance.2 Growing evidence demonstrates that exposing VLBW infants to mother's own milk (MOM) throughout neonatal intensive care unit (NICU) hospitalization reduces the incidence and severity of short- and long- term morbidities.3–7 MOM contains beneficial immunologic, antimicrobial, anti-inflammatory, antioxidant, epigenetic, growth-promoting, and gut-colonizing properties, many of which are present in greater concentrations in the mother's milk of premature infants.8 The protection offered by MOM has been shown to be dose- and time-dependent, with higher doses of mother's milk providing the greatest protection during critical periods after birth.8–10 Evidence from several studies support that the first 14 to 28 days of life are especially important for infants to receive high doses of MOM in order to decrease the incidence, severity, and risk of sepsis, NEC, and other mentioned morbidities.3,4,8–11 However, achieving and maintaining a high dose of MOM feeding are challenging for most mothers and current recommendations suggest VLBW infants should receive pasteurized donor human milk (DHM) if MOM is unavailable or insufficient to meet the nutritional needs of preterm infants.12

In recent years, provision of human milk has become the standard of care for premature infants throughout the world.12 The American Academy of Pediatrics and the ESPGHAN Committee on Nutrition recommends that premature infants receive MOM, and, if unavailable, pasteurized DHM should be provided.12 However, the same protective composition and bioactivity in MOM are not present in DHM.13,14 Pasteurization of DHM may reduce or eliminate many of the protective elements in MOM, including immunoglobulins, lactoferrin, lysozymes, and anti-inflammatory cytokines believed to decrease prematurity-related complications related to an infant's immature immune system.13–15 Pasteurization also eliminates the commensal microbiome present in MOM that confers protection against neonatal morbidities including NEC. In addition, factors other than pasteurization, including freeze–thaw cycles that are used for storage and processing of DHM, affect the composition of DHM in clinically important ways.15 Furthermore, pooled pasteurized DHM usually includes human milk from mothers who have delivered at full-term and are at a different stage of mammary gland maturity and lactation and thus lack the uniquely biologic benefits inherent in MOM specific to her premature infant.15 For example, DHM is lower than MOM in protein, energy, and fat content, which are all crucial to preterm growth.15 The benefits and protection against morbidities appear to be limited and not dose-dependent in DHM. Furthermore, compared with MOM, DHM is not associated with a reduction in sepsis, chronic lung disease, or neurodevelopmental morbidity in very premature infants.15–17 While studies suggest that compared with preterm formula (PF), DHM may reduce the risk, incidence, and severity of NEC,17 the lack of information regarding the quantity of DHM the infants receive reduces the significance of this reduced risk.15

Recent evidence suggests that a substantial increase in DHM availability and use across NICUs potentially contributes to decreased exposure to MOM feedings, primarily among certain minority groups.18,19 Despite similar lactation initiation rates, fewer Black and Hispanic VLBW infants continue to receive MOM feedings at NICU discharge than non-Hispanic White infants20–22 and may explain disparities in neonatal morbidity present in these infants. Black and Hispanic VLBW infants, compared with non-Hispanic White VLBW infants, have a 2- to 4-fold increased risk for developing severe neonatal morbidities including NEC, BPD, ROP, and intraventricular hemorrhage (IVH).23,24 The trend toward an increased utilization of DHM is concerning because DHM exposure is intended to minimize use of PF and the risk for severe disease for which MOM has demonstrated superior protection. Yet, additional evidence is needed to determine differences in neonatal outcomes among infants primarily exposed to MOM versus DHM feeding. Presently, most extant evidence is focused on comparing health outcomes of infants exposed to PF versus DHM or “human milk” (consisting of combined MOM and DHM feeding) versus PF. Uncovering this gap is the focus of this systematic review. We hypothesize that the benefits of exposure to predominately MOM feeds outweigh DHM exposure in improving health outcomes for preterm infants during critical neonatal periods. Thus, the purpose of this review is to compile and analyze the existing evidence to determine differences in neonatal outcomes among premature infants exposed to predominately MOM versus DHM. With a rising prevalence of DHM use, coupled with the demonstrated benefits of MOM, additional research is needed to justify and inform evidence-based practices for increasing MOM provision while optimizing the use of DHM when MOM is inadequate or unavailable.

What This Study Adds

  • A systematic review on neonatal outcome differences in preterm infants exposed to MOM vs DHM.
  • What the evidence reveals on benefits of preterm exposure to MOM compared with DHM.
  • A direction of future practice and research needs to promote MOM expression while optimizing use of DHM.

METHODS/SEARCH STRATEGY

The authors followed the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) during the development of this systematic review.25 A comprehensive search of the literature was conducted between June 12, 2020, and May 3, 2021, for the purpose of locating published research answering our study question. Consultation and assistance from an allied health librarian facilitated the structured systematic search. The initial search strategy included broad and inclusive criteria to capture all available published articles using 3 databases: PubMed, Cumulative Index for Nursing and Allied Health Literature (CINAHL), and Cochrane databases. Database searches were based on the following main key words: preterm infant, premature infant, very low birth weight, breast milk, mother's milk, human milk, donor human milk, lactation, health outcomes, late onset sepsis, necrotizing enterocolitis, ventilator associated pneumonia, length of stay, and neonatal intensive care unit. Each term was searched separately and then combined to enhance the search field (see Supplemental Digital Content Tables 1-3, available at: https://links.lww.com/ANC/A157).

Inclusion criteria included English language, peer-reviewed, full-text journal articles published since 1990 and addressing neonatal health outcomes of premature infants exposed to MOM versus DHM during hospital stay. Excluded from this review were studies not published in English, those that were not easily available in full text through library resources, and those that (a) used a “human milk” metric to compare outcomes of infants receiving a mixture of MOM and DHM versus PF, (b) compared outcomes between DHM versus PF feeding, and (c) did not compare neonatal outcomes based on the proportion of MOM versus DHM exposure. We purposely looked back 30 years because we wanted to capture all possible studies related to this subject matter. We wanted to better understand whether there were any changes over time in the use of human milk to support the nutritional status of preterm infants in the NICU.

RESULTS

Initially, there were 574 articles after searching the databases. An additional 11 articles were identified through manual search of reference lists. A total of 502 articles were obtained after removing duplicates. After a more focused review of the titles and abstracts, 466 articles were excluded. Thirty-six full-text articles were reviewed, and of these, 25 were excluded. Most of these articles were excluded because neonatal outcomes were examined in relation to exposure to “human milk,” a metric including mixture of both MOM and DHM feeding, without information on the relative proportions of each or the exposure periods for the 2 feeding types. A total of 11 studies met criteria for inclusion in this review.26–36 Two reviewers (first 2 authors) independently conducted an appraisal of the studies that met inclusion criteria. Disagreement was resolved by full-text review and discussion of eligibility criteria. A diagram of the decision-making process for inclusion of studies in this systematic review is illustrated in Figure 1.

F1
FIGURE 1:
Selection of included articles. MOM indicates mother's own milk; DHM, donor human milk.

Description of the Studies

In total 11 studies met inclusion criteria and examined the effect of type of human milk feeding on the health outcomes of preterm infants. Although all studies examined use of MOM, DHM, or PF, each study criteria varied in the proportion or amount used as a cutoff to assess effects on measured neonatal outcomes. Four studies included neonates exposed to only MOM or DHM31,33,35,36; however, most studies (7/11) measured outcomes based on the percentage of feedings received and consisting of MOM, DHM, or PF.26–30,32,34 This review specifically emphasizes comparison of health outcomes for exposure to MOM versus DHM. Most of the studies utilized a standard NICU protocol for initiation and advancing of feeds, as well as introduction of fortification. All infants were monitored for adequate weight gain and diet adjusted accordingly as routine practice. MOM and DHM were fortified to provide the necessary macronutrients and meet protein requirements. In most studies (8/11),26–29,33–36 infants received a bovine-based human milk fortifier (HMF). One study fortified with a DHM-derived fortifier,30 and 2 other studies did not specify type fortification.31,32

A variety of study designs and methods were employed in the included studies, including 7 prospective,26,28–32,36 3 retrospective cohort studies,27,34,35 and 1 randomized controlled trial (RCT).33 Studies took place across the United States (8/11), as well as internationally, one each in France,26 Spain,32 and Greece.29 Sample population sizes varied from 33 to 551 infants. Infants' gestational age was used as inclusion criterion in most studies (total of 9 studies), with 8 using criteria of 32 weeks' gestation or less26,27,31–36 and one study including infants less than 30 weeks' gestation.33 Four of the studies used birth weight as a criterion, either alone or in conjunction with gestational age. Two studies used a weight criterion of 1250 g or less,28,29 3 included infants weighing 1500 g or less,30,32,34 one enrolled infants at less than 1800 g,27 and another study included infants weighing less than 1000 g.35 The health outcomes discussed in this review were measured at different gestational or postmenstrual age (PMA) and/or at discharge from the NICU.

The John Hopkins levels and quality of evidence method were applied to rate the evidence.37 Level I evidence includes RCTs or systematic reviews of RCTs, level II evidence includes quasi-experimental studies or systematic reviews of quasi-experimental studies, level III evidence includes nonexperimental studies or mixed-methods design, or systematic reviews of nonexperimental studies. The quality of the evidence was assessed as (a) high, (b) good, or (c) low quality according to John Hopkins levels and quality of evidence guidelines. Studies in this review included level I—high (n = 1), but most studies were at evidence level III—low (n = 10). After appraisal and synthesis of the included studies, the evidence was organized by neonatal outcome “themes” including growth parameters (weight, length, and head circumference) (n = 8),26–30,33–35 neonatal morbidity (NEC, BPD, ROP, LOS, IVH, healthcare-acquired infections [HCAIs], feeding intolerance, and length of stay) (n = 7),26,28–30,33–35 and gut microbiome patterns (n = 4).30–32,36 A summary of major findings from this review is provided using the aforementioned categories (Table 1). See Supplemental Digital Content Table 4 (available at: https://links.lww.com/ANC/A158) for further description of studies.

TABLE 1. - Summary of Neonatal Outcomes Among Infants Exposed to Mother's Own Milk Versus Donor Human Milk
Study Exposures Outcomes
Growth Parameters NEC LOS BPD ROP IVH Feeding Tolerance Length of Stay Microbiome Diversity
Schanler et al (2005)33 (n = 243) Exclusive MOM vs mostly DHM No difference Favors MOM Favors MOM ... Favors MOM ... ... Favors MOM ...
Montjaux-Regis et al (2011)26 (n = 48) <20%, ≥20% to <80% and ≥80% MOM vs DHM Favors MOM No difference No difference ... ... ... No difference ... ...
Colaizy et al (2012)28 (n = 88) >75% MOM vs >75% DHM Favors less DHM No difference No difference No difference No difference No difference ... ... ...
Dritsakou et al (2016)29 (n = 384) ≥70% MOM vs ≥30% DHM Favors MOM Favors MOM Favors MOM Favors MOM Favors MOM Favors MOM ...
Gregory et al (2016)31 (n = 30) 100% MOM vs DHM ... ... ... ... ... ... ... ... Favors MOM
Cong et al (2017)36 (n = 33) >70% of total frequency of MOM vs DHM ... ... ... ... ... ... ... ... Favors MOM
Madore et al (2017)35 (n = 81) 100% MOM vs >50% DHM Favors MOM No difference No difference No difference No difference No difference No difference ...
Sisk et al (2017)34 (n = 551) ≥50% MOM vs ≥50% DHM No difference No difference No difference No difference No difference ... ... ... ...
Brownell et al (2018)27 (n = 314) 10% of total diet increments of MOM vs DHM Favors MOM ... ... ... ... ... ... ... ...
Parra-Llorca et al (2018)32 (n = 69) ≥80% MOM vs ≥80% DHM ... ... ... ... ... ... ... ... Favors MOM
Ford et al (2019)30 (n = 117) >50% MOM vs >50% DHM Favors MOM Favors MOM Favors MOM Favors MOM ... ... Favors MOM ... Favors MOM
Abbreviations: BPD, bronchopulmonary dysplasia; DHM, donor human milk; IVH, intraventricular hemorrhage; LOS, late-onset sepsis; MOM, mother's own milk; NEC, necrotizing enterocolitis; ROP, retinopathy of prematurity; ..., not applicable.

Study Outcomes

Growth Parameters

Preterm infants, especially VLBW infants, are already considered at risk for postnatal growth restriction (growth falls well under the predicted growth curve norms). Postnatal growth trajectories are measured through changes in weight, length, and head circumference. Eight of the included studies examined preterm infant growth parameters.26–30,33–35 All included weight gain as an outcome, 6 included length and head circumference,27,29,30,33–35 and 2 either length or head circumference measures.26,28

Weight Gain

Infants' weight gain was the most common growth parameter reported. Four of the studies identified a slower weight gain related to DHM feeding.26,27,30,35 In a large study of 314 infants, researchers found a decrease in weight gain for every 10% increase in exposure to DHM feedings. There was also a significant decrease in weight z-score with increasing amounts of DHM, demonstrating a dose–response relationship between the proportion of DHM and growth trajectory.27 In a similar but smaller study, Madore et al35 compared weight gain of preterm infants who received predominantly DHM (>50%) with preterm infants fed only MOM. Infants exposed to DHM gained weight more slowly than those fed MOM. In a prospective observational study in France, researchers examined weight gain in a sample of preterm infants from beginning of full enteral nutrition until infants attained a weight of 1400 g and corrected age of 32 weeks' PMA. They compared 3 groups of preterm infants: more than 80% MOM; 20% to 80% MOM; and less than 20% MOM. Results showed infants exposed to higher MOM proportion (>80%) had the highest rate of growth during the specified study time period.26 Finally, in a prospective cohort study comparing preterm infants fed on average 91% MOM with a cohort fed 14% or less MOM, weight gain was improved for those infants receiving more than 50% MOM.30

Despite the aforementioned evidence demonstrating improved weight gain in infants receiving predominately MOM, similar studies reported no significant differences between the MOM- and DHM-fed groups.28,29,33,34 In a retrospective cohort study by Colaizy et al,28 researchers found no group differences in weight z-score between those receiving DHM and MOM at discharge. However, a further subanalysis of infants receiving more than 75% human milk indicated that infants receiving more than 75% DHM had higher rates of growth failure defined as being less than 10th percentile for PMA at discharge than those fed primarily MOM (>75%) or a combination of MOM and DHM.28 In another cohort study, VLBW and low birth-weight infants predominately exposed to MOM (70% MOM and 30% DHM) were compared with infants fed a combination of DHM and PF.29 Infants exposed to higher proportions of MOM regained their birth weight earlier; however, there was no significant difference in body weight at NICU discharge between groups. The authors concluded lack of differences in weight at discharge could be attributed to PF supplementation in the DHM group. The authors also note that for infants receiving more than 75% human milk (MOM or DHM), additional protein and caloric supplementation was provided beyond the standard 24 kcal/oz. Within the only RCT included in this review, Schanler et al33 compared extremely premature infants (<30 weeks' PMA) receiving MOM, DHM, or PF. Authors found no significant difference in weight gain among infants exposed to MOM versus DHM when this parameter was measured at attainment of feeding of 50 mL/kg. Similarly, Sisk et al34 identified no differences in weight gain between those infants who received 50% or more MOM and those infants who received 50% or more DHM. Findings could be explained by the fact that outcomes may not differ for infants exposed to, for instance, 51% MOM than for those receiving 49% DHM.

Head Circumference

Seven studies examined differences in growth of head circumference in relationship to receiving primarily MOM or DHM.27–30,33–35 Four failed to identify differences in head circumference growth in infants exposed to predominately MOM versus those receiving more than 50% DHM.28,33–35 However, 3 similar studies demonstrated differences in head circumference growth between the MOM and DHM groups.27,29,30 Brownell and associates27 found an inverse relationship between head circumference z-scores and the proportion of exposure to DHM. Ford et al30 showed an increase in head circumference in infants receiving a greater proportion of MOM (>50%), whereas Dritsakou et al29 identified similar results in infants exposed to 70% MOM.

Linear Growth

A total of 7 studies examined infants' length or linear growth in relationship to feeding type.26,27,29,30,33–35 Researchers in 3 studies demonstrated no group differences in length among infants exposed to MOM versus DHM.26,27,35 In contrast, other researchers identified an increase in length for infants exposed to a greater proportion of MOM. Dritsakou et al29 found infants exposed to MOM (70% MOM and 30% DHM) presented with greater length at discharge than infants exposed to DHM for the first 3 weeks of life, followed by PF. In a similar but smaller cohort study, linear growth at discharge was significantly higher for those exposed to MOM (>50%) than to DHM (>50%).30 Interestingly, and contradicting results from the previous studies, in an RCT, infants exposed to MOM experienced significantly less linear growth at 90 days postbirth or discharge.33

Neonatal Morbidities

Despite improvement in preterm-related morbidity rates, premature infants remain highly susceptible to life-threatening conditions.2 These common morbidities and adverse health outcomes include NEC, BPD, ROP, and LOS.2 Seven studies included in this systematic review examined the occurrence of NEC,26,28–30,33–35 and in all but 2 studies,30,33 the occurrence of NEC was not significantly different for those infants receiving primarily MOM versus DHM.26,28,29,34,35 However, in the RCT by Schanler et al,33 the presence of NEC was negatively correlated with the quantity of MOM received. Sisk et al34 found that NEC rates were significantly different by feeding type (MOM: 5.3%; DHM: 4.3%; PF: 11.4%; P = .04). In this study, infants in the DHM group continued to receive a proportion of MOM up to 50%. This dose–response relationship implies that an even greater dose of MOM is needed to provide enhanced protection.

The occurrence of BPD among MOM- and DHM-exposed infants was examined in 3 studies; no significant between-group differences in the occurrence or degree of BPD were found in any of these studies.30,34,35 Contradicting findings related to the occurrence of ROP were evident in 4 studies.28,29,34,35 Researchers in 2 studies28,34 found no between-group differences, whereas in another study,29 a decrease in ROP was identified in infants exposed to primarily MOM; however, this finding was not statistically significant. Furthermore, differences in the stage of ROP developed during hospitalization were evaluated; infants exposed to DHM demonstrated worse stages of ROP (median: stage 2 ROP) than infants in the MOM group (median: stage 1 ROP).34 LOS was evaluated in 5 studies,28,30,33–35 with 2 of them reporting a significant lower incidence of LOS in MOM-exposed groups than in DHM groups.30,33 In contrast, 3 other studies similar in design but with sharply different sample sizes (n = 81 vs 551) reported no significant difference in LOS between groups.28,34,35

Other premature-related outcomes measured in some of the studies include IVH, HCAIs, feeding intolerance, and length of stay. Only 3 studies examined the occurrence of IVH.28,29,35 Dritsakou et al29 noticed a decrease in IVH and HCAIs in infants exposed to MOM; however, the results were not statistically significant. In contrast, other studies found no difference in IVH28,35 or HCAIs26 between the MOM and DHM groups. Feeding intolerance was assessed in 3 studies, with all showing fewer episodes of feeding intolerance in infants exposed to MOM.26,29,30 Ford et al30 found that primarily MOM intake contributed to 60% reduction in feeding intolerance and composite score of severe morbidity compared with infants receiving mostly DHM. Interestingly, feeding intolerance was not consistently assessed among the studies and ranged from measuring enteral feeding initiation,29 number of feeds held per total days of enteral feeding, number of days required to reach feeding volume goal, days with no enteral feedings after feeding was initiated, days of total parenteral nutrition,30 pregavage residuals, and existence of digestive events such as abdominal distension.26 Length of stay was measured in 3 studies, all concluding a shorter length of hospitalization for infants receiving MOM versus DHM.29,33,35 It is important to notice that outcome measures of morbidity were obtained at different time points postnatally or at discharge and may have contributed to differences in results among the studies.

Gut Microbiome

Feeding type is recognized as one of the most impactful factors influencing the early development of intestinal microbiome in premature infants.38 Compared with DHM, MOM is more effective in improving intestinal maturity by increasing the diversity and richness of gut microbial community in preterm infants.30–32,36,38 Four studies in this review examined the intestinal microbiome composition of preterm infants exposed to MOM versus DHM.30–32,36 The method used to study the intestinal microbiome was similar in all the studies, the 16s rRNA gene sequencing, and thus facilitates synthesis of findings. Overall, all studies concur that exposure of premature infants to predominately MOM contributes to greater intestinal microbial diversity than to DHM.30–32,36 Furthermore, microbial diversity and richness increased over time and remained higher in infants fed MOM.30–32 Feeding type significantly influenced microbial composition, with MOM feeding resulting in higher colonization with beneficial bacteria (Clostridiales, Bacillales and Lactobacillales, Bifidobacteriaceae, Bifidobacterium, and Bacteroid)30,32,36 than with DHM (Enterobacteriales, Staphylococcaceae, Clostridiaceae, and Pasteurellaceae).30,32,36 Compared with PF, feedings consisting of DHM appear to partially promote an increase in microbial diversity similar to MOM.31

DISCUSSION

The superior qualities and benefits of exposing premature infants to MOM compared with PF are well identified in the literature, but there are limited studies comparing MOM with DHM. The purpose of this review was to determine differences in health outcomes among premature infants exposed to predominately MOM versus DHM. Although the available evidence is limited and lacks consistency and rigor, results suggest that neonatal exposure to DHM is a beneficial and suitable alternative but not equivalent to MOM exposure. MOM remains the most superior source of nutrition for premature infants when appropriately fortified to provide adequate protein, fat, and macronutrients.29,34,39 Benefits do exist for premature infants receiving only partial MOM feeding, but evidence clearly suggests that exposure to a higher proportion of feedings from MOM offers greater benefits, particularly when given early in the postnatal period (a dose–time-dependent effect).8,15 This review supports enhanced preterm growth outcomes with higher doses of MOM than with DHM. In addition, emerging evidence suggests differences in selected neonatal morbidities and gut microbial diversity, with more beneficial outcomes with increased MOM exposure.

Results of early growth rates appear consistent with previous observations, which collectively report that premature infants exhibit faster growth velocity26,30 postnatally and during the first 30 days of life35 when consuming predominately MOM. Overall, many infants exposed to primarily MOM regained their birth weight faster and continued to have more rapid growth than those fed primarily DHM.26,27,29,35 When comparing growth rates after 30 days or at discharge, the differences in weight by human milk type disappear.28,33,34 These contradicting findings may be attributed to differing nutritional practices across NICUs worldwide. Growth parameters are routinely monitored in the NICU and adjustments made in protein and caloric content based on an individual infant's growth trajectory. Target caloric content was 20 to 24 kcal/oz in most studies, but some fortified human milk up to 30 kcal/oz depending on the infant's growth. Timing of human milk fortification, and the approach, also varies among centers and can influence early growth rates. Some centers utilize a standard approach to fortification that does not consider variability in macronutrient composition or the individual infant's nutritional needs. In addition, it is assumed that DHM is approximately 20 cal/oz, but caloric content can vary. An individualized or adjustable approach to fortification is recommended as this is tailored to the specific needs of the preterm.40

Findings of most studies measuring growth parameters concur that weight gain correlates with the proportion of MOM intake compared with DHM.26,27,29,35 In contrast, an increased proportion of DHM feeding was not correlated with improved outcomes. Brownell et al27 found that for every 10% increase in DHM feeding, VLBW infants experienced weight loss of 0.17 g. The compromised weight gain seen in DHM-fed infants has been attributed to altered composition of pasteurized and pooled DHM often deficient in micronutrients that are essential for optimal preterm infant growth.15 Dritsakou et al29 attributed a faster weight gain for infants receiving “raw” MOM to the greater protein and energy content of colostrum and early premature human milk. In other studies, lack of differences in weight at discharge28,29,33,34 may be explained by the fact that DHM-fed infants experienced faster growth rates after transitioning to PF at 32 to 34 weeks' PMA, as this is the protocol in most institutions.35 In addition, and as previously mentioned, bovine-based HMF was used in most of the reviewed studies to support adequate growth of human milk–fed infants. Findings should be interpreted in the context of various NICU protocols mandating feeding practices and provide evidence for urgently needed standardized evidence-based practices around how to improve MOM availability and best utilize DHM during critical growth periods for premature infants.41

Adequate postnatal growth should not be measured by weight gain alone, and it is essential to evaluate linear growth and head circumference in conjunction with weight gain as markers of appropriate overall growth. The effect of exposure to MOM versus DHM feeding on changes in other growth parameters appears less conclusive. Most studies measuring growth in head circumference and/or length at discharge showed no between-group differences among infants-fed MOM or DHM,26,28,33–35 except for 3 studies reporting increased growth in these parameters in infants exposed to a higher proportion of MOM.27,29,30 The lack of differences among groups in these growth parameters is intriguing, given the observed effect of exposure to a higher proportion of MOM on increased weight gain in some of the studies.26,29,35 However, these results should be interpreted with caution as growth was not measured similarly across studies, with some reporting z-scores and others using growth velocity. Perhaps, more important is the overall body composition and growth quality that have implications for long-term outcomes.42,43

Emerging evidence demonstrate that MOM feeding offers the best protection against severe morbidity of prematurity.3–7,9 The protection offered by DHM does not appear equivalent to MOM, although there is some empiric evidence suggesting an NEC reduction.17,19 Nevertheless, in multiple cohort studies, the benefits of MOM over DHM were not evident in improving health outcomes including rates of NEC, BPD, or LOS.26,29,34,35 Although the protective immunologic and anti-inflammatory properties found in MOM are decreased in DHM primarily due to the effects of pasteurization, lack of differing results between exposure to MOM versus DHM in the prevention of serious neonatal morbidity may indicate a greater DHM benefit than theorized, particularly if supplemented with MOM. DHM feeding practices, including supplementation with MOM or PF, may be associated with different outcomes as well. Furthermore, many of the cohort studies lacked adequate power to detect outcome differences and may have included multiple potential confounding variables influencing the results. Timing of fortification, use of bovine-based fortifiers, and transition to PF prior to discharge may influence outcomes. Evidence on the benefits of DHM over PF is clear, primarily in the prevention of NEC, but well-designed and appropriately powered studies are required to further test the hypothesized benefits of DHM in comparison with MOM in reducing neonatal morbidities, particularly LOS.

The gut microbiome of premature infants is influenced by gestational age, birth weight, mode of delivery, antibiotic exposure, postnatal time, and type of feeding.31,38,44 Findings from this review concur with the existing body of evidence showing that MOM- and DHM-fed infants have significant differences in gut microbiota, with increased microbial diversity and prevalence of beneficial bacteria seen in MOM-fed infants. Feeding of predominantly MOM increased intestinal microbial diversity compared with DHM, and even small quantities of MOM were associated with a more favorable microbial community in all but one of the studies.30,31,36,38 Although Parra-Llorca et al32 were unable to detect differences in microbial diversity and richness, they concluded that feeding type significantly influenced the preterm intestinal microbial composition, with infants fed MOM showing a significant greater presence of nonpathogenic bacteria. In contrast, a higher abundance of potentially pathogenic bacterial was identified in infants fed DHM.30,32,36 Increased microbiome diversity and abundance of Bifidobacterium as well as Bacteroides were associated with healthier outcomes in VLBW infants including a lower incidence of NEC.30 MOM appears to consistently protect the gut health by promoting the growth of beneficial bacterial and inhibiting overgrowth of pathogens.30,44

Early feeding of small amounts of MOM beginning 2 hours postbirth seems to promote intestinal maturity as well as enhance gut microbial development of premature infants.30 Gregory et al31 found that compared with DHM or PF, MOM feeding has a significant impact on gut colonization initially and, overtime, contributing to short- and long-term health outcomes of preterm infants. This finding has important clinical implications as even small amounts of MOM promote gut maturity and microbial development, with growth of beneficial bacteria during hospitalization when preterm infants are more vulnerable to NICU environmental hazards contributing to their higher risk for infection. Compositional differences in DHM may partially explain the differing intestinal microbiota in DHM-fed infants compared with MOM. Maternal lactational stage of the DHM and the pasteurization process are 2 important factors that potentially influence the preterm gut microbiota. As previously described, DHM usually contains a lower amount of essential nutritional components and a great variability in essential fatty acids and amino acids important for promoting intestinal colonization.15,45 Pasteurization processes eliminate beneficial bacteria present in MOM that may contribute to more protective preterm microbiota.15,30,31,36 Improved pasteurization techniques procuring MOM biologic properties are needed to improve microbiome development and health outcomes of preterm infants exposed to DHM.

Collectively, these findings suggest that promoting increased MOM exposure should be a top priority in neonatal care. Clearly informing mothers of the value of MOM over DHM should be explained during the consent process. Presenting the DHM consent separate from the bundle of general medical consents, required during hospitalization, can provide a time for more in-depth discussion and reflection.46 Early and ongoing discussions should occur, reinforcing the importance of even small amounts of MOM for healthy infant outcomes. Implementation of critical strategies such as early human milk expression 6 to 8 hours after birth, oral care with colostrum, non-nutritional sucking, skin-to-skin care, and feeding at breast, when possible, will contribute to improved MOM provision.47 Ideally, conversations regarding the benefits of MOM and strategies to maximize human milk production would begin prenatally if a premature delivery were anticipated. NICUs need to continually assess their environment for barriers hindering the promotion of MOM exposure and monitor key quality metrics for maximizing MOM production. Education regarding MOM versus DHM and strategies to promote human milk exposure should include labor and delivery and postpartum units, as well as NICU residents and ancillary staff. Implementing a “Wee Pump” campaign and having a “Kangaroo-a-Thon” can help promote these interventions and emphasize the importance to staff and families.48

Limitations

There were limitations to this review. Several studies were excluded from this review if the outcome measures were discussed as effects of exposure to “human milk.” Using “human milk” as a metric without differentiating between the type of human milk feeding is increasingly common in research and quality initiative (QI) projects seeking to improve the use of human milk in the NICU. This trend is concerning because of the intrinsic differences in MOM and DHM. Also, in studies in which use of “human milk” fails to reduce adverse health outcomes, these findings are often generalized to exposure of both, MOM and DHM.15 A major issue potentially contributing to conflicting findings was the lack of consistent definitions of feedings. In some studies, investigators defined MOM feedings as receipt of more than 80% whereas others defined MOM feeding as more than 50%. Furthermore, a synthesized analysis was challenging because of inconsistencies in feeding protocols among the participating NICUs. For example, besides differences in the proportion of human milk feeding (MOM vs DHM), there were important differences in fortification practices with either bovine- or human milk–based fortifiers, and in some studies, PF was used to supplement inadequate MOM or DHM intake. Differences in outcome measures, primarily growth parameters, may have resulted from many other variables besides feeding protocols, most notably, the frequency of skin-to-skin care, which has shown to increase MOM exposure.47 Other limitations relate to most of the studies being observational in nature, included small samples, and collected outcome indices measured at different points during hospitalization (ie, specific PMA vs discharge), making comparisons between studies difficult.

Implications for Practice and Research

DHM is an optimal source of nutrition for premature infants when MOM is insufficient or unavailable.15,47 Achieving and maintaining high dose of MOM feedings are challenging for most mothers of VLBW infants because they must depend on a breast pump to obtain milk for their infant, may experience incomplete mammary gland development due to premature delivery, often have delayed secretory activation, commonly referred to as “milk letdown,” and have a greater incidence of comorbidities known to negatively affect lactation.8,41 Nonetheless, the availability of DHM should be framed as a bridge to promote a sustainable provision of MOM during hospitalization, with an emphasis on supporting maternal lactation efforts of premature infants when possible. Lactation support is of upmost importance among minority mothers who are less likely to provide MOM,49,50 and perhaps more so, if there is a zealous promotion of DHM use in the NICU. Evidence suggests that increased DHM availability may contribute to decreased exposure to MOM feedings mostly in low-socioeconomic Black mothers.18,19 It is vital for neonatal clinicians and nurses to advocate and promote targeted lactation education and support leading to increased MOM feeding for all infants, instructing mothers on the superior qualities of MOM even at small quantities, and encouraging to set lactation goals prior to delivery as these measures have shown to increase lactation in minority groups.41,51–53

Furthermore, from this review, it is evident that standardized and evidence-based feeding practices or protocols for premature infants are needed. These practices should clearly delineate best use of DHM without undermining maternal and NICU staff efforts to support and promote provision of MOM. Clear guidelines should recognize differences in macronutrients, fat, and protein content in MOM and DHM and propose measures for tailored fortification based on type of human milk feeding.29 Most importantly, best feeding practices are essential to support maternal lactation efforts and maximize exposure to MOM, leading to improved health outcomes for all premature infants.

Future well-developed and powered studies are required to further examine differences in neonatal outcomes among infants exposed to predominately MOM or DHM in settings using standardized and evidence-based feeding practices. These studies should further explore the effect of “dose” (quantity of MOM vs DHM as a proportion of total enteral feeding) as well as other variables such as respiratory protocols and frequency of skin-skin care on outcome differences. In addition, QI projects should prioritize implementation and evaluation of evidence-based practices and resources to maximize the provision of MOM in the NICU and decrease prematurity-related morbidities for which MOM is known to be protective without similar evidence for DHM.

CONCLUSION

Findings from this systematic review confirm previous reports on the importance for premature infants to receive a greater proportion of feedings from MOM during critical exposure periods to eliminate adverse health outcomes. Future research should focus on interventions that support and promote evidence-based practices to increase mothers' ability to provide adequate milk for their premature infants despite availability of DHM. Although DHM possesses some similar qualities to MOM and has shown to offer more protection than PF feeding primarily against the occurrence of NEC, additional evidence is needed to support the increased access and demonstrate best practices to optimize the use of DHM as a nutritional alternative when MOM is inadequate or not available.

-
What we know:
  • Evidence supports the superiority of MOM in reducing the comorbidities common to prematurity and VLBW.

  • MOM has protective bioactive components not present in DHM.

  • DHM is a suitable alternative when MOM is inadequate or unavailable.

  • DHM utilization has increased across NICUs.

  • Increased DHM availability may contribute to decreased MOM feedings mostly in Black mothers.

What needs to be studied:
  • Large, multicenter, randomized controlled trials evaluating differences in health outcomes among premature infants exposed to predominately MOM vs DHM in settings using standardized and evidence-based feeding practices.

  • Standardized feeding practices clearly delineating optimal use of DHM while promoting maternal and neonatal staff efforts to support increased provision of MOM.

  • Evaluation of measures and best practices for tailored fortification based on type of human milk feeding.

  • Studies evaluating effect of multilevel lactation support interventions focused on improving MOM provision and decreasing lactation disparities most prevalent among Hispanic and Black mothers.

What can we do today:
  • Educate mothers on the superior qualities of MOM, even at small quantities.

  • Encourage women to set lactation goals prior to delivery as these measures have shown to increase lactation in minority groups.

  • Advocate and promote targeted lactation education and support leading to increased MOM feeding for all infants beginning <6 hours after birth.

  • Explore barriers to continued MOM expression and assist mothers with identifying solutions.

  • Frame DHM use as a bridge to promote a sustainable provision of MOM during hospitalization and at discharge.

  • Educate NICU staff on the importance to promote and maximize use of MOM despite easily available DHM.

  • Implement campaigns such as “Wee Pump” and “Kangaroo-a-Thon” to promote and emphasize the importance of MOM to staff and families.


References

1. March of Dimes. March of Dimes Foundation Data Book for Policy Makers. Maternal, Infant, and Child Health in the United States. Arlington, VA: March of Dimes; 2016.
2. Manuck TA, Rice MM, Bailit JL, et al. Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort. Am J Obstet Gynecol. 2016;215(1):103.e101–103.e114.
3. Patel AL, Johnson TJ, Engstrom JL, et al. Impact of early human milk on sepsis and health-care costs in very low birth weight infants. J Perinatol. 2013;33(7):514–519.
4. Furman L, Taylor G, Minich N, Hack M. The effect of maternal milk on neonatal morbidity of very low-birth-weight infants. Arch Pediatr Adolesc Med. 2003;157(1):66–71.
5. Corpeleijn WE, Kouwenhoven SM, Paap MC, et al. Intake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. Neonatology. 2012;102(4):276–281.
6. Zhou J, Shukla VV, John D, Chen C. Human milk feeding as a protective factor for retinopathy of prematurity: a meta-analysis. Pediatrics. 2015;136(6):e1576–e1586.
7. Spiegler J, Preuss M, Gebauer C, Bendiks M, Herting E, Gopel W. Does breast milk influence the development of bronchopulmonary dysplasia? J Pediatr. 2016;169:76–80.e74.
8. Meier PP, Engstrom JL, Patel AL, Jegier BJ, Bruns NE. Improving the use of human milk during and after the NICU stay. Clin Perinatol. 2010;37(1):217–245.
9. Johnson TJ, Patel AL, Bigger HR, Engstrom JL, Meier PP. Economic benefits and costs of human milk feedings: a strategy to reduce the risk of prematurity-related morbidities in very-low-birth-weight infants. Adv Nutr. 2014;5(2):207–212.
10. Patel AL, Meier PP, Engstrom JL. The evidence for use of human milk in very low-birth weight preterm infants. NeoReviews. 2007;8(11):e459–e466.
11. 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;27(7):428–433.
12. Moro GE, Arslanoglu S, Bertino E, et al. XII. Human milk in feeding premature infants: consensus statement. J Pediatr Gastroenterol Nutr. 2015;61(suppl 1):S16–S19.
13. Peila C, Moro GE, Bertino E, et al. The effect of holder pasteurization on nutrients and biologically-active components in donor human milk: a review. Nutrients. 2016;8(8):477.
14. 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(2):175–182.
15. Meier P, Patel A, Esquerra-Zwiers A. Donor human milk update: evidence, mechanisms, and priorities for research and practice. J Pediatr. 2017;180:15–21.
16. Corpeleijn WE, de Waard M, Christmann V, et al. Effect of donor milk on severe infections and mortality in very low-birth-weight infants: the Early Nutrition Study Randomized Clinical Trial. JAMA Pediatr. 2016;170(7):654–661.
17. Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2018;6:CD002971.
18. Parker LA, Cacho N, Engelmann C, et al. Consumption of mother's own milk by infants born extremely preterm following implementation of a donor human milk program: a retrospective cohort study. J Pediatr. 2019;211:33–38.
19. Kantorowska A, Wei JC, Cohen RS, Lawrence RA, Gould JB, Lee HC. Impact of donor milk availability on breast milk use and necrotizing enterocolitis rates. Pediatrics. 2016;137(3):e20153123.
20. Lee HC, Gould JB. Factors influencing breast milk versus formula feeding at discharge for very low birth weight infants in California. J Pediatr. 2009;155(5):657–662.e1-2.
21. Liu J, Parker MG, Lu T, et al. Racial and ethnic disparities in human milk intake at neonatal intensive care unit discharge among very low birth weight infants in California. J Pediatr. 2020;218:49–56.e43.
22. Parker MG, Gupta M, Melvin P, et al. Racial and ethnic disparities in the use of mother's milk feeding for very low birth weight infants in Massachusetts. J Pediatr. 2018;204:134–141.el.
23. Howell EA, Janevic T, Hebert PL, Egorova NN, Balbierz A, Zeitlin J. Differences in morbidity and mortality rates in Black, White, and Hispanic very preterm infants among New York city hospitals. JAMA Pediatr. 2018;172(3):269–277.
24. Profit J, Gould JB, Bennett M, et al. Racial/ethnic disparity in NICU quality of care delivery. Pediatrics. 2017;140(3):e2017091.
25. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred Reporting Items for Systematic reviews and Meta-Analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
26. Montjaux-Regis N, Cristini C, Arnaud C, Glorieux I, Vanpee M, Casper C. Improved growth of preterm infants receiving mother's own raw milk compared with pasteurized donor milk. Acta Paediatr. 2011;100(12):1548–1554.
27. Brownell EA, Matson AP, Smith KC, et al. Dose–response relationship between donor human milk, mother's own milk, preterm formula, and neonatal growth outcomes. J Pediatr Gastroenterol Nutr. 2018;67(1):90–96.
28. 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;12:124.
29. Dritsakou K, Liosis G, Valsami G, Polychronopoulos E, Skouroliakou M. Improved outcomes of feeding low birth weight infants with predominantly raw human milk versus donor banked milk and formula. J Matern Fetal Neonatal Med. 2016;29(7):1131–1138.
30. Ford SL, Lohmann P, Preidis GA, et al. Improved feeding tolerance and growth are linked to increased gut microbial community diversity in very-low-birth-weight infants fed mother's own milk compared with donor breast milk. Am J Clin Nutr. 2019;109(4):1088–1097.
31. Gregory KE, Samuel BS, Houghteling P, et al. Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants. Microbiome. 2016;4(1):68.
32. Parra-Llorca A, Gormaz M, Alcantara C, et al. Preterm gut microbiome depending on feeding type: significance of donor human milk. Front Microbiol. 2018;9:1376.
33. Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants. Pediatrics. 2005;116(2):400–406.
34. Sisk PM, Lambeth TM, Rojas MA, et al. Necrotizing enterocolitis and growth in preterm infants fed predominantly maternal milk, pasteurized donor milk, or preterm formula: a retrospective study. Am J Perinatol. 2017;34(7):676–683.
35. Madore LS, Bora S, Erdei C, Jumani T, Dengos AR, Sen S. Effects of donor breast milk feeding on growth and early neurodevelopmental outcomes in preterm infants: an observational study. Clin Ther. 2017;39(6):1210–1220.
36. Cong X, Judge M, Xu W, et al. Influence of feeding type on gut microbiome development in hospitalized preterm infants. Nurs Res. 2017;66(2):123–133.
37. Dang D, Dearholt S.Johns Hopkins Evidence-Based Practice: Models and Guidelines. Indianapolis, IN: Sigma Theta Tau International; 2017.
38. Desorcy-Scherer K, Bendixen MM, Parker LA. Determinants of the very low-birth-weight infant's intestinal microbiome: a systematic review. J Perinat Neonatal Nurs. 2020;34(3):257–275.
39. Sullivan S, Schanler RJ, Kim JH, et al. 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;156(4):562–567.e561.
40. Arslanoglu S, King C, Lamireau D, et al. Fortification of human milk for preterm infants: update and recommendations of the European Milk Bank Association (EMBA) working group on human milk fortification. Front Pediatr. 2019;7:76. doi:10.3389/fped.2019.00076.
41. Meier PP, Johnson TJ, Patel AL, Rossman B. Evidence-based methods that promote human milk feeding of preterm infants: an expert review. Clin Perinatol. 2017;44(1):1–22.
42. Cerasani J, Ceroni F, De Cosmi V, et al. Human milk feeding and preterm infants' growth and body composition: a literature review. Nutrients. 2020;12(4):1155. doi:10.3390/nu12041155.
43. Simon L HM, Frondas-Chauty A, Darmaun D, et al. Neonatal growth velocity of preterm infants: the weight Z-score change versus Patel exponential model. PLoS One. 2019;14(6):e0218746. doi:10.1371/journal.pone.0218746.
44. Xu W, Judge MP, Maas K, et al. Systematic review of the effect of enteral feeding on gut microbiota in preterm infants. J Obstet Gynecol Neonatal Nurs. 2018;47(3):451–463.
45. Perrin MT, Belfort MB, Hagadorn JI, et al. The nutritional composition and energy content of donor human milk: a systematic review. Adv Nutr. 2020;11(4):960–970.
46. McGlothen-Bell K, Cleveland L, Pados BF. To consent, or not to consent, that is the question: ethical issues of informed consent for the use of donor human milk in the NICU setting. Adv Neonatal Care. 2019;19(5):371–375. doi:10.1097/ANC.0000000000000651.
47. Parker MG, Stellwagen LM, Noble L, et al. Promoting human milk and breastfeeding for the very low birth weight infant. Pediatrics. 2021;148(5):e2021054272.
48. Kalluri NS, Burnham LA, Lopera AM, et al. A quality improvement project to increase mother's milk use in an inner-city NICU. Pediatr Qual Saf. 2019;4(5):e204.
49. Patel AL, Schoeny ME, Hoban R, et al. Mediators of racial and ethnic disparity in mother's own milk feeding in very low birth weight infants. Pediatr Res. 2019;85(5):662–670.
50. Parker MG, Burnham LA, Melvin P, et al. Addressing disparities in mother's milk for VLBW infants through statewide quality improvement. Pediatrics. 2019;144(1):e20183809.
51. Hoban R, Bigger H, Patel AL, Rossman B, Fogg LF, Meier P. Goals for human milk feeding in mothers of very low birth weight infants: how do goals change and are they achieved during the NICU hospitalization? Breastfeed Med. 2015;10(6):305–311.
52. Parker LA, Sullivan S, Krueger C, Kelechi T, Mueller M. Strategies to increase milk volume in mothers of VLBW infants. MCN Am J Matern Child Nurs. 2013;38(6):385–390.
53. Cartagena D, McGrath JM, Reyna B, Parker LA, McInnis J. Strategies to improve mother's own milk expression in Black and Hispanic mothers of premature infants. Adv Neonatal Care. 2022;22(1):59–68. doi:10.1097/ANC.0000000000000866.
Keywords:

donor human milk, gut microbiome, human milk, mother's own milk, preterm infant; very low birth weight

Supplemental Digital Content

© 2022 by The National Association of Neonatal Nurses.