Donor Human Milk Use in Populations Other than the Preterm Infant: A Systematic Scoping Review

Abstract

Introduction:

Exclusive breastfeeding is recommended for an infant's first 6 months of life. If unable to breastfeed, expressed breast milk, including donor human milk (DHM), is recommended for optimal nutrition. Benefits of DHM in preterm infants have been established by extensive research. However, less is known about DHM use in other populations.

Objective:

To conduct a scoping review of the literature regarding DHM use in populations other than preterm infants.

Materials and Methods:

PubMed and Clinicaltrials.gov were used to search for articles and clinical trials published between January 1, 2000 and February 29, 2020. In total, 182 articles and reports were identified and screened by 2 independent reviewers.

Results:

Twenty-six articles met inclusion criteria and were reviewed. Studies were mostly observational in design and included infants born >35 weeks gestational age with health risks (9/26) and healthy infants (14/26). Most studies in infants with health risks (7/9) investigated clinical outcomes, with small, observational studies suggesting potential improvements in feeding tolerance and gastrointestinal health. Regarding healthy infants, no studies addressed growth, only one study measured clinical outcomes, and findings related to breastfeeding outcomes were conflicting. Over half of the studies reviewed (15/26) were not designed to establish a potential relationship between DHM use and relevant health-related outcomes.

Conclusion:

The current evidence of DHM use in populations other than preterm infants is limited by lack of direct health measures and infrequent use of randomized trials. More research is warranted to investigate clinical, growth, and breastfeeding outcomes.

Introduction

The American Academy of Pediatrics (AAP) and World Health Organization (WHO) recommend exclusive breastfeeding for an infant's first 6 months of life and continued breastfeeding for at least 1 year.^1,2 These recommendations are backed by studies that have reported several benefits of breastfeeding for the infant, including reduced risk of respiratory tract infections, gastrointestinal tract infections, allergic disease, and infant mortality.¹

However, not all infants are able to be breastfed or receive their mother's expressed milk. Regardless of the mother's decision to breastfeed, preterm infants weighing <1,500 g are recommended to receive an exclusive human milk diet, either mother's own milk (MOM) and/or donor human milk (DHM).³ These recommendations are supported by evidence of reduced necrotizing enterocolitis (NEC) in preterm infants receiving DHM compared to bovine formula.^4,5 DHM use with preterm infants has rapidly increased in United States over the past 10 years with the majority of neonatal intensive care units (NICU) now utilizing DHM.^6,7

For healthy term breastfed infants, the AAP and WHO also recommend feeding DHM if MOM is unavailable or inadequate, although the extent that this is practiced is not well understood.^1,2 The WHO recommendations are part of the Baby-Friendly Hospital Initiative (BFHI) that was launched in 1991 to ensure mothers receive proper breastfeeding education and support in the first days postpartum. Step six of BFHI states that infants are not fed any fluids or foods other than breast milk, which promotes the use of DHM when infants are unable to receive MOM.⁸ The number of BFHI hospitals in the United States increased from 60 in 2007 to more than 600 in 2019, with births in BFHI hospitals now accounting for almost 30% of U.S. births.⁸

There is little known about the extent or impact of DHM use in populations other than the preterm infant. Therefore, the primary purpose of this scoping review was to describe the nature and findings of research using DHM in populations other than the preterm NICU infant and identify gaps in the existing literature.

Methods

We conducted a systematic scoping review of peer-reviewed research, conference abstracts, and registered clinical trials related to DHM use in populations other than premature infants in the NICU.⁹ The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist were utilized to guide the reporting process. Electronic sources used to identify articles were PubMed and Clinicaltrials.gov. Keywords and MeSH terms used in the electronic searches included the following: ((“donor milk” or “donor human milk”) NOT (preterm or VLBW or “very low” or review)) for PubMed, and (“donor human milk” or “donor milk”) for Clinicaltrials.gov. Additional studies were located through hand-review of references from the articles identified in the primary search and author familiarity.

Clinical reports, original research articles, conference abstracts, and registered clinical trials that were published or registered between January 1, 2000 and February 29, 2020 were included in this review. Two reviewers (S.M. and M.T.P.) independently assessed all registered trials and study abstracts for inclusion/exclusion criteria. Abstracts were excluded for the following reasons: intended DHM recipient was only premature infants <35 weeks gestational age; did not use DHM, including milk sharing only studies; review article or commentary; not written in English; or did not discuss intended recipients (milk only studies). Trials identified through the online Clinical Trials database were included if the protocol described providing DHM to nonpreterm infant populations. Publications from these trials were identified online at the Clinical Trials database and by individual searches using the investigator name. Trials without published results were included as pending studies. Trials that had been canceled were excluded from the review. Publications that passed abstract review were subject to a full review by two independent reviewers using the same exclusion criteria applied to abstract reviews.

Included studies were abstracted by two reviewers for the following information: intended DHM recipient, intended DHM use, study design, study population, study location, funding source, outcome measures, and results. Studies were categorized into five categories based on the DHM recipient: adult; child; infants born at least 35 weeks gestation with health risks; healthy infants born at least 35 weeks gestation; or postdischarge preterm infants. Six categories were created to organize outcome measures: DHM use patterns (e.g., percent of level 1 hospitals offering DHM, reasons for DHM use, volume of DHM used); knowledge and beliefs about DHM (e.g., perceived benefits and risks); clinical-related outcomes (e.g., length of hospital stay, days parenteral feeding); biomarkers (e.g., bacterial abundance, intestinal inflammation, thymic size); growth (e.g., length, weight, head circumference); and breastfeeding status at or after hospital discharge. Outcomes for each study were coded as positive outcomes (+), negative/detrimental outcomes (−), neutral ( = ), or present, with no longitudinal or control group comparison (P). All reviewer discrepancies were resolved through discussion. Considerations of bias were informed by the Agency for Healthcare Research Quality (AHRQ) methods guide on health care research reviews and included: poor and/or inadequate reporting bias (related to unclear or missing reporting of results and/or methods); study design bias (limitations and weaknesses of methods used); and directness of outcomes bias (research that does not link DHM to an infant health outcome).¹⁰ Studies that only measured patterns of DHM use or knowledge/attitudes about DHM were considered to have not measured direct infant health outcomes. Potential sources of bias for each study were identified and discussed by two reviewers.

Results

An overview of the review process is detailed in Figure 1. The initial PubMed search yielded 151 articles, the Clinicaltrials.gov search yielded 16 studies, 7 articles were found through hand bibliography review of PubMed included articles, and 8 articles were identified from researchers' previous knowledge. After review of the abstracts and study descriptions, 144 articles were excluded leaving 33 articles and 5 clinical trials for full review. Twelve articles/trials were excluded after a full-text review leaving 26 included in this systematic scoping review of DHM use in populations other than the premature, NICU infant.^11–36 Included studies were predominantly conducted in the United States in healthy term or late preterm infants (Table 1). Study methods were predominantly observational and descriptive, with only three studies using an experimental design. Study population, intended DHM use, outcome measures, and key findings are summarized in Table 2 by recipient type and intended use. Reasons for DHM use included cancer therapy in adults; pre- and postoperative feedings in infants and children; primary feeding of foster children; and supplementation for healthy breastfeeding infants in the hospital and at home. The frequency of studies by type of outcomes reported was as follows: patterns of use (n = 13), knowledge and beliefs (n = 6), clinical (n = 8), biomarkers (n = 3), growth (n = 4), and breastfeeding (n = 7). Over half of the studies (15/26) were not designed to establish a potential relationship with DHM use and health-related outcomes because they did not compare DHM use to an alternative feeding strategy, they combined DHM with MOM for analysis, or they did not measure infant health-related outcomes.

FIG. 1.

PRISMA flow diagram of the literature search process used to identify studies addressing the use of donor human milk in non-premature infant populations. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1.

Summary of Studies Included in the Systematic Scoping Review of Donor Human Milk Use in Nonpremature Infant Populations

Year	First author	Intended DHM recipient	Study design	Study location	Funding source
2003	Jeppesen¹¹	Uninfected infants born to HIV+ mothers	Observational cohort	Denmark	Not addressed
2009	Rough¹²	Adult cancer patients	Observational qualitative	United States	San Jose State University
2009	Szucs¹³	Postdischarge preterm quintuplets	Case study	United States	Not addressed
2013	Jeppesen¹⁴	Uninfected infants born to HIV+ mothers	Observational cohort	Denmark	Foundations of Sygekassernes Helsefond, Det Sundhedsvidenskabelige Forskningsra °d, and Fonden
2014	Kair¹⁵	Healthy term and late-preterm infants experiencing hypoglycemia	Case reports	United States	Not addressed
2017	Alexander¹⁶	Term infants with Neonatal Abstinence Syndrome	Case control	United States	Medolac Laboratories provided milk for the study
2017	Kair¹⁷	Healthy term and late preterm infants	Observational qualitative	United States	University of Iowa Stead Family Department of Pediatrics
2018	Belfort¹⁸	Healthy infants born at least 35 weeks gestation	Cross-sectional observational	United States	National Institutes of Health; Brigham and Women's Hospital; and W.K. Kellogg Foundation
2018	Lewis¹⁹	Infants in the level 1 mother baby unit	Retrospective observational	United States	W.K. Kellogg Foundation
2018	Mannel²⁰	Healthy late preterm infants	Retrospective observational	United States	No funding relationships
2018	Rabinowitz²¹	Healthy term infants	Observational qualitative	United States	No funding relationships
2018	Reimers²²	Medically vulnerable infants	Case reports	South Africa	Not addressed
2018	Sen²³	Healthy term and late preterm infants	Retrospective observational	United States	National Institutes of Health
2019	Cognata²⁴	Infants of all gestational ages with an isolated cardiac lesion	Retrospective cohort	United States	Texas Children's Hospital (Evie Whitlock Grant) and National Institutes of Health
2019	Drouin²⁵	Healthy infants born at least 35 weeks gestation	Cross-sectional observational	United States	Brigham and Women's Hospital
2019	Ferrarello²⁶	Healthy term infants experiencing hypoglycemia	Observational qualitative	United States	No funding relationships
2019	Ferrarello²⁷	Healthy term infants experiencing hypoglycemia	Observational (quality initiative)	United States	Not addressed
2019	Kair²⁸	Clinically stable, breastfeeding infants born at least 35 weeks gestation and weighing at least 1,750 g at birth	Retrospective cohort	United States	The University of Iowa and National Institutes of Health
2019	Kair²⁹	Healthy, term infants who lost at least 4.5% of their birthweight in the first 36 hours of life	Randomized controlled trial	United States	The Gerber Foundation, the Children's Miracle Network, and National Institutes of Health
2019	Khandelwal³⁰	Children 5 years and younger who received bone marrow transplant	Unblinded randomized trial	United States	Prolacta Bioscience
2019	Lehman³¹	Term NICU infants when mother's milk not available	Retrospective observational	Poland	Not addressed
2019	Mannel³²	Term AGA foster infant with formula intolerance experiencing failure to thrive	Case report	United States	No funding relationships
2019	Meeks³³	Late preterm and term infants admitted to the NICU	Observational	New Zealand	Not addressed
2019	Merjaneh³⁴	Healthy infants in Level 1 nursery	Retrospective observational	United States	Not addressed
2020	Hoban³⁵	Infants born at least 33 weeks gestation and/or weighing at least 1,500 g admitted to the NICU for gastroschisis and/or intestinal atresia (75% born >36 weeks gestational)	Retrospective cohort	Canada	No funding relationships
N/A^a	Thoene³⁶	Healthy term or later preterm infants experiencing hypoglycemia	Randomized controlled trial	United States	University of Nebraska

Registered clinical trial with no results published yet.

AGA, appropriate for gestational age; DHM, donor human milk; HIV, human immunodeficiency virus; NICU, neonatal intensive care unit.

Table 2.

Results of Studies Investigating Donor Human Milk for Nonpreterm Population by Intended Recipient and Use

Intended recipient type	First author	Year	Intended DHM use	Study population (n)	Outcomes measured	Results	Types of results
Intended recipient type	First author	Year	Intended DHM use	Study population (n)	Outcomes measured	Results	Use patterns	Knowledge	Clinical	Biomarkers	Growth	Breastfeeding
Adults	Rough¹²	2009	Cancer therapy	Adult cancer patients (n = 5) and family proxies (n = 5)	Motivations and experiences of DHM use, duration and dose of DHM	Daily doses of DHM ranged from 3.5 to 16 oz; duration of DHM use ranged from 1 to 62 months; majority reported perceived benefits of DHM use	P	P
Children (0–5 years old)	Khandelwal ³⁰	2019	Pre- and post-bone marrow transplant feeding	Children fed DHM (n = 18), mother's milk (n = 6) or standard formula feeding (control; n = 14)	Markers of inflammation, stool microbiome and metabolomics	Higher markers of intestinal inflammation in controls; higher abundance of some bacteria in controls				+
Infants born at least 35 weeks gestation (with health risks)	Hoban³⁵	2020	Post-gastrointestinal surgery supplementation	Infants supplemented post-operatively with formula (n = 70) or DHM (n = 70)	Hospital LOS, growth, NEC and sepsis risk, days on parenteral nutrition, days with central line	No difference in any outcomes between groups; when excluding large bowel atresia, infants with small bowel atresia, and gastroschisis had significantly shorter hospital stays and central line days when receiving DHM			= +		=
	Cognata²⁴	2019	Pre-cardiac surgery feedings	Infants with cardiac abnormalities (n = 546), including those who received exclusive human milk diet (n = 198)	Incidence of NEC	An exclusive unfortified human milk diet was associated with a reduced risk of NEC			+
	Reimers²²	2018	Primary feeding (at home)	Foster infants in transition home in South Africa (n = 7)	Duration of DHM use, health outcomes, growth	DHM use duration ranged 2 weeks to 2 years; variety of improvements reported including growth, feeding tolerance, and decreased infections and eczema	P		+		+
	Mannel³²	2019	Primary feeding (at home)	Foster infant (n = 1) diagnosed with Failure to Thrive (weight dropped from 56 to 1 percentile) fed DHM for >200 days	Feeding tolerance and weight gain	Vomiting, fussiness, emesis, or abdominal discomfort decreased; growth remained below 5th percentile			+		−
	Jeppesen¹¹	2003	Primary feeding (at home and in hospital)	HIV-exposed uninfected infants fed DHM (n = 12), HIV-unexposed infants by feeding type (n = 47)	Thymic size at birth and 4 months	No significant difference between thymic size at birth when adjusting for weight; greater thymic size at 4 months was seen in HIV-exposed uninfected infants fed DHM compared to HIV-unexposed infants fed formula (23.8 versus 18.3)				+
	Jeppesen¹⁴	2013	Primary feeding (at home and in hospital)	HIV-exposed uninfected infants fed DHM (n = 18), HIV-unexposed infants by feeding type (controls; n = 47)	Thymic size and clinical outcomes	Thymic size was not different at 8 and 12 months age; between 8 and 12 months, DHM fed infants had significantly fewer infections than controls			+	=
	Alexander¹⁶	2017	Primary feeding (in hospital)	Term infants with Neonatal Abstinence Syndrome fed DHM (n = 9) and matched control infants fed formula (n = 9)	Infant growth, Finnegan's scores, and gastrointestinal sub-scores	Head circumference gains was lower among DHM group; Finnegan scores were not significantly different; DHM group had fewer infants with gastrointestinal sub-scores >2 (p < 0.001)			= +		−
	Lehman³¹	2019	Supplementation (in hospital)	Term NICU infants (n = 17)	Days and volume of DHM used, feeding mode at hospital discharge	Infants received on average almost 900 mL DHM for 4.4 days; 82.4% of infants were receiving mom's milk at discharge	P					P
	Meeks³³	2019	Supplementation (in hospital)	Term infants in NICU (n = unknown)	Days of DHM	NICU term infants received DHM for an average of 5–6 days	P
Healthy infants born at least 35 weeks gestation	Kair¹⁵	2014	Supplementation (hypoglycemia)	Term small for gestational age (n = 1) and late-preterm (n = 1) infants	Amount of DHM received and breastfeeding at 1–2 weeks post-discharge	45–147 mL of DHM used in the hospital; mothers were breast milk feeding at 1–2 weeks post-discharge	P					P
	Ferrarello²⁶	2019	Supplementation (hypoglycemia)	Term mother-infant dyads (n = 83)	Prevalence of mothers choosing DHM for supplementation and breastfeeding rates at discharge	76% of parents chose DHM for supplementation; 98% of infants were still breastfeeding at discharge; 52% of infants who received DHM were exclusively breastfeeding at discharge compared to 0% of infants who declined DHM	P					+
	Ferrarello²⁷	2019	Supplementation (hypoglycemia)	Nurses working in labor and delivery or on the mother and baby unit at Baby-Friendly Hospital (n = 20)	Nurses opinions and knowledge of DHM	Nurses lacked knowledge of DHM, but presumed safe; logistical concerns for implementing a DHM policy in a well-baby nursery		P
	Thoene ³⁶	Not yet published	Supplementation (hypoglycemia)	Infants with hypoglycemia (n = 62)	Blood glucose levels, exclusive breastfeeding duration	No results yet (registered clinical trial)
	Kair¹⁷	2017	Supplementation (in hospital)	Post-partum mothers of healthy term and late preterm infants (n = 30)	Themes related to maternal perspectives of supplementation with DHM versus formula	Four themes identified: formula is familiar and DHM is not, DHM is costly and logistically challenging, DHM is temporary and formula is ongoing, and DHM is “healthier”		P
	Belfort¹⁸	2018	Supplementation (in hospital)	Massachusetts Hospitals and/or hospitals serviced by Mother's Milk Bank Northeast (n = 71)	DHM utilization, clinician knowledge and opinions of DHM, exclusive breastfeeding rates at discharge	32% Hospitals were using DHM for healthy infants; 78% of clinicians believed that studies show benefits of DHM use in healthy infants; hospitals using DHM for healthy infants reported higher rates exclusive breastfeeding at discharge compared to those who do not (77% versus 56%, p = 0.02)	P	P				+
	Lewis¹⁹	2018	Supplementation (in hospital)	Healthy infants in an inner-city Baby Friendly Hospital mother-baby unit (n = unknown)	Uses of DHM	Three most common uses of DHM: excessive weight loss, mother–child separation, and small for gestational age	P
	Mannel²⁰	2018	Supplementation (in hospital)	Late preterm infants at a single center breastfeeding only (n = 27), supplemented with DHM (n = 20), supplemented with any formula (n = 93), or formula only (n = 43)	Hospital LOS and breastfeeding status at discharge	LOS did not differ in breastfed infants by type of supplement; infants receiving formula supplementation were less likely to be breastfeeding at discharge than those supplemented with expressed human milk or DHM (RR = 0.84; 95% CI 0.77–0.92)			=			+
	Rabinowitz²¹	2018	Supplementation (in hospital)	Post-partum mothers of term newborns (n = 24)	Maternal perspectives of DHM	58% Mothers preferred DHM over formula; themes emerged regarding concerns of safety and lack of information about DHM	P	P
	Sen²³	2018	Supplementation (in hospital)	Healthy infants who received DHM (n = 363) between 2013 and 2016	Trends in DHM use	Percent of healthy newborns using DHM increased 0.04–4.7% and average bottles per infant increased from 0.6 to 4.6 (100 mL bottles) throughout the duration of the study; indications for DHM: infant excessive weight loss/dehydration (17%), late preterm birth (15%), poor latch (13%), and delayed lactogenesis (11%)	P
	Drouin²⁵	2019	Supplementation (in hospital)	Northeast United States Level I Maternity hospitals using DHM (n = 15)	Hospital policies on DHM use	87% of policies stated criteria for DHM use; all required consent; 27% stated that DHM was the preferred supplementation; 53% of policies indicated DHM use for hypoglycemia and/or hyperbilirubinemia	P
	Kair²⁸	2019	Supplementation (in hospital)	Mother-infant dyads who supplemented with formula (n = 376) or DHM (n = 306)	Maternal characteristics by supplemental feeding type	DHM use less likely in mothers who were non-white, publicly insured, and non-English speaking	P
	Merjaneh³⁴	2019	Supplementation (in hospital)	Infants in level 1 nursery who were supplemented with formula (n = 39) or DHM (n = 33)	Exclusive breastfeeding at 6 months of life	Infants supplemented with DHM had five times greater odds of exclusive breastfeeding at 6 months of life after adjusting for delivery type and WIC (CI 1.37–19.23, p = 0.015)						+
	Kair ²⁹	2019	Supplementation (in hospital and at home)	Healthy term infants with ≥4.5% weight loss randomized to limited DHM (n = 30) or exclusive breastfeeding (control; n = 30)	Formula use a 1 week, prevalence of any breast milk feeding and breastfeeding without formula at 1, 2, 3 months	No significant differences in formula use at 1 week; control group had greater Any Breast Milk feeding at 1 month, and greater Feeding at the Breast at 1 and 3 months compared to DHM group						= −
Post-discharge preterm infants	Szucs¹³	2009	Supplementation (at home)	Preterm quintuplets discharged at 3 months and fed DHM as a supplement to mother's milk until at least 6 months (n = 5)	Mother's experience, volume of DHM supplementation, infants' health status at 6 months of life	Mother strongly advocated for DHM; used 420 oz DHM per week; clinicians reported that infants were healthy developing normally at 6 months of life	P	P	P

Studies listed in bold are randomized controlled trials. Types of results: P present (no comparisons); + present with favorable outcomes for DHM; − present with unfavorable outcomes for DHM; = present with no difference in outcomes. CI, confidence interval; LOS, length of stay; NEC, necrotizing enterocolitis; RR, relative risk; WIC, Special Supplemental Nutrition Program for Women, Infants, and Children.

Adults

A study of 10 adult cancer patients or their proxies reported on DHM use patterns and beliefs.¹² A range of 3.5–16 oz. of DHM was used per day and the majority of participants reported perceived benefits from DHM use; however, no actual clinical outcomes were measured.¹²

Children

A single randomized controlled trial (RCT) was conducted in children aged 0–5 undergoing bone marrow transplants.³⁰ Compared to the controls who received standard formula feeding (n = 14), those who received DHM (n = 18) or MOM (n = 6) had lower markers of intestinal inflammation and lower abundance of certain bacteria posttransplant.

Infants born >35 weeks gestational age with health risks

Patterns of use

Three studies reported DHM use patterns among infants with health risks.^22,31,33 In a case study of South African foster children with human immunodeficiency virus (HIV) or malnutrition, DHM was used as a primary source of feeding for 2 weeks to 2 years.²² In a study of term infants admitted to the NICU (n = 17), Lehman et al. reported that infants were supplemented an average of 900 mL DHM for 4.4 days.³¹ Meeks et al. assessed supplementation among term infants admitted to the NICU and found that they received DHM for an average of 5–6 days.³³

Clinical outcomes

Six observational studies measured clinical outcomes in infants with a variety of illnesses and reported a combination of neutral and positive effects with DHM use. Hoban et al. found that infants supplemented with DHM undergoing gastrointestinal surgery (n = 70) did not differ in hospital length of stay, NEC and/or sepsis risk, parenteral nutrition days, or central lines days compared to infants supplemented with formula (n = 70); however, in a subanalysis, including only small bowel atresia and gastroschisis surgeries, infants receiving DHM (n = 58) had significantly shorter hospital stays and central line days than those who received formula (n = 47).³⁵ Cognata et al. studied infants undergoing cardiac surgery (n = 546) and found that an exclusive unfortified human milk diet (n = 198), including MOM and DHM, was associated with a significantly lower incidence of NEC.²⁴ Alexander et al. reported that fewer infants with neonatal abstinence syndrome (NAS) fed DHM (n = 9) had Finnegan gastrointestinal subscores above 2 compared to those fed formula (n = 9), but overall Finnegan scores were not different.¹⁶ Mannel and Bennett³² and Reimers et al.²² investigated foster infants (n = 1–7) receiving DHM and reported improved feeding tolerance, reduced eczema, and lower infection incidence. Jeppesen et al. reported that HIV-exposed uninfected infants receiving DHM (n = 18) had fewer infections at 8–12 months compared to HIV-unexposed infants receiving formula (n = 47).¹⁴

Biomarkers outcomes

Two studies reported thymic size in HIV-exposed uninfected infants.^11,14 Infant's thymic size was greater in HIV-exposed uninfected infants who received DHM (n = 12) at 4 months of age compared to HIV-unexposed infants fed formula (n = 47).¹¹ However, a later study found no difference in thymic size at 8 and 12 months of age.¹⁴

Growth outcomes

Four observational studies reported mixed findings related to growth.^16,22,32,35 Among infants undergoing gastrointestinal surgery, there was no difference in weight or head circumference between infants supplemented postoperatively with DHM (n = 70) and formula (n = 70).³⁵ In a case study of seven foster infants, Reimers et al. reported improved weight gain after introduction of DHM as their primary feeding.²² In contrast, a case study of a foster infant whose birth weight dropped from the 56th percentile to the 1st percentile due to formula intolerance reported that the infant's weight remained below the 5th percentile after being fed DHM for over 200 days.³² In a case–control study of hospitalized infants with NAS, head circumference gains were lower in infants fed DHM (n = 9) compared to infants fed formula (n = 9).¹⁶

Healthy infants born >35 weeks gestational age

Patterns of use

Two studies reported patterns of DHM supplementation for hypoglycemia among healthy infants.^15,27 A case study of two infants reported that a range of 45–147 mL of DHM was utilized for supplementation.¹⁵ Ferrarello et al. found that among 83 mother-infant dyads, 76% of parents chose DHM as a supplement for hypoglycemia over formula.²⁷

Six studies investigated DHM patterns of use for other supplementation reasons among healthy infants.^{18,19,21,23,25,28} In a 2018 regional survey of 71 maternity hospitals, 32% of hospitals reported that they were using DHM for healthy infants.¹⁸ Sen et al. investigated supplementation patterns at a single U.S. hospital from 2013 to 2016 and found that the percentage of healthy infants receiving DHM increased from 0.04% to 4.7%, with common indications for use, including excessive weight loss, late preterm birth, poor latch, and delayed lactogenesis.²³ Lewis et al. investigated indications for DHM in a level 1 mother baby unit and reported that the three most common reasons for supplementation among healthy infants were excessive weight loss, mother-infant separation, and small for gestational age.¹⁹ Rabinowitz et al. surveyed breastfeeding mothers of healthy infants (n = 24) and reported that 58% preferred DHM supplementation over formula.²¹ Regarding hospital policies, Drouin et al. surveyed level 1 maternity hospitals in the Northeast using DHM (n = 15) and found that 87% had policies that stated criteria for DHM, 27% stated DHM was preferred, and all required consent.²⁵ Kair et al. investigated maternal characteristics by supplemental feeding type and found that dyads that received formula supplementation (n = 376) were more likely to be nonwhite, publicly insured, and/or non-English speaking than dyads who received DHM supplementation (n = 306), raising concerns about health care inequities in DHM access.²⁸

Knowledge of DHM

Four studies investigated clinician and family knowledge and opinions about DHM supplementation for healthy infants.^17,18,21,26 Rabinowitz et al. interviewed postpartum mothers (n = 24) and reported maternal concerns related to safety of DHM and a lack of information.²¹ In another study that interviewed postpartum mothers (n = 30), Kair and Flaherman identified four themes, including that formula is familiar and DHM is not, DHM is costly and logistically challenging, DHM is temporary and formula is ongoing, and DHM is “healthier.”¹⁷ Ferrarello et al. reported that nurses (n = 20) lacked knowledge of DHM and presented logistical concerns for implementing a DHM policy in a well-baby nursery.²⁶ In a survey of clinicians at maternity hospitals in the northeastern United States (n = 71), 78% believed that studies showed benefits of using DHM in healthy term infants, and 94% believed that DHM improved exclusive breastfeeding rates.¹⁸

Clinical outcomes

One study reported clinical outcomes for infants receiving level 1 care.²⁰ Mannel and Peck found that hospital length of stay did not differ in late preterm infants (n = 183) by feeding type (MOM, DHM, and formula).²⁰ Thoene is currently investigating DHM supplementation among term infants experiencing hypoglycemia in an RCT that is registered to report blood glucose outcomes.³⁶

Breastfeeding outcomes

Six studies reported on how DHM use influenced breastfeeding outcomes in healthy infants with conflicting findings between observational studies and a single RCT.^{15,18,20,27,29,34} Ferrarello et al. reported that among infants supplemented with DHM for hypoglycemia (n = 63), 52% were exclusively breastfeeding at discharge compared to 0% of infants supplemented with formula (n = 20).²⁶ Belfort et al. found that hospitals who reported using DHM to supplement healthy infants had higher rates of exclusive breastfeeding at discharge compared to those who did not (77% versus 56%, p = 0.02).¹⁸ Mannel and Peck found that the risk ratio of breastfeeding at discharge was 0.84 for infants who received any formula supplementation (n = 93) compared to infants who received expressed human milk (n = 20; 95% confidence interval [CI] 0.77–0.92).²⁰ Merjaneh et al. found that breastfed infants supplemented with DHM (n = 33) had five times greater odds of exclusive breastfeeding at 6 months compared to infants supplemented with formula (n = 39; 95% CI 1.37–19.23; p = 0.015).³⁴ Conversely, Kair et al. conducted an RCT of healthy infants with >4.5% weight loss in first 36 hours of life and found that infants randomized to receive early, limited-volume DHM supplementation (n = 30) were not more likely to be breast milk feeding at 3 months than the control group who was instructed to exclusive breastfeed unless otherwise advised by a health care provider (n = 30).²⁹

Postdischarge preterm infants

Szucs et al. studied supplementation of DHM among postdischarge preterm quintuplets and reported that they received ∼420 oz. DHM per week in addition to mother's milk and were developing normally at 6 months.¹³

Discussion

In this systematic scoping review of research using DHM in populations other than hospitalized preterm infants, we found that the majority of studies were conducted in healthy infants (14/26), or infants >35 weeks gestation with health complications (9/26). More than half of the studies (15/26) were not intended to establish a potential relationship between DHM use and health-related outcomes, which suggests a high level of directness of outcome bias in the existing literature.

DHM use in noninfant populations

Research into DHM use in noninfant populations is scarce, with only a single study identified in adult cancer patients that was influenced by selection bias (all participants had independently sought DHM). In addition, no clinical outcomes were directly measured, so potential efficacy of DHM as an adult cancer therapy could not be evaluated. Studies are also limited regarding DHM use in children, with only one RCT investigating DHM use during bone marrow transplants. While the study reported positive outcomes related to intestinal inflammation and bacterial abundance, interpretation is limited by reporting bias due to combining infants who received DHM with those who received MOM when reporting findings.

DHM use in infants born >35 weeks gestational age with health risks

The majority of studies in infants with health risks (7/9) measured health-related outcomes, including clinical findings, biomarkers, and/or growth; however, due to high heterogeneity between populations studied (including infants with NAS, feeding intolerances, HIV-exposure, and cardiac and gastrointestinal anomalies), there was limited ability to synthesize findings across studies. In small case studies of infants experiencing failure-to-thrive, there was consensus of improved feeding tolerance.^22,32 In studies measuring growth outcomes, there were inconsistent results, with 2/4 studies reporting inferior growth with DHM feedings.^16,22,32,35 Findings of slower growth is in agreement with studies among preterm infants that have reported slower growth with DHM feedings compared to preterm formula,^4,37–39 suggesting that future studies should investigate growth outcomes and also measure the macronutrient content of the DHM, as this was not addressed in any of the growth studies included in this review. Future research is also needed in how DHM use among ill infants influences breastfeeding outcomes as limited studies have considered this.

Limitations of research in infants with health risks include the use of study designs that were predominantly observational, cross-sectional, and contained <20 participants who received DHM. Moreover, three studies compared infant groups from two eras separated by multiple years.^11,14,35 Due to the time difference, changes in standard of care may have confounded study findings. Of final note is the reporting bias present in two studies that grouped MOM and DHM feedings together when reporting results, which inhibits any conclusions specific to DHM.^14,24

DHM use in healthy infants born >35 weeks gestational age

Fourteen studies were conducted in the last 6 years using DHM in healthy infant populations, suggesting that this is a growing topic of interest. A 2018 regional study of 71 maternity hospitals reported that 32% of hospitals were using DHM for healthy infants, although whether these patterns hold nationally remains to be established.¹⁸ Reported uses of DHM included hypoglycemia and/or hyperbilirubinemia, excessive weight loss, delayed lactogenesis, small for gestational age, and maternal-infant separation.^19,23,25 Differential patient access to DHM was reported in one study that found nonwhite, publicly insured, and/or non-English speaking mothers received DHM as a supplement less often, raising concerns about health care inequities.²⁸

The most common health-related outcome studied among infants in level 1 care receiving DHM was the impact on breastfeeding, with conflicting findings reported.^{15,18,20,26,29,34} Four observational studies reported a positive impact on breastfeeding outcomes at hospital discharge or up to 6 months postpartum. In observational studies, reverse-causation may have been present when DHM use is counted toward definitions of exclusive breastfeeding at discharge, thus confounding findings. Conversely, one RCT showed that no improvement in breastfeeding rates at 3 months postpartum in infants receiving early, limited-volume DHM supplementation for excessive weight loss.²⁹ Recent RCTs have found that early, limited-volume formula supplementation in the hospital did not impact breastfeeding status at 1 and 6 months among healthy, term infants, which aligns with the findings of the RCT in this review.^40,41 Collectively, these RCTs suggest that limited-volume supplementation in hospital, regardless of whether it is formula or DHM, may have minimal impact on breastfeeding outcomes.

Only a single study considered clinical outcomes (length of hospital stay) among healthy infants receiving DHM,¹⁹ and no studies investigated growth outcomes. Directness of outcomes bias is prevalent in the current body of research, with the majority of studies in healthy infants not designed to establish a relationship between DHM use and health-related outcomes. Future research should include randomized trials to investigate the impact of DHM versus formula supplementation on health-related outcomes, including breastfeeding status, clinical outcomes, and growth.

Conclusion

The studies presented in this scoping review identify that DHM is increasingly being used in infant populations other than the preterm, NICU infant. Overall, studies are limited due to directness of outcomes bias, with 15/26 studies not designed to establish a relationship with DHM use and health-related outcomes. More research is warranted regarding DHM use in nonpreterm infants and should include randomized trials investigating clinical, growth, and breastfeeding outcomes. The fact that 80% of the studies in this review were conducted in the last 3 years suggests that DHM use beyond the preterm NICU infant is a rapidly evolving practice and warrants regular reviews of the literature.

Footnotes

Authors' Contributions

S.M. and M.T.P. contributed to study conception, study design, data collection, and data interpretation. S.M. had primary responsibility for writing the article. Both authors reviewed, edited, read, and approved the article.

Disclosure Statement

M.T.P. serves on the Board of Directors for the Human Milk Banking Association of North America in an unpaid capacity. S.M. has no conflicts of interest to report.

Funding Information

The authors report no funding was received for this project.

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