Clinical Therapeutics/Volume ], Number ], 2017
Effects of Donor Breastmilk Feeding on Growth and Early Neurodevelopmental Outcomes in Preterm Infants: An Observational Study Laura S. Madore, MD1,2,†; Samudragupta Bora, PhD2,‡; Carmina Erdei, MD1,3; Tina Jumani, DO1,¶; Allison R. Dengos, DO1,¥; and Sarbattama Sen, MD1,3 1
Department of Pediatric Newborn Medicine, Tufts Medical Center, Boston, Massachusetts; 2Department of Pediatric Newborn Medicine, Baystate Medical Center, Springfield, Massachusetts; and 3Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
ABSTRACT Purpose: Donor breastmilk (DBM) has gained popularity as an alternative to formula when mother’s own milk (MOM) is unavailable. The objective of this study was to evaluate the effects of a predominantly DBM diet on growth and subsequent neurodevelopment in preterm infants at a level 3 neonatal intensive care unit (NICU). Methods: This single-center, observational cohort study compared data from preterm infants supplemented with predominantly (450%) DBM to those from age- and weight-matched infants fed only MOM or supplemented with predominantly (450%) preterm formula (PF). The primary outcome was inhospital weight gain, and the secondary outcome was neurodevelopment, as assessed by the Bayley III scale at 1 and 2 years’ corrected age. Exclusion criteria were major congenital defects, death prior to discharge from the NICU, or supplementation volumes of o50% over the first month of life. We compared the outcomes among the 3 feeding groups with the χ2 test, ANOVA, and ANCOVA, with post hoc pairwise comparisons after adjustment for the following confounders: bronchopulmonary dysplasia, multiple births, and social work involvement. Findings: In the entire cohort, the mean gestational age was 27.1 weeks and the mean birthweight was
914 g. The DBM (n ¼ 27) and PF (n ¼ 25) groups were similar with regard to socioeconomic characteristics. DBM infants regained birthweight more slowly over the first month of life compared with infants fed MOM (n ¼ 29) or PF (mean [SD], 17.9 [5.7], 22.0 [6.8], and 20.3 [5.7] g/kg/d, respectively; P ¼ 0.05); however, this growth difference was attenuated at later time points. In a fully adjusted model, the DBM group scored significantly lower in cognition at both 1 year (P ¼ 0.005) and 2 years (P ¼ 0.03) of age compared with the infants fed non-DBM diets. Implications: The findings from this study suggest that in this NICU, preterm infants supplemented with predominantly DBM had compromised early inhospital weight gain and, possibly, early cognitive delays compared with infants fed only MOM or infants supplemented with predominantly PF. These findings reinforce the need for further research on the optimal use of DBM in the preterm population and a continued need for promoting breastfeeding efforts to supply MOM. (Clin Ther. 2017;]:]]]–]]]) & 2017 Elsevier HS Journals, Inc. All rights reserved. Key words: donor breastmilk, growth, neurodevelopment, preterm infants.
INTRODUCTION †
Department of Pediatric Newborn Medicine, Baystate Medical Center, Springfield, Massachusetts. ‡ Mothers, Babies and Women’s Health Program, Mater Research Institute–The University of Queensland, Aubigny Place, South Brisbane, Australia. ¶ Department of Pediatrics, Albany Medical Center, Albany, New York. ¥ Department of Pediatrics, Rutgers–Robert Wood Johnson Medical School, New Brunswick, New Jersey.
] 2017
Mother’s own milk (MOM) is the optimal form of nutrition in all infants, particularly the vulnerable preterm population.1 Compared with formula feeding, breastmilk feeding has been associated with Accepted for publication May 9, 2017. http://dx.doi.org/10.1016/j.clinthera.2017.05.341 0149-2918/$ - see front matter & 2017 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics enhanced immunity and gut maturation; decreased rates of necrotizing enterocolitis (NEC), allergies, asthma, and obesity; and improved neurodevelopmental and behavioral outcomes.2–5 However, some mothers who deliver prematurely struggle to produce breastmilk. Historically, when MOM was unavailable or in low supply, preterm formula (PF) was the only alternative feeding option. A more recently available alternative to PF is human donor breastmilk (DBM). DBM is pooled, pasteurized breastmilk donated to milk banks by mothers with excess, primarily term, pumped milk.6,7 DBM use has increased over the past decade and, as of 2014, over half of all US neonatal intensive care units (NICUs) offered DBM as an option in preterm infants despite its expense and limited research investigating the short- and long-term risks and benefits.8,9 A recent trial from the Netherlands investigated the impact of DBM on NEC and sepsis and found that DBM supplementation, compared with formula supplementation, did not decrease the rates of these morbidities.10 However, MOM composed 85% to 90% of the infants’ diet during the first 10 days of life, when the intervention was administered. Another recent trial from Canada measured the effects of DBM supplementation on infant neurodevelopment and found in a post-hoc exploratory analysis that infants randomized to DBM were more likely to have cognitive neuroimpairment (defined as a Bayley III cognitive score of o85) at 18 months compared with infants who received PF supplementation, despite no significant difference in mean cognitive scores (the primary outcome).11 In this population, MOM composed 56% to 63% of the infants’ diet, and the intervention was continued until age 90 days or hospital discharge. Notably, from the first administration, DBM was routinely fortified with extra protein. Despite varied nutritional practices, a meta-analysis of data from 9 older trials showed that supplementation with DBM, as opposed to formula, reduced the prevalence of NEC; however, it also significantly compromised growth.12 With updated nutritional strategies, more recent studies have shown evidence both for and against the association of DBM with growth failure.5,11,13–16 In the extremely preterm infant, suboptimal nutrition and inadequate weight gain are linked to compromised neurodevelopmental outcomes (NDOs).17–19
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Ehrenkranz et al17 identified a strong relationship between poor in-hospital growth and compromised NDOs at age 18 to 22 months. Stephens et al18 demonstrated that optimized protein intake during the first week of life confers later cognitive benefits: each 1-g/kg/d protein intake was associated with an 8.2-point increase in the Mental Developmental Index at 18 months. Given the routine processing that DBM undergoes and the concern for poor growth in preterm infants fed DBM, there is a need for assessing the impact of routine DBM use on developmental outcomes. The aims of the present study were to understand the impact of DBM supplementation on neonatal growth, the primary outcome, and to explore the association between DBM feeding and NDOs. We hypothesized that compared with preterm infants fed MOM or PF, those fed predominantly DBM would have impaired growth and compromised NDOs.
PATIENTS AND METHODS Patients and Practices In 2011, the Tufts Medical Center NICU (Boston, Massachusetts) began to offer DBM in infants whose birthweight was o1 kg and in all multiples if at least 1 sibling’s birthweight was o1 kg. Before that time, all infants received either MOM or PF, or a combination of the two. Once this DBM policy was initiated, parents were given the option of PF or DBM when MOM was unavailable or in low supply. DBM was provided only after parental consent was obtained. DBM and PF were used either as a sole enteral diet or, more commonly, as a supplement to MOM, as MOM was prioritized in each case as availability allowed. Regardless of feed type, enteral trophic feeds were initiated in all infants (whose clinical status allowed) by 3 days of life. Feeds were advanced as tolerated by 20 mL/kg/d until full feeds of 130 to 150 mL/kg/d were reached. Fortification was initiated at 100 mL/kg/d. DBM and MOM were fortified in the same way; a bovine-based fortifier was added to 24 kcal/oz, followed by protein supplementation, and, if needed, medium-chain triglycerides and hydrolyzed cornstarch were added to increase calories further to a maximum of 30 kcal/oz. PF was fortified using increasing concentrations of formula powder, as per formula instructions. In all infants, regardless of feed type, the need for fortification was determined using a
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L.S. Madore, et al. weekly analysis of growth curves with the guidance of the NICU nutritionist, with a goal growth rate of Z15 g/kg/d. All infants receiving DBM were transitioned to PF at 32 weeks’ postmenstrual age or earlier if there was persistent poor growth despite adequate fortification. DBM was purchased from the Mothers’ Milk Bank of New England (Newton, Massachusetts), which complies with the Human Milk Banking Association of North America’s published guideline on screening, collection, holder pasteurization, processing, and distribution.20 DBM use at the NICU was tracked using a DBM logbook, in which each patient’s name and medical record number, DBM batch numbers, and volumes administered were recorded. The protocol of this single-center, observational cohort study was approved by the institutional review board at Tufts Medical Center. Cohort assignment was based on each infant’s predominant feed type (DBM, MOM, or PF). The criterion for inclusion in the MOM group was the receipt of a diet of only MOM over the first month of life (no DBM or PF supplementation provided). The criterion for inclusion in the DBM and PF groups was the receipt of 450% of feeds as DBM or PF, respectively, over the first month of life. This reflects typical “supplemental” use in the NICU, as DBM and PF are now commonly utilized as a “bridge” until enough MOM is available. In all groups, exclusion criteria were any major congenital or cardiac malformation, and death prior to NICU discharge. Additionally, infants who received a minority (o50%) of feeds as DBM or PF over the first month of life were excluded because MOM was the dominant feed type in these cases. Based on these criteria, 27 infants qualified for inclusion in the DBM cohort, with birthdates between April 2011 and November 2012 (28 of 55 DBM-fed infants were excluded, 23 due to only a minority of DBM received, 3 due to death, and 1 due to congenital malformation). Two birthweight- and gestational age–matched comparison groups were identified using the admission logbook, evaluated for inclusion and exclusion criteria, and then further classified based on feed type as abstracted from the medical records. The first comparison cohort was fed only MOM (n ¼ 29; birthdate range, October 2010 to September 2012). The second comparison cohort was fed predominantly PF (n ¼ 25; birthdate ] 2017
range, April 2009 to October 2012). After the initiation of the DBM policy, most families opted for DBM; thus, birthdates in the PF comparison group spanned a longer time period. However, all other feeding practices remained consistent throughout this period.
Outcomes Growth Growth data were abstracted from medical records and converted to age-adjusted percentiles using the Fenton 2013 growth charts for preterm infants. Weight gain (in g/kg/d), the primary outcome, was calculated over the first 30 days and the first 60 days of life. Due to initial weight loss, weight gain was also calculated from the day on which an infant had regained birthweight until 30 and 60 days of life. Rates of growth (in cm/wk) of crown–heel length and head circumference, measured using the tape-measure technique, were calculated using the difference between admission and discharge measurements. At approximately 1 and 2 years’ corrected age (CA), children were evaluated in the Tufts Medical Center NICU Follow-Up Program. At each time point, infants’ weight, head circumference, and length were measured by trained providers. If an infant did not present for follow-up, then data on these growth parameters were obtained from the medical records of primary care or subspecialty visits. Measurements were converted to age-adjusted z-score equivalents using the 2000 growth charts from the Centers for Disease Control and Prevention.
Neurodevelopment For the NDO exploratory analysis, the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III) were administered in the Tufts Medical Center NICU Follow-up Program at both the 1- and 2-year CA visits. The Bayley III was administered by 1 of 4 trained clinicians who were blinded to infants’ NICU feed type. All follow-up visits were part of routine follow-up care at the institution. The resultant CA-adjusted composite scores in each domain of neurodevelopment (cognition, language, and motor skills) were abstracted from the medical records.
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Clinical Therapeutics
Covariates Illness Severity and Neonatal Morbidities The following markers of illness severity and morbidity were abstracted from the medical records and assessed as covariates: Apgar score, Critical Risk Index for Babies score, days intubated, preand postnatal exposure to corticosteroids, length of hospital stay, NEC (defined as Bell stage ZII), brain injury (defined as intraventricular hemorrhage grade ZIII and/or the presence of periventricular leukomalacia), bronchopulmonary dysplasia (BPD; defined as a persistent oxygen requirement or need for positive airway pressure at 36 weeks’ postmenstrual age), surgically treated retinopathy of prematurity, surgically treated patent ductus arteriosus, and culture-positive late-onset sepsis. Sociodemographic Information Clinical and sociodemographic data on each mother were collected from the medical records and by using a questionnaire administered at the 2-year follow-up visit or by phone call. Data collected were maternal age, race, marital status, level of education, type of medical insurance, reported household income, social work involvement, and frequency of reading to the child.
Statistical Analysis With a minimum of 25 infants per group and a type I error of 0.05, there was 80% power to detect a between-group difference in growth rate of 3.5 g/kg/d. Data analysis was conducted in 3 stages: 1. The associations between feed type and infant growth, as well as feed type and NDOs, were examined using 1-way ANOVA, with the least significant difference procedure for post hoc pairwise comparisons. 2. Covariates were screened as potential confounders of growth and NDOs based on between-group differences using ANOVA for continuously distributed variables, the Pearson χ2 test for independent variables, and the Fisher exact test for dichotomous variables, using a P value of o0.10. Model fitting was performed using both forward and backward variable selection for identifying the most parsimonious model. Using this methodology, 3 significant confounders of NDOs were identified: multiples, BPD, and social work involvement.
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3. All reported associations were reanalyzed after adjustment for these confounders using the 1-way analysis of covariance (ANCOVA), with Bonferroni correction for post hoc pairwise comparisons. A P value of r0.05 was used for indicating statistical significance. Only data available from each follow-up time point were analyzed, as reported in the tables. All statistical analysis was conducted using IBM SPSS Statistics software version 22.0 (IBM Corporation, Armonk, New York).
RESULTS Infants’ Characteristics In the entire cohort, the mean gestational age was 27.1 weeks and the mean birthweight was 914 g. As shown in Table I, the 3 feeding groups were similar with regard to clinical and sociodemographic characteristics, birth measurements, sex, corticosteroid exposure, and severity and rates of morbidities (NEC, BPD, and late-onset sepsis) were not significantly different among groups. There were fewer multiples in the PF group compared with the DBM and MOM groups (P ¼ 0.06). The DBM and PF groups had similar sociodemographic characteristics, and compared with the MOM group, both appeared to be more socially disadvantaged: They were more likely to have a single parent (P ¼ 0.01), have less maternal education (P ¼ 0.07), have a lower household income (P ¼ 0.04), receive public insurance (P ¼ 0.06), have social work involvement (P ¼ 0.04), and have less exposure to reading (P ¼ 0.05). The majority (74%) of infants in the DBM group received DBM due to an inadequate supply of MOM. At discharge or transfer, 62% of infants in the MOM group continued to receive exclusive MOM feedings, while the remainder of infants had been transitioned to PF either as a supplement to MOM or as the sole feed type.
Growth
As seen in Table II, growth in the first 30 days was analyzed in 2 ways. First, total weight gain between birth and day of life 30 (which included weight lost in the first weeks of life) was measured. DBM-fed infants had a slower rate of weight gain in the first 30 days compared with infants fed MOM or PF (mean [SD],
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L.S. Madore, et al.
Table I. Neonatal clinical and socioeconomic characteristics. Characteristic Neonatal baseline characteristics Gestational age at birth, mean (SD), wk Birthweight, mean (SD), g Birthweight, mean (SD), % Small for gestational age, no. (%) Birth length, mean (SD), % Birth head circumference, mean (SD), % Apgar at 1 min after birth, mean (SD) Apgar at 5 min after birth, mean (SD) Critical Risk Index for Babies, mean (SD) Male sex, no. (%) Multiple gestation, no. (%) Outborn delivery, no. (%) Antenatal corticosteroid exposure, no. (%) Birth date, mo/y, range Infant acquired clinical characteristics Indomethacin exposure, no. (%) Bronchopulmonary dysplasia, no. (%) Late-onset sepsis, no. (%) Postnatal corticosteroid exposure, no. (%) Brain injury, no. (%) Necrotizing enterocolitis, no. (%) Retinopathy of prematurity, no. (%) Patent ductus arteriosus, no. (%) Length of hospital stay, mean (SD), d Family socioeconomic characteristics Maternal age, mean (SD), y Nonwhite race, no. (%) Single parent, no. (%) College educated, n/N (%) Household income 4$60K, n/N (%) Public insurance, no. (%) Social work involvement, no. (%) Daily reading exposure, n/N (%) *
Mother’s Own Milk (n ¼ 29)
Preterm Formula (n ¼ 25)
Donor Breast Milk (n ¼ 27)
27.0 (1.5) 936.6 (211.0) 48.4 (22.7) 2 (6.9) 45.3 (27.6) 49.2 (24.0) 4.5 (2.4) 6.7 (2.0) 2.7 (3.0) 18 (62.1) 14 (48.3) 2 (6.9) 23 (79.3) 10/2010–9/2012
27.3 (2.1) 913.8 (222.6) 42.0 (25.1) 4 (16.0) 38.7 (27.3) 38.0 (25.2) 4.8 (2.3) 6.8 (1.8) 3.5 (3.1) 14 (56.0) 5 (20.0) 1 (4.0) 22 (88.0) 4/2009–10/2012
27.1 (1.9) 890.5 (175.8) 40.5 (19.1) 2 (7.4) 35.9 (29.4) 36.9 (24.1) 4.4 (2.4) 6.9 (1.6) 3.5 (3.0) 18 (66.7) 13 (48.1) 6 (22.2) 21 (77.8) 4/2011–11/2012
12 11 2 2 2 2 2 1 81.3
(41.4) (37.9) (6.9) (6.9) (6.9) (6.9) (6.9) (3.4) (37.4)
8 (32.0) 14 (56.0) 4 (16.0) 4 (16.0) 3 (12.0) 2 (8.0) 0 2 (8.0) 86.5 (46.6)
29.9 16 6 19/26 14/26 11 2 18/26
(4.6) (55.2) (20.7) (73.1) (53.8) (37.9) (6.9) (69.2)
28.2 13 12 7/18 4/16 17 7 9/22
(7.1) (52.0) (48.0) (38.9) (25.0) (68.0) (28.0) (40.9)
P* 0.85 0.70 0.38 0.46 0.44 0.12 0.80 0.92 0.56 0.73 0.06 0.11 0.59
11 12 3 1 3 1 3 2 65.3
(40.7) (44.4) (11.1) (3.7) (11.1) (3.7) (11.1) (7.4) (35.5)
0.74 0.41 0.55 0.28 0.81 0.86 0.31 0.73 0.14
31.8 17 16 12/22 6/18 17 9 8/22
(5.7) (63.0) (59.3) (54.5) (33.3) (63.0) (33.3) (36.4)
0.09 0.71 0.01 0.07 0.04 0.06 0.04 0.05
P based on 1-way ANOVA for continuous variables and χ2 or Fisher exact test for categorical variables.
9.7 [3.6], 12.6 [3.7], and 12.3 [3.9] g/kg/d, respectively; P ¼ 0.01). These results remained unchanged after adjustment for early neonatal clinical covariates. Second, weight gain from the day on which birthweight was regained to day of life 30 was analyzed.
] 2017
While there was no difference in days to regained birthweight among groups, the DBM group demonstrated a slower rate of weight gain compared with those in the MOM and PF groups (mean [SD], 17.9 [5.7], 22 [6.8], and 20.3 [5.7] g/kg/d; P ¼ 0.05).
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Clinical Therapeutics
Table II. Associations between feed type and growth outcomes at 1 and 2 years. Growth Outcome† Neonatal Weight gain, g/kg/d Birth to day of life 30 Regain birthweight to day of life 30 Birth to day of life 60 Regain birthweight to day of life 60 Time to regain birthweight, d Growth, cm/wk Head circumference Longitudinal Feeds Time to reach feeds of 100 mL/kg/d, d Maximum enteral calories received, kcal/oz 1-y corrected age, z score Weight Length Weight for length Head circumference 2-y corrected age, z score Weight Length Weight for length Head circumference * †
Mother’s Own Milk Preterm Formula Donor Breast Milk n ¼ 29 12.6 22.0 19.7 24.9 12.2
12.3 20.3 18.9 23.5 11.6
(3.9) (5.7) (5.0) (5.9) (3.5)
n ¼ 27 9.7 17.9 18.4 23.8 13.6
(3.6) (5.7) (3.6) (4.4) (3.9)
0.01 0.05 0.54 0.55 0.20
0.7 (0.2) 1.0 (0.3)
0.7 (0.2) 0.9 (0.3)
0.7 (0.3) 1.0 (0.4)
0.78 0.47
14.0 (6.2) 27.9 (2.0)
17.5 (7.4) 27.7 (1.9)
16.3 (7.3) 27.4 (1.9)
0.17 0.71
n ¼ 21 –0.8 (1.2) –0.3 (1.4) –0.2 (1.3) 0.02 (1.1) n ¼ 20 –0.5 (1.3) –0.05 (1.3) –0.3 (1.3) 0.2 (1.1)
n ¼ 16 –1.4 (1.2) –0.8 (1.1) –0.6 (1.4) –0.1 (1.0) n ¼ 15 –0.7 (1.2) –0.6 (1.2) –0.2 (1.8) 0.3 (1.1)
n ¼ 22 –1.3 (1.5) –0.6 (1.4) –0.8 (1.6) –0.6 (1.6) n ¼ 19 –0.9 (1.6) –0.1 (1.2) –0.9 (1.8) –0.5 (1.4)
0.32 0.51 0.39 0.29 0.67 0.38 0.39 0.13
P based on 1-way ANOVA. Data are given as mean (SD).
Although infants fed DBM had slower weight gain in the first 30 days, this difference did not persist to 60 days of life. There was no difference in weight gain between groups from birth to day 60 or from days 30 to 60. There was no difference in length or head circumference growth during the NICU stay. Additionally, there were no differences among the 3 groups in time to reach feeds of 100 mL/kg/d (P ¼ 0.17) (suggesting that rate of feeding advancement was not the cause of early growth failure in the DBM group) or in maximum enteral calories received (P ¼ 0.71) (suggesting that higher caloric fortification was not the reason for similar growth in all 3 groups by 60 days of life). At both 1 and 2 years’ CA, there were no differences in z scores on weight, length, head circumference, or weight/length among groups.
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(3.7) (6.8) (4.5) (4.7) (4.7)
n ¼ 25
P*
Neurodevelopment At 1 year, the DBM group scored lower than did the MOM and PF groups in all domains of NDO assessment using Bayley III scores in an unadjusted analysis (Table III). After adjustment for significant confounders (multiple births, BPD, and social work involvement), the DBM group continued to score lower than did the PF-fed infants at 1 year in the domains of cognition and language, while the difference in motor skills was attenuated (mean [SD] scores: cognition: MOM, 93.0 [9.6]; PF, 97.1 [11.8]; and DBM, 83.1 [11.6] [DBM vs PF, P ¼ 0.002; DBM vs MOM, P ¼ 0.064]; language: MOM, 86.1 [14.7]; PF, 91.1 [17.5]; and DBM, 74.1 [8.8] [DBM vs PF, P ¼ 0.025; DBM vs MOM, P ¼ 0.095]). At 2 years, the DBM group continued to score significantly lower
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L.S. Madore, et al.
Table III. Associations between feed type and neurodevelopmental outcomes at 1 and 2 years. Bayley III score, mean (SD) 1-y corrected age Cognition Language Motor 2-y corrected age Cognition Language Motor
Mother’s Own Milk
Preterm Formula
DBM
n ¼ 15 93.0 (9.6) 86.1 (14.7) 91.1 (9.9) n ¼ 18 93.9 (12.2) 91.9 (17.6) 89.0 (13.4)
n ¼ 13 97.1 (11.8) 91.1 (17.5) 93.1 (7.8) n ¼ 13 94.7 (15.1) 88.7 (17.3) 92.4 (15.4)
n ¼ 18 83.1 (11.6) 74.1 (8.8) 82.4 (16.5) n ¼ 16 83.1 (13.9) 79.3 (9.2) 80.5 (12.5)
P*
P†
0.003‡,§ 0.02‡,§ 0.05
0.005§ 0.04§ 0.09
0.04‡,§ 0.06 0.06
0.03§ 0.09 0.16
*
P based on 1-way ANOVA. P based on 1-way ANCOVA adjusted for multiples, bronchopulmonary dysplasia, and social work involvement. ‡ Post hoc pairwise comparisons of donor breastmilk vs mother’s own milk; P o 0.05. § Post hoc pairwise comparisons of donor breastmilk vs preterm formula; P o 0.05. †
in cognition (MOM, 93.9 [12.2]; PF, 94.7 [15.1]; and DBM, 83.1 [13.9] [DBM vs PF, P ¼ 0.014; DBM vs MOM, P ¼ 0.056]), but there were no significant differences in language or motor scores among groups in the fully adjusted models. Interestingly, adjustment of NDO scores for growth over the first 30 days did not attenuate the effects of DBM feeding on Bayley III scores.
Feed type was not associated with death after discharge, age at follow-up, the percentage of males presenting to clinic, or the percentage lost to follow-up (Table IV). The overall follow-up rate at 1 year was 58% and at 2 years was 59%. There were no significant differences between those who presented for follow-up and those who were lost to follow-up in terms of clinical and sociodemographic characteristics at 1 year of age,
Table IV. Characteristics of infants who presented to the neonatal intensive care unit follow-up program. Measure
Mother’s Own Milk (n ¼ 29)
Preterm Formula (n ¼ 25)
Death after discharge,† no. (%) 1-y follow-up, no. (%) Corrected age, mean (SD), mo Gestational age at birth, mean (SD), wk Birthweight, mean (SD), g Male, n/N (%) 2-y follow-up, no. (%) Corrected age, mean (SD), mo Gestational age at birth, mean (SD), wk Birthweight, mean (SD), g Male, n/N (%) Lost to all follow-up, no. (%)
0 15 (51.7) 12.6 (1.9) 26.9 (1.2) 950.6 (159.5) 9/15 (60.0) 18 (62.1) 24.9 (4.5) 27.1 (1.2) 939.2 (178.3) 10/18 (55.6) 10 (34.5)
0 13 (52.0) 13.9 (3.3) 27.4 (1.8) 964.2 (253.1) 8/13 (61.5) 13 (52.0) 23.8 (4.0) 27.2 (2.2) 979.9 (177.4) 8/13 (61.5) 11 (44.0)
* †
DBM (n ¼ 27) 1 18/26 12.9 27.2 921.8 12/18 16/26 23.2 27.4 961.7 11/16 5/26
(3.7) (69.2) (1.4) (1.7) (200.8) (66.7) (61.5) (4.7) (2.0) (257.3) (68.8) (19.2)
P* 0.36 0.34 0.29 0.69 0.84 0.92 0.68 0.50 0.85 0.84 0.73 0.16
P based on 1-way ANOVA for continuous variables and χ2 or Fisher exact test for categorical variables. One death after discharge in the donor breastmilk group due to sudden infant death syndrome.
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Clinical Therapeutics but at 2 years those lost to follow-up had lower birthweight, birth length percentile, birth head circumference, and 1-minute Apgar score, and a higher rate of sepsis compared with those who presented for follow-up.
DISCUSSION At the Tufts Medical Center NICU, a predominantly DBM diet in preterm infants was associated with compromised early in-hospital weight gain, and cognitive delays at both 1 and 2 years. To our knowledge, this is the first study to investigate both growth and NDOs in preterm infants fed 3 differing diets: MOM only, majority DBM, and majority PF. These results suggest that a predominantly DBM diet per the clinical policies at this NICU may not be an adequate replacement for MOM. As more NICUs utilize DBM, the findings from this study reinforce the need for more research to optimize the practices around how to best utilize DBM. This is the first study to analyze growth in DBMfed infants at such an early time point (30 days of life). Most study designs analyzing growth use the difference between admission and discharge weights, which may miss subtle in-hospital growth discrepancies and therefore miss opportunities to identify early windows for nutritional optimization. In this cohort, DBM-fed infants were more likely to experience poor growth in the first 30 days of life. This difference in growth between feed groups did not persist beyond the first month, likely because of the DBM-fed infants’ being switched to PF (either due to growth failure despite maximal caloric fortification or per protocol at 32 weeks’ postmenstrual age), and less likely because of increased fortification as there was no difference between groups in maximum enteral calories received. Additionally, there were no growth differences at 1 or 2 years’ CA, which is similar to findings from other studies that continued to follow growth after discharge.11,12 Prior studies have had differing results regarding whether DBM feeding is associated with in-hospital growth impairment. These differences may have been due to differing nutritional practices that have evolved in NICUs worldwide. For example, the recent “DoMINO” trial by O’Connor et al11 did not find a difference in growth, but unlike Tufts Medical Center, fortified the DBM with additional protein before the first DBM feeding. Another difference is that we included only infants who
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received DBM as 450% of their feed volumes. Most other studies, including the 2 recent trials10,11, have compared a smaller amount of DBM with formula, which may have affected outcomes, as the benefits of breastmilk are likely volume dependent.21 Thus, it is important to understand how variation in DBM feeding practices may be associated with different outcomes. These differences in study findings should be interpreted in the context of these methods and practices, as this will provide evidence for urgently needed best practices with regard to DBM supplementation. The early compromised growth in DBM-fed infants that we and others have found may also be attributable to the altered nutritional composition of DBM, which is pooled and pasteurized. While the high heat of pasteurization enhances the tolerability of the milk by eliminating infectious contaminants, it also inactivates many important bioactive factors in the milk.22,23 Studies have shown significant decreases in fat, protein, and vitamins after routine DBM processing.23–25 Additionally, DBM is primarily term milk, which does not meet the nutritional needs of preterm infants. Compared with preterm milk, term milk is lower in protein, energy, and fat, which are all crucial to preterm growth and brain growth.25,26 Over the duration of lactation, the protein concentration in the breastmilk decreases, and most DBM is from mothers who have been lactating for many months, which augments the protein deficit found in DBM samples.26,27 Improved DBM processing through novel methods, such as ultrapasteurization or nonthermal methods, may be a strategy for improving DBM composition in preterm infants. General protein supplementation, as was done in the DoMINO trial, or individualized macronutrient supplementation using the emerging technology of human milk analyzers, may be another way of enhancing the nutritional composition of DBM.28 Lastly, developing a supply of “preterm” DBM for preterm infants may be another strategy for matching the nutritional needs of preterm infants. We found that among infants followed up with neurodevelopmental testing, DBM supplementation was associated with lower cognitive scores in a fully adjusted analysis. Additionally, in a post hoc exploratory analysis of data from the DoMINO trial11, infants supplemented with DBM were more likely to have cognitive neuroimpairment (cognitive composite
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L.S. Madore, et al. score of o85) compared with the PF group despite early aggressive protein supplementation of DBM and a lower percentage of DBM exposure (adjusted risk difference, 10.6%; P ¼ 0.02). These same infants will be followed up until age 5.5 years. An ongoing largescale, multicenter, randomized trial (National Institute of Child Health and Human Development’s Milk Trial) is evaluating the impact of DBM on later outcomes.29 Given that growth and neurodevelopment are strongly linked, it is possible that the lower NDO scores in the DBM group as seen in the exploratory analysis of the present study were a result of the compromised early growth found at the day-30 time point. However, DBM feeding remained associated with lower cognitive scores even after adjustment for growth in the first 30 days of life. This finding suggests that the association between DBM feeding and poor NDOs may be mediated by additional factors beyond poor early growth. It is plausible that DBM may not provide adequate neuroprotective factors for the developing preterm brain. In the last trimester of pregnancy and in the first 2 years of life, there is rapid myelination of the brain. Fatty acids, particularly long-chain polyunsaturated fatty acids, are the “building blocks” of this process and are obtained solely from breastmilk in the neonatal period. In comparison to MOM, DBM has a lower fat content, specifically, lower concentrations of the long-chain polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid.30–32 Additionally, infants fed DBM have impaired fat absorption,13,24 likely due to pasteurization-induced inactivation of bile salt–stimulated lipase, which is involved in fat digestion and absorption.32–34 Antioxidants, such as glutathione, as well as total antioxidant capacity are also significantly reduced in pasteurized milk,35 which is concerning given that the preterm brain is particularly susceptible to oxidative damage.36 There is emerging evidence that oligosaccharides in human milk provide sialic acid, a potentially essential nutrient for brain development and cognition; sialic acid is altered in pasteurized DBM samples compared with MOM samples.37,38 Lastly, the gut microbiome has recently emerged as an important immune mediator that may play a role in early brain development and function.39 The relative sterility and reduced anti-infective properties of DBM may play a role in the compromised NDOs we report. Future research should focus
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on identifying and potentially supplementing neuroprotective, nutritional, and immunomodulatory factors that may be diminished in DBM. Our study had limitations. This study was observational, which allows for measured and unmeasured confounders that may influence findings. This study was adequately powered to detect differences in the primary outcome (growth), but was not powered for our exploratory outcome of NDOs. Additionally, only 69% of study participants had data available from at least 1 follow-up visit during the study period. While this follow-up rate is similar to the general follow-up rate at this urban center, this could introduce bias. Mothers who provided their own milk tended to have more to education, higher household incomes, and less social work involvement, which can all independently and positively influence NDOs. However, we were able to provide the PF-fed cohort for comparison, which, despite having sociodemographic characteristics notably similar to those of the DBM cohort, did not have impaired growth or NDOs. This finding further supports the finding that DBM feeding was linked to poor early growth and long-term NDOs. The DBM and PF feed types in the present study were not exclusive, but constituted a majority of feeding volume, which reflects typical “supplemental” use as provided in some US NICUs and strengthens the generalizability of the findings from this study. Lastly, the delays in NDOs as identified by Bayley III scores at 2 years of age correlate inconsistently with later outcomes40; thus, the prediction of long-term functioning continues to be difficult.
CONCLUSIONS In the present single-center, observational study, supplementing preterm infants with predominantly DBM was associated with compromised early growth and, in an exploratory analysis, lower cognitive scores at 1 and 2 years of age compared with those fed only MOM or supplemented with PF. These results serve to provide evidence regarding the impact of different nutritional strategies on infant growth and development, and further highlight a key knowledge gap regarding the optimization of DBM use in preterm infants. Our findings also underscore the need for supporting maternal breastfeeding efforts to exclusively provide MOM to the most vulnerable infants.
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ACKNOWLEDGMENTS This work was supported by a small internal grant from the Natalie V. Zucker Research Center for Women Scholars at Tufts University School of Medicine. The funding source had no involvement in project design, interpretation, or submission of the manuscript. Thank you to Hannah Prange and Emily Farrell for their assistance with data collection. All of the authors approved the final article as submitted.
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CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article.
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REFERENCES 1. American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012;129:827–841. 2. Hack M. Young adult outcomes of very-low-birth-weight children. Semin Fetal Neonatal Med. 2006;11:127–137. 3. Lucas A, Morley R, Cole TJ, et al. Breast milk and subsequent intelligence quotient in children born preterm. Lancet. 1992;339:261–264. 4. Vohr BR, Poindexter BB, Dusick AM, et al. Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics. 2007;120:953–959. 5. 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;156:562–567. 6. Jones F. History of North American donor milk banking: one hundred years of progress. J Hum Lact. 2003;19:313–318. 7. Kim JH, Unger S. Human milk banking. Paediatr Child Health. 2010;15:595–598. 8. Hagadorn JI, Brownell EA, Lussier MM, et al. Variability of criteria for pasteurized donor human milk use: a survey of US neonatal intensive care unit medical directors. JPEN J Parenter Enteral Nutr. 2016;40:326–333. 9. Arslanoglu S, Corpeleijn W, Moro G, et al, European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr. 2013;57:535–542. 10. Corpeleijn WE, de Waard M, Christmann V, et al. Effect of donor milk on severe infections and mortality in very low-
10
16.
17.
18.
19.
20.
21.
22.
23.
24.
birth-weight infants: the early nutrition study randomized clinical trial. JAMA Pediatr. 2016;170:654–661. O’Connor DL, Gibbins S, Kiss A, et al, Greater Toronto Area DoMINO Feeding Group. Effect of supplemental donor human milk compared with preterm formula on neurodevelopment of very low-birth-weight infants at 18 months: a randomized clinical trial. JAMA. 2016;316:1897–1905. Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2014;4:1–92. Andersson Y, Savman K, Blackberg L, Hernell O. Pasteurization of mother’s own milk reduces fat absorption and growth in preterm infants. Acta Paediatr. 2007;96:1445–1449. Montjaux-Régis N, Cristini C, Arnaud C, et al. Improved growth of preterm infants receiving mother’s own raw milk compared with pasteurized donor milk. Acta Paediatr. 2011;100:1548–1554. 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. 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. 2016. [Epub ahead of print]. Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117:1253–1261. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics. 2009;123:1337–1343. Chan SH, Johnson MJ, Leaf AA, Vollmer B. Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review. Acta Paediatr. 2016;105:587–599. Guidelines for the Establishment and Operation of a Donor Human Milk Bank. Fort Worth, TX: Human Milk Banking Association of North America; 2013. Lechner BE, Vohr BR. Neurodevelopmental outcomes of preterm infants fed human milk: a systematic review. Clin Perinatol. 2017;44:69–83. Ewaschuk JB, Unger S, O’Connor DL, et al. Effect of pasteurization on selected immune components of donated human breast milk. J Perinatol. 2011;31:593–598. Lawrence RA. Milk banking: The influence of storage procedures and subsequent processing on immunologic components of human milk. Adv Nutr Res. 2001;10:389– 404. Vieira AA, Soares FV, Pimenta HP, et al. Analysis of the influence of pasteurization, freezing/thawing, and offer processes on human milk’s macronutrient concentrations. Early Hum Dev. 2011;87:577–580.
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L.S. Madore, et al. 25. Wojcik KY, Rechtman DJ, Lee ML, et al. Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc. 2009;109:137–140. 26. Radmacher PG, Lewis SL, Adamkin DH. Individualizing fortification of human milk using real time human milk analysis. J Neonatal Perinatal Med. 2013;6:319–323. 27. Bauer J, Gerss J. Longitudinal analysis of macronutrients and minerals in human milk produced by mothers of preterm infants. Clin Nutr. 2011;30:215–220. 28. de Halleux V, Rigo J. Variability in human milk composition: benefit of individualized fortification in verylow-birth-weight infants. Am J Clin Nutr. 2013;98:529–535. 29. National Institute of Child Health and Human Development, Neonatal Research Network. Donor milk vs. formula in extremely low birth weight (ELBW) infants. Available at: https://clinicaltrials.gov/ct2/ show/NCT01534481?term=donorþ milk&rank=3. Accessed 03/15/2017. 30. Valentine CJ, Morrow G, Fernandez S, et al. Docosahexaenoic acid and amino acid contents in pasteurized donor milk are low for preterm infants. J Pediatr. 2010;157:906–910. 31. Baack ML, Norris AW, Yao J, Colaizy T. Long-chain polyunsaturated fatty acid levels in US donor human milk: meeting the needs of premature infants? J Perinatol. 2012;32:598–603. 32. Henderson TR, Fay TN, Hamosh M. Effect of pasteurization on longchain polyunsaturated fatty acid levels and enzyme activities of human milk. J Pediatr. 1998;132:876–878. 33. Wardell JM, Wright AJ, Bardsley WG, D’Souza SW. Bile salt-stimulated lipase and esterase activity in human milk after collection, storage, and heating: nutritional implications. Pediatr Res. 1984;18:382–386. 34. Hernell O. Human milk lipases III. Physiological implications of the bile salt stimulated lipase. Eur J Clin Invest. 1975;5:267–272. 35. Silvestre D, Miranda M, Muriach M, et al. Antioxidant capacity of human
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milk: effect of thermal conditions for the pasteurization. Acta Paediatr. 2008;97:1070–1074. 36. Shim SY, Kim HS. Oxidative stress and the antioxidant enzyme system in the developing brain. Korean J Pediatr. 2013;56:107–111. 37. Wang B. Sialic acid is an essential nutrient for brain development and cognition. Annu Rev Nutr. 2009;29: 177–222. 38. Marx C, Bridge R, Wolf AK, et al. Human milk oligosaccharide composition differs between donor
milk and mother’s own milk in the NICU. J Hum Lact. 2014;30: 54–61. 39. Keunen K, van Elburg RM, van Bel F, Benders MJ. Impact of nutrition on brain development and its neuroprotective implications following preterm birth. Pediatr Res. 2015;77: 148–155. 40. Spencer-Smith MM, Spittle AJ, Lee KJ, et al. Bayley-III cognitive and language scales in preterm children. Pediatrics. 2015;135: 1258–1265.
Address correspondence to: Laura S. Madore, MD, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199. E-mail: Laura. [email protected]
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Effects of Donor Breastmilk Feeding on Growth and Early Neurodevelopmental Outcomes in Preterm Infants: An Observational Study Laura S. Madore, MD1,2,†; Samudragupta Bora, PhD2,‡; Carmina Erdei, MD1,3; Tina Jumani, DO1,¶; Allison R. Dengos, DO1,¥; and Sarbattama Sen, MD1,3 1
Department of Pediatric Newborn Medicine, Tufts Medical Center, Boston, Massachusetts; 2Department of Pediatric Newborn Medicine, Baystate Medical Center, Springfield, Massachusetts; and 3Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
ABSTRACT Purpose: Donor breastmilk (DBM) has gained popularity as an alternative to formula when mother’s own milk (MOM) is unavailable. The objective of this study was to evaluate the effects of a predominantly DBM diet on growth and subsequent neurodevelopment in preterm infants at a level 3 neonatal intensive care unit (NICU). Methods: This single-center, observational cohort study compared data from preterm infants supplemented with predominantly (450%) DBM to those from age- and weight-matched infants fed only MOM or supplemented with predominantly (450%) preterm formula (PF). The primary outcome was inhospital weight gain, and the secondary outcome was neurodevelopment, as assessed by the Bayley III scale at 1 and 2 years’ corrected age. Exclusion criteria were major congenital defects, death prior to discharge from the NICU, or supplementation volumes of o50% over the first month of life. We compared the outcomes among the 3 feeding groups with the χ2 test, ANOVA, and ANCOVA, with post hoc pairwise comparisons after adjustment for the following confounders: bronchopulmonary dysplasia, multiple births, and social work involvement. Findings: In the entire cohort, the mean gestational age was 27.1 weeks and the mean birthweight was
914 g. The DBM (n ¼ 27) and PF (n ¼ 25) groups were similar with regard to socioeconomic characteristics. DBM infants regained birthweight more slowly over the first month of life compared with infants fed MOM (n ¼ 29) or PF (mean [SD], 17.9 [5.7], 22.0 [6.8], and 20.3 [5.7] g/kg/d, respectively; P ¼ 0.05); however, this growth difference was attenuated at later time points. In a fully adjusted model, the DBM group scored significantly lower in cognition at both 1 year (P ¼ 0.005) and 2 years (P ¼ 0.03) of age compared with the infants fed non-DBM diets. Implications: The findings from this study suggest that in this NICU, preterm infants supplemented with predominantly DBM had compromised early inhospital weight gain and, possibly, early cognitive delays compared with infants fed only MOM or infants supplemented with predominantly PF. These findings reinforce the need for further research on the optimal use of DBM in the preterm population and a continued need for promoting breastfeeding efforts to supply MOM. (Clin Ther. 2017;]:]]]–]]]) & 2017 Elsevier HS Journals, Inc. All rights reserved. Key words: donor breastmilk, growth, neurodevelopment, preterm infants.
INTRODUCTION †
Department of Pediatric Newborn Medicine, Baystate Medical Center, Springfield, Massachusetts. ‡ Mothers, Babies and Women’s Health Program, Mater Research Institute–The University of Queensland, Aubigny Place, South Brisbane, Australia. ¶ Department of Pediatrics, Albany Medical Center, Albany, New York. ¥ Department of Pediatrics, Rutgers–Robert Wood Johnson Medical School, New Brunswick, New Jersey.
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Mother’s own milk (MOM) is the optimal form of nutrition in all infants, particularly the vulnerable preterm population.1 Compared with formula feeding, breastmilk feeding has been associated with Accepted for publication May 9, 2017. http://dx.doi.org/10.1016/j.clinthera.2017.05.341 0149-2918/$ - see front matter & 2017 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics enhanced immunity and gut maturation; decreased rates of necrotizing enterocolitis (NEC), allergies, asthma, and obesity; and improved neurodevelopmental and behavioral outcomes.2–5 However, some mothers who deliver prematurely struggle to produce breastmilk. Historically, when MOM was unavailable or in low supply, preterm formula (PF) was the only alternative feeding option. A more recently available alternative to PF is human donor breastmilk (DBM). DBM is pooled, pasteurized breastmilk donated to milk banks by mothers with excess, primarily term, pumped milk.6,7 DBM use has increased over the past decade and, as of 2014, over half of all US neonatal intensive care units (NICUs) offered DBM as an option in preterm infants despite its expense and limited research investigating the short- and long-term risks and benefits.8,9 A recent trial from the Netherlands investigated the impact of DBM on NEC and sepsis and found that DBM supplementation, compared with formula supplementation, did not decrease the rates of these morbidities.10 However, MOM composed 85% to 90% of the infants’ diet during the first 10 days of life, when the intervention was administered. Another recent trial from Canada measured the effects of DBM supplementation on infant neurodevelopment and found in a post-hoc exploratory analysis that infants randomized to DBM were more likely to have cognitive neuroimpairment (defined as a Bayley III cognitive score of o85) at 18 months compared with infants who received PF supplementation, despite no significant difference in mean cognitive scores (the primary outcome).11 In this population, MOM composed 56% to 63% of the infants’ diet, and the intervention was continued until age 90 days or hospital discharge. Notably, from the first administration, DBM was routinely fortified with extra protein. Despite varied nutritional practices, a meta-analysis of data from 9 older trials showed that supplementation with DBM, as opposed to formula, reduced the prevalence of NEC; however, it also significantly compromised growth.12 With updated nutritional strategies, more recent studies have shown evidence both for and against the association of DBM with growth failure.5,11,13–16 In the extremely preterm infant, suboptimal nutrition and inadequate weight gain are linked to compromised neurodevelopmental outcomes (NDOs).17–19
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Ehrenkranz et al17 identified a strong relationship between poor in-hospital growth and compromised NDOs at age 18 to 22 months. Stephens et al18 demonstrated that optimized protein intake during the first week of life confers later cognitive benefits: each 1-g/kg/d protein intake was associated with an 8.2-point increase in the Mental Developmental Index at 18 months. Given the routine processing that DBM undergoes and the concern for poor growth in preterm infants fed DBM, there is a need for assessing the impact of routine DBM use on developmental outcomes. The aims of the present study were to understand the impact of DBM supplementation on neonatal growth, the primary outcome, and to explore the association between DBM feeding and NDOs. We hypothesized that compared with preterm infants fed MOM or PF, those fed predominantly DBM would have impaired growth and compromised NDOs.
PATIENTS AND METHODS Patients and Practices In 2011, the Tufts Medical Center NICU (Boston, Massachusetts) began to offer DBM in infants whose birthweight was o1 kg and in all multiples if at least 1 sibling’s birthweight was o1 kg. Before that time, all infants received either MOM or PF, or a combination of the two. Once this DBM policy was initiated, parents were given the option of PF or DBM when MOM was unavailable or in low supply. DBM was provided only after parental consent was obtained. DBM and PF were used either as a sole enteral diet or, more commonly, as a supplement to MOM, as MOM was prioritized in each case as availability allowed. Regardless of feed type, enteral trophic feeds were initiated in all infants (whose clinical status allowed) by 3 days of life. Feeds were advanced as tolerated by 20 mL/kg/d until full feeds of 130 to 150 mL/kg/d were reached. Fortification was initiated at 100 mL/kg/d. DBM and MOM were fortified in the same way; a bovine-based fortifier was added to 24 kcal/oz, followed by protein supplementation, and, if needed, medium-chain triglycerides and hydrolyzed cornstarch were added to increase calories further to a maximum of 30 kcal/oz. PF was fortified using increasing concentrations of formula powder, as per formula instructions. In all infants, regardless of feed type, the need for fortification was determined using a
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L.S. Madore, et al. weekly analysis of growth curves with the guidance of the NICU nutritionist, with a goal growth rate of Z15 g/kg/d. All infants receiving DBM were transitioned to PF at 32 weeks’ postmenstrual age or earlier if there was persistent poor growth despite adequate fortification. DBM was purchased from the Mothers’ Milk Bank of New England (Newton, Massachusetts), which complies with the Human Milk Banking Association of North America’s published guideline on screening, collection, holder pasteurization, processing, and distribution.20 DBM use at the NICU was tracked using a DBM logbook, in which each patient’s name and medical record number, DBM batch numbers, and volumes administered were recorded. The protocol of this single-center, observational cohort study was approved by the institutional review board at Tufts Medical Center. Cohort assignment was based on each infant’s predominant feed type (DBM, MOM, or PF). The criterion for inclusion in the MOM group was the receipt of a diet of only MOM over the first month of life (no DBM or PF supplementation provided). The criterion for inclusion in the DBM and PF groups was the receipt of 450% of feeds as DBM or PF, respectively, over the first month of life. This reflects typical “supplemental” use in the NICU, as DBM and PF are now commonly utilized as a “bridge” until enough MOM is available. In all groups, exclusion criteria were any major congenital or cardiac malformation, and death prior to NICU discharge. Additionally, infants who received a minority (o50%) of feeds as DBM or PF over the first month of life were excluded because MOM was the dominant feed type in these cases. Based on these criteria, 27 infants qualified for inclusion in the DBM cohort, with birthdates between April 2011 and November 2012 (28 of 55 DBM-fed infants were excluded, 23 due to only a minority of DBM received, 3 due to death, and 1 due to congenital malformation). Two birthweight- and gestational age–matched comparison groups were identified using the admission logbook, evaluated for inclusion and exclusion criteria, and then further classified based on feed type as abstracted from the medical records. The first comparison cohort was fed only MOM (n ¼ 29; birthdate range, October 2010 to September 2012). The second comparison cohort was fed predominantly PF (n ¼ 25; birthdate ] 2017
range, April 2009 to October 2012). After the initiation of the DBM policy, most families opted for DBM; thus, birthdates in the PF comparison group spanned a longer time period. However, all other feeding practices remained consistent throughout this period.
Outcomes Growth Growth data were abstracted from medical records and converted to age-adjusted percentiles using the Fenton 2013 growth charts for preterm infants. Weight gain (in g/kg/d), the primary outcome, was calculated over the first 30 days and the first 60 days of life. Due to initial weight loss, weight gain was also calculated from the day on which an infant had regained birthweight until 30 and 60 days of life. Rates of growth (in cm/wk) of crown–heel length and head circumference, measured using the tape-measure technique, were calculated using the difference between admission and discharge measurements. At approximately 1 and 2 years’ corrected age (CA), children were evaluated in the Tufts Medical Center NICU Follow-Up Program. At each time point, infants’ weight, head circumference, and length were measured by trained providers. If an infant did not present for follow-up, then data on these growth parameters were obtained from the medical records of primary care or subspecialty visits. Measurements were converted to age-adjusted z-score equivalents using the 2000 growth charts from the Centers for Disease Control and Prevention.
Neurodevelopment For the NDO exploratory analysis, the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III) were administered in the Tufts Medical Center NICU Follow-up Program at both the 1- and 2-year CA visits. The Bayley III was administered by 1 of 4 trained clinicians who were blinded to infants’ NICU feed type. All follow-up visits were part of routine follow-up care at the institution. The resultant CA-adjusted composite scores in each domain of neurodevelopment (cognition, language, and motor skills) were abstracted from the medical records.
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Clinical Therapeutics
Covariates Illness Severity and Neonatal Morbidities The following markers of illness severity and morbidity were abstracted from the medical records and assessed as covariates: Apgar score, Critical Risk Index for Babies score, days intubated, preand postnatal exposure to corticosteroids, length of hospital stay, NEC (defined as Bell stage ZII), brain injury (defined as intraventricular hemorrhage grade ZIII and/or the presence of periventricular leukomalacia), bronchopulmonary dysplasia (BPD; defined as a persistent oxygen requirement or need for positive airway pressure at 36 weeks’ postmenstrual age), surgically treated retinopathy of prematurity, surgically treated patent ductus arteriosus, and culture-positive late-onset sepsis. Sociodemographic Information Clinical and sociodemographic data on each mother were collected from the medical records and by using a questionnaire administered at the 2-year follow-up visit or by phone call. Data collected were maternal age, race, marital status, level of education, type of medical insurance, reported household income, social work involvement, and frequency of reading to the child.
Statistical Analysis With a minimum of 25 infants per group and a type I error of 0.05, there was 80% power to detect a between-group difference in growth rate of 3.5 g/kg/d. Data analysis was conducted in 3 stages: 1. The associations between feed type and infant growth, as well as feed type and NDOs, were examined using 1-way ANOVA, with the least significant difference procedure for post hoc pairwise comparisons. 2. Covariates were screened as potential confounders of growth and NDOs based on between-group differences using ANOVA for continuously distributed variables, the Pearson χ2 test for independent variables, and the Fisher exact test for dichotomous variables, using a P value of o0.10. Model fitting was performed using both forward and backward variable selection for identifying the most parsimonious model. Using this methodology, 3 significant confounders of NDOs were identified: multiples, BPD, and social work involvement.
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3. All reported associations were reanalyzed after adjustment for these confounders using the 1-way analysis of covariance (ANCOVA), with Bonferroni correction for post hoc pairwise comparisons. A P value of r0.05 was used for indicating statistical significance. Only data available from each follow-up time point were analyzed, as reported in the tables. All statistical analysis was conducted using IBM SPSS Statistics software version 22.0 (IBM Corporation, Armonk, New York).
RESULTS Infants’ Characteristics In the entire cohort, the mean gestational age was 27.1 weeks and the mean birthweight was 914 g. As shown in Table I, the 3 feeding groups were similar with regard to clinical and sociodemographic characteristics, birth measurements, sex, corticosteroid exposure, and severity and rates of morbidities (NEC, BPD, and late-onset sepsis) were not significantly different among groups. There were fewer multiples in the PF group compared with the DBM and MOM groups (P ¼ 0.06). The DBM and PF groups had similar sociodemographic characteristics, and compared with the MOM group, both appeared to be more socially disadvantaged: They were more likely to have a single parent (P ¼ 0.01), have less maternal education (P ¼ 0.07), have a lower household income (P ¼ 0.04), receive public insurance (P ¼ 0.06), have social work involvement (P ¼ 0.04), and have less exposure to reading (P ¼ 0.05). The majority (74%) of infants in the DBM group received DBM due to an inadequate supply of MOM. At discharge or transfer, 62% of infants in the MOM group continued to receive exclusive MOM feedings, while the remainder of infants had been transitioned to PF either as a supplement to MOM or as the sole feed type.
Growth
As seen in Table II, growth in the first 30 days was analyzed in 2 ways. First, total weight gain between birth and day of life 30 (which included weight lost in the first weeks of life) was measured. DBM-fed infants had a slower rate of weight gain in the first 30 days compared with infants fed MOM or PF (mean [SD],
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Table I. Neonatal clinical and socioeconomic characteristics. Characteristic Neonatal baseline characteristics Gestational age at birth, mean (SD), wk Birthweight, mean (SD), g Birthweight, mean (SD), % Small for gestational age, no. (%) Birth length, mean (SD), % Birth head circumference, mean (SD), % Apgar at 1 min after birth, mean (SD) Apgar at 5 min after birth, mean (SD) Critical Risk Index for Babies, mean (SD) Male sex, no. (%) Multiple gestation, no. (%) Outborn delivery, no. (%) Antenatal corticosteroid exposure, no. (%) Birth date, mo/y, range Infant acquired clinical characteristics Indomethacin exposure, no. (%) Bronchopulmonary dysplasia, no. (%) Late-onset sepsis, no. (%) Postnatal corticosteroid exposure, no. (%) Brain injury, no. (%) Necrotizing enterocolitis, no. (%) Retinopathy of prematurity, no. (%) Patent ductus arteriosus, no. (%) Length of hospital stay, mean (SD), d Family socioeconomic characteristics Maternal age, mean (SD), y Nonwhite race, no. (%) Single parent, no. (%) College educated, n/N (%) Household income 4$60K, n/N (%) Public insurance, no. (%) Social work involvement, no. (%) Daily reading exposure, n/N (%) *
Mother’s Own Milk (n ¼ 29)
Preterm Formula (n ¼ 25)
Donor Breast Milk (n ¼ 27)
27.0 (1.5) 936.6 (211.0) 48.4 (22.7) 2 (6.9) 45.3 (27.6) 49.2 (24.0) 4.5 (2.4) 6.7 (2.0) 2.7 (3.0) 18 (62.1) 14 (48.3) 2 (6.9) 23 (79.3) 10/2010–9/2012
27.3 (2.1) 913.8 (222.6) 42.0 (25.1) 4 (16.0) 38.7 (27.3) 38.0 (25.2) 4.8 (2.3) 6.8 (1.8) 3.5 (3.1) 14 (56.0) 5 (20.0) 1 (4.0) 22 (88.0) 4/2009–10/2012
27.1 (1.9) 890.5 (175.8) 40.5 (19.1) 2 (7.4) 35.9 (29.4) 36.9 (24.1) 4.4 (2.4) 6.9 (1.6) 3.5 (3.0) 18 (66.7) 13 (48.1) 6 (22.2) 21 (77.8) 4/2011–11/2012
12 11 2 2 2 2 2 1 81.3
(41.4) (37.9) (6.9) (6.9) (6.9) (6.9) (6.9) (3.4) (37.4)
8 (32.0) 14 (56.0) 4 (16.0) 4 (16.0) 3 (12.0) 2 (8.0) 0 2 (8.0) 86.5 (46.6)
29.9 16 6 19/26 14/26 11 2 18/26
(4.6) (55.2) (20.7) (73.1) (53.8) (37.9) (6.9) (69.2)
28.2 13 12 7/18 4/16 17 7 9/22
(7.1) (52.0) (48.0) (38.9) (25.0) (68.0) (28.0) (40.9)
P* 0.85 0.70 0.38 0.46 0.44 0.12 0.80 0.92 0.56 0.73 0.06 0.11 0.59
11 12 3 1 3 1 3 2 65.3
(40.7) (44.4) (11.1) (3.7) (11.1) (3.7) (11.1) (7.4) (35.5)
0.74 0.41 0.55 0.28 0.81 0.86 0.31 0.73 0.14
31.8 17 16 12/22 6/18 17 9 8/22
(5.7) (63.0) (59.3) (54.5) (33.3) (63.0) (33.3) (36.4)
0.09 0.71 0.01 0.07 0.04 0.06 0.04 0.05
P based on 1-way ANOVA for continuous variables and χ2 or Fisher exact test for categorical variables.
9.7 [3.6], 12.6 [3.7], and 12.3 [3.9] g/kg/d, respectively; P ¼ 0.01). These results remained unchanged after adjustment for early neonatal clinical covariates. Second, weight gain from the day on which birthweight was regained to day of life 30 was analyzed.
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While there was no difference in days to regained birthweight among groups, the DBM group demonstrated a slower rate of weight gain compared with those in the MOM and PF groups (mean [SD], 17.9 [5.7], 22 [6.8], and 20.3 [5.7] g/kg/d; P ¼ 0.05).
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Clinical Therapeutics
Table II. Associations between feed type and growth outcomes at 1 and 2 years. Growth Outcome† Neonatal Weight gain, g/kg/d Birth to day of life 30 Regain birthweight to day of life 30 Birth to day of life 60 Regain birthweight to day of life 60 Time to regain birthweight, d Growth, cm/wk Head circumference Longitudinal Feeds Time to reach feeds of 100 mL/kg/d, d Maximum enteral calories received, kcal/oz 1-y corrected age, z score Weight Length Weight for length Head circumference 2-y corrected age, z score Weight Length Weight for length Head circumference * †
Mother’s Own Milk Preterm Formula Donor Breast Milk n ¼ 29 12.6 22.0 19.7 24.9 12.2
12.3 20.3 18.9 23.5 11.6
(3.9) (5.7) (5.0) (5.9) (3.5)
n ¼ 27 9.7 17.9 18.4 23.8 13.6
(3.6) (5.7) (3.6) (4.4) (3.9)
0.01 0.05 0.54 0.55 0.20
0.7 (0.2) 1.0 (0.3)
0.7 (0.2) 0.9 (0.3)
0.7 (0.3) 1.0 (0.4)
0.78 0.47
14.0 (6.2) 27.9 (2.0)
17.5 (7.4) 27.7 (1.9)
16.3 (7.3) 27.4 (1.9)
0.17 0.71
n ¼ 21 –0.8 (1.2) –0.3 (1.4) –0.2 (1.3) 0.02 (1.1) n ¼ 20 –0.5 (1.3) –0.05 (1.3) –0.3 (1.3) 0.2 (1.1)
n ¼ 16 –1.4 (1.2) –0.8 (1.1) –0.6 (1.4) –0.1 (1.0) n ¼ 15 –0.7 (1.2) –0.6 (1.2) –0.2 (1.8) 0.3 (1.1)
n ¼ 22 –1.3 (1.5) –0.6 (1.4) –0.8 (1.6) –0.6 (1.6) n ¼ 19 –0.9 (1.6) –0.1 (1.2) –0.9 (1.8) –0.5 (1.4)
0.32 0.51 0.39 0.29 0.67 0.38 0.39 0.13
P based on 1-way ANOVA. Data are given as mean (SD).
Although infants fed DBM had slower weight gain in the first 30 days, this difference did not persist to 60 days of life. There was no difference in weight gain between groups from birth to day 60 or from days 30 to 60. There was no difference in length or head circumference growth during the NICU stay. Additionally, there were no differences among the 3 groups in time to reach feeds of 100 mL/kg/d (P ¼ 0.17) (suggesting that rate of feeding advancement was not the cause of early growth failure in the DBM group) or in maximum enteral calories received (P ¼ 0.71) (suggesting that higher caloric fortification was not the reason for similar growth in all 3 groups by 60 days of life). At both 1 and 2 years’ CA, there were no differences in z scores on weight, length, head circumference, or weight/length among groups.
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(3.7) (6.8) (4.5) (4.7) (4.7)
n ¼ 25
P*
Neurodevelopment At 1 year, the DBM group scored lower than did the MOM and PF groups in all domains of NDO assessment using Bayley III scores in an unadjusted analysis (Table III). After adjustment for significant confounders (multiple births, BPD, and social work involvement), the DBM group continued to score lower than did the PF-fed infants at 1 year in the domains of cognition and language, while the difference in motor skills was attenuated (mean [SD] scores: cognition: MOM, 93.0 [9.6]; PF, 97.1 [11.8]; and DBM, 83.1 [11.6] [DBM vs PF, P ¼ 0.002; DBM vs MOM, P ¼ 0.064]; language: MOM, 86.1 [14.7]; PF, 91.1 [17.5]; and DBM, 74.1 [8.8] [DBM vs PF, P ¼ 0.025; DBM vs MOM, P ¼ 0.095]). At 2 years, the DBM group continued to score significantly lower
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L.S. Madore, et al.
Table III. Associations between feed type and neurodevelopmental outcomes at 1 and 2 years. Bayley III score, mean (SD) 1-y corrected age Cognition Language Motor 2-y corrected age Cognition Language Motor
Mother’s Own Milk
Preterm Formula
DBM
n ¼ 15 93.0 (9.6) 86.1 (14.7) 91.1 (9.9) n ¼ 18 93.9 (12.2) 91.9 (17.6) 89.0 (13.4)
n ¼ 13 97.1 (11.8) 91.1 (17.5) 93.1 (7.8) n ¼ 13 94.7 (15.1) 88.7 (17.3) 92.4 (15.4)
n ¼ 18 83.1 (11.6) 74.1 (8.8) 82.4 (16.5) n ¼ 16 83.1 (13.9) 79.3 (9.2) 80.5 (12.5)
P*
P†
0.003‡,§ 0.02‡,§ 0.05
0.005§ 0.04§ 0.09
0.04‡,§ 0.06 0.06
0.03§ 0.09 0.16
*
P based on 1-way ANOVA. P based on 1-way ANCOVA adjusted for multiples, bronchopulmonary dysplasia, and social work involvement. ‡ Post hoc pairwise comparisons of donor breastmilk vs mother’s own milk; P o 0.05. § Post hoc pairwise comparisons of donor breastmilk vs preterm formula; P o 0.05. †
in cognition (MOM, 93.9 [12.2]; PF, 94.7 [15.1]; and DBM, 83.1 [13.9] [DBM vs PF, P ¼ 0.014; DBM vs MOM, P ¼ 0.056]), but there were no significant differences in language or motor scores among groups in the fully adjusted models. Interestingly, adjustment of NDO scores for growth over the first 30 days did not attenuate the effects of DBM feeding on Bayley III scores.
Feed type was not associated with death after discharge, age at follow-up, the percentage of males presenting to clinic, or the percentage lost to follow-up (Table IV). The overall follow-up rate at 1 year was 58% and at 2 years was 59%. There were no significant differences between those who presented for follow-up and those who were lost to follow-up in terms of clinical and sociodemographic characteristics at 1 year of age,
Table IV. Characteristics of infants who presented to the neonatal intensive care unit follow-up program. Measure
Mother’s Own Milk (n ¼ 29)
Preterm Formula (n ¼ 25)
Death after discharge,† no. (%) 1-y follow-up, no. (%) Corrected age, mean (SD), mo Gestational age at birth, mean (SD), wk Birthweight, mean (SD), g Male, n/N (%) 2-y follow-up, no. (%) Corrected age, mean (SD), mo Gestational age at birth, mean (SD), wk Birthweight, mean (SD), g Male, n/N (%) Lost to all follow-up, no. (%)
0 15 (51.7) 12.6 (1.9) 26.9 (1.2) 950.6 (159.5) 9/15 (60.0) 18 (62.1) 24.9 (4.5) 27.1 (1.2) 939.2 (178.3) 10/18 (55.6) 10 (34.5)
0 13 (52.0) 13.9 (3.3) 27.4 (1.8) 964.2 (253.1) 8/13 (61.5) 13 (52.0) 23.8 (4.0) 27.2 (2.2) 979.9 (177.4) 8/13 (61.5) 11 (44.0)
* †
DBM (n ¼ 27) 1 18/26 12.9 27.2 921.8 12/18 16/26 23.2 27.4 961.7 11/16 5/26
(3.7) (69.2) (1.4) (1.7) (200.8) (66.7) (61.5) (4.7) (2.0) (257.3) (68.8) (19.2)
P* 0.36 0.34 0.29 0.69 0.84 0.92 0.68 0.50 0.85 0.84 0.73 0.16
P based on 1-way ANOVA for continuous variables and χ2 or Fisher exact test for categorical variables. One death after discharge in the donor breastmilk group due to sudden infant death syndrome.
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Clinical Therapeutics but at 2 years those lost to follow-up had lower birthweight, birth length percentile, birth head circumference, and 1-minute Apgar score, and a higher rate of sepsis compared with those who presented for follow-up.
DISCUSSION At the Tufts Medical Center NICU, a predominantly DBM diet in preterm infants was associated with compromised early in-hospital weight gain, and cognitive delays at both 1 and 2 years. To our knowledge, this is the first study to investigate both growth and NDOs in preterm infants fed 3 differing diets: MOM only, majority DBM, and majority PF. These results suggest that a predominantly DBM diet per the clinical policies at this NICU may not be an adequate replacement for MOM. As more NICUs utilize DBM, the findings from this study reinforce the need for more research to optimize the practices around how to best utilize DBM. This is the first study to analyze growth in DBMfed infants at such an early time point (30 days of life). Most study designs analyzing growth use the difference between admission and discharge weights, which may miss subtle in-hospital growth discrepancies and therefore miss opportunities to identify early windows for nutritional optimization. In this cohort, DBM-fed infants were more likely to experience poor growth in the first 30 days of life. This difference in growth between feed groups did not persist beyond the first month, likely because of the DBM-fed infants’ being switched to PF (either due to growth failure despite maximal caloric fortification or per protocol at 32 weeks’ postmenstrual age), and less likely because of increased fortification as there was no difference between groups in maximum enteral calories received. Additionally, there were no growth differences at 1 or 2 years’ CA, which is similar to findings from other studies that continued to follow growth after discharge.11,12 Prior studies have had differing results regarding whether DBM feeding is associated with in-hospital growth impairment. These differences may have been due to differing nutritional practices that have evolved in NICUs worldwide. For example, the recent “DoMINO” trial by O’Connor et al11 did not find a difference in growth, but unlike Tufts Medical Center, fortified the DBM with additional protein before the first DBM feeding. Another difference is that we included only infants who
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received DBM as 450% of their feed volumes. Most other studies, including the 2 recent trials10,11, have compared a smaller amount of DBM with formula, which may have affected outcomes, as the benefits of breastmilk are likely volume dependent.21 Thus, it is important to understand how variation in DBM feeding practices may be associated with different outcomes. These differences in study findings should be interpreted in the context of these methods and practices, as this will provide evidence for urgently needed best practices with regard to DBM supplementation. The early compromised growth in DBM-fed infants that we and others have found may also be attributable to the altered nutritional composition of DBM, which is pooled and pasteurized. While the high heat of pasteurization enhances the tolerability of the milk by eliminating infectious contaminants, it also inactivates many important bioactive factors in the milk.22,23 Studies have shown significant decreases in fat, protein, and vitamins after routine DBM processing.23–25 Additionally, DBM is primarily term milk, which does not meet the nutritional needs of preterm infants. Compared with preterm milk, term milk is lower in protein, energy, and fat, which are all crucial to preterm growth and brain growth.25,26 Over the duration of lactation, the protein concentration in the breastmilk decreases, and most DBM is from mothers who have been lactating for many months, which augments the protein deficit found in DBM samples.26,27 Improved DBM processing through novel methods, such as ultrapasteurization or nonthermal methods, may be a strategy for improving DBM composition in preterm infants. General protein supplementation, as was done in the DoMINO trial, or individualized macronutrient supplementation using the emerging technology of human milk analyzers, may be another way of enhancing the nutritional composition of DBM.28 Lastly, developing a supply of “preterm” DBM for preterm infants may be another strategy for matching the nutritional needs of preterm infants. We found that among infants followed up with neurodevelopmental testing, DBM supplementation was associated with lower cognitive scores in a fully adjusted analysis. Additionally, in a post hoc exploratory analysis of data from the DoMINO trial11, infants supplemented with DBM were more likely to have cognitive neuroimpairment (cognitive composite
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L.S. Madore, et al. score of o85) compared with the PF group despite early aggressive protein supplementation of DBM and a lower percentage of DBM exposure (adjusted risk difference, 10.6%; P ¼ 0.02). These same infants will be followed up until age 5.5 years. An ongoing largescale, multicenter, randomized trial (National Institute of Child Health and Human Development’s Milk Trial) is evaluating the impact of DBM on later outcomes.29 Given that growth and neurodevelopment are strongly linked, it is possible that the lower NDO scores in the DBM group as seen in the exploratory analysis of the present study were a result of the compromised early growth found at the day-30 time point. However, DBM feeding remained associated with lower cognitive scores even after adjustment for growth in the first 30 days of life. This finding suggests that the association between DBM feeding and poor NDOs may be mediated by additional factors beyond poor early growth. It is plausible that DBM may not provide adequate neuroprotective factors for the developing preterm brain. In the last trimester of pregnancy and in the first 2 years of life, there is rapid myelination of the brain. Fatty acids, particularly long-chain polyunsaturated fatty acids, are the “building blocks” of this process and are obtained solely from breastmilk in the neonatal period. In comparison to MOM, DBM has a lower fat content, specifically, lower concentrations of the long-chain polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid.30–32 Additionally, infants fed DBM have impaired fat absorption,13,24 likely due to pasteurization-induced inactivation of bile salt–stimulated lipase, which is involved in fat digestion and absorption.32–34 Antioxidants, such as glutathione, as well as total antioxidant capacity are also significantly reduced in pasteurized milk,35 which is concerning given that the preterm brain is particularly susceptible to oxidative damage.36 There is emerging evidence that oligosaccharides in human milk provide sialic acid, a potentially essential nutrient for brain development and cognition; sialic acid is altered in pasteurized DBM samples compared with MOM samples.37,38 Lastly, the gut microbiome has recently emerged as an important immune mediator that may play a role in early brain development and function.39 The relative sterility and reduced anti-infective properties of DBM may play a role in the compromised NDOs we report. Future research should focus
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on identifying and potentially supplementing neuroprotective, nutritional, and immunomodulatory factors that may be diminished in DBM. Our study had limitations. This study was observational, which allows for measured and unmeasured confounders that may influence findings. This study was adequately powered to detect differences in the primary outcome (growth), but was not powered for our exploratory outcome of NDOs. Additionally, only 69% of study participants had data available from at least 1 follow-up visit during the study period. While this follow-up rate is similar to the general follow-up rate at this urban center, this could introduce bias. Mothers who provided their own milk tended to have more to education, higher household incomes, and less social work involvement, which can all independently and positively influence NDOs. However, we were able to provide the PF-fed cohort for comparison, which, despite having sociodemographic characteristics notably similar to those of the DBM cohort, did not have impaired growth or NDOs. This finding further supports the finding that DBM feeding was linked to poor early growth and long-term NDOs. The DBM and PF feed types in the present study were not exclusive, but constituted a majority of feeding volume, which reflects typical “supplemental” use as provided in some US NICUs and strengthens the generalizability of the findings from this study. Lastly, the delays in NDOs as identified by Bayley III scores at 2 years of age correlate inconsistently with later outcomes40; thus, the prediction of long-term functioning continues to be difficult.
CONCLUSIONS In the present single-center, observational study, supplementing preterm infants with predominantly DBM was associated with compromised early growth and, in an exploratory analysis, lower cognitive scores at 1 and 2 years of age compared with those fed only MOM or supplemented with PF. These results serve to provide evidence regarding the impact of different nutritional strategies on infant growth and development, and further highlight a key knowledge gap regarding the optimization of DBM use in preterm infants. Our findings also underscore the need for supporting maternal breastfeeding efforts to exclusively provide MOM to the most vulnerable infants.
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ACKNOWLEDGMENTS This work was supported by a small internal grant from the Natalie V. Zucker Research Center for Women Scholars at Tufts University School of Medicine. The funding source had no involvement in project design, interpretation, or submission of the manuscript. Thank you to Hannah Prange and Emily Farrell for their assistance with data collection. All of the authors approved the final article as submitted.
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CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article.
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REFERENCES 1. American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012;129:827–841. 2. Hack M. Young adult outcomes of very-low-birth-weight children. Semin Fetal Neonatal Med. 2006;11:127–137. 3. Lucas A, Morley R, Cole TJ, et al. Breast milk and subsequent intelligence quotient in children born preterm. Lancet. 1992;339:261–264. 4. Vohr BR, Poindexter BB, Dusick AM, et al. Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics. 2007;120:953–959. 5. 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;156:562–567. 6. Jones F. History of North American donor milk banking: one hundred years of progress. J Hum Lact. 2003;19:313–318. 7. Kim JH, Unger S. Human milk banking. Paediatr Child Health. 2010;15:595–598. 8. Hagadorn JI, Brownell EA, Lussier MM, et al. Variability of criteria for pasteurized donor human milk use: a survey of US neonatal intensive care unit medical directors. JPEN J Parenter Enteral Nutr. 2016;40:326–333. 9. Arslanoglu S, Corpeleijn W, Moro G, et al, European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr. 2013;57:535–542. 10. Corpeleijn WE, de Waard M, Christmann V, et al. Effect of donor milk on severe infections and mortality in very low-
10
16.
17.
18.
19.
20.
21.
22.
23.
24.
birth-weight infants: the early nutrition study randomized clinical trial. JAMA Pediatr. 2016;170:654–661. O’Connor DL, Gibbins S, Kiss A, et al, Greater Toronto Area DoMINO Feeding Group. Effect of supplemental donor human milk compared with preterm formula on neurodevelopment of very low-birth-weight infants at 18 months: a randomized clinical trial. JAMA. 2016;316:1897–1905. Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2014;4:1–92. Andersson Y, Savman K, Blackberg L, Hernell O. Pasteurization of mother’s own milk reduces fat absorption and growth in preterm infants. Acta Paediatr. 2007;96:1445–1449. Montjaux-Régis N, Cristini C, Arnaud C, et al. Improved growth of preterm infants receiving mother’s own raw milk compared with pasteurized donor milk. Acta Paediatr. 2011;100:1548–1554. 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. 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. 2016. [Epub ahead of print]. Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117:1253–1261. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics. 2009;123:1337–1343. Chan SH, Johnson MJ, Leaf AA, Vollmer B. Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review. Acta Paediatr. 2016;105:587–599. Guidelines for the Establishment and Operation of a Donor Human Milk Bank. Fort Worth, TX: Human Milk Banking Association of North America; 2013. Lechner BE, Vohr BR. Neurodevelopmental outcomes of preterm infants fed human milk: a systematic review. Clin Perinatol. 2017;44:69–83. Ewaschuk JB, Unger S, O’Connor DL, et al. Effect of pasteurization on selected immune components of donated human breast milk. J Perinatol. 2011;31:593–598. Lawrence RA. Milk banking: The influence of storage procedures and subsequent processing on immunologic components of human milk. Adv Nutr Res. 2001;10:389– 404. Vieira AA, Soares FV, Pimenta HP, et al. Analysis of the influence of pasteurization, freezing/thawing, and offer processes on human milk’s macronutrient concentrations. Early Hum Dev. 2011;87:577–580.
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L.S. Madore, et al. 25. Wojcik KY, Rechtman DJ, Lee ML, et al. Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc. 2009;109:137–140. 26. Radmacher PG, Lewis SL, Adamkin DH. Individualizing fortification of human milk using real time human milk analysis. J Neonatal Perinatal Med. 2013;6:319–323. 27. Bauer J, Gerss J. Longitudinal analysis of macronutrients and minerals in human milk produced by mothers of preterm infants. Clin Nutr. 2011;30:215–220. 28. de Halleux V, Rigo J. Variability in human milk composition: benefit of individualized fortification in verylow-birth-weight infants. Am J Clin Nutr. 2013;98:529–535. 29. National Institute of Child Health and Human Development, Neonatal Research Network. Donor milk vs. formula in extremely low birth weight (ELBW) infants. Available at: https://clinicaltrials.gov/ct2/ show/NCT01534481?term=donorþ milk&rank=3. Accessed 03/15/2017. 30. Valentine CJ, Morrow G, Fernandez S, et al. Docosahexaenoic acid and amino acid contents in pasteurized donor milk are low for preterm infants. J Pediatr. 2010;157:906–910. 31. Baack ML, Norris AW, Yao J, Colaizy T. Long-chain polyunsaturated fatty acid levels in US donor human milk: meeting the needs of premature infants? J Perinatol. 2012;32:598–603. 32. Henderson TR, Fay TN, Hamosh M. Effect of pasteurization on longchain polyunsaturated fatty acid levels and enzyme activities of human milk. J Pediatr. 1998;132:876–878. 33. Wardell JM, Wright AJ, Bardsley WG, D’Souza SW. Bile salt-stimulated lipase and esterase activity in human milk after collection, storage, and heating: nutritional implications. Pediatr Res. 1984;18:382–386. 34. Hernell O. Human milk lipases III. Physiological implications of the bile salt stimulated lipase. Eur J Clin Invest. 1975;5:267–272. 35. Silvestre D, Miranda M, Muriach M, et al. Antioxidant capacity of human
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milk: effect of thermal conditions for the pasteurization. Acta Paediatr. 2008;97:1070–1074. 36. Shim SY, Kim HS. Oxidative stress and the antioxidant enzyme system in the developing brain. Korean J Pediatr. 2013;56:107–111. 37. Wang B. Sialic acid is an essential nutrient for brain development and cognition. Annu Rev Nutr. 2009;29: 177–222. 38. Marx C, Bridge R, Wolf AK, et al. Human milk oligosaccharide composition differs between donor
milk and mother’s own milk in the NICU. J Hum Lact. 2014;30: 54–61. 39. Keunen K, van Elburg RM, van Bel F, Benders MJ. Impact of nutrition on brain development and its neuroprotective implications following preterm birth. Pediatr Res. 2015;77: 148–155. 40. Spencer-Smith MM, Spittle AJ, Lee KJ, et al. Bayley-III cognitive and language scales in preterm children. Pediatrics. 2015;135: 1258–1265.
Address correspondence to: Laura S. Madore, MD, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199. E-mail: Laura. [email protected]
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