Background DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific. Results For each of 10 donors from the NIH Genotype-Tissue Expression (GTEx) program, CpG methylation is measured by deep whole-genome bisulfite sequencing of genomic DNA from tissues representing the three germ layer lineages: thyroid (endoderm), heart (mesoderm), and brain (ectoderm). We develop a computational algorithm to identify genomic regions at which interindividual variation in DNA methylation is consistent across all three lineages. This approach identifies 9926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, are inter-correlated over long genomic distances, associated with transposable elements and subtelomeric regions, conserved across diverse human ethnic groups, sensitive to periconceptional environment, and associated with genes implicated in a broad range of human disorders and phenotypes. CoRSIV methylation in one tissue can predict expression of associated genes in other tissues. Conclusions In addition to charting a previously unexplored molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease. Electronic supplementary material The online version of this article (10.1186/s13059-019-1708-1) contains supplementary material, which is available to authorized users.

Objective: The aim of this study was to compare outcomes of infants pre and post initiation of a feeding protocol providing an exclusive human milk–based diet (HUM).Materials and Methods: In a multicenter retrospective cohort study, infants with a birth weight <1,250 g who received a bovine-based diet (BOV) of mother's own milk fortified with bovine fortifier and/or preterm formula were compared to infants who received a newly introduced HUM feeding protocol. Infants were excluded if they had major congenital anomalies or died in the first 12 hours of life. Data were collected 2–3 years prior to and after introduction of an exclusive HUM diet. Primary outcomes were necrotizing enterocolitis (NEC) and mortality. Secondary outcomes included late-onset sepsis, retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD).Results: A total of 1,587 infants were included from four centers in Texas, Illinois, Florida, and California. There were no differences in baseline demographics or growth of infants. The HUM group had significantly lower incidence of proven NEC (16.7% versus 6.9%, p < 0.00001), mortality (17.2% versus 13.6%, p = 0.04), late-onset sepsis (30.3% versus 19.0%, p < 0.00001), ROP (9% versus 5.2%, p = 0.003), and BPD (56.3% versus 47.7%, p = 0.0015) compared with the BOV group.Conclusions: Extremely premature infants who received an exclusive HUM diet had a significantly lower incidence of NEC and mortality. The HUM group also had a reduction in late-onset sepsis, BPD, and ROP. This multicenter study further emphasizes the many benefits of an exclusive HUM diet, and demonstrates multiple improved outcomes after implementation of such a feeding protocol.

Background Mother's own milk (MOM) is protective against gut microbiota alterations associated with necrotizing enterocolitis (NEC) and feeding intolerance among preterm infants. It is unclear whether this benefit is preserved with donor milk (DM) feeding. Objective We aimed to compare microbiota development, growth, and feeding tolerance in very-low-birth-weight (VLBW) infants fed an exclusively human milk diet of primarily MOM or DM. Methods One hundred and twenty-five VLBW infants born at Texas Children's Hospital were enrolled and grouped into cohorts based on percentage of MOM and DM in enteral feeds. Feeds were fortified with DM-derived fortifier per unit protocol. Weekly stool samples were collected for 6 wk for microbiota analysis [16S ribosomal RNA (rRNA) sequencing]. A research nurse obtained weekly anthropometrics. Clinical outcomes were compared via Wilcoxon's rank-sum test and Fisher's exact test, as well as multivariate analysis. Results The DM cohort (n = 43) received on average 14% mothers’ milk compared with 91% for the MOM cohort (n = 74). Diversity of gut microbiota across all time points (n = 546) combined was increased in MOM infants (P < 0.001). By 4 and 6 wk of life, microbiota in MOM infants contained increased abundance of Bifidobacterium (P = 0.02) and Bacteroides (P = 0.04), whereas DM-fed infants had increased abundance of Staphylococcus (P = 0.02). MOM-fed infants experienced a 60% reduction in feeding intolerance (P = 0.03 by multivariate analysis) compared with DM-fed infants. MOM-fed infants had greater weight gain than DM-fed infants. Conclusions Compared with DM-fed infants, MOM-fed infants have increased gut microbial community diversity at the phylum and genus levels by 4 and 6 wk of life, as well as better feeding tolerance. MOM-fed infants had superior growth. The incidence of NEC and other gastrointestinal morbidity is low among VLBW infants fed an exclusively human milk diet including DM-derived fortifier. This trial was registered at clinicaltrials.gov as NCT02573779.

BackgroundDespite current nutritional strategies, premature infants remain at high risk for extrauterine growth restriction. The use of an exclusive human milk-based diet is associated with decreased incidence of necrotizing enterocolitis (NEC), but concerns exist about infants achieving adequate growth. The objective of this study was to evaluate growth velocities and incidence of extrauterine growth restriction in infants ≤ 1250 grams (g) birth weight (BW) receiving an exclusive human milk-based diet with early and rapid advancement of fortification using a donor human milk derived fortifier.MethodsIn a single center, prospective observational cohort study, preterm infants weighing ≤ 1250 g BW were fed an exclusive human milk-based diet until 34 weeks postmenstrual age. Human milk fortification with donor human milk derived fortifier was started at 60 mL/kg/d and advanced to provide 6 to 8 additional kilocalories per ounce (or 0.21 to 0.28 kilocalories per gram). Data for growth were compared to historical growth standards and previous human milk-fed cohorts.ResultsWe consecutively evaluated 104 infants with mean gestational age of 27.6 ± 2.0 weeks and BW of 913 ± 181 g (mean ± standard deviation). Weight gain was 24.8 ± 5.4 g/kg/day with length 0.99 ± 0.23 cm/week and head circumference 0.72 ± 0.14 cm/week. There were 3 medical NEC cases and 1 surgical NEC case. 22 infants (21%) were small for gestational age at birth. Overall, 45 infants (43%) had extrauterine growth restriction. Weight velocity was affected by day of fortification (p = 0.005) and day of full feeds (p = 0.02). Our cohort had significantly greater growth in weight and length compared to previous entirely human milk-fed cohorts.ConclusionsA feeding protocol for infants ≤ 1250 g BW providing an exclusive human milk-based diet with early and rapid advancement of fortification leads to growth meeting targeted standards with a low rate of extrauterine growth restriction. Consistent nutritional policies using this approach may be considered for this population.

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Premature infants who received HM-derived cream to fortified HM had improved weight and length velocity compared with the control group. HM-derived cream should be considered an adjunctive supplement to an exclusive HM-based diet to improve growth rates in premature infants.

Objectives: To evaluate the association of preoperative risk factors and postoperative outcomes in infants with complex congenital heart disease. Design: Single-center retrospective cohort study. Setting: Neonatal ICU and cardiovascular ICU. Patients: Infants of all gestational ages, born at Texas Children’s Hospital between 2010 and 2016, with complex congenital heart disease requiring intervention prior to discharge. Interventions: None. Measurements and Main Results: A total of 399 patients were enrolled in the study. Preoperative risk factors included feeding, type of feeding, feeding route, and cardiac lesion. Postoperative outcomes included necrotizing enterocolitis, hospital length of stay, and days to full feeds. The occurrence rate of postoperative necrotizing enterocolitis (all stages) was 8%. Preoperative feeding, type of feeding, feeding route, and cardiac lesion were not associated with higher odds of postoperative necrotizing enterocolitis. Cardiac lesions with ductal-dependent systemic blood flow were associated with a hospital length of stay of 19.6 days longer than those with ductal-dependent pulmonary blood flow (p < 0.001) and 2.9 days longer to reach full feeds than those with ductal-dependent pulmonary blood flow (p < 0.001), after controlling for prematurity. Nasogastric feeding route preoperatively was associated with a length of stay of 29.8 days longer than those fed by mouth (p < 0.001) and 2.4 days longer to achieve full feeds (p < 0.001), after controlling for prematurity and cardiac lesion. Preoperative diet itself was not associated with significant change in length of stay or days to reach full feeds. Conclusions: Although cardiac lesions with ductal-dependent systemic blood flow are considered high risk and may increase length of stay and days to achieve full feeds, they are not associated with a higher risk of postoperative necrotizing enterocolitis. Nasogastric route is not associated with a significantly higher risk of necrotizing enterocolitis, but longer length of stay and days to reach full feeds. These findings challenge our perioperative management strategies in caring for these infants, as they may incur more hospital costs and resources without significant medical benefit.

ObjectiveTo compare postdischarge growth, adiposity and metabolic outcomes of appropriate for gestational age (AGA) versus small for gestational age (SGA) premature infants fed an exclusive human milk (HM)-based diet in the neonatal intensive care unit.DesignPremature infants (birth weight ≤1250 g) fed an exclusive HM-based diet were examined at 12–15 months corrected gestational age (CGA) (visit 1) for anthropometrics, serum glucose and non-fasting insulin, and at 18–22 months CGA (visit 2) for body composition by dual-energy X-ray absorptiometry.ResultsOf 51 children, 33 were AGA and 18 were SGA at birth. The SGA group had weight gain (g/day) equal to AGA group during the follow-up period. SGA had a significantly greater body mass index (BMI) z-score gain from visit 1 to visit 2 (0.25±1.10 vs −0.21±0.84, p=0.02) reflecting catch-up growth. There were no significant differences in total fat mass (FM) and trunk FM between groups. SGA had significantly lower insulin level (5.0±3.7 vs 17.3±15.1 µU/mL, p=0.02) and homeostatic model of assessment-insulin resistance (1.1±0.9 vs 4.3±4.1, p=0.02). Although regional trunk FM correlated with insulin levels in SGA (r=0.893, p=0.04), they had lower insulin level compared with AGA and no difference in adiposity.ConclusionsSGA premature infants who received an exclusive HM-based diet exhibited greater catch-up growth without increased adiposity or elevated insulin resistance compared with AGA at 2 years of age. An exclusive HM-based diet may improve long-term body composition and metabolic outcomes of premature infants with ≤1250 g birth weight, specifically SGA.