Early-life nutrition is associated with processing speed at age 5 in children born preterm with very low birth weight.

OBJECTIVE: Processing speed is suboptimal among preterm-born children which is of concern as it is a foundational skill supporting higher-level cognitive functions. The study objective was to evaluate associations between early-life nutrition and processing speed in childhood. METHODS: Macronutrient and human milk (mother's own, donor) intakes from 137 children born preterm with very low birth weight enrolled in a nutrition feeding trial were included. Processing speed was evaluated at age 5 using the Wechsler Preschool and Primary Scale of Intelligence-fourth edition Processing Speed Index. Associations between early-life nutrition and processing speed were explored through linear regression. RESULTS: Children had a mean (standard deviation [SD]) birth gestational age of 28.1 (2.5) weeks, weight of 1036 (260) g and 52% were male. The mean (SD) assessment age was 5.7 (0.2) years. Sex-dependent relationships were identified between first postnatal month protein, lipid and energy intakes and processing speed at 5 years. For females, lower protein (per 0.1 g/kg/d: -0.88, 95% confidence interval [CI]: -1.53, -0.23; p = 0.01) and energy (per 10 kcal/kg/d: -2.38, 95% CI: -4.70, -0.05; p = 0.03) intakes were related to higher processing speed scores. Mother's milk provision was positively associated (per 10% increase: 0.80, 95% CI: 0.22, 1.37; p = 0.01) and donor milk was negatively associated (per 10% increase: -1.15, 95% CI: -2.22, -0.08; p = 0.04) with processing speed scores; no sex differences were observed. CONCLUSIONS: First postnatal month nutrition was related to processing speed at age 5 in children born preterm with very low birth weight. Early-life nutrition that supports processing speed may be leveraged to improve later cognitive outcomes for this vulnerable population.

Association of Postnatal Growth Changes and Neurodevelopmental Outcomes in Preterm Neonates of <29 Weeks' Gestation.

OBJECTIVE: To examine associations between weight and head circumference (HC) changes and neurodevelopment in preterm infants. STUDY DESIGN: This retrospective cohort study of Canadian Neonatal Network and Canadian Neonatal Follow-Up Network sites included preterm infants born 2010-2018. Logistic regression and model diagnostics evaluated relationships between changes in z score and velocity of weight and HC from birth to discharge from a tertiary neonatal intensive care unit, discharge to 18-24 months corrected age (CA), and birth to 18-24 months CA and significant cognitive/motor impairment at 18-24 months CA classified using a Bayley Scales of Infant and Toddler Development-Third Edition cognitive or motor composite score <70. RESULTS: In total, 4530 infants (53.0% male) with a mean (SD) gestational age of 26.3 (1.4) weeks and birth weight of 920 (227) g were included. Weight and HC changes were associated with lower odds of significant cognitive/motor impairment including an OR of 0.87 (95% CI: 0.83, 0.91; P < .001) for a 1-g/d increase in weight from discharge to 18-24 months CA and 0.81 (95% CI: 0.75, 0.88; P < .001) for a 1-unit increase in HC z score from birth to 18-24 months CA. Associations were not statistically significant in morbidity-free neonates. Weight and HC gains poorly discriminated between infants with and without significant cognitive/motor impairment (areas under the receiver operating characteristic curve of <0.64). No growth measure had a clinically useful balance of sensitivity and specificity. CONCLUSIONS: Weight and HC changes were associated with significant cognitive/motor impairment but had poor discriminatory capability. Neonatal morbidities may make a larger contribution than postnatal growth to neurodevelopment.

Examination of school readiness and factors related to developmental vulnerability in children born very low birth weight.

BACKGROUND: Many children born very low birth weight (VLBW) experience school struggles with preparedness requiring adequate physical, social, behavioural, cognitive and communication skills. A global assessment of proficiency is necessary to identify those at risk in any such area and direct early intervention accordingly. Study objectives were to characterize developmental vulnerability and school readiness scores in these key domains in a sample of children born VLBW versus their provincial public school system peers and identify early-life infant and parent factors related to suboptimal school readiness. METHODS: The Early Development Instrument teacher assessments of school readiness were collected for a Canadian VLBW sample (NCT02759809). Comparisons between children born VLBW and peers were made. Group differences between children born VLBW considered vulnerable (<10th percentile, not developmentally ready for learning) and not vulnerable were tested and linear regression explored associations between early-life factors and domain scores. RESULTS: Of 77 available Early Development Instrument assessments, median (interquartile range) assessment age was 6.0 (5.7, 6.2) years, birth weight 950 (793, 1250) grammes and birth gestation 27.4 (25.6, 29.7) weeks. A higher proportion of children born VLBW versus peers exhibited vulnerability in Physical Health and Well-being (24.7% vs. 16.1%, p = 0.04), Communication Skills and General Knowledge (23.4% vs. 10.2%, p = 0.0001) and vulnerability in ≥2 domains (26.0% vs. 14.4%, p = 0.004). Children born VLBW classified as vulnerable versus not vulnerable had lower birth gestation and 5-min Apgar. Adjusted regression models found Apgar <7 associated with lower scores for Physical Health and Well-being (-0.86; 95%CI: -1.71, -0.00; p = 0.049), Social Competence (-1.77; 95%CI: -2.92, -0.62; p = 0.003), Emotional Maturity (-1.55; 95%CI: -2.43, -0.66; p = 0.0009) and Communication Skills and General Knowledge (-1.63; 95%CI: -3.19, -0.06; p = 0.04). CONCLUSIONS: This VLBW sample exhibited poor school readiness in multiple domains. Identification of lower birth gestation and Apgar may assist targeted early interventions to mitigate vulnerability.

State of the evidence from clinical trials on human milk fortification for preterm infants.

Infants born preterm or low birth weight are at risk for morbidity, mortality and later neuroimpairment. Appropriate early post-natal growth is associated with better outcomes in-hospital and post-discharge. Therefore, nutritional strategies that support growth may improve the long-term health of this population. Mother's milk with donor milk as a supplement are preferred sources of nutrition for these infants but may not always support growth, especially amongst infants born of very low birth weight (<1500 g) and or those with a major morbidity. Systematic reviews of randomised controlled trials to date demonstrate that multi-nutrient fortification of human milk improves in-hospital growth of preterm infants although data on long-term neurodevelopment are lacking. Further, individualised approaches to fortification based on milk analysis or the infant's metabolic response may improve growth over standard fortification. The evidence is insufficient to inform the timing of introducing fortifier, routine fortification of feeds post-discharge or routine use of fortifiers made from human instead of bovine milk. Importantly, there is insufficient data to determine if these fortification practices improve relevant clinical or neurodevelopmental outcomes. In sum, there is an urgent need for well-designed clinical trials to assess potential benefits and risks of fortification practices and at what cost.

Adiposity and Fat-Free Mass of Children Born with Very Low Birth Weight Do Not Differ in Children Fed Supplemental Donor Milk Compared with Those Fed Preterm Formula.

BACKGROUND: Many mothers of very-low-birth-weight (VLBW) infants (<1500 g) are unable to provide sufficient breast milk, and supplemental pasteurized donor human milk (donor milk) or preterm formula is required. The composition of donor milk differs from that of mother's milk and infants fed with donor milk often exhibit slower growth during hospitalization. The long-term impact of nutrient-enriched donor milk on growth, body composition, or blood pressure is unknown. OBJECTIVE: We aimed to determine the effects of nutrient-enriched donor milk compared with preterm formula on growth, body composition, and blood pressure of children born preterm and with VLBW. Associations with in-hospital mother's milk intake were explored. METHODS: This study was a follow-up of children at 5.5-y of age who participated in a randomized controlled trial evaluating the effect of nutrient-enriched donor milk (commencing at ≥120 mL·kg-1·d-1) or preterm formula fed as a supplement when mother's milk was unavailable. The trial intervention lasted 90 d or until hospital discharge, whichever occurred first. In this follow-up investigation, differences in total body fat percentage determined by using air displacement plethysmography (primary outcome), fat-free mass, skinfold thickness, waist circumference, BMI z scores, and blood pressure] were evaluated using linear regressions. RESULTS: Of 316 surviving infants from the earlier trial, 158 (50%) participated in the current study (53% male). Mean ± SD birth weight and gestational age were 1013 ± 264 g and 27.9 ± 2.5 wk. The median (IQR) intervention period was 67.5 d (52.0-91.0 d). Mean ± SD age and BMI z score at follow-up were 5.7 ± 0.2 y and -0.3 ± 1.2. Supplemental nutrient-enriched donor milk, compared to preterm formula, was not associated with growth, body composition, or blood pressure. In-hospital mother's milk intake was positively associated with height z score at 5.5 y (ß: 0.07; 95% CI: 0.004, 0.1; P = 0.04). CONCLUSIONS: Supplemental nutrient-enriched donor milk and preterm formula during initial hospitalization results in comparable long-term growth and body composition in young children born VLBW. This trial was registered at clinicaltrials.gov as NCT02759809 and at isrctn.com as ISRCTN35317141.

Associations between Diet Quality and Body Composition in Young Children Born with Very Low Body Weight.

BACKGROUND: Very low birth weight (VLBW; <1500 g) infants have increased adiposity and metabolic disease risk in adulthood. Limited evidence suggests low-quality childhood diets are a predisposing risk factor. Despite this, to our knowledge no study has yet examined associations between diet quality and body composition in VLBW individuals. OBJECTIVE: The objective of this study was to determine associations between Healthy Eating Index-2010 (HEI-2010) scores and consumption of fruits/vegetables, added sugars, and macronutrients with body composition in 5.5-y-old children born VLBW. We hypothesized HEI-2010 scores were inversely associated with adiposity. METHODS: This cohort study leveraged the 5.5-y follow-up to the Donor Milk for Improved Neurodevelopmental Outcomes randomized controlled trial. From June 2016 to July 2018, participants attended a follow-up visit at The Hospital for Sick Children, Canada, or were visited in their home. All 316 surviving infants from the trial were eligible, and the caregivers of 158 children (50%; 53% male) consented to follow-up. Diet quality (HEI-2010) and usual intake of fruits/vegetables, added sugars, and macronutrients were determined from two 24-h dietary recalls (ASA24). Linear regressions evaluated associations of diet with BMI (kg/m2) and waist circumference z-scores, total fat, fat-free mass (air displacement plethysmography), and skinfolds. RESULTS: Mean ± SD age at follow-up was 5.7 ± 0.2 y, birth weight was 1013 ± 264 g, and gestational age was 27.9 ± 2.5 wk. Dietary data and BMI z-scores were available for all children; 123 completed air displacement plethysmography. HEI-2010 score was 58.2 ± 12.4 out of 100, and 27% of children had poor quality diets (scores ≤50). HEI-2010 scores were inversely associated with BMI z-score, but only in children with obese mothers. A 10-point increase in HEI-2010 score was associated with reduced BMI (ß: -0.5 SD; 95% CI: -0.7, -0.2) and subscapular (-0.3 SD; 95% CI: -0.6, -0.06) z-scores. CONCLUSIONS: Improving diet quality in children born VLBW with obese mothers may be an important strategy to prevent excess adiposity. This trial was registered at clinicaltrials.gov as Optimizing Mothers' Milk for Preterm Infants (OptiMoM) Program of Research: Study 1-Impact of Donor Milk at Kindergarten, NCT02759809.

Independent of Birth Mode or Gestational Age, Very-Low-Birth-Weight Infants Fed Their Mothers' Milk Rapidly Develop Personalized Microbiotas Low in Bifidobacterium.

Background: Very-low-birth-weight (VLBW; born weighing <1500 g) infant feeding with mother's own milk (mother's milk) is associated with numerous beneficial health outcomes. Several interventions, including the prophylactic use of probiotics, are being adopted to promote a gastrointestinal microbiota favorable to the gut health of VLBW infants. An improved understanding of the microbiota that results from mother's milk feeding would therefore facilitate progress in this field. Objective: A preplanned primary objective of this research was to characterize the development of the gut microbiota in exclusively mother's milk-fed VLBW infants and describe the reference taxonomic profile that results from mother's milk feeding. Methods: In this prospective longitudinal cohort study, we collected weekly stool samples from exclusively mother's milk-fed VLBW infants admitted to Mount Sinai Hospital and profiled their gastrointestinal microbiota development from birth (primary outcome of stool collection). In total, we profiled 231 stools from 54 exclusively mother's milk-fed VLBW infants with the use of V6-16S ribosomal RNA gene sequencing. Results: Bacterial evenness, but not bacterial richness, increased over time in VLBW infants (P < 0.001). Bifidobacterium relative abundances were consistently low in all microbiotas at all time points (<0.5% in 97% of samples). VLBW infant microbiotas did not cluster by birth mode, gestational age, or weeks after birth and instead clustered as a function of patient identity (R2 = 0.51, P < 0.001). Conclusions: Exclusively mother's milk-fed VLBW infants rapidly develop personalized gut microbiotas that show increasing evenness and are seemingly unaffected by birth mode or gestational age at birth. The benefits from mother's milk feeding are likely modulated through microbes or pathways that are not dependent on Bifidobacterium because these microbes are present at low levels in VLBW infants. These results help define a reference VLBW infant microbiota profile derived from mother's milk, the optimal source of nutrition for these infants. This trial was registered at ISRCTN (http://www.isrctn.com/) as ISRCTN35317141.

Postdischarge Feeding of Very-low-birth-weight Infants: Adherence to Nutrition Guidelines.

OBJECTIVES: Infant feeding guidelines are important public health strategies to promote optimal growth, development, and chronic disease prevention, but their effectiveness is contingent upon families' ability to adhere to them. Little is known of adherence to guidelines among nutritionally vulnerable infants, specifically those born very-low-birth-weight (VLBW) (<1500 g). This study investigated whether postdischarge feeding practices for VLBW infants align with current recommendations and explored parental and infant baseline sociodemographics related to these practices. METHODS: Prospectively collected data from families of 300 VLBW infants participating in a randomized clinical trial (ISRCTN35317141) were used. Baseline demographics were obtained at enrollment and postdischarge feeding practices via monthly telephone questionnaires to 6 months corrected age (CA). RESULTS: At discharge, 4 and 6 months CA, 72%, 39%, and 29% of infants received any amount of mother's milk, respectively; exclusive breast-feeding rates were 49%, 20%, and 6%, respectively. Among infants receiving mother's milk, rates of vitamin D supplementation were ≥83%. Recommendations for introducing solids between 4 and 6 months CA were followed by 71% of the cohort and for iron supplementation by 58%. Overall, 12% of infants adhered to all aforementioned recommendations. Mothers with university degrees were more likely to provide mother's milk, whereas mothers of Middle Eastern/South Asian ethnicity were less likely to provide mother's milk. CONCLUSIONS: Low rates of partial and exclusive breast-feeding of VLBW infants to 6 months CA were reported. Overall adherence to iron supplementation was low. Strategies to provide increased support for mothers identified as at-risk should be developed.

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.

Importance: For many very low-birth-weight (VLBW) infants, there is insufficient mother's milk, and a supplement of pasteurized donor human milk or preterm formula is required. Awareness of the benefits of mother's milk has led to an increase in use of donor milk, despite limited data evaluating its efficacy. Objective: To determine if nutrient-enriched donor milk compared with formula, as a supplement to mother's milk, reduces neonatal morbidity, supports growth, and improves neurodevelopment in VLBW infants. Design, Setting, and Participants: In this pragmatic, double-blind, randomized trial, VLBW infants were recruited from 4 neonatal units in Ontario, Canada, within 96 hours of birth between October 2010 and December 2012. Follow-up was completed in July 2015. Interventions: Infants were fed either donor milk or formula for 90 days or to discharge when mother's milk was unavailable. Main Outcomes and Measures: The primary outcome was the cognitive composite score on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 18 months' corrected age (standardized mean, 100 [SD, 15]; minimal clinically important difference, 5 points). Secondary outcomes included Bayley-III language and motor composite scores, growth, and a dichotomous mortality and morbidity index. Results: Of 840 eligible infants, 363 (43.2%) were randomized (181 to donor milk and 182 to preterm formula); of survivors, 299 (92%) had neurodevelopment assessed. Mean birth weight and gestational age of infants was 996 (SD, 272) g and 27.7 (2.6) weeks, respectively, and 195 (53.7%) were male. No statistically significant differences in mean Bayley-III cognitive composite score (adjusted scores, 92.9 in donor milk group vs 94.5 in formula group; fully adjusted mean difference, -2.0 [95% CI, -5.8 to 1.8]), language composite score (adjusted scores, 87.3 in donor milk group vs 90.3 in formula group; fully adjusted mean difference, -3.1 [95% CI, -7.5 to 1.3]), or motor composite score (adjusted scores, 91.8 in donor milk group vs 94.0 in formula group; fully adjusted mean difference, -3.7 [95% CI, -7.4 to 0.09]) were observed between groups. There was no statistically significant difference in infants positive for the mortality and morbidity index (43% in donor milk group, 40% in formula group) or changes in growth z scores. Conclusions and Relevance: Among VLBW infants, use of supplemental donor milk compared with formula did not improve neurodevelopment at 18 months' corrected age. If donor milk is used in settings with high provision of mother's milk, this outcome should not be considered a treatment goal. Trial Registration: isrctn.org Identifier: ISRCTN35317141.

Mother's milk microbiota is associated with the developing gut microbial consortia in very-low-birth-weight infants.

Mother's milk contains diverse bacterial communities, although their impact on microbial colonization in very-low-birth-weight (VLBW, <1,500 g) infants remains unknown. Here, we examine relationships between the microbiota in preterm mother's milk and the VLBW infant gut across initial hospitalization (n = 94 mother-infant dyads, 422 milk-stool pairs). Shared zero-radius operational taxonomic units (zOTUs) between milk-stool pairs account for ∼30%-40% of zOTUs in the VLBW infant's gut. We show dose-response relationships between intakes of several genera from milk and their concentrations in the infant's gut. These relationships and those related to microbial sharing change temporally and are modified by in-hospital feeding practices (especially direct breastfeeding) and maternal-infant antibiotic use. Correlations also exist between milk and stool microbial consortia, suggesting that multiple milk microbes may influence overall gut communities together. These results highlight that the mother's milk microbiota may shape the gut colonization of VLBW infants by delivering specific bacteria and through intricate microbial interactions.

Early nutritional influences on brain regions related to processing speed in children born preterm: A secondary analysis of a randomized trial.

BACKGROUND: Processing speed is a foundational skill supporting intelligence and executive function, areas often delayed in preterm-born children. The impact of early-life nutrition on gray matter facilitating processing speed for this vulnerable population is unknown. METHODS: Magnetic resonance imaging and the Wechsler Preschool and Primary Scale of Intelligence-IV Processing Speed Index were acquired in forty 5-year-old children born preterm with very low birth weight. Macronutrient (grams per kilogram per day) and mother's milk (percentage of feeds) intakes were prospectively collected in the first postnatal month and associations between early-life nutrition and the primary outcome of brain regions supporting processing speed were investigated. RESULTS: Children had a mean (SD) gestational age of 27.8 (1.8) weeks and 45% were male. Macronutrient intakes were unrelated, but mother's milk was positively related, to greater volumes in brain regions, including total cortical gray matter, cingulate gyri, and occipital gyri. CONCLUSION: First postnatal month macronutrient intakes showed no association, but mother's milk was positively associated, with volumetric measures of total and regional cortical gray matter related to processing speed in preterm-born children. This exploratory analysis suggests early-life mother's milk supports processing speed by impacting structural underpinnings. Further research is needed on this potential strategy to improve preterm outcomes.

A comparison of tertiary level NICU costs for infants born <1250 g supplemented with human versus bovine milk-based fortifiers.

BACKGROUND: Human milk-based fortifiers (HMBF) are more costly than bovine milk-based fortifiers (BMBF); but, the efficacy of human or bovine fortification for infants born <1250 g has yet to be fully elucidated. Our objective was to determine the effect of fortifier source on tertiary neonatal costs. METHODS: Costs associated with tertiary neonatal care, including direct and indirect hospital expenditures, feed-related costs and physician billing were analysed retrospectively for participants of OptiMoM (NCT02137473), a blinded RCT comparing fortifier type for babies born <1250 g. A generalized linear model of cost according to fortifier type was created. RESULTS: Mean [95% confidence interval] daily costs per patient, adjusted for birth gestation and weight, was significantly greater in the human than the BMBF group ($3,452 [$3,186 - $3,740] Canadian dollars (CAD) versus $2,451 [$2,257 - $2,662] CAD) respectively, p < 0.0001). CONCLUSION: HMBF usage entails additional costs on NICU stay that should be considered with implementation.

Diet Quality and Cognitive Performance in Children Born Very Low Birth Weight.

Children born very low birth weight (VLBW, <1,500 g) are at high risk for cognitive and academic difficulties later in life. Although early nutrition (e.g., breastfeeding) is positively correlated with IQ in children born VLBW, the association between dietary intake in childhood and cognitive performance is unknown. Thus, our study is the first to investigate the relationship between diet quality, as measured by the Healthy Eating Index-2010 (HEI-2010) and cognitive performance in a Canadian cohort of 5-year-old children born VLBW (n = 158; 47% female). Diet quality was measured using two 24-h diet recalls obtained from parents and cognitive performance was assessed using the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV). To account for additional sociodemographic factors that could influence neurodevelopment, linear regression analyses were adjusted for sex, household income above/below the poverty line, maternal education, birth weight and breastfeeding duration. Mean ± SD HEI-2010 score was 58.2 ± 12.4, with most children (67%) having diets in "need of improvement" (scores 51-80). HEI-2010 scores were not significantly associated with IQ or any other WPPSI-IV composite score. Significant predictors of IQ in our model were birth weight, sex, and maternal education. Our findings emphasize the important role of maternal education and other sociodemographic factors on neurodevelopment in children born VLBW. Further, despite not finding any significant association between HEI-2010 scores and IQ, our results highlight the need to improve diet quality in young children born VLBW. Further research is needed to confirm the impact of diet quality on cognitive performance in this vulnerable population.

Social-emotional functioning and dietary intake among children born with a very low birth weight.

Very low birth weight (VLBW, <1500 g)  infants are at an elevated risk of neurodevelopmental disorders, later obesity and cardiometabolic disease; if and how neurodevelopmental disorders impact chronic disease risk is poorly understood. The most common neurodevelopmental disorders experienced by VLBW children are those of social-emotional functioning. We compared dietary patterns and body composition between VLBW children with poor vs. typical social-emotional functioning using linear mixed models adjusted for sex, gestational age, cognitive impairment, parental education, and body mass index (BMI). VLBW children (n=158) attending the Donor Milk for Improved Neurodevelopmental Outcomes trial with 5.5-year follow-up participated. Poor social-emotional functioning was based on standardized parent-rated questionnaires and/or parent-reported physician diagnosis of autism spectrum or attention-deficit/hyperactivity disorders. Most children had diets categorized as "needs improvement" (67%) or "poor" (27%) and 29% of children exhibited poor social-emotional functioning. Poor social-emotional functioning was positively associated with 100% fruit juice (ß=0.3 cup equivalents/day; 95% CI 0.1, 0.5) and energy intake (ß=118.1 kcal/day; 95% CI 0.9, 235.2). Children with poor social-emotional functioning were more likely to have a limited food repertoire (p=0.02), but less likely to exceed dietary fat recommendations (p=0.04). No differences in overall diet quality or body composition were observed. Diet counselling and research are essential to improving the nutrition of VLBW children to mitigate chronic disease risk. Trial registration - Optimizing Mothers' Milk for Preterm Infants Program of Research: Study 1 - Impact of Donor Milk at Kindergarten, NCT02759809, https://clinicaltrials.gov/ct2/show/NCT02759809. Novelty: Overall diet quality and body composition did not differ between VLBW children with poor vs. typical social-emotional functioning. Most had diets "needing improvement" or "poor" according to the Healthy Eating Index-2010. Diet counselling may help mitigate chronic disease risk in this vulnerable population.

Intake of mother's milk by very-low-birth-weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years of age.

BACKGROUND: Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES: We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS: This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS: EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS: In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.

Social-Cognitive Network Connectivity in Preterm Children and Relations With Early Nutrition and Developmental Outcomes.

Infants born very low birth weight (VLBW, < 1,500 g) are at a heightened risk for structural brain abnormalities and social-cognitive deficits, which can impair behavioural functioning. Resting-state fMRI, reflecting a baseline level of brain activity and underlying social-cognitive processes, has also been reported to be altered in children born VLBW. Yet very little is known about the functional networks underlying social cognition using magnetoencephalography (MEG) and how it relates to neonatal factors and developmental outcomes. Thus, we investigated functional connectivity at rest in VLBW children and the associations with early nutrition and IQ and behavioural problems. We collected resting-state MEG recordings and measures of IQ and social-cognitive behaviour, as well as macronutrient/energy intakes during initial hospitalisation in 5-year-old children born VLBW (n = 37) compared to full-term (FT; n = 27) controls. We examined resting-state network differences controlling for sex and age at scan. Functional connectivity was estimated using the weighted phase lag index. Associations between functional connectivity with outcome measures and postnatal nutrition were also assessed using regression analyses. We found increased resting-state functional connectivity in VLBW compared to FT children in the gamma frequency band (65-80 Hz). This hyper-connected network was primarily anchored in frontal regions known to underlie social-cognitive functions such as emotional processing. In VLBW children, increased functional connectivity was related to higher IQ scores, while reduced connectivity was related to increased behavioural problems at 5 years of age. These within-group associations were found in the slower frequency bands of theta (4-7 Hz) and alpha (8-12 Hz), frequently linked to higher-order cognitive functions. We also found significant associations between macronutrient (protein and lipid) and energy intakes during the first postnatal month with functional connectivity at preschool-age, highlighting the long-term impacts of postnatal nutrition on preterm brain development. Our findings demonstrate that at preschool-age, VLBW children show altered resting-state connectivity despite IQ and behaviour being in the average range, possibly reflecting functional reorganisation of networks to support social-cognitive and behavioural functioning. Further, our results highlight an important role of early postnatal nutrition in the development of resting-state networks, which in turn may improve neurodevelopmental outcomes in this vulnerable population.

Human milk nutrient fortifiers alter the developing gastrointestinal microbiota of very-low-birth-weight infants.

Nutrient fortifiers are added to human milk to support the development of very-low-birth-weight infants. Currently, bovine-milk-based fortifiers (BMBFs) are predominantly administered, with increasing interest in adopting human-milk-based fortifiers (HMBFs). Although beneficial for growth, their effects on the gastrointestinal microbiota are unclear. This triple-blind, randomized clinical trial (NCT02137473) tested how nutrient-enriching human milk with HMBF versus BMBF affects the gastrointestinal microbiota of infants born < 1,250 g during hospitalization. HMBF-fed infants (n = 63, n = 269 stools) showed lower microbial diversity, altered microbial community structure, and changes in predicted microbial functions compared with BMBF-fed infants (n = 56, n = 239 stools). HMBF-fed infants had higher relative and normalized abundances of unclassified Enterobacteriaceae and lower abundances of Clostridium sensu stricto. Post hoc analyses identified dose-dependent relationships between individual feed components (volumes of mother's milk, donor milk, and fortifiers) and the microbiota. These results highlight how nutrient fortifiers impact the microbiota of very-low-birth-weight infants during a critical developmental window.

Higher Energy, Lipid, and Carbohydrate Provision to Very Low-Birth-Weight Infants Is Differentially Associated With Neurodevelopment at 18 Months, Despite Consistent Improvements in Weight Gain.

BACKGROUND: The impact of suboptimal intakes on neurodevelopment of very low-birth-weight (VLBW, <1500 g) infants, particularly those born small for gestational age, <26 weeks, <1000 g, or with morbidities is not well defined. We investigated how macronutrient/energy intakes are associated with growth and neurodevelopment among VLBW infants, adjusted for the aforementioned vulnerabilities. Our hypothesis was that higher nutrient intakes would be positively associated with weight gain and neurodevelopment. METHODS: Daily macronutrient/energy intakes and weekly weights from birth until 36+0 weeks were collected prospectively from VLBW infants (n = 302) enrolled in a previous trial (ISRCTN35317141). Neurodevelopment was assessed by the Bayley-III at 18 months' corrected gestational age. Relationships between quartiles of macronutrient/energy intakes, growth, and neurodevelopment were assessed. RESULTS: Infants born <1000 g, <26 weeks, or with morbidities had lower nutrient intakes and slower growth than infants born ≥1000 g, ≥26 weeks, or with no morbidities, respectively (P < 0.05). Higher quartiles of energy, lipid, and carbohydrate intakes were positively associated with growth velocity (P = <0.0001-0.007); no association was observed for protein intake. Energy, protein-to-energy ratio and lipid intakes were associated with cognitive scores (P = 0.001-0.004); however, intakes within the second and third quartiles were generally associated with the highest cognitive scores. No nutrient intakes were associated with language or motor scores across the entire study period. CONCLUSION: Smaller, more immature VLBW infants and those with morbidity have the greatest risk of poor nutrition and growth. Increasing macronutrient/energy intakes are generally associated with improved weight gain, but not necessarily improved neurodevelopment.

Altered functional connectivity during face processing in children born with very low birth weight.

Structural brain alterations have been reported in key emotional face processing regions following preterm birth; however, few studies have investigated the functional networks underlying these processes in children born with very low birth weight (VLBW). Using magnetoencephalography (MEG), we examined the functional networks related to the implicit processing of happy and angry faces in 5-year-old VLBW (n = 28) and full-term (FT; n = 24) children. We found that VLBW children showed atypical recruitment of emotional face processing networks in theta (4-7 Hz) compared to FT children. VLBW children showed reduced theta connectivity during processing of angry faces only. This hypo-connected theta-band network was anchored in the left orbitofrontal and parietal regions, involved in the higher level processing of faces and emotion regulation. At the behavioural level, despite VLBW children performing within the normal range, FT children had significantly higher affect recognition scores. Our MEG results suggest a selective impairment in processing angry faces, which would negatively impact social functioning in VLBW children. In FT children, greater recruitment of this theta-band network was positively associated with improved affect recognition scores. Thus, our findings suggest an important role of theta oscillations in early face processing, deficits which may contribute to broader socio-emotional impairments in VLBW children.

White matter alterations and cognitive outcomes in children born very low birth weight.

BACKGROUND: Very low birth weight (VLBW) infants are at risk for disrupted white matter maturation, yet little is known about the contributing factors, particularly at preschool-age when cognitive difficulties begin to emerge. We examined white matter microstructure in five-year-old VLBW and full-term (FT) children, and its association with cognitive outcomes and birth weight. METHODS: Multi-shell diffusion and MR images were obtained for 41 VLBW (mean birth weight: 1028.6 ± 256.8 g) and 26 FT (3295.4 ± 493.9 g) children. Fractional anisotropy (FA), radial diffusivity (RD), neurite orientation dispersion index (ODI) and density index (NDI) were estimated using diffusion tensor and neurite orientation dispersion and density imaging models. Between-group analyses used a general linear model with group and sex as explanatory variables. Within-group associations between white matter microstructure, cognitive outcomes and birth weight were also investigated. RESULTS: VLBW compared to FT children showed lower FA and NDI across widespread white matter regions. Smaller clusters of atypical ODI were also found in VLBW children. Within-group analyses in FT children revealed that lower RD and higher NDI were associated with vocabulary acquisition and working memory. In VLBW children, higher FA and NDI, and lower RD and ODI, were associated with improved processing speed. In both groups, FA was positively associated with birth weight. CONCLUSIONS: Our findings demonstrate white matter alterations in young VLBW children, including widespread reductions in axon density that may reflect sustained myelination disruptions. The associations with cognitive outcomes may also highlight which of the VLBW children are at higher risk for later cognitive difficulties.