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.

Early nutrition and white matter microstructure in children born very low birth weight.

Infants born at very low birth weight (<1500 g) are vulnerable to nutritional deficits during their first postnatal month, which are associated with poor neurodevelopmental outcomes. Despite this knowledge, the impact of early postnatal nutrition on white matter microstructure in children born with very low birth weight has not been investigated. In this prospective cohort study, we employed a whole-brain approach to investigate associations between precise estimates of nutrient intake within the first postnatal month with white matter microstructure at 5 years of age. Detailed information about breastmilk, macronutrient and energy intakes during this period were prospectively recorded for all participants. Multi-shell diffusion and T1-weighted MRIs were acquired in 41 children (21 males; mean scan age: 5.75 ± 0.22 years; mean birth weight: 1028.6 ± 256.8 g). The diffusion tensor imaging and neurite orientation dispersion and density imaging models were used to obtain maps of fractional anisotropy, radial diffusivity, orientation dispersion and neurite density indices. Tract-based spatial statistics was used to test associations between metrics of white matter microstructure with breastmilk, macronutrient (protein, lipids and carbohydrate) and energy intake. Associations between white matter microstructure and cognitive outcomes were also examined. Compared to children who did not meet enteral feeding recommendations, those who achieved enteral protein, lipid and energy recommendations during the first postnatal month showed improved white matter maturation at 5 years. Among the macronutrients, greater protein intake contributed most to the beneficial effect of nutrition, showing widespread increases in fractional anisotropy and reductions in radial diffusivity. No significant associations were found between white matter metrics with breastmilk or carbohydrate intake. Voxel-wise analyses with cognitive outcomes revealed significant associations between higher fractional anisotropy and neurite density index with higher processing speed scores. Lower radial diffusivity and orientation dispersion index were also associated with improved processing speed. Our findings support the long-term impacts of early nutrition on white matter microstructure, which in turn is related to cognitive outcomes. These results provide strong support for early postnatal nutritional intervention as a promising strategy to improve long-term cognitive outcomes of infants born at very low birth weight.

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.

Optimizing the growth of very-low-birth-weight infants requires targeting both nutritional and nonnutritional modifiable factors specific to stage of hospitalization.

BACKGROUND: Data on how baseline characteristics, acuity, morbidity, and nutrition work in combination to affect the growth of very-low-birth-weight (VLBW, <1500 g) infants are limited. OBJECTIVE: We aimed to determine factors associated with in-hospital weight, length, and head circumference (HC) trajectories of VLBW infants. METHODS: VLBW infants (n = 316) from the GTA-DoMINO trial were included. Linear mixed-effects models assessed relations of baseline characteristics, acuity (at birth, across hospitalization), major morbidities, and nutrition (enteral feeding type, macronutrient/energy intakes) with changes in anthropometrics over hospitalization (days 1-8, 9-29, 30-75). RESULTS: Specific factors and the strength of their associations with growth depended on in-hospital time interval. Small-for-gestational-age infants experienced weight gain (4.3 g · kg-1 · d-1; 95% CI: 2.0, 6.5 g · kg-1 · d-1) during days 1-8, versus weight loss (-4.6 g · kg-1 · d-1; 95% CI: -5.6, -3.7 g · kg-1 · d-1) among appropriate-for-gestational-age infants (P < 0.001). Positive-pressure ventilation (versus oxygen/room air) was associated with slower weight (-1.8 g · kg-1 · d-1) and HC (-0.25 cm/wk) gain during days 9-29 (P < 0.001). Morbidities were negatively associated with growth after days 1-8, with patent ductus arteriosus (PDA) showing negative associations with weight (-2.7 g · kg-1 · d-1), length (-0.11 cm/wk), and HC (-0.21 cm/wk) gain during days 9-29 (P < 0.001). Macronutrient/energy intakes were associated with weight across hospitalization (P ≤ 0.01), with greater weight gain (1.3-3.0 g · kg-1 · d-1) among infants achieving macronutrient/energy recommendations during days 9-29 and 30-75. Macronutrient/energy intakes were associated with HC during the first month (P = 0.013-0.003), with greater HC gain (0.07-0.12 cm/wk) among infants achieving protein, lipid, and energy recommendations during days 9-29. CONCLUSIONS: Baseline characteristics, acuity, morbidity, and nutrition factors were independently associated with VLBW infant growth. A focus on achieving macronutrient/energy recommendations and improving nutrient delivery to PDA-diagnosed infants may yield improvements to their growth. This trial was registered at www.isrctn.com as ISRCTN35317141.

Nutrient Enrichment of Human Milk with Human and Bovine Milk-Based Fortifiers for Infants Born <1250 g: 18-Month Neurodevelopment Follow-Up of a Randomized Clinical Trial.

BACKGROUND: Bovine milk-based fortifiers (BMBF) have been standard of care for nutrient fortification of feeds for very low birth weight (VLBW) infants, however, there is increasing use of human milk-based fortifiers (HMBF) in neonatal care despite additional costs and limited supporting data. No randomized clinical trial has followed infants fed these fortifiers after initial hospitalization. OBJECTIVE: To compare neurodevelopment in infants born weighing <1250 g fed maternal milk with supplemental donor milk and either a HMBF or BMBF. METHODS: This is a follow-up of a completed pragmatic, triple-blind, parallel group randomized clinical trial conducted in Southern Ontario between August 2014 and March 2016 (NCT02137473) with feeding tolerance as the primary outcome. Infants weighing <1250 g at birth were block randomized by an online third-party service to receive either HMBF (n = 64) or BMBF (n = 63) added to maternal milk with supplemental donor milk during hospitalization. Neurodevelopment was assessed at 18-mo corrected age using the Bayley Scales of Infant and Toddler Development, Third Edition. Follow-up was completed in October 2017. RESULTS: Of the 127 infants randomized, 109 returned for neurodevelopmental assessment. No statistically significant differences between fortifiers were identified for cognitive composite scores [adjusted mean scores 94.7 in the HMBF group and 95.9 in the BMBF group; fully adjusted mean difference, -1.1 (95% CI: -6.5 to 4.4)], language composite scores [adjusted scores 92.4 in the HMBF group and 93.1 in the BMBF; fully adjusted mean difference, -1.2 (-7.5 to 5.1)], or motor composite scores [adjusted scores 95.6 in the HMBF group and 97.7 in the BMBF; fully adjusted mean difference, -1.1 (-6.3 to 4.2)]. There was no difference in the proportion of participants that died or had neurodevelopmental impairment or disability between groups. CONCLUSIONS: Providing HMBF compared with BMBF does not improve neurodevelopmental scores at 18-mo corrected age in infants born <1250 g otherwise fed a human milk diet. This trial was registered at clinicaltrials.gov as NCT02137473.

Neonatal Morbidity Count Is Associated With a Reduced Likelihood of Achieving Recommendations for Protein, Lipid, and Energy in Very Low Birth Weight Infants: A Prospective Cohort Study.

BACKGROUND: Serious morbidity may elevate nutrient requirements and affect adherence to feeding guidelines for very low birth weight (VLBW) infants. An understanding of factors affecting nutrient intakes of VLBW infants will facilitate development of strategies to improve nutrient provision. Our aim was to examine the impact of neonatal morbidity count on achieving recommended nutrient intakes in VLBW infants. METHODS: VLBW infants enrolled in the Donor Milk for Improved Neurodevelopmental Outcomes trial (ISRCTN35317141, n = 363) were included. Serious morbidities and daily parenteral and enteral intakes were collected prospectively. RESULTS: Median intakes of infants with and without ≥1 morbidity met protein recommendations (3.5-4.5 g/kg/d) by week 2, although not maintained after week 4. Infants with ≥1 morbidity (vs without) were 2 weeks slower in achieving lipid (4.8-6.6 g/kg/d; week 4 vs 2) and energy (110-130 kcal/kg/d; week 5 vs 3) and 1 week slower in achieving carbohydrate recommendations (11.6-13.2 g/kg/d; week 4 vs 3). Adjusted hazard ratios of first achieving recommendations on any given day in infants with any 1 or 2 morbidities were 0.6 (95% confidence interval [CI], 0.5-0.9) and 0.6 (0.4-0.9), respectively, for protein; 0.5 (0.4-0.7) and 0.3 (0.2-0.5) for lipid; and 0.5 (0.4-0.7) and 0.3 (0.2-0.4) for energy. CONCLUSION: Morbidity is associated with a decreased likelihood of achieving lipid and consequently energy recommendations. This and the decline in protein intakes after the early neonatal period require further investigation to ensure optimal nutrition in this vulnerable population.

How Close Are We to Achieving Energy and Nutrient Goals for Very Low Birth Weight Infants in the First Week?

BACKGROUND: Emerging evidence suggests intakes of protein and energy as early as the first week of life in preterm very low birth weight (VLBW) infants are associated with improved neurodevelopment. In response, many neonatal intensive care units (NICUs) have launched new, more aggressive early feeding guidelines. The aim of this study was to evaluate enteral and parenteral energy and macronutrient intakes during the first postnatal week in VLBW infants admitted to NICUs that have introduced more aggressive early feeding guidelines. MATERIALS AND METHODS: Estimated energy and macronutrient intakes were prospectively collected from VLBW infants fed exclusively mother's own milk and/or parenteral nutrition and compared with expert recommendations. Days to reach full enteral feeds (150 mL/kg/d) and discharge anthropometrics were examined. RESULTS: By days 6 and 7, median protein and lipid intakes, respectively, reached recommended values (3.5 and 3.0 g/kg/d). However, by day 8, many infants remained below recommended intakes for protein (34%), lipid (34%), carbohydrate (68%), and energy (71%). Late-onset sepsis was associated with a decreased likelihood of reaching full enteral feeds on any given day (hazard ratio, 0.2; 95% confidence interval, 0.1-0.5; P ≤ .0009). There was no significant relationship between week 1 nutrient intakes and anthropometrics at discharge. CONCLUSION: Despite the introduction of more aggressive early feeding guidelines and improved energy and nutrient intakes compared with literature values, many VLBW infants remain below recommended nutrition goals in the first week.