Associations between neonatal nutrition and visual outcomes in 7-year-old children born very preterm.

PURPOSE: There is uncertainty about the effect of increased neonatal protein intake on neurodevelopmental outcomes following preterm birth. The aim of this study was to assess the effect of a change in neonatal nutrition protocol at a major tertiary neonatal intensive care unit intended to increase protein intake on ophthalmic and visual development in school-age children born very preterm. METHODS: The study cohort comprised children (n = 128) with birthweight <1500 g or gestational age < 30 weeks born at Auckland City Hospital before (OldPro group, n = 55) and after (NewPro group, n = 73) a reformulation of parenteral nutrition that resulted in increased total protein intake during the first postnatal week and decreased carbohydrate, total parenteral fluid and sodium intake. Clinical and psychophysical vision assessments were completed at 7 years' corrected age, including visual acuity, global motion perception (a measure of dorsal stream function), stereoacuity, ocular motility and ocular health. Composite measures of favourable overall visual, binocular and functional visual outcomes along with individual vision measures were compared between the groups using logistic and linear regression models. RESULTS: Favourable overall visual outcome did not differ between the two groups. However, global motion perception was better in the NewPro group (p = 0.04), whereas the OldPro group were more likely to have favourable binocular visual outcomes (60% vs. 36%, p = 0.02) and passing stereoacuity (p = 0.02). CONCLUSIONS: These results indicate subtle but complex associations between early neonatal nutrition after very preterm birth and visual development at school age.

Amygdala subnuclei volumes, functional connectivity, and social-emotional outcomes in children born very preterm.

Children born very preterm can demonstrate social-cognitive impairments, which may result from limbic system dysfunction. Altered development of the subnuclei of the amygdala, stress-sensitive regions involved in emotional processing, may be key predictors of social-skill development. In a prospective cohort study, 7-year-old children born very preterm underwent neurodevelopmental testing and brain MRI. The Child Behavioral Checklist was used to assess social-emotional outcomes. Subnuclei volumes were extracted automatically from structural scans (n = 69) and functional connectivity (n = 66) was examined. General Linear Models were employed to examine the relationships between amygdala subnuclei volumes and functional connectivity values and social-emotional outcomes. Sex was a significant predictor of all social-emotional outcomes (P < 0.05), with boys having poorer social-emotional outcomes. Smaller right basal nuclei volumes (B = -0.043, P = 0.014), smaller right cortical volumes (B = -0.242, P = 0.02) and larger right central nuclei volumes (B = 0.85, P = 0.049) were associated with increased social problems. Decreased connectivity strength between thalamic and amygdala networks and smaller right basal volumes were significant predictors of greater social problems (both, P < 0.05), effects which were stronger in girls (P = 0.025). Dysregulated maturation of the amygdala subnuclei, along with altered connectivity strength in stress-sensitive regions, may reflect stress-induced dysfunction and can be predictive of social-emotional outcomes.

Neurodevelopmental impairment is associated with altered white matter development in a cohort of school-aged children born very preterm.

Individuals born very preterm (<32 weeks gestation) have altered brain growth and white matter maturation relative to their full-term peers, and approximately 30% will experience neurodevelopmental impairment. We investigated the relationship between neurodevelopmental impairment and MRI measures of white matter microstructure and brain volume. Children born before 30 weeks' gestation or who had very low birthweight (< 1500 g) underwent neurodevelopmental assessment and MRI at age 7 years as part of the PIANO study, a New Zealand-based cohort study. Fractional anisotropy (FA) and diffusivity measures were derived from diffusion tensor imaging to index white matter microstructure. Volumes were derived from T1-weighted imaging. Neurodevelopmental impairment was defined as a score < 85 on the Wechsler Intelligence Scale for Children, <5th centile on the Movement Assessment Battery for Children or a diagnosis of cerebral palsy by a paediatrician. Relationships between MRI and neurodevelopmental impairment were assessed with general linear models adjusted for sex, gestational age at birth, birthweight z-score, age at assessment, New Zealand Deprivation index score and multiplicity. Children with neurodevelopmental impairment (n = 38) had smaller total brain, cortical grey matter and cerebral white matter volumes compared to children without neurodevelopmental impairment (n = 62) (p < 0.05, false discovery rate corrected), but the regional volume differences did not remain significant after adjustment for total brain volume. Lower FA and higher radial diffusivity were observed in the superior longitudinal fasciculi, uncinate fasciculi and right hemisphere corticospinal tract in children with neurodevelopmental impairment. This may reflect differences in cellular properties such as myelination or axonal packing. Neurodevelopmental impairment may reflect smaller overall brain volume and altered microstructure in white matter tracts that are important for language, cognitive and motor functioning.

Early protein intake predicts functional connectivity and neurocognition in preterm born children.

Nutritional intake can promote early neonatal brain development in very preterm born neonates (< 32 weeks' gestation). In a group of 7-year-old very preterm born children followed since birth, we examined whether early nutrient intake in the first weeks of life would be associated with long-term brain function and neurocognitive skills at school age. Children underwent resting-state functional MRI (fMRI), intelligence testing (Wechsler Intelligence Scale for Children, 5th Ed) and visual-motor processing (Beery-Buktenica, 5th Ed) at 7 years. Relationships were assessed between neonatal macronutrient intakes, functional connectivity strength between thalamic and default mode networks (DMN), and neuro-cognitive function using multivariable regression. Greater functional connectivity strength between thalamic networks and DMN was associated with greater intake of protein in the first week (ß = 0.17; 95% CI 0.11, 0.23, p < 0.001) but lower intakes of fat (ß = - 0.06; 95% CI - 0.09, - 0.02, p = 0.001) and carbohydrates (ß = - 0.03; 95% CI - 0.04, - 0.01, p = 0.003). Connectivity strength was also associated with protein intake during the first month (ß = 0.22; 95% CI 0.06, 0.37, p = 0.006). Importantly, greater thalamic-DMN connectivity strength was associated with higher processing speed indices (ß = 26.9; 95% CI 4.21, 49.49, p = 0.02) and visual processing scores (ß = 9.03; 95% CI 2.27, 15.79, p = 0.009). Optimizing early protein intake may contribute to promoting long-term brain health in preterm-born children.

The contributions of intelligence and executive function to behaviour problems in school-age children born very preterm.

AIM: To examine the contributions of specific neurocognitive skills to behaviour problems in children born very preterm. METHODS: We assessed children born <30 weeks' gestation or <1500 g at age 7 years using subtests of the Wechsler Intelligence Scale for Children Fourth Edition, performance and questionnaire-based measures of executive function, and Child Behavior Checklist and Teacher Rating Form. We evaluated the contributions of IQ and executive function to behaviour problems and the moderating effect of sex using multiple regression. RESULTS: The 129 children (mean age = 7.2 years) had lower IQ, inferior executive function and increased internalising problems compared with normative samples. Verbal comprehension skills and working memory were associated with total, internalising and externalising problems at school. Performance-based and questionnaire-based executive function were associated with total and externalising behaviour problems both at home and school. Sex moderated the relationships between information processing and parent-reported total problems, and between teacher-rated executive function and total problems. CONCLUSION: Both IQ and executive function are related to behaviour problems in children born very preterm, but the relationships are different in boys and girls. Executive function may be a useful target for intervention.

Do preterm girls need different nutrition to preterm boys? Sex-specific nutrition for the preterm infant.

Boys born preterm are recognised to be at higher risk of adverse outcomes than girls born preterm. Despite advances in neonatal intensive care and overall improvements in neonatal morbidity and mortality, boys born preterm continue to show worse short- and long-term outcomes than girls. Preterm birth presents a nutritional crisis during a critical developmental period, with postnatal undernutrition and growth-faltering common complications of neonatal intensive care. Furthermore, this preterm period corresponds to that of rapid in utero brain growth and development, and the developmental window relating to foetal programming of adult non-communicable diseases, the prevalence of which are associated both with preterm birth and sex. There is increasing evidence to show that from foetal life, boys and girls have different responses to maternal nutrition, that maternal breastmilk composition differs based on foetal sex and that early neonatal nutritional interventions affect boys and girls differently. This narrative review examines the evidence that sex is an important moderator of the outcomes of preterm nutrition intervention, and describes what further knowledge is required before providing nutrition intervention for infants born preterm based on their sex. IMPACT: This review examines the increasing evidence that boys and girls respond differently to nutritional stressors before birth, that maternal breastmilk composition differs by foetal sex and that nutritional interventions have different responses based on infant sex. Boys and girls born preterm are given standard nutritional support which does not take infant sex into account, and few studies of neonatal nutrition consider infant sex as a potential mediator of outcomes. By optimising early nutrition for boys and girls born preterm, we may improve outcomes for both sexes. We propose future studies of neonatal nutritional interventions should consider infant sex.

Relationships between intelligence, executive function and academic achievement in children born very preterm.

BACKGROUND: Children born very preterm are at higher risk of adverse neurocognitive and educational outcomes. However, how low intelligence (IQ) and low executive function may each contribute to poorer academic outcomes at school age requires clarification. AIM: To examine the associations between intelligence, executive function and academic achievement in children born very preterm. DESIGN/METHODS: This cohort study assessed children born <30 weeks' gestation or <1500 g at age 7 years using the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for IQ, and the Test of Everyday Attention for Children (TEA-Ch) and Behavior Rating Inventory of Executive Function (BRIEF) for executive function. Academic achievement was rated by teachers against curriculum standards. RESULTS: Of the 76 children (35 girls, 41 boys, mean age = 7.2 year), 22 (28%) were rated below expected level for reading, 32 (42%) for writing and 38 (50%) for mathematics. After adjustment for sex and socioeconomic status, low IQ (OR's 9.0-12.3) and most low executive function measures (OR's 4.1-9.3) were associated with below-expected achievement. After further adjustment for IQ, low cognitive flexibility (OR = 9.3, 95% CI = 1.2-71.5) and teacher ratings of executive function (OR = 5.3, 95% CI = 1.4-20.2) were associated with below-expected achievement. Mediation analysis showed IQ had indirect effects on writing (b = 1.5, 95% CI = 0.6-3.1) via attentional control; and on reading (b = 1.0, 95% CI = 0.2-3.2) and writing (b = 0.8, 95% CI = 0.1-2.5) via cognitive flexibility. CONCLUSIONS: Both low IQ and low executive function are associated with below-expected teacher-rated academic achievement in children born very preterm. IQ may influence academic achievement in part through executive function.

Effects of Neonatal Hyperglycemia on Retinopathy of Prematurity and Visual Outcomes at 7 Years of Age: A Matched Cohort Study.

OBJECTIVE: To determine whether neonatal hyperglycemia is associated with retinopathy of prematurity (ROP), visual outcomes, and ocular growth at 7 years of age. STUDY DESIGN: Children born preterm (<30 weeks of gestational age) at a tertiary hospital in Auckland, New Zealand, who developed neonatal hyperglycemia (2 blood glucose concentrations ≥153 mg/dL [8.5 mmol/L] 4 hours apart) were matched with children who were not hyperglycemic (matching criteria: sex, gestational age, birth weight, age, socioeconomic status, and multiple birth) and assessed at 7 years of corrected age. The primary outcome, favorable overall visual outcome (visual acuity ≤0.3 logarithm of the minimum angle of resolution, no strabismus, stereoacuity ≤240 arcsec, not requiring spectacles) was compared between groups using generalized matching criteria-adjusted linear regression models. RESULTS: Assessments were performed on 57 children with neonatal hyperglycemia (hyperglycemia group) and 54 matched children without hyperglycemia (control group). There were no differences in overall favorable visual outcome (OR 0.95, 95% CI 0.42-2.13, P = .90) or severe ROP incidence (OR 2.20, 95% CI 0.63-7.63, P = .21) between groups. Children with hyperglycemia had poorer binocular distance visual acuity (mean difference 0.08, 95% CI 0.03-0.14 logarithm of the minimum angle of resolution, P < .01), more strabismus (OR 6.22, 95% CI 1.31-29.45, P = .02), and thicker crystalline lens (mean difference 0.14, 95% CI 0.04-0.24 mm, P < .01). Maximum blood glucose concentration was greater in the ROP-treated group compared with the ROP-not treated and no ROP groups after adjusting for sex, gestational age, and birth weight z score (P = .02). CONCLUSIONS: Neonatal hyperglycemia was not associated with overall visual outcomes at 7 years of age. However, there were between-group differences for specific outcome measures relating to interocular lens growth and binocular vision. Further follow-up is required to determine implications on long-term visual outcome.

Relationships Between Early Neonatal Nutrition and Neurodevelopment at School Age in Children Born Very Preterm.

OBJECTIVES: The aim of this study was to determine whether a new nutrition protocol designed to increase early protein intakes while reducing fluid volume in infants born very preterm was associated with altered neurodevelopment and growth in childhood. METHODS: A retrospective, observational cohort study of children born <30 weeks' gestation or <1500 g and admitted to the neonatal unit, National Women's Hospital, Auckland, New Zealand, before and after a change in nutrition protocol. The primary outcome was neurodevelopmental impairment at 7 years (any of Wechsler Intelligence Scale for Children full scale IQ < 85, Movement Assessment Battery for Children-2 total score ≤5th centile, cerebral palsy, blind, or deaf requiring aids). Outcomes were compared between groups and for the overall cohort using generalized linear regression, adjusted for sex and birth weight z score. RESULTS: Of 201 eligible children, 128 (64%) were assessed (55/89 [62%] exposed to the old nutrition protocol, 73 of 112 [65%] to the new protocol). Children who experienced the new protocol received more protein, less energy, and less carbohydrate in postnatal days 1 to 7. Neurodevelopmental impairment was similar at 7 years (30/73 [41%] vs 25/55 [45%], adjusted odds ratio [AOR] [95% confidence interval] 0.78 [0.35-1.70], P = 0.55), as was the incidence of cerebral palsy (AOR 7.36 [0.88-61.40], P = 0.07). Growth and body composition were also similar between groups. An extra 1 g/kg parenteral protein intake in postnatal days 1 to 7 was associated with a 27% increased odds of cerebral palsy (AOR 1.27 [1.03-1.57], P = 0.006). CONCLUSIONS: Higher early protein intakes do not change overall rates of neurodevelopmental impairment or growth at 7 years. Further research is needed to determine the effects of higher early parenteral protein intake on motor development.

Sex-specific relationships between early nutrition and neurodevelopment in preterm infants.

BACKGROUND: Although early nutrition is associated with neurodevelopmental outcome at 2 years' corrected age in children born very preterm, it is not clear if these associations are different in girls and boys. METHODS: Retrospective cohort study of infants born <30 weeks' gestational age or <1500 g birth weight in Auckland, NZ. Macronutrient, energy and fluid volumes per kg per day were calculated from daily nutritional intakes and averaged over days 1-7 (week 1) and 1-28 (month 1). Primary outcome was survival without neurodevelopmental impairment at 2 years corrected age. RESULTS: More girls (215/478) survived without neurodevelopmental impairment at 2 years (82% vs. 72%, P = 0.02). Overall, survival without neurodevelopmental impairment was positively associated with more energy, fat, and enteral feeds in week 1, and more energy and enteral feeds in month 1 (P = 0.005-0.03), but all with sex interactions (P = 0.008-0.02). In girls but not boys, survival without neurodevelopmental impairment was positively associated with week 1 total intakes of fat (OR(95% CI) for highest vs. lowest intake quartile 62.6(6.6-1618.1), P < 0.001), energy (22.9(2.6-542.0), P = 0.03) and enteral feeds (1.9 × 109(9.5-not estimable), P < 0.001). CONCLUSIONS: Higher early fat and enteral feed intakes are associated with improved outcome in girls, but not boys. Future research should determine sex-specific neonatal nutritional requirements.

Relationships Between Early Nutrition and Blood Glucose Concentrations in Very Preterm Infants.

OBJECTIVES: The aim of the study was to determine whether changes to early nutrition are associated with levels of glycemia in very preterm infants. METHODS: A retrospective, observational study of infants <1500 g or <30 weeks' gestation admitted to Neonatal Intensive Care, National Women's Hospital, New Zealand, before (Old Protocol) and after (New Protocol) a change in nutritional protocol. Nutritional intakes were calculated and averaged by day for postnatal days 1 to 7 (week 1) and 1 to 28 (month 1). Relationships between glycemia measures, macronutrient intakes, and achievement of 10% enteral feeds (≥10% total intake) were explored using logistic regression. RESULTS: Old Protocol (n = 190) and New Protocol (n = 267) groups had similar baseline characteristics. In week 1, New Protocol infants received more protein, less fat, and carbohydrate, had lower mean blood glucose concentrations (BGCs) (mean ±â€ŠSD 4.9 ±â€Š1.2 vs 5.6 ±â€Š1.4 mmoll/L, P < 0.0001), less hyperglycemia (BGC > 8.5 mmol/L, 71 [27%] vs 80 [42%], P = 0.0005), but similar hypoglycemia (BGC < 2.6). In month 1, New Protocol infants also had less hyperglycemia (105 [39%] vs 96 [51%], P = 0.02) and lower mean BGC (5.0 ±â€Š1.1 vs 5.5 ±â€Š1.1 mmol/L, P < 0.0001), but insulin usage was similar. After adjustment for birth weight z score and gestational age, hyperglycemia was significantly associated with week 1 intakes (g ·â€Škg ·â€Šday) of protein (odds ratio [95% confidence intervals] 0.47 [0.23-0.79], P = 0.004), fat (0.54 [0.40-0.74], P < 0.0001), and carbohydrate (1.25 [1.09-1.44], P < 0.0001). These relationships were similar for month 1. Each additional day to achieve 10% enteral feeds was associated with increased odds of hypoglycemia (1.09 [1.00-1.18], P = 0.04) and hyperglycemia (1.16 [1.06-1.28], P = 0.002). CONCLUSIONS: In very preterm infants, macronutrient balance and small, early enteral feeds may assist glycemic control.

Long-Term Outcomes of Hyperglycemic Preterm Infants Randomized to Tight Glycemic Control.

OBJECTIVE: To determine whether tight glycemic control of neonatal hyperglycemia changes neurodevelopment, growth, and metabolism at school age. STUDY DESIGN: Children born very low birth weight and randomized as hyperglycemic neonates to a trial of tight vs standard glycemic control were assessed at 7 years corrected age, including Wechsler Intelligence Scale for Children Fourth Edition, Movement Assessment Battery for Children 2, visual and neurologic examinations, growth measures, dual X-ray absorptiometry, and frequently sampled intravenous glucose tolerance test. The primary outcome was survival without neurodevelopmental impairment at age 7 years. Outcomes were compared using linear regression, adjusted for sex, small for gestational age, birth plurality, and the clustering of twins. Data are reported as number (%) or mean (SD). RESULTS: Of the 88 infants randomized, 11 (13%) had died and 57 (74% of eligible children) were assessed at corrected age 7 years. Survival without neurodevelopmental impairment occurred in 25 of 68 children (37%), with no significant difference between tight (14 of 35; 40%) and standard (11 of 33; 33%) glycemic control groups (P = .60). Children in the tight group were shorter than those in the standard group (121.3 [6.3] cm vs 125.1 [5.4] cm; P < .05), but had similar weight and head circumference. Children in the tight group had greater height-adjusted lean mass (18.7 [0.3] vs 17.6 [0.2] kg; P < .01) and lower fasting glucose concentrations (84.6 [6.30] vs 90.0 [5.6] mg⋅dL-1; P < .05), but no other differences in measures of body composition or insulin-glucose metabolism. CONCLUSION: Tight glycemic control for neonatal hyperglycemia does not change survival without neurodevelopmental impairment, but reduces height, increases height-adjusted lean mass, and reduces fasting blood glucose concentrations at school age. TRIAL REGISTRATION: ACTRN: 12606000270516.

Presence and pattern of scarring in children born very preterm.

The long-term scarring burden of preterm infants undergoing modern neonatal intensive care is not known. This observational cohort study aimed to document the presence and pattern of scarring in children born <30 weeks' gestation or <1500 g birth weight and cared for at the National Women's Health neonatal intensive care unit, Auckland, New Zealand. Children were examined at 7 years' corrected age and the presence, size, number and distribution of scars documented. Scarring was seen in 90% of 129 children assessed, with 81% having multiple scars, 60% having large scars (85% of whom had no history of major neonatal surgery) and 75% having more than one body area scarred. Scarring was more common in boys and in children of non-European ethnicity. Despite modern neonatal intensive care practices, children born very preterm are frequently and extensively scarred at school age.

Relationship between Measures of Neonatal Glycemia, Neonatal Illness, and 2-Year Outcomes in Very Preterm Infants.

OBJECTIVES: To investigate relationships between early neonatal glycemia, neonatal characteristics, neonatal illness, and developmental outcomes in very preterm infants. STUDY DESIGN: A retrospective, observational cohort study of 443 infants born weighing <1500 g or <30 weeks of gestation, and admitted within 24 hours to National Women's Hospital, Auckland, New Zealand. Glucose variability was defined as the standard deviation around the mean after log transformation of all blood glucose concentrations. Absolute glycemic excursions in the first week were used to divide the infants into 4 groups: normoglycemic; hypoglycemic; hyperglycemic, and unstable. RESULTS: Compared with normoglycemic infants, hypoglycemic and unstable infants had lower birth weight z-scores, and hyperglycemic and unstable infants were of lower birth weight. Hypoglycemic infants had similar outcomes to normoglycemic infants. Hyperglycemic and unstable infants were less likely to survive without neonatal morbidity and less likely to survive without neurodevelopmental impairment at 2 years of age. Higher mean blood glucose concentration was seen in the hyperglycemic and unstable groups, and was associated with worse neonatal and 2-year outcomes. Greater glucose variability was seen in the hypoglycemic and unstable groups, and was associated with worse neonatal illness but not outcome at 2 years. No associations between measures of neonatal glycemia and neonatal or 2-year outcomes remained after correction for gestation, birth weight z-score, and socioeconomic status. CONCLUSIONS: In very preterm infants, measures of neonatal glycemia are markers of gestational age and intrauterine growth, and are not independent predictors of neonatal illness or outcomes at 2 years of age.