Dolphin CONTINUE: a multi-center randomized controlled trial to assess the effect of a nutritional intervention on brain development and long-term outcome in infants born before 30 weeks of gestation.

BACKGROUND: Preterm born infants are at risk for brain injury and subsequent developmental delay. Treatment options are limited, but optimizing postnatal nutrition may improve brain- and neurodevelopment in these infants. In pre-clinical animal models, combined supplementation of docosahexaenoic acid (DHA), choline, and uridine-5-monophosphate (UMP) have shown to support neuronal membrane formation. In two randomized controlled pilot trials, supplementation with the investigational product was associated with clinically meaningful improvements in cognitive, attention, and language scores. The present study aims to assess the effect of a similar nutritional intervention on brain development and subsequent neurodevelopmental outcome in infants born very and extremely preterm. METHODS: This is a randomized, placebo-controlled, double-blinded, parallel-group, multi-center trial. A total of 130 infants, born at less than 30 weeks of gestation, will be randomized to receive a test or control product between term-equivalent age and 12 months corrected age (CA). The test product is a nutrient blend containing DHA, choline, and UMP amongst others. The control product contains only fractions of the active components. Both products are isocaloric powder supplements which can be added to milk and solid feeds. The primary outcome parameter is white matter integrity at three months CA, assessed using diffusion-tensor imaging (DTI) on MRI scanning. Secondary outcome parameters include volumetric brain development, cortical thickness, cortical folding, the metabolic and biochemical status of the brain, and product safety. Additionally, language, cognitive, motor, and behavioral development will be assessed at 12 and 24 months CA, using the Bayley Scales of Infant Development III and digital questionnaires (Dutch version of the Communicative Development Inventories (N-CDI), Ages and Stages Questionnaire 4 (ASQ-4), and Parent Report of Children's Abilities - Revised (PARCA-R)). DISCUSSION: The investigated nutritional intervention is hypothesized to promote brain development and subsequent neurodevelopmental outcome in preterm born infants who have an inherent risk of developmental delay. Moreover, this innovative study may give rise to new treatment possibilities and improvements in routine clinical care. TRIAL REGISTRATION: WHO International Clinical Trials Registry: NL-OMON56181 (registration assigned October 28, 2021).

Early life lipid profile and metabolic programming in very young children.

BACKGROUND AND AIMS: Lipid derangements during early postnatal life may induce stable epigenetic changes and alter metabolic programming. We investigated associations between serum lipid profiles in very young children and DNA methylation of tumor necrosis factor-alpha (TNFα) and leptin (LEP). Secondly, we explored if the maternal serum lipid profile modifies DNA methylation in the child. METHODS AND RESULTS: In 120 healthy children at 17 months of age, DNA methylation of TNFα and LEP was measured in DNA derived from whole blood. Linear mixed models were used to calculate exposure-specific differences and associations. Total cholesterol in children was associated with decreased methylation of TNFα (-5.8%, p = 0.036), and HDL-cholesterol was associated with decreased methylation of both TNFα (-6.9%, p = 0.013) and LEP (-3.4%, p = 0.021). Additional adjustment for gestational age at birth, birth weight, sex, breastfeeding and educational level attenuated the effects, TNFα (-6.1%, p = 0.058) and LEP (-3.1%, p = 0.041). In mothers, HDL-cholesterol only was associated with decreased methylation of TNFα in the child (-8.7%, p = 0.001). CONCLUSION: Our data support the developmental origin of health and disease hypothesis by showing that total cholesterol and HDL-cholesterol levels in very young children are associated with epigenetic metabolic programming, which may affect their vulnerability for developing cardiovascular diseases in later life.

Cardiovascular diseases in grandparents and the risk of congenital heart diseases in grandchildren.

Hyperglycemia, dyslipidemia and hyperhomocysteinemia are associated with both adult cardiovascular disease (CVD) and having a child with a congenital heart disease (CHD). We investigated associations between CVD in grandparents and the risk of CHD in grandchildren. In a case-control family study, we obtained detailed questionnaire information on CVD and CHD in 247 families with a CHD child and 203 families without a CHD child. Grandparents with CVD or intermittent claudication (IC) were significantly associated with an increased risk for CHD in grandchildren [OR 1.39 (95% CI 1.03-1.89) and OR 2.77 (95% CI 1.02-7.56), respectively]. The risk of CHD grandchildren was particularly increased in paternal grandfathers with CVD [OR 1.85 (95% CI 1.01-3.37)]. Overall, having a grandparent with CVD increased the risk for CHD in the grandchild by 1.65 (95% CI 1.12-2.41). After adjustment for potential maternal confounders, this risk was 1.44 (95% CI 0.94-2.21). Having two or more grandparents with CVD was associated with an approximately threefold risk for CHD grandchildren [OR adjusted 2.72 (95% CI 1.08-6.89)]. Our data suggest that CVD and IC in grandparents are associated with an increased risk of having a CHD grandchild. These first findings may be explained by shared causality of derangements in metabolic pathways and are in line with the fetal origins of health and disease.

Periconception maternal smoking and low education are associated with methylation of INSIGF in children at the age of 17 months.

Maternal smoking during pregnancy and a low socioeconomic status (SES) lead to increased risks of adverse pregnancy outcome. Maternal education is often used as proxy for SES. We explored the programming of the insulin pathway genes IGF2 DMR (insulin growth factor 2 differentially methylated region), IGF2R (insulin growth factor 2 receptor) and INSIGF [the overlapping region of IGF2 and insulin (INS)] in the child through any periconception maternal smoking and education level. In 120 children at 17 months of age, methylation of DNA derived from white blood cells was measured. Periconception smoking and low education were independently associated with INSIGF methylation and showed a relative increase in methylation of +1.3%; P = 0.043 and +1.6%; P = 0.021. Smoking and low education showed an additive effect on INSIGF methylation (+2.8%; P = 0.011). There were no associations with IGF2 DMR and IGF2R methylation. Our data suggest that periconception maternal smoking and low education are associated with epigenetic marks on INSIGF in the very young child, this warrants further study in additional populations.

A maternal dietary pattern characterised by fish and seafood in association with the risk of congenital heart defects in the offspring.

OBJECTIVE: To identify maternal dietary patterns related to biomarkers of methylation and to investigate associations between these dietary patterns and the risk of congenital heart defects (CHDs) in the offspring. DESIGN: Case-control study. SETTING: Western part of the Netherlands, 2003-08. POPULATION: One hundred and seventy-nine mothers of children with CHD and 231 mothers of children without a congenital malformation. METHODS: Food intake was obtained by food frequency questionnaires. The reduced rank regression method was used to identify dietary patterns related to the biomarker concentrations of methylation in blood. MAIN OUTCOME MEASURES: Dietary patterns, vitamin B and homocysteine concentrations, biomarkers of methylation (S-adenosylmethionine [SAM] and S-adenosylhomocysteine [SAH]) and the risk of CHD estimated by odds ratios and 95% confidence intervals. RESULTS: The one-carbon-poor dietary pattern, comprising a high intake of snacks, sugar-rich products and beverages, was associated with SAH (ß = 0.92, P < 0.001). The one-carbon-rich dietary pattern with high fish and seafood intake was associated with SAM (ß = 0.44, P < 0.001) and inversely with SAH (ß =-0.08, P < 0.001). Strong adherence to this dietary pattern resulted in higher serum (P <0.05) and red blood cell (P < 0.01) folate and a reduced risk of CHD in offspring: odds ratio, 0.3 (95% confidence interval, 0.2-0.6). CONCLUSIONS: The one-carbon-rich dietary pattern, characterised by the high intake of fish and seafood, is associated with a reduced risk of CHD. This finding warrants further investigation in a randomised intervention trial.