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Context Low birth weight, as seen in Silver-Russell syndrome (SRS), is associated with later cardiometabolic disease. Data on long-term outcomes and adult body composition in SRS are limited. Objective To evaluate body composition and metabolic health in adults with SRS. Methods This was an observational study of 25 individuals with molecularly confirmed SRS, aged ≥ 18 years, from research facilities across the UK. Body composition and metabolic health were assessed at a single appointment. Individuals with SRS were compared with unaffected men and women (from the Southampton Women's Survey [SWS]). Fat mass, lean mass, bone mineral density (BMD), blood pressure, lipids, and blood glucose were measured. Results Twenty-five adults with SRS were included (52% female). The median age was 32.9 years (range, 22.0 to 69.7). Fat percentage was greater in the SRS group than the SWS cohort (44.1% vs 30.3%, P <.001). Fat mass index was similar (9.6 vs 7.8, P =.3). Lean mass percentage (51.8% vs 66.2%, P <.001) and lean mass index (13.5 kg/m2 vs 17.3 kg/m2, P <.001) were lower in the SRS group than the SWS cohort. BMD was lower in the SRS group than the SWS cohort (1.08 vs 1.24, P <.001; all median values). Total cholesterol was ≥ 5 mmol/L in 52.0%. Triglyceride levels were ≥ 1.7 mmol/L in 20.8%. Fasting blood glucose levels were ≥ 6.1 mmol/L in 25.0%. Hypertension was present in 33.3%. Conclusion Adults with SRS have an unfavorable body composition and predisposition to cardiometabolic disease. These results support the need for a health surveillance strategy to mitigate adverse outcomes. [ABSTRACT FROM AUTHOR]

Background Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). Methods MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. Results A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P  = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P  = 0.054) overall], but similar when stratified by delivery mode. Conclusions Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD. [ABSTRACT FROM AUTHOR]

Aims To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. Methods and results Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (−0.53 mmHg; 95% CI:−1.59 to 0.53), DBP (−0.24 mmHg; −0.83 to 0.35), or HR (0.02 beat/min; −0.91 to 0.94). Total cholesterol (2.59%; 0.10–5.07), HDL cholesterol (4.16%; 2.52–5.81), LDL cholesterol (4.95%; 0.47–9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. Conclusion These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease. [ABSTRACT FROM AUTHOR]

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter‐born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long‐term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single‐center follow‐up of a double‐blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25‐hydroxyvitamin D level 25–100 nmol/L from three research centers (2008–2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013–2018). Anthropometry and dual‐energy X‐ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4‐year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472–0.481) g/cm2; placebo group: 0.470 (95% CI, 0.466–0.475) g/cm2, p = 0.048). Associations were consistent for BMC and lean mass, and in age‐ and sex‐adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal‐child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Background: Choline status has been positively associated with weight and fat mass in animal and human studies. As evidence examining maternal circulating choline concentrations and offspring body composition in human infants/children is lacking, we investigated this in two cohorts.Methods: Maternal choline concentrations were measured in the UK Southampton Women's Survey (SWS; serum, n = 985, 11 weeks' gestation) and Singapore Growing Up Towards healthy Outcomes (GUSTO); n = 955, 26-28 weeks' gestation) mother-offspring cohorts. Offspring anthropometry was measured at birth and up to age 5 years. Body fat mass was determined using dual-energy x-ray absorptiometry at birth and age 4 years for SWS; and using air-displacement plethysmography at birth and age 5 years for GUSTO. Linear-regression analyses were performed, adjusting for confounders.Results: In SWS, higher maternal choline concentrations were associated with higher neonatal total body fat mass {β = 0.60 standard deviation [SD]/5 µmol/L maternal choline [95% confidence interval (CI) 0.04-1.16]} and higher subscapular skinfold thickness [β = 0.55 mm/5 µmol/L (95% CI, 0.12-1.00)] at birth. In GUSTO, higher maternal choline concentrations were associated with higher neonatal body mass index-for-age z-score [β = 0.31 SD/5 µmol/L (0.10-0.51)] and higher triceps [β = 0.38 mm/5 µmol/L (95% CI, 0.11-0.65)] and subscapular skinfold thicknesses [β = 0.26 mm/5 µmol/L (95% CI, 0.01-0.50)] at birth. No consistent trends were observed between maternal choline and offspring gain in body mass index, skinfold thicknesses, abdominal circumference, weight, length/height and adiposity measures in later infancy and early childhood.Conclusion: Our study provides evidence that maternal circulating choline concentrations during pregnancy are positively associated with offspring BMI, skinfold thicknesses and adiposity at birth, but not with growth and adiposity through infancy and early childhood to the age of 5 years. [ABSTRACT FROM AUTHOR]

Background Fucosyltransferase 2 (FUT2) controls the production of digestive and respiratory epithelia of histo-blood group antigens involved in the attachment of pathogens. The aim of our study was to relate FUT2 variants to reported gastrointestinal and respiratory illnesses in infancy. Methods In the Southampton Women's Survey, FUT2 genetic variants (single-nucleotide polymorphisms [SNPs] rs601338 and rs602662) were genotyped in 1831 infants and related to infant illnesses, after adjustment for sex, breastfeeding duration, and potential confounders. Results For FUT2 SNP rs601338, the risk ratios for ≥1 bout of diarrhea during ages 6–12 months and ages 12–24 months per additional risk (G) allele were 1.23 (95% confidence interval [CI], 1.08–1.4; P =.002) and 1.41 (95% CI, 1.24–1.61; P = 1.7 × 10−7), respectively; the risk ratio for ≥1 diagnosis of a lower respiratory illness (ie, pneumonia or bronchiolitis) during ages 12–24 months per additional G allele was 2.66 (95% CI, 1.64–4.3; P =.00007). Similar associations were found between rs602662 and gastrointestinal and respiratory illnesses, owing to the high linkage disequilibrium with rs601338 (R2 = 0.92). Longer breastfeeding duration predicted a lower risk of diarrhea, independent of infant FUT2 genotype. Conclusions We confirmed that FUT2 G alleles are associated with a higher risk of infant gastrointestinal illnesses and identified novel associations with respiratory illnesses. FUT2 locus variants need consideration in future studies of gastrointestinal and respiratory illnesses among infants. [ABSTRACT FROM AUTHOR]

We have previously demonstrated inverse associations between maternal 25(OH)‐vitamin D status and perinatal DNA methylation at the retinoid‐X‐receptor‐alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double‐blind, randomized, placebo‐controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks' gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at −80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol‐supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was −1.98% (95% CI, −3.65 to −0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer‐related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that prenatal exposure to n-3 long-chain fatty acids protects against asthma and other allergy-related diseases later in childhood. The extent to which fish intake in pregnancy protects against child asthma and rhinitis symptoms remains unclear. We aimed to assess whether fish and seafood consumption in pregnancy is associated with childhood wheeze, asthma and allergic rhinitis.Methods: We pooled individual data from 60 774 mother-child pairs participating in 18 European and US birth cohort studies. Information on wheeze, asthma and allergic rhinitis prevalence was collected using validated questionnaires. The time periods of interest were: infancy (0-2 years), preschool age (3-4 years), and school age (5-8 years). We used multivariable generalized models to assess associations of fish and seafood (other than fish) consumption during pregnancy with child respiratory outcomes in cohort-specific analyses, with subsequent random-effects meta-analyses.Results: The median fish consumption during pregnancy ranged from 0.44 times/week in The Netherlands to 4.46 times/week in Spain. Maternal fish intake during pregnancy was not associated with offspring wheeze symptoms in any age group nor with the risk of child asthma [adjusted meta-analysis relative risk (RR) per 1-time/week = 1.01, 95% confidence interval 0.97-1.05)] and allergic rhinitis at school age (RR = 1.01, 0.99-1.03). These results were consistently found in further analyses by type of fish and seafood consumption and in sensitivity analyses.Conclusion: We found no evidence supporting a protective association of fish and seafood consumption during pregnancy with offspring symptoms of wheeze, asthma and allergic rhinitis from infancy to mid childhood. [ABSTRACT FROM AUTHOR]

Background: Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but, as yet, there is little direct evidence for such mechanisms in humans.Method: We examined the relation between DNA methylation at birth and child neuropsychological outcomes in two culturally diverse populations using a genome-wide methylation analysis and validation by pyrosequencing.Results: Within the UK Southampton Women's Survey (SWS) we first identified 41 differentially methylated regions of interest (DMROI) at birth associated with child's full-scale IQ at age 4 years. Associations between HES1 DMROI methylation and later cognitive function were confirmed by pyrosequencing in 175 SWS children. Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS 7-year-olds. Finally, we examined a pathway for this relationship within a Singaporean cohort (n = 108). Here, HES1 DMROI methylation predicted differences in early infant behaviour, known to be associated with academic success. In vitro, methylation of HES1 inhibited ETS transcription factor binding, suggesting a functional role of this site.Conclusions: Thus, our findings suggest that perinatal epigenetic processes mark later neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development. [ABSTRACT FROM AUTHOR]

ABSTRACT Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X receptor-alpha (RXRA) is an essential cofactor in the action of 1,25-dihydroxyvitamin D (1,25[OH]2-vitamin D), and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based mother-offspring cohort (Southampton Women's Survey). Relationships between maternal plasma 25-hydroxyvitamin D (25[OH]-vitamin D) concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, a higher percent methylation at four of six RXRA CpG sites measured was correlated with lower offspring bone mineral content (BMC) corrected for body size (β = −2.1 to −3.4 g/SD, p = 0.002 to 0.047). In a second independent cohort ( n = 64), similar negative associations at two of these CpG sites, but positive associations at the two remaining sites, were observed; however, none of the relationships in this replication cohort achieved statistical significance. The maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β = −3.3 SD/unit, p = 0.03). Thus, perinatal epigenetic marking at the RXRA promoter region in umbilical cord was inversely associated with offspring size-corrected BMC in childhood. The potential mechanistic and functional significance of this finding remains a subject for further investigation. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The article discusses the result of a study which investigated prenatal influences on bone health. The findings suggest that intrauterine growth may influence postnatal volumetric density and skeletal size and that the tracking of skeletal development originates in the prenatal period. It also indicates that the factors affecting late intrauterine growth may have lasting effects on postnatal skeletal development. It concludes that the velocity of femur growth from 19 to 34 weeks predicts childhood skeletal size at four years.

This paper reports on the results of an intensive study of the costs and cost-effectiveness of the Expanded Programme on Immunization (EPI) in The Gambia. Costs in 1988, for the nation as a whole and for a large sample of specific local delivery sites, and their relation to vaccination coverage are presented. The total and average costs of the full national EPI fell impressively in The Gambia from about US$1.50 per dose in the early 1980s to US$0.60 in 1988. That conclusion is reinforced by improvements in vaccination coverage and by a very large decline in cost per fully immunized child from about US$19.00 to US$5.64. Comparisons of the latter finding with the earlier Gambian value, and with other developing countries' figures, suggest a highly cost-effective EPI for 1988. Some of the major reasons for this were good administration, widespread deployment of delivery teams, and effective social mobilization (community awareness) efforts. The study offers site-specific cost estimates that reveal large variations in average costs among centres. Lower average costs appear to be based on economies of scale and greater intensity of use of facilities and teams, together with better management. As with the estimates for the full national programme, these variations are not explicable simply as artefacts of methodological techniques and assumptions. Although recent (1988) Gambian data indicate relatively low costs and high cost-effectiveness, the continuation of, and probable increase in, other threats to health than vaccine-preventable diseases pose daunting challenges to all parties concerned with improving the allocation of scarce resources for the wellbeing of the Gambian people, and of others in the developing world. [ABSTRACT FROM PUBLISHER]