Body composition and metabolism in adults with molecularly-confirmed Silver-Russell syndrome.

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. DESIGN: This was an observational study. 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)). SETTING: Clinical research facilities across the UK. PARTICIPANTS: 25 individuals with molecularly-confirmed SRS aged ≥18 years. MAIN OUTCOME MEASURES: Fat mass, lean mass, bone mineral density (BMD), blood pressure, lipids, and blood glucose were measured. RESULTS: 25 adults with SRS were included (52% female). The median age was 32.9 years (range 22.0-69.7). Fat percentage was greater in the SRS group than the SWS cohort (44.1% vs 30.3%, p<0.001). Fat mass index was similar (9.6 vs 7.8, p=0.3). Lean mass percentage (51.8% vs 66.2%, p<0.001) and lean mass index (13.5 kg/m2 vs 17.3 kg/m2, p<0.001) 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<0.001) (all median values). Total cholesterol was ≥5mmol/L in 52.0%. Triglyceride levels were ≥1.7mmol/L in 20.8%. Fasting blood glucose levels were ≥6.1mmol/L in 25.0%. Hypertension was present in 33.3%. CONCLUSIONS: Adults with SRS have an unfavourable body composition and predisposition to cardiometabolic disease. These results support the need for a health surveillance strategy to mitigate adverse outcomes.

Sleep duration in preschool age and later behavioral and cognitive outcomes: an individual participant data meta-analysis in five European cohorts.

Short sleep duration has been linked to adverse behavioral and cognitive outcomes in schoolchildren, but few studies examined this relation in preschoolers. We aimed to investigate the association between parent-reported sleep duration at 3.5 years and behavioral and cognitive outcomes at 5 years in European children. We used harmonized data from five cohorts of the European Union Child Cohort Network: ALSPAC, SWS (UK); EDEN, ELFE (France); INMA (Spain). Associations were estimated through DataSHIELD using adjusted generalized linear regression models fitted separately for each cohort and pooled with random-effects meta-analysis. Behavior was measured with the Strengths and Difficulties Questionnaire. Language and non-verbal intelligence were assessed by the Wechsler Preschool and Primary Scale of Intelligence or the McCarthy Scales of Children's Abilities. Behavioral and cognitive analyses included 11,920 and 2981 children, respectively (34.0%/13.4% of the original sample). In meta-analysis, longer mean sleep duration per day at 3.5 years was associated with lower mean internalizing and externalizing behavior percentile scores at 5 years (adjusted mean difference: - 1.27, 95% CI [- 2.22, - 0.32] / - 2.39, 95% CI [- 3.04, - 1.75]). Sleep duration and language or non-verbal intelligence showed trends of inverse associations, however, with imprecise estimates (adjusted mean difference: - 0.28, 95% CI [- 0.83, 0.27] / - 0.42, 95% CI [- 0.99, 0.15]). This individual participant data meta-analysis suggests that longer sleep duration in preschool age may be important for children's later behavior and highlight the need for larger samples for robust analyses of cognitive outcomes. Findings could be influenced by confounding or reverse causality and require replication.

Associations of Maternal Educational Level, Proximity to Greenspace During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood: A Proof-of-Concept Federated Analysis in 18 Birth Cohorts.

International sharing of cohort data for research is important and challenging. We explored the feasibility of multi-cohort federated analyses by examining associations between three pregnancy exposures (maternal education, exposure to green vegetation and gestational diabetes) with offspring BMI from infancy to 17 years. We used data from 18 cohorts (n=206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13 and 14-17 years. Associations were estimated using linear regression via one-stage IPD meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z-score comparing low with high education age 2-3 years = 0.03 [95% CI 0.00, 0.05], 4-7 years = 0.16 [95% CI 0.14, 0.17], 8-13 years = 0.24 [95% CI 0.22, 0.26]). Gestational diabetes was positively associated with BMI from 8 years (BMI z-score difference = 0.18 [CI 0.12, 0.25]) but not at younger ages; however associations attenuated towards the null when restricted to cohorts which measured GDM via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age one but not at older ages. Opportunities of cross-cohort federated analyses are discussed.

Lifestyle patterns in European preschoolers: Associations with socio-demographic factors and body mass index.

BACKGROUND: Energy balance-related behaviours (EBRBs), that is, dietary intake, screen, outdoor play and sleep, tend to combine into 'lifestyle patterns', with potential synergistic influences on health. To date, studies addressing this theme mainly focused on school children and rarely accounted for sleep, with a cross-country perspective. OBJECTIVES: We aimed at comparing lifestyle patterns among preschool-aged children across Europe, their associations with socio-demographic factors and their links with body mass index (BMI). METHODS: Harmonized data on 2-5-year-olds participating in nine European birth cohorts from the EU Child Cohort Network were used (EBRBs, socio-demographics and anthropometrics). Principal component analysis and multivariable linear and logistic regressions were performed. RESULTS: The most consistent pattern identified across cohorts was defined by at least three of the following EBRBs: discretionary consumption, high screen time, low outdoor play time and low sleep duration. Consistently, children from low-income households and born to mothers with low education level had higher scores on this pattern compared to their socioeconomically advantaged counterparts. Furthermore, it was associated with higher BMI z-scores in the Spanish and Italian cohorts (ß = 0.06, 95% CI = [0.02; 0.10], both studies). CONCLUSION: These findings may be valuable in informing early multi-behavioural interventions aimed at reducing social inequalities in health at a European scale.

Correction: Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.

[This corrects the article DOI: 10.1371/journal.pmed.1004036.].

Longitudinal dietary trajectories from pregnancy to 3 years post delivery in women with obesity: relationships with adiposity.

OBJECTIVE: The study aim was to examine the relationships between longitudinal dietary trajectories from early pregnancy to 3 years post delivery and adiposity measures in women with obesity. METHODS: The diets of 1208 women with obesity in the UPBEAT (UK Pregnancy Better Eating and Activity Trial) study were assessed using a food frequency questionnaire (FFQ) at 15+0 to 18+6 weeks' gestation (baseline), 27+0 to 28+6 weeks' gestation, and 34+0 to 36+0 weeks' gestation, as well as 6 months and 3 years post delivery. Using factor analysis of the baseline FFQ data, four dietary patterns were identified: fruit & vegetable, African/Caribbean, processed, and snacking. The baseline scoring system was applied to the FFQ data at the four subsequent time points. Group-based trajectory modeling was used to extract longitudinal dietary pattern trajectories. Using adjusted regression, associations between dietary trajectories and log-transformed/standardized adiposity measures (BMI and waist and mid-upper arm circumferences) at 3 years post delivery were examined. RESULTS: Two trajectories were found to best describe the data for the four individual dietary patterns; these were characterized as high and low adherence. A high adherence to the processed pattern was associated with a higher BMI (ß = 0.38 [95% CI: 0.06-0.69]) and higher waist (ß = 0.35 [0.03-0.67]) and mid-upper arm circumferences (ß = 0.36 [0.04-0.67]) at 3 years post delivery. CONCLUSIONS: In women with obesity, a processed dietary pattern across pregnancy and 3 years post delivery is associated with higher adiposity.

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis.

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.

Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. METHODS AND FINDINGS: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries. CONCLUSIONS: This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

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.

Measures of Early-life Behavior and Later Psychopathology in the LifeCycle Project - EU Child Cohort Network: A Cohort Description.

BACKGROUND: The EU LifeCycle Project was launched in 2017 to combine, harmonize, and analyze data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview of the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project. METHODS: Data on cognitive, behavioral, and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures. RESULTS: The mental health data in LifeCycle contain longitudinal and cross-sectional data from birth throughout the life course, covering domains across a wide range of behavioral and psychopathology indicators and outcomes, including executive function, depression, ADHD, and cognition. These data span a unique combination of qualitative data collected through behavioral/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of imaging (MRI, fetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts. CONCLUSION: Mental health data harmonized through the LifeCycle project can be used to study life-course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

Evaluation and interpretation of latent class modelling strategies to characterise dietary trajectories across early life: a longitudinal study from the Southampton Women's Survey.

There is increasing interest in modelling longitudinal dietary data and classifying individuals into subgroups (latent classes) who follow similar trajectories over time. These trajectories could identify population groups and time points amenable to dietary interventions. This paper aimed to provide a comparison and overview of two latent class methods: group-based trajectory modelling (GBTM) and growth mixture modelling (GMM). Data from 2963 mother-child dyads from the longitudinal Southampton Women's Survey were analysed. Continuous diet quality indices (DQI) were derived using principal component analysis from interviewer-administered FFQ collected in mothers pre-pregnancy, at 11- and 34-week gestation, and in offspring at 6 and 12 months and 3, 6-7 and 8-9 years. A forward modelling approach from 1 to 6 classes was used to identify the optimal number of DQI latent classes. Models were assessed using the Akaike and Bayesian information criteria, probability of class assignment, ratio of the odds of correct classification, group membership and entropy. Both methods suggested that five classes were optimal, with a strong correlation (Spearman's = 0·98) between class assignment for the two methods. The dietary trajectories were categorised as stable with horizontal lines and were defined as poor (GMM = 4 % and GBTM = 5 %), poor-medium (23 %, 23 %), medium (39 %, 39 %), medium-better (27 %, 28 %) and best (7 %, 6 %). Both GBTM and GMM are suitable for identifying dietary trajectories. GBTM is recommended as it is computationally less intensive, but results could be confirmed using GMM. The stability of the diet quality trajectories from pre-pregnancy underlines the importance of promotion of dietary improvements from preconception onwards.

The association between number and ages of children and the physical activity of mothers: Cross-sectional analyses from the Southampton Women's Survey.

BACKGROUND: Physical activity (PA) has many health benefits, but motherhood is often associated with reduced PA. Considering that ages and number of children may be associated with maternal PA, and that PA patterns may change as children transition to formal schooling, we aimed to investigate the associations between ages and number of children and device-measured maternal PA. METHODS: Cross-sectional analyses were conducted using data from 848 mothers from the Southampton Women's Survey at two different timepoints. Two-level random intercept linear models were used to investigate associations between ages (≤4y(ears) ("younger"), school-aged, both age groups) and number (1, 2, ≥3) of children, and their interaction, and accelerometer-assessed minutes of maternal moderate or vigorous PA (log-transformed MVPA) and light, moderate or vigorous PA (LMVPA). RESULTS: Women with any school-aged children engaged in more MVPA than those with only ≤4y (e.g. % difference in minutes of MVPA [95% confidence interval]: 46.9% [22.0;77.0] for mothers with only school-aged vs only ≤4y). Mothers with multiple children did less MVPA than those with 1 child (e.g. 12.5% [-1.1;24.3] less MVPA for those with 2 children). For mothers with multiple children, those with any school-aged children did less LMVPA than those with only ≤4y (e.g. amongst mothers with 2 children, those with only school-aged children did 34.0 [3.9;64.1] mins/day less LMVPA). For mothers with any ≤4y, those with more children did more LMVPA (e.g. amongst mothers with only ≤4y, those with 2 children did 42.6 [16.4;68.8] mins/day more LMVPA than those with 1 child). CONCLUSIONS: Mothers with multiple children and only children aged ≤4y did less MVPA. Considering that many of these women also did more LMVPA than mothers with fewer or older children, interventions and policies are needed to increase their opportunities for higher intensity PA to maximise health benefits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04715945.

Acceptability of the FIGO Nutrition Checklist in Preconception and Early Pregnancy to Assess Nutritional Status and Prevent Excess Gestational Weight Gain: A Study of Women and Healthcare Practitioners in the UK.

Optimum nutrition and weight before and during pregnancy are associated with a lower risk of conditions such as pre-eclampsia and gestational diabetes. There is a lack of user-friendly tools in most clinical settings to support healthcare practitioners (HCPs) in implementing them. This study aimed to evaluate the acceptability of (1) using a nutrition checklist designed by the International Federation of Gynecology and Obstetrics (FIGO) for nutritional screening of women in the preconception and early pregnancy period and (2) routine discussion of nutrition and weight in clinical care. An online cross-sectional survey was conducted with women (aged 18-45) and HCPs (e.g., general practitioners, obstetricians, and midwives). Quantitative statistical analysis and qualitative content analysis were performed. The concept and content of the checklist were acceptable to women (n = 251) and HCPs (n = 47) (over 80% in both groups). Several barriers exist to implementation such as lack of time, training for HCPs, and the need for sensitive and non-stigmatizing communication. Routine discussion of nutrition was considered important by both groups; however, results suggest that nutrition is not regularly discussed in perinatal visits in the UK. The FIGO nutrition checklist presents a valuable resource for use in clinical practice, offering long-term and intergenerational benefits for both mother and baby.

Pregnancy Vitamin D Supplementation and Childhood Bone Mass at Age 4 Years: Findings From the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial.

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.

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood.

Importance: People conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population. Objective: To investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study. Design, Setting, and Participants: This cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022. Exposures: Conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction). Main Outcomes and Measures: The main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups. Results: Up to 158 066 offspring (4329 conceived by ART) were included in each age-group meta-analysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were -0.27 (95% CI, -0.39 to -0.16) SD units at age younger than 3 months, -0.16 (95% CI, -0.22 to -0.09) SD units at age 17 to 23 months, -0.07 (95% CI, -0.10 to -0.04) SD units at age 6 to 9 years, and -0.02 (95% CI, -0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was -0.14 [95% CI, -0.20 to -0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, -0.15 to 0.15] SD units for frozen embryo transfer vs NC). More marked differences were seen for body fat measurements, and there was imprecise evidence that offspring conceived by ART developed greater adiposity by early adulthood (eg, ART vs NC difference in fat mass index at age older than 17 years: 0.23 [95% CI, -0.04 to 0.50] SD units). Conclusions and Relevance: These findings suggest that people conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.

Activity Behaviors in British 6-Year-Olds: Cross-Sectional Associations and Longitudinal Change During the School Transition.

BACKGROUND: To explore activity behaviors at school entry, we describe temporal/demographic associations with accelerometer-measured physical activity in a population-based sample of British 6-year-olds, and examine change from ages 4 to 6. METHODS: A total of 712 six-year-olds (308 at both ages) wore Actiheart accelerometers for ≥3 (mean 6.0) days. We derived minutes per day sedentary (<20 cpm) and moderate to vigorous physical activity (MVPA, ≥460 cpm), also segmented across mornings (06:00 AM to 09:00 AM), school (09:00 AM to 3:00 PM), and evenings (3:00 PM to 11:00 PM). Using mixed effects linear regression, we analyzed associations between temporal/demographic factors and children's activity intensities at age 6, and change between ages 4 and 6. RESULTS: Six-year-old children engaged in MVPA (mean [SD]): 64.9 (25.7) minutes per day (53% met UK guidelines). Girls did less MVPA than boys, particularly during school hours. Children were less active on weekends (vs weekdays) and more active on spring/summer evenings (vs winter). Longitudinally, 6-year-old children did less light physical activity (-43.0; 95% confidence interval, -47.5 to -38.4 min/d) but were more sedentary (29.4; 24.6 to 34.2), and engaged in greater MVPA (7.1; 5.2 to 9.1) compared to when they were aged 4. CONCLUSION: Half of 6-year-old children met current activity guidelines; MVPA levels were lower in girls and at weekends. UK children became more sedentary but did more MVPA as they entered formal schooling. Physical activity promotion efforts should capitalize on these changes in MVPA, to maintain positive habits.

Maternal antenatal vitamin D supplementation and offspring risk of atopic eczema in the first 4 years of life: evidence from a randomized controlled trial.

BACKGROUND: Evidence linking prenatal maternal vitamin D supplementation with the offspring's risk of atopic eczema is inconsistent, with most data coming from observational studies. OBJECTIVES: To examine the influence of maternal cholecalciferol supplementation during pregnancy on the risk of atopic eczema in the offspring at ages 12, 24 and 48 months. METHODS: Within the UK Maternal Vitamin D Osteoporosis Study (MAVIDOS) double-blind, randomized placebo-controlled trial, we examined the relationship of maternal vitamin D supplementation during pregnancy with offspring atopic eczema at ages 12, 24 and 48 months. In MAVIDOS, pregnant women were allocated to either cholecalciferol 1000 IU per day or matched placebo, taken from around 14 weeks' gestation until delivery, with the primary outcome of neonatal whole-body bone mineral content. The prevalence of atopic eczema in the offspring was ascertained at ages 12 (n = 635), 24 (n = 610) and 48 (n = 449) months, based on the UK Working Party criteria for the definition of atopic dermatitis. The trial was registered with ISRCTN (82927713) and EudraCT (2007-001716-23). RESULTS: The characteristics of mothers and offspring were similar between the intervention and placebo groups, apart from longer breastfeeding duration in the intervention group. Adjusting for breastfeeding duration, offspring of mothers who received cholecalciferol 1000 IU daily had a lower odds ratio (OR) of atopic eczema at age 12 months [OR 0·55, 95% confidence interval (CI) 0·32-0·97, P = 0·04]; this effect weakened and was not statistically significant at ages 24 months (OR 0·76, 95% CI 0·47-1·23) or 48 months (OR 0·75, 95% CI 0·37-1·52). The statistical interaction of intervention and breastfeeding duration in relation to eczema at age 12 months was not significant (P = 0·41), but stratification showed reduced infantile eczema risk in the intervention group for infants breastfed for ≥ 1 month (OR 0·48, 95% CI 0·24-0·94, P = 0·03) but not in those breastfed for < 1 month (OR 0·80, 95% CI 0·29-2·17, P = 0·66). CONCLUSIONS: Our data provide the first randomized controlled trial evidence of a protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema, with the effect potentially being via increased breast milk cholecalciferol levels. The findings support a developmental influence on atopic eczema, and point to a potentially modifiable perinatal influence on atopic eczema. What is already known about this topic? There are currently no antenatal interventions proven to reduce the incidence of infantile atopic eczema in the general population. However, observational studies have led to speculation that antenatal vitamin D supplementation may be beneficial.

Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children.

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

Height and body mass index in molecularly confirmed Silver-Russell syndrome and the long-term effects of growth hormone treatment.

OBJECTIVE: Silver-Russell syndrome (SRS) causes short stature. Growth hormone (GH) treatment aims to increase adult height. However, data are limited on the long-term outcomes of GH in patients with molecularly confirmed SRS. This study evaluated height, body mass index (BMI) and GH treatment in molecularly confirmed SRS. DESIGN: An observational study with retrospective data collection. PATIENTS: Individuals with molecularly confirmed SRS aged ≥13 years. MEASUREMENTS: Data were collected on height, height gain (change in height standard deviation score [SDS] from childhood to final or near-final height), BMI and gain in BMI (from childhood to adulthood) and previous GH treatment. RESULTS: Seventy-one individuals (40 female) were included. The median age was 22.0 years (range 13.2-69.7). The molecular diagnoses: H19/IGF2:IG-DMR LOM in 80.3% (57/71); upd(7)mat in 16.9% (12/71) and IGF2 mutation in 2.8% (2/71). GH treatment occurred in 77.5% (55/71). Total height gain was greater in GH-treated individuals (median 1.53 SDS vs. 0.53 SDS, p = .007), who were shorter at treatment initiation (-3.46 SDS vs. -2.91 SDS, p = .04) but reached comparable heights to GH-untreated individuals (-2.22 SDS vs. -2.74 SDS, p = .7). In GH-treated individuals, BMI SDS was lower at the most recent assessment (median -1.10 vs. 1.66, p = .002) with lower BMI gain (2.01 vs. 3.58, p = .006) despite similar early BMI SDS to GH-untreated individuals (median -2.65 vs. -2.78, p = .3). CONCLUSIONS: These results support the use of GH in SRS for increasing height SDS. GH treatment was associated with lower adult BMI which may reflect improved metabolic health even following discontinuation of therapy.

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit.

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.