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.].

Differences in birth weight between immigrants' and natives' children in Europe and Australia: a LifeCycle comparative observational cohort study.

OBJECTIVE: Research on adults has identified an immigrant health advantage, known as the 'immigrant health paradox', by which migrants exhibit better health outcomes than natives. Is this health advantage transferred from parents to children in the form of higher birth weight relative to children of natives? SETTING: Western Europe and Australia. PARTICIPANTS: We use data from nine birth cohorts participating in the LifeCycle Project, including five studies with large samples of immigrants' children: Etude Longitudinale Française depuis l'Enfance-France (N=12 494), the Raine Study-Australia (N=2283), Born in Bradford-UK (N=4132), Amsterdam Born Children and their Development study-Netherlands (N=4030) and the Generation R study-Netherlands (N=4877). We include male and female babies born to immigrant and native parents. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is birth weight measured in grams. Different specifications were tested: birth weight as a continuous variable including all births (DV1), the same variable but excluding babies born with over 4500 g (DV2), low birth weight as a 0-1 binary variable (1=birth weight below 2500 g) (DV3). Results using these three measures were similar, only results using DV1 are presented. Parental migration status is measured in four categories: both parents natives, both born abroad, only mother born abroad and only father born abroad. RESULTS: Two patterns in children's birth weight by parental migration status emerged: higher birth weight among children of immigrants in France (+12 g, p<0.10) and Australia (+40 g, p<0.10) and lower birth weight among children of immigrants in the UK (-82 g, p<0.05) and the Netherlands (-80 g and -73 g, p<0.001) compared with natives' children. Smoking during pregnancy emerged as a mechanism explaining some of the birth weight gaps between children of immigrants and natives. CONCLUSION: The immigrant health advantage is not universally transferred to children in the form of higher birth weight in all host countries. Further research should investigate whether this cross-national variation is due to differences in immigrant communities, social and healthcare contexts across host countries.

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.

Associations of maternal and infant metabolite profiles with foetal growth and the odds of adverse birth outcomes.

BACKGROUND: Adaptations in maternal and foetal metabolic pathways may predispose to altered foetal growth and adverse birth outcomes. OBJECTIVE: To assess the associations of maternal early-pregnancy metabolite profiles and infant metabolite profiles at birth with foetal growth from first trimester onwards and the odds of adverse birth outcomes. METHODS: In a prospective population-based cohort among 976 Dutch pregnant women and their children, serum concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL) and carnitines in maternal early-pregnancy blood and in cord blood were obtained by liquid-chromatography tandem mass spectrometry. Information on foetal growth was available from first trimester onwards. RESULTS: After false discovery rate correction for multiple testing, higher infant total and individual NEFA concentrations were associated with a lower weight, length, and head circumference at birth. Higher infant total and individual acyl-lysophosphatidylcholine (lyso.PC.a) and alkyl-lysophosphatidylcholine concentrations were associated with higher weight and head circumference (lyso.PC.a only) at birth, higher odds of LGA and lower odds of SGA. Few individual maternal metabolites were associated with foetal growth measures in third trimester and at birth, but not with the odds of adverse birth outcomes. CONCLUSIONS: Our results suggest that infant metabolite profiles, particularly total and individual lyso.PC.a and NEFA concentrations, were strongly related to growth measures at birth and the odds of adverse birth outcomes. Few individual maternal early-pregnancy metabolites, but not total metabolite concentrations, are associated with foetal growth measures in third trimester and at birth.

Maternal Body Mass Index, Early-Pregnancy Metabolite Profile, and Birthweight.

CONTEXT: Maternal prepregnancy body mass index (BMI) has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. OBJECTIVE: First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. DESIGN, SETTING, AND PARTICIPANTS: Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. MAIN OUTCOME MEASURES: Maternal nonfasting targeted amino acids, nonesterified fatty acid, phospholipid, and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight was obtained from medical records. RESULTS: A higher prepregnancy BMI was associated with 72 altered amino acids, nonesterified fatty acid, phospholipid and carnitine concentrations, and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress, and lipid metabolic processes (P-values < 0.05). Using penalized regression models, a metabolite profile was selected including 15 metabolites and 4 metabolite ratios based on its association with birthweight in addition to prepregnancy BMI. The adjusted R2 of birthweight was 6.1% for prepregnancy BMI alone, 6.2% after addition of glucose and lipid concentrations, and 12.9% after addition of the metabolite profile. CONCLUSIONS: A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, nonesterified fatty acids, phospholipids, and carnitines. Using these metabolites, we identified a maternal metabolite profile that improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

Associations of maternal bisphenol urine concentrations during pregnancy with neonatal metabolomic profiles.

BACKGROUND: Fetal exposure to bisphenols is associated with altered fetal growth, adverse birth outcomes and childhood cardio-metabolic risk factors. Metabolomics may serve as a tool to identify the mechanisms underlying these associations. We examined the associations of maternal bisphenol urinary concentrations in pregnancy with neonatal metabolite profiles from cord blood. METHODS: In a population-based prospective cohort study among 225 mother-child pairs, maternal urinary bisphenol A, S and F concentrations in first, second and third trimester were measured. LC-MS/MS was used to determine neonatal concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL), and carnitines in cord blood. RESULTS: No associations of maternal total bisphenol concentrations with neonatal metabolite profiles were present. Higher maternal average BPA concentrations were associated with higher neonatal mono-unsaturated alkyl-lysophosphatidylcholine concentrations, whereas higher maternal average BPS was associated with lower neonatal overall and saturated alkyl-lysophosphatidylcholine (p-values < 0.05).Trimester-specific analyses showed that higher maternal BPA, BPS and BPF were associated with alterations in neonatal NEFA, diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholine, sphingomyelines and acyl-carnitines, with the strongest effects for third trimester maternal bisphenol and neonatal diacyl-phosphatidylcholine, sphingomyeline and acyl-carnitine metabolites (p-values < 0.05). Associations were not explained by maternal socio-demographic and lifestyle characteristics or birth characteristics. DISCUSSION: Higher maternal bisphenol A, F and S concentrations in pregnancy are associated with alterations in neonatal metabolite profile, mainly in NEFA, PL and carnitines concentrations. These findings provide novel insight into potential mechanisms underlying associations of maternal bisphenol exposure during pregnancy with adverse offspring outcomes but need to be replicated among larger, diverse populations.

The EU Child Cohort Network's core data: establishing a set of findable, accessible, interoperable and re-usable (FAIR) variables.

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community.

Maternal First-Trimester Cow-Milk Intake Is Positively Associated with Childhood General and Abdominal Visceral Fat Mass and Lean Mass but Not with Other Cardiometabolic Risk Factors at the Age of 10 Years.

BACKGROUND: Higher maternal cow-milk intake during pregnancy is associated with higher fetal growth measures and higher birth weight. OBJECTIVE: The aim of this study was to assess the associations of maternal milk intake during pregnancy with body fat measures and cardiometabolic risk factors at the age of 10 y. METHODS: In a population-based cohort of Dutch mothers and their children (n = 2466) followed from early pregnancy onwards, we assessed maternal first-trimester milk intake (milk and milk drinks) by food-frequency questionnaire. Maternal milk intake was categorized into 0-0.9, 1-1.9, 2-2.9, 3-3.9, 4-4.9, and ≥5 glasses/d, with 1 glass equivalent to 150 mL milk. For children at the age of 10 y, we calculated BMI and obtained detailed measures of body and organ fat by DXA and MRI. We also measured blood pressure and lipid, insulin, and glucose concentrations. Data were analyzed using linear and logistic regression models. RESULTS: Compared with children whose mothers consumed 0-0.9 glass of milk/d during their pregnancy, those whose mothers consumed ≥5 glasses of milk/d had a 0.29 SD (95% CI: 0.10, 0.48) higher BMI, 0.27 SD (95% CI: 0.08, 0.47) higher fat mass, 0.26 SD (95% CI: 0.07, 0.46) higher lean mass, 0.30 SD (95% CI: 0.09, 0.50) higher android-to-gynoid fat mass ratio and 0.38 SD (95% CI: 0.09, 0.67) higher abdominal visceral fat mass. After correction for multiple comparisons, groups of maternal milk intake were not associated with pericardial fat mass index, liver fat fraction, blood pressure, or lipid, insulin, or glucose concentrations (P values >0.0125). CONCLUSIONS: Our results suggest that maternal first-trimester milk intake is positively associated with childhood general and abdominal visceral fat mass and lean mass, but not with other cardiometabolic risk factors.

Maternal Glucose Concentrations in Early Pregnancy and Cardiometabolic Risk Factors in Childhood.

OBJECTIVE: This study aimed to examine the associations of maternal early-pregnancy glucose and insulin concentrations with offspring cardiometabolic risk factors and fat distribution. METHODS: In a population-based prospective cohort study among 3,737 mothers and their children, random maternal glucose and insulin concentrations were measured at a median gestational age of 13.2 (95% range 10.5-17.1) weeks. Childhood fat, blood pressure, and blood concentrations of lipids, glucose, and insulin at the age of 10 years were measured. RESULTS: Higher maternal early-pregnancy glucose and insulin concentrations were associated with a higher risk of childhood overweight, and higher maternal early-pregnancy insulin concentrations were associated with an increased childhood risk of clustering of cardiometabolic risk factors (all P < 0.05). These associations were explained by maternal prepregnancy BMI. Independent of maternal prepregnancy BMI, one SD score (SDS) higher maternal early-pregnancy glucose and insulin concentrations were associated with higher childhood glucose (0.08 SDS, 95% CI: 0.04-0.11) and insulin concentrations (0.07 SDS, 95% CI: 0.03-0.10), but not with childhood blood pressure, lipids, and fat measures. CONCLUSIONS: These results suggest that maternal early-pregnancy random glucose and insulin concentrations are associated with childhood glucose and insulin concentrations but not with other childhood cardiometabolic risk factors.

Second and third trimester fetal ultrasound population screening for risks of preterm birth and small-size and large-size for gestational age at birth: a population-based prospective cohort study

BACKGROUND: Preterm birth, small size for gestational age (SGA) and large size for gestational age (LGA) at birth are major risk factors for neonatal and long-term morbidity and mortality. It is unclear which periods of pregnancy are optimal for ultrasound screening to identify fetuses at risk of preterm birth, SGA or LGA at birth. We aimed to examine whether single or combined second and third trimester ultrasound in addition to maternal characteristics at the start of pregnancy are optimal to detect fetuses at risk for preterm birth, SGA and LGA. METHODS: In a prospective population-based cohort among 7677 pregnant women, we measured second and third trimester estimated fetal weight (EFW), and uterine artery pulsatility and umbilical artery resistance indices as placenta flow measures. Screen positive was considered as EFW or placenta flow measure < 10th or > 90th percentile. Information about maternal age, body mass index, ethnicity, parity, smoking, fetal sex and birth outcomes was available from questionnaires and medical records. Screening performance was assessed via receiver operating characteristic (ROC) curves and area under the curve (AUC) along with sensitivity at different false-positive rates. RESULTS: Maternal characteristics only and in combination with second trimester EFW had a moderate performance for screening for each adverse birth outcome. Screening performance improved by adding third trimester EFW to the maternal characteristics (AUCs for preterm birth 0.64 (95%CI 0.61 to 0.67); SGA 0.79 (95%CI 0.78 to 0.81); LGA 0.76 (95%CI 0.75; 0.78)). Adding third trimester placenta measures to this model improved only screening for risk of preterm birth (AUC 0.72 (95%CI 0.66 to 0.77) with sensitivity 37% at specificity 90%) and SGA (AUC 0.83 (95%CI 0.81 to 0.86) with sensitivity 55% at specificity 90%). Combining second and third trimester fetal and placental ultrasound did not lead to a better performance as compared to using only third trimester results. CONCLUSIONS: Combining single third trimester fetal and placental ultrasound results with maternal characteristics has the best screening performance for risks of preterm birth, SGA and LGA. As compared to second trimester screening, third trimester screening may double the detection of fetuses at risk of common adverse birth outcomes.

A population-based resource for intergenerational metabolomics analyses in pregnant women and their children: the Generation R Study.

INTRODUCTION: Adverse exposures in early life may predispose children to cardio-metabolic disease in later life. Metabolomics may serve as a valuable tool to disentangle the metabolic adaptations and mechanisms that potentially underlie these associations. OBJECTIVES: To describe the acquisition, processing and structure of the metabolomics data available in a population-based prospective cohort from early pregnancy onwards and to examine the relationships between metabolite profiles of pregnant women and their children at birth and in childhood. METHODS: In a subset of 994 mothers-child pairs from a prospective population-based cohort study among pregnant women and their children from Rotterdam, the Netherlands, we used LC-MS/MS to determine concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines in blood serum collected in early pregnancy, at birth (cord blood), and at child's age 10 years. RESULTS: Concentrations of diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholines and sphingomyelines were the highest in early pregnancy, concentrations of amino acids and non-esterified fatty acids were the highest at birth and concentrations of alkyl-lysophosphatidylcholines, free carnitine and acyl-carnitines were the highest at age 10 years. Correlations of individual metabolites between pregnant women and their children at birth and at the age of 10 years were low (range between r = - 0.10 and r = 0.35). CONCLUSION: Our results suggest that unique metabolic profiles are present among pregnant women, newborns and school aged children, with limited intergenerational correlations between metabolite profiles. These data will form a valuable resource to address the early metabolic origins of cardio-metabolic disease.

Associations of maternal caffeine intake during pregnancy with abdominal and liver fat deposition in childhood.

BACKGROUND: Maternal caffeine intake during pregnancy is associated with an increased risk of childhood obesity. Studies in adults suggest that caffeine intake might also directly affect visceral and liver fat deposition, which are strong risk factors for cardio-metabolic disease. OBJECTIVE: To assess the associations of maternal caffeine intake during pregnancy with childhood general, abdominal, and liver fat mass at 10 years of age. METHODS: In a population-based cohort from early pregnancy onwards among 4770 mothers and children, we assessed maternal caffeine intake during pregnancy and childhood fat mass at age 10 years. RESULTS: Compared with children whose mothers consumed <2 units of caffeine per day during pregnancy, those whose mothers consumed 4-5.9 and ≥6 units of caffeine per day had a higher body mass index, total body fat mass index, android/gynoid fat mass ratio, and abdominal subcutaneous and visceral fat mass indices. Children whose mothers consumed 4-5.9 units of caffeine per day had a higher liver fat fraction. The associations with abdominal visceral fat and liver fat persisted after taking childhood total body fat mass into account. CONCLUSIONS: High maternal caffeine intake during pregnancy was associated with higher childhood body mass index, total body fat, abdominal visceral fat, and liver fat. The associations with childhood abdominal visceral fat and liver fat fraction were independent of childhood total body fat. This suggests differential fat accumulation in these depots, which may increase susceptibility to cardio-metabolic disease in later life.

Associations of maternal quitting, reducing, and continuing smoking during pregnancy with longitudinal fetal growth: Findings from Mendelian randomization and parental negative control studies.

BACKGROUND: Maternal smoking during pregnancy is an established risk factor for low infant birth weight, but evidence on critical exposure windows and timing of fetal growth restriction is limited. Here we investigate the associations of maternal quitting, reducing, and continuing smoking during pregnancy with longitudinal fetal growth by triangulating evidence from 3 analytical approaches to strengthen causal inference. METHODS AND FINDINGS: We analysed data from 8,621 European liveborn singletons in 2 population-based pregnancy cohorts (the Generation R Study, the Netherlands 2002-2006 [n = 4,682]) and the Born in Bradford study, United Kingdom 2007-2010 [n = 3,939]) with fetal ultrasound and birth anthropometric measures, parental smoking during pregnancy, and maternal genetic data. Associations with trajectories of estimated fetal weight (EFW) and individual fetal parameters (head circumference, femur length [FL], and abdominal circumference [AC]) from 12-16 to 40 weeks' gestation were analysed using multilevel fractional polynomial models. We compared results from (1) confounder-adjusted multivariable analyses, (2) a Mendelian randomization (MR) analysis using maternal rs1051730 genotype as an instrument for smoking quantity and ease of quitting, and (3) a negative control analysis comparing maternal and mother's partner's smoking associations. In multivariable analyses, women who continued smoking during pregnancy had a smaller fetal size than non-smokers from early gestation (16-20 weeks) through to birth (p-value for each parameter < 0.001). Fetal size reductions in continuing smokers followed a dose-dependent pattern (compared to non-smokers, difference in mean EFW [95% CI] at 40 weeks' gestation was -144 g [-182 to -106], -215 g [-248 to -182], and -290 g [-334 to -247] for light, moderate, and heavy smoking, respectively). Overall, fetal size reductions were most pronounced for FL. The fetal growth trajectory in women who quit smoking in early pregnancy was similar to that of non-smokers, except for a shorter FL and greater AC around 36-40 weeks' gestation. In MR analyses, each genetically determined 1-cigarette-per-day increase was associated with a smaller EFW from 20 weeks' gestation to birth in smokers (p = 0.01, difference in mean EFW at 40 weeks = -45 g [95% CI -81 to -10]) and a greater EFW from 32 weeks' gestation onwards in non-smokers (p = 0.03, difference in mean EFW at 40 weeks = 26 g [95% CI 5 to 47]). There was no evidence that partner smoking was associated with fetal growth. Study limitations include measurement error due to maternal self-report of smoking and the modest sample size for MR analyses resulting in unconfounded estimates being less precise. The apparent positive association of the genetic instrument with fetal growth in non-smokers suggests that genetic pleiotropy may have masked a stronger association in smokers. CONCLUSIONS: A consistent linear dose-dependent association of maternal smoking with fetal growth was observed from the early second trimester onwards, while no major growth deficit was found in women who quit smoking early in pregnancy except for a shorter FL during late gestation. These findings reinforce the importance of smoking cessation advice in preconception and antenatal care and show that smoking reduction can lower the risk of impaired fetal growth in women who struggle to quit.

High maternal early-pregnancy blood glucose levels are associated with altered fetal growth and increased risk of adverse birth outcomes.

AIMS/HYPOTHESIS: The study aimed to assess the associations of maternal early-pregnancy blood glucose levels with fetal growth throughout pregnancy and the risks of adverse birth outcomes. METHODS: In a population-based prospective cohort study among 6116 pregnant women, maternal non-fasting glucose levels were measured in blood plasma at a median 13.2 weeks of gestation (95% range 9.6-17.6). We measured fetal growth by ultrasound in each pregnancy period. We obtained information about birth outcomes from medical records and maternal sociodemographic and lifestyle factors from questionnaires. RESULTS: Higher maternal early-pregnancy non-fasting glucose levels were associated with altered fetal growth patterns, characterised by decreased fetal growth rates in mid-pregnancy and increased fetal growth rates from late pregnancy onwards, resulting in an increased length and weight at birth (p ≤0.05 for all). A weaker association of maternal early-pregnancy non-fasting glucose levels with fetal head circumference growth rates was present. Higher maternal early-pregnancy non-fasting glucose levels were also associated with an increased risk of delivering a large-for-gestational-age infant, but decreased risk of delivering a small-for-gestational-age infant (OR 1.28 [95% CI 1.16, 1.41], OR 0.88 [95% CI 0.79, 0.98] per mmol/l increase in maternal early-pregnancy non-fasting glucose levels, respectively). These associations were not explained by maternal sociodemographic factors, lifestyle factors or BMI. Maternal early-pregnancy non-fasting glucose levels were not associated with preterm birth or delivery complications. CONCLUSIONS/INTERPRETATION: Higher maternal early-pregnancy non-fasting glucose levels are associated with decreased fetal growth rates in mid-pregnancy and increased fetal growth rates from late pregnancy onwards, and an increased risk of delivering a large-for-gestational-age infant. Future preventive strategies need to focus on screening for an impaired maternal glucose metabolism from preconception and early pregnancy onwards to improve birth outcomes.

Association of Gestational Weight Gain With Adverse Maternal and Infant Outcomes.

Importance: Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges. Objectives: To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories. Design, Setting, and Participants: Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015. Exposures: Gestational weight gain. Main Outcomes and Measures: The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth. Results: Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI <18.5); 133 788 (68.0%), normal weight (BMI, 18.5-24.9); 38 828 (19.7%), overweight (BMI, 25.0-29.9); 11 992 (6.1%), obesity grade 1 (BMI, 30.0-34.9); 3284 (1.7%), obesity grade 2 (BMI, 35.0-39.9); and 969 (0.5%), obesity grade 3 (BMI, ≥40.0). Overall, any adverse outcome occurred in 37.2% (n = 73 161) of women, ranging from 34.7% (2706 of 7809) among women categorized as underweight to 61.1% (592 of 969) among women categorized as obesity grade 3. Optimal gestational weight gain ranges were 14.0 kg to less than 16.0 kg for women categorized as underweight; 10.0 kg to less than 18.0 kg for normal weight; 2.0 kg to less than 16.0 kg for overweight; 2.0 kg to less than 6.0 kg for obesity grade 1; weight loss or gain of 0 kg to less than 4.0 kg for obesity grade 2; and weight gain of 0 kg to less than 6.0 kg for obesity grade 3. These gestational weight gain ranges were associated with low to moderate discrimination between those with and those without adverse outcomes (range for area under the receiver operating characteristic curve, 0.55-0.76). Results for discriminative performance in the validation sample were similar to the corresponding results in the main study sample (range for area under the receiver operating characteristic curve, 0.51-0.79). Conclusions and Relevance: In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights. The estimates of optimal gestational weight gain may inform prenatal counseling; however, the optimal gestational weight gain ranges had limited predictive value for the outcomes assessed.

The association between GAD65 antibody levels and incident Type 2 Diabetes Mellitus in an adult population: A meta-analysis.

CONTEXT: Antibodies to the 65 kD isoform of glutamic acid decarboxylase (GAD65) have been associated with incident Type 2 Diabetes Mellitus, however results are inconsistent. OBJECTIVE: To assess the association between GAD65 antibody positivity and incident Type 2 Diabetes Mellitus in a non-diabetic adult (≥18 years) population, in a systematic review and meta-analysis. DATA SOURCES: A systematic literature search was conducted in Pubmed (MEDLINE) and Embase until January 14th, 2019. STUDY SELECTION: Included studies were 1) prospective studies on the association between GAD65 antibodies and incident Type 2 Diabetes Mellitus; 2) in a non-diabetic adult (≥18 years) population. To strengthen the review, unpublished data from 1302 Hoorn Study participants were included. DATA EXTRACTION: Data extraction and quality assessment were performed independently by two observers. Ten studies were rated for methodological quality and seven were pooled using a random-effects meta-analysis, of which 2 strong, 2 moderate and 3 of low methodological quality. DATA SYNTHESIS: The pooled risk estimate of incident Type 2 Diabetes Mellitus for GAD65 antibody positivity, compared to GAD65 antibody negativity was 3.36 (95% CI: 1.9-5.9). This result was robust to sensitivity analyses. Heterogeneity between studies was significant with I2 statistic of 79% (p < 0.0001). However, excluding one study showed a decrease of I2 to 19% (p < 0.0001), explaining a large part of the heterogeneity. CONCLUSION: GAD65 antibody positivity was associated with an increased risk of future Type 2 Diabetes Mellitus in adults.

Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis.

BACKGROUND: Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. METHODS AND FINDINGS: We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. CONCLUSIONS: In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.

Subcutaneous fat mass in infancy and abdominal, pericardial and liver fat assessed by Magnetic Resonance Imaging at the age of 10 years.

BACKGROUND/OBJECTIVES: Fat mass development in infancy contributes to later adiposity, but its relation to ectopic fat depots is unknown. We examined the associations of infant subcutaneous fat with childhood general and organ-specific fat. SUBJECTS/METHODS: Among 593 children from a population-based prospective cohort study, we obtained total subcutaneous fat mass (as sum of biceps, triceps, suprailiacal, and subscapular skinfolds thickness), central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thickness/total subcutaneous fat) at 1.5, 6 and 24 months of age. At 10 years, we assessed BMI, fat mass index (FMI) based on total body fat by dual-energy X-ray absorptiometry, and abdominal subcutaneous, visceral and pericardial fat mass indices, and liver fat fraction by Magnetic Resonance Imaging. RESULTS: A higher central-to-total subcutaneous fat ratio at 1.5 months only and higher total subcutaneous fat at 6 and 24 months were associated with higher BMI, FMI and subcutaneous fat mass index at 10 years. The observed associations were the strongest between total subcutaneous fat at 24 months and these childhood outcomes (difference per 1-SDS increase in total subcutaneous fat: 0.15 SDS (95% Confidence Interval (CI) 0.08, 0.23), 0.17 SDS (95% CI 0.10, 0.24), 0.16 SDS (95% CI 0.08, 0.23) for BMI, FMI and childhood subcutaneous fat mass index, respectively). Infant subcutaneous fat measures at any time point were not associated with visceral and pericardial fat mass indices, and liver fat fraction at 10 years. CONCLUSIONS: Our results suggest that infant subcutaneous fat is associated with later childhood abdominal subcutaneous fat and general adiposity, but not with other organ-specific fat depots.

Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania.

BACKGROUND: Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. METHODS: We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. RESULTS: We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4-17.4) for underweight women, 14.5 kg (11.5-17.7) for normal weight women, 13.9 kg (10.1-17.9) for overweight women, and 11.2 kg (7.0-15.7), 8.7 kg (4.3-13.4) and 6.3 kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. CONCLUSIONS: Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.