Effect of common pregnancy and perinatal complications on offspring metabolic traits across the life course: a multi-cohort study.

BACKGROUND: Common pregnancy and perinatal complications are associated with offspring cardiometabolic risk factors. These complications may influence multiple metabolic traits in the offspring and these associations might differ with offspring age. METHODS: We used data from eight population-based cohort studies to examine and compare associations of pre-eclampsia (PE), gestational hypertension (GH), gestational diabetes (GD), preterm birth (PTB), small (SGA) and large (LGA) for gestational age (vs. appropriate size for gestational age (AGA)) with up to 167 plasma/serum-based nuclear magnetic resonance-derived metabolic traits encompassing lipids, lipoproteins, fatty acids, amino acids, ketones, glycerides/phospholipids, glycolysis, fluid balance, and inflammation. Confounder-adjusted regression models were used to examine associations (adjusted for maternal education, parity age at pregnancy, ethnicity, pre/early pregnancy body mass index and smoking, and offspring sex and age at metabolic trait assessment), and results were combined using meta-analysis by five age categories representing different periods of the offspring life course: neonates (cord blood), infancy (mean ages: 1.1-1.6 years), childhood (4.2-7.5 years); adolescence (12.0-16.0 years), and adulthood (22.0-67.8 years). RESULTS: Offspring numbers for each age category/analysis varied from 8925 adults (441 PTB) to 1181 infants (135 GD); 48.4% to 60.0% were females. Pregnancy complications (PE, GH, GD) were each associated with up to three metabolic traits in neonates (P≤0.001) with some evidence of persistence to older ages. PTB and SGA were associated with 32 and 12 metabolic traits in neonates respectively, which included an adjusted standardised mean difference of -0.89 standard deviation (SD) units for albumin with PTB (95% CI: -1.10 to -0.69, P=1.3×10-17) and -0.41 SD for total lipids in medium HDL with SGA (95% CI: -0.56 to -0.25, P=2.6×10-7), with some evidence of persistence to older ages. LGA was inversely associated with 19 metabolic traits including lower levels of cholesterol, lipoproteins, fatty acids, and amino acids, with associations emerging in adolescence, (e.g. -0.11 SD total fatty acids, 95% CI: -0.18 to -0.05, P=0.0009), and attenuating with older age across adulthood. CONCLUSIONS: These reassuring findings suggest little evidence of wide-spread and long-term impact of common pregnancy and perinatal complications on offspring metabolic traits, with most associations only observed for newborns rather than older ages, and for perinatal rather than pregnancy complications.

Genetic Obesity Disorders: Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population.

OBJECTIVE: We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening. STUDY DESIGN: This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated. RESULTS: We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P < .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity. CONCLUSIONS: Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities.

Maternal Early-Pregnancy Glucose Concentrations and Liver Fat Among School-Age Children.

BACKGROUND AND AIMS: Gestational diabetes seems to be associated with offspring NAFLD. We hypothesized that maternal glucose concentrations across the full range may have persistent effects on offspring liver fat accumulation. APPROACH AND RESULTS: In a multiethnic, population-based, prospective cohort study among 2,168 women and their offspring, maternal early-pregnancy glucose concentrations were measured at a median of 13.1 weeks' gestation (95% CI, 9.6-17.2). Liver fat fraction was measured at 10 years by MRI. NAFLD was defined as liver fat fraction ≥5.0%. We performed analyses among all mothers with different ethnic backgrounds and those of European ancestry only. The multiethnic group had a median maternal early-pregnancy glucose concentration of 4.3 mmol/L (interquartile range, 3.9-4.9) and a 2.8% (n = 60) prevalence of NAFLD. The models adjusted for child age and sex only showed that in the multiethnic group, higher maternal early-pregnancy glucose concentrations were associated with higher liver fat accumulation and higher odds of NAFLD, but these associations attenuated into nonsignificance after adjustment for potential confounders. Among mothers of European ancestry only, maternal early-pregnancy glucose concentrations were associated with increased odds of NAFLD (OR, 1.95; 95% CI, 1.32; 2.88, after adjustment for confounders) per 1-mmol/L increase in maternal early-pregnancy glucose concentration. These associations were not explained by maternal prepregnancy and childhood body mass index, visceral fat, and metabolic markers. CONCLUSIONS: In this study, maternal early-pregnancy glucose concentrations were only among mothers of European ancestry associated with offspring NAFLD. The associations of higher maternal early-pregnancy glucose concentrations with offspring NAFLD may differ between ethnic groups.

Associations of dietary glycemic index and load during pregnancy with blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders.

PURPOSE: The aim of this study was to examine the associations of dietary glycemic index and load with gestational blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders. METHODS: In a population-based cohort among 3378 pregnant Dutch women, dietary glycemic index and load were assessed from food frequency questionnaires at median 13.4 (95% range 9.9-22.9) weeks gestation. Blood pressure was measured in early-, mid- and late-pregnancy. Placental hemodynamic parameters were measured in mid- and late-pregnancy by ultrasound. Data on gestational hypertensive disorders was acquired from medical records. RESULTS: Mean dietary glycemic index (SD) was 58 (3) and mean dietary glycemic load (SD) was 155 (47). Dietary glycemic index was not associated with blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders. Higher dietary glycemic load SDS was associated with a higher diastolic blood pressure in early-pregnancy, remaining after adjustment for socio-demographic and lifestyle factors ((0.98 (95% CI 0.35-1.61) mmHg per SDS increase in glycemic load). No other associations of glycemic load with blood pressure or placental hemodynamic parameters and the risk of gestational hypertensive disorders were present. No significant associations of dietary glycemic index and load quartiles with longitudinal blood pressure patterns from early to late-pregnancy were present. CONCLUSION: Within this low-risk pregnant population, we did not find consistent associations of dietary glycemic index and load with blood pressure, placental hemodynamic parameters and the risk of gestational hypertensive disorders. Further studies need to assess whether the effects on gestational hemodynamic adaptations are more pronounced among high-risk women with an impaired glucose metabolism.

Preconception and early-pregnancy risk prediction for birth complications: development of prediction models within a population-based prospective cohort.

BACKGROUND: Suboptimal maternal health already from preconception onwards is strongly linked to an increased risk of birth complications. To enable identification of women at risk of birth complications, we aimed to develop a prediction model for birth complications using maternal preconception socio-demographic, lifestyle, medical history and early-pregnancy clinical characteristics in a general population. METHODS: In a population-based prospective cohort study among 8340 women, we obtained information on 33 maternal characteristics at study enrolment in early-pregnancy. These characteristics covered the preconception period and first half of pregnancy (< 21 weeks gestation). Preterm birth was < 37 weeks gestation. Small-for-gestational-age (SGA) and large-for-gestational-age (LGA) at birth were gestational-age-adjusted birthweight in the lowest or highest decile, respectively. Because of their co-occurrence, preterm birth and SGA were combined into a composite outcome. RESULTS: The basic preconception model included easy obtainable maternal characteristics in the preconception period including age, ethnicity, parity, body mass index and smoking. This basic preconception model had an area under the receiver operating characteristics curve (AUC) of 0.63 (95% confidence interval (CI) 0.61 to 0.65) and 0.64 (95% CI 0.62 to 0.66) for preterm birth/SGA and LGA, respectively. Further extension to more complex models by adding maternal socio-demographic, lifestyle, medical history and early-pregnancy clinical characteristics led to small, statistically significant improved models. The full model for prediction of preterm birth/SGA had an AUC 0.66 (95% CI 0.64 to 0.67) with a sensitivity of 22% at a 90% specificity. The full model for prediction of LGA had an AUC of 0.67 (95% CI 0.65 to 0.69) with sensitivity of 28% at a 90% specificity. The developed models had a reasonable level of calibration within highly different socio-economic subsets of our population and predictive performance for various secondary maternal, delivery and neonatal complications was better than for primary outcomes. CONCLUSIONS: Prediction of birth complications is limited when using maternal preconception and early-pregnancy characteristics, which can easily be obtained in clinical practice. Further improvement of the developed models and subsequent external validation is needed.

Maternal early pregnancy dietary glycemic index and load, fetal growth, and the risk of adverse birth outcomes.

PURPOSE: Maternal hyperglycemia is associated with adverse birth outcomes. Maternal dietary glycemic index and load influence postprandial glucose concentrations. We examined the associations of maternal early pregnancy dietary glycemic index and load with fetal growth and risks of adverse birth outcomes. METHODS: In a population-based cohort study of 3471 pregnant Dutch women, we assessed dietary glycemic index and load using a food frequency questionnaire at median 13.4 (95% range 10.6; 21.2) weeks gestation. We measured fetal growth in mid- and late-pregnancy by ultrasound and obtained birth outcomes from medical records. RESULTS: Mean maternal early pregnancy dietary glycemic index and load were 57.7 (SD 3.3, 95% range 52.8; 63.5) and 155 (SD 47, 95% range 87; 243), respectively. Maternal early pregnancy dietary glycemic index was not associated with fetal growth parameters. A higher maternal early pregnancy dietary glycemic load was associated with a higher fetal abdominal circumference and estimated fetal weight in late-pregnancy (p values < 0.05), but not with mid-pregnancy or birth growth characteristics. A higher maternal early pregnancy dietary glycemic index was associated with a lower risk of a large-for-gestational-age infant (p value < 0.05). Maternal early pregnancy glycemic index and load were not associated with other adverse birth outcomes. CONCLUSION: Among pregnant women without an impaired glucose metabolism, a higher early pregnancy dietary glycemic load was associated with higher late-pregnancy fetal abdominal circumference and estimated fetal weight. No consistent associations of maternal dietary glycemic index and load with growth parameters in mid-pregnancy and at birth were present. A higher glycemic index was associated with a lower risk of a large-for-gestational-age infant.

Is the association between mothers' autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?

BACKGROUND: Previous studies showed that there is a positive association between mothers' and children's autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). METHOD: The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). RESULT: Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; ßadjusted = 0.20, p < 0.01), in early childhood (Generation R; ßadjusted = 0.19, p < 0.01), and in early adolescence (Generation R; ßadjusted = 0.16, p < 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (ßadjusted = 0.03, p < 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. CONCLUSION: We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.

Maternal polyunsaturated fatty acid concentrations during pregnancy and childhood liver fat accumulation.

BACKGROUND & AIMS: Maternal polyunsaturated fatty acids (PUFA) concentrations in pregnancy are essential for fetal lipid metabolism and adipocyte differentiation. Whether suboptimal maternal gestational PUFA concentrations adversely affect offspring liver fat development is unknown. We aimed to examine the associations of maternal n-3 and n-6 PUFA concentrations in pregnancy with childhood liver fat accumulation. METHODS: In a population-based prospective cohort study among 2424 mother-child pairs, we measured maternal total and individual n-3 and n-6 PUFA plasma concentrations at mean gestational age of 20.6 ± 1.1 weeks. Childhood liver fat fraction was obtained by MRI at 10 years. Non-alcoholic fatty liver disease was a liver fat fraction ≥5.0%. RESULTS: We observed that 1-Standard deviation (SD) higher maternal n-3 PUFA concentrations, especially DHA, was associated with a lower childhood liver fat fraction [-0.07 SD-score (95% CI -0.11 to -0.02, p-value = 0.001) for both total n-3 PUFA and DHA concentrations]. Of n-6 PUFAs, 1-SD higher maternal dihomo-gamma-linolenic acid concentrations was associated with a higher childhood liver fat fraction [0.06 SD-score (95% CI 0.02-0.10, p-value = 0.004)]. Associations were not explained by maternal or childhood socio-demographic and lifestyle characteristics. Associations were stronger among boys and less consistent among girls. Among boys, higher maternal total n-3 PUFA concentrations were associated with a lower risk of childhood non-alcohol fatty liver disease [odds ratio 0.42 (95% CI 0.25-0.70, p-value = 0.001)]. CONCLUSIONS: Maternal lower n-3 PUFA and higher n-6 PUFA concentrations in pregnancy are associated with offspring liver fat accumulation in childhood. Optimizing maternal PUFA concentrations during pregnancy may be a target for preventing liver fat accumulation in their offspring.

Associations of Early Pregnancy Metabolite Profiles with Gestational Blood Pressure Development.

Blood pressure development plays a major role in both the etiology and prediction of gestational hypertensive disorders. Metabolomics might serve as a tool to identify underlying metabolic mechanisms in the etiology of hypertension in pregnancy and lead to the identification of novel metabolites useful for the prediction of gestational hypertensive disorders. In a population-based, prospective cohort study among 803 pregnant women, liquid chromatography­mass spectrometry was used to determine serum concentrations of amino-acids, non-esterified fatty acids, phospholipids and carnitines in early pregnancy. Blood pressure was measured in each trimester of pregnancy. Information on gestational hypertensive disorders was obtained from medical records. Higher individual metabolite concentrations of the diacyl-phosphatidylcholines and acyl-lysophosphatidylcholines group were associated with higher systolic blood pressure throughout pregnancy (Federal Discovery Rate (FDR)-adjusted p-values < 0.05). Higher concentrations of one non-esterified fatty acid were associated with higher diastolic blood pressure throughout pregnancy (FDR-adjusted p-value < 0.05). Using penalized regression, we identified 12 individual early-pregnancy amino-acids, non-esterified fatty acids, diacyl-phosphatidylcholines and acyl-carnitines and the glutamine/glutamic acid ratio, that were jointly associated with larger changes in systolic and diastolic blood pressure from first to third trimester. These metabolites did not improve the prediction of gestational hypertensive disorders in addition to clinical markers. In conclusion, altered early pregnancy serum metabolite profiles mainly characterized by changes in non-esterified fatty acids and phospholipids metabolites are associated with higher gestational blood pressure throughout pregnancy within the physiological ranges. These findings are important from an etiological perspective and, after further replication, might improve the early identification of women at increased risk of gestational hypertensive disorders.

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 early-pregnancy dietary glycemic index with childhood general, abdominal and ectopic fat accumulation.

BACKGROUND & AIMS: Maternal hyperglycemia during pregnancy is an important risk factor for childhood adiposity. Maternal dietary glycemic index during pregnancy directly influences maternal and fetal glucose concentrations. We examined the associations of maternal early-pregnancy dietary glycemic index with offspring general, abdominal and ectopic fat accumulation among normal weight and overweight or obese pregnant women and their offspring. METHODS: In a population-based cohort study among 2488 Dutch pregnant women and their children, we assessed maternal dietary glycemic index by food frequency questionnaire at median 13.4 (95% range 10.7; 21.1) weeks gestation. Dietary glycemic index was used continuously and categorized into low (≤55), normal (56-69) and high (≥70) glycemic index diet. We measured offspring BMI, total fat mass and android/gynoid fat mass ratio by DXA, and visceral fat mass and liver fat fraction by MRI at 10 years. RESULTS: No associations of maternal early-pregnancy dietary glycemic index with offspring adiposity were present among normal weight women and their children. Among overweight and obese women and their children, 1-Standard Deviation Score (SDS) increase in maternal early-pregnancy dietary glycemic index was associated with higher childhood BMI (0.10 SDS, 95% Confidence Interval (CI) 0.01; 0.19), total fat mass index (0.13 SDS, 95% CI 0.05; 0.22), visceral fat mass index (0.19 SDS, 95% CI 0.07; 0.32) and tended to be associated with a higher android/gynoid fat mass ratio (0.09 SDS, 95% CI -0.01; 0.19) and higher risk of childhood overweight (Odds Ratio (OR) 1.20, 95% CI 0.97; 1.48). Overweight and obese women consuming an early-pregnancy low-glycemic index diet, as compared to an early-pregnancy normal-glycemic index diet, had children with lower BMI, total fat mass index, visceral fat mass index and android/gynoid fat mass ratio at 10 years (p-values<0.05). No women consumed a high-glycemic index diet. No associations were explained by maternal socio-economic, lifestyle and dietary characteristics, birth or childhood characteristics. No associations with liver fat fraction were present. CONCLUSIONS: In overweight or obese women and their children, a higher maternal early-pregnancy dietary glycemic index is associated with childhood general, abdominal and visceral fat accumulation, but not with liver fat. Intervention studies among overweight and obese pregnant women may need to target the dietary glycemic index to prevent childhood adiposity.

Prediction of Healthy Pregnancy Outcomes in Women with Overweight and Obesity: The Role of Maternal Early-Pregnancy Metabolites.

Women with obesity receive intensified antenatal care due to their increased risk of pregnancy complications, even though not all of these women develop complications. We developed a model based on maternal characteristics for prediction of healthy pregnancy outcomes in women with obesity or who are overweight. We assessed whether early-pregnancy metabolites improved prediction. In a population-based cohort study among a subsample of 1180 Dutch pregnant women with obesity or who are overweight, we developed a prediction model using 32 maternal socio-demographic, lifestyle, physical and pregnancy-related characteristics. We determined early-pregnancy amino acids, nonesterifed fatty acids, phospholipids and carnitines in blood serum using liquid chromatography-tandem mass spectrometry. A healthy pregnancy outcome was the absence of fetal death, gestational hypertension, preeclampsia, gestational diabetes, caesarian section, preterm birth, large-for-gestational-age at birth, macrosomia, postpartum weight retention and offspring overweight/obesity at 5 years. Maternal age, relationship status, parity, early-pregnancy body mass index, mid-pregnancy gestational weight gain, systolic blood pressure and estimated fetal weight were selected into the model using backward selection (area under the receiver operating characteristic curve: 0.65 (95% confidence interval 0.61 to 0.68)). Early-pregnancy metabolites did not improve model performance. Thus, in women with obesity or who are overweight, maternal characteristics can moderately predict a healthy pregnancy outcome. Maternal early-pregnancy metabolites have no incremental value in the prediction of a healthy pregnancy outcome.

Smoking cessation in early-pregnancy, gestational weight gain and subsequent risks of pregnancy complications.

OBJECTIVE: Smoking cessation is associated with weight gain. We first examined the associations of smoking cessation in early-pregnancy with gestational weight gain and subsequently evaluated the risks of pregnancy complications among women who quit smoking in early-pregnancy according to their gestational weight gain. METHODS: In a population-based prospective cohort study among 7,389 women, we measured weight in each pregnancy period. Information on smoking and pregnancy complications was obtained from questionnaires and medical records. RESULTS: As compared to continued smoking during pregnancy, smoking cessation in early-pregnancy was not associated with gestational weight gain. Smoking cessation in early-pregnancy was associated with decreased risks of delivering small-for-gestational-age infants (Odds Ratio (OR) 0.52 (95 % Confidence Interval (CI) 0.37, 0.75)), but with increased risks of pre-eclampsia (OR 2.07 (95 % CI 1.01, 4.27)) and delivering large-for-gestational-age infants (OR 2.11 (95 % CI 1.45, 3.09)). Among women who quit smoking in early-pregnancy with >12 kg weight gain, the risks of pre-eclampsia and delivering large-for-gestational-age infants were slightly increased. CONCLUSION: As compared to continued smoking during pregnancy, smoking cessation in early-pregnancy is not associated with increased gestational weight gain. Among women who quit smoking in early-pregnancy, higher gestational weight gain does not strongly affect their risks of pregnancy complications.

Associations of Maternal Glycemia in the First Half of Pregnancy With Alterations in Cardiac Structure and Function in Childhood.

OBJECTIVE: Gestational diabetes mellitus has been associated with offspring cardiac congenital malformations, ventricular hypertrophy, and diastolic dysfunction in large observational cohort studies and experimental animal models. We assessed the associations of maternal random glucose concentrations across the full range with childhood cardiac ventricular structure and function. RESEARCH DESIGN AND METHODS: In a population-based prospective cohort among 1,959 women and their offspring, maternal random glucose concentrations were measured at a median 13.1 weeks' gestation (95% range 10.5-16.8 weeks). We obtained offspring cardiac outcomes, relative to body size, through cardiac MRI at 10 years. RESULTS: The mean maternal random glucose concentration was 4.4 mmol/L (SD 0.8). The highest quintile of maternal glucose concentrations, compared with the lowest quintile, was associated with a lower childhood left ventricular mass (-0.19 SD score [SDS]; 95% CI -0.31, -0.07) and left ventricular end-diastolic volume (-0.17 SDS; 95% -0.28, -0.05). Also, higher maternal glucose concentrations across the full range per 1 mmol/L increase were associated with a lower childhood left ventricular mass and left ventricular end-diastolic volume (P values ≤0.05). Adjustment for maternal prepregnancy BMI, gestational age, and weight at birth or childhood BMI and blood pressure did not influence the effect estimates. Maternal glucose concentrations were not significantly associated with childhood right ventricular end-diastolic volume or left and right ventricular ejection fraction. CONCLUSIONS: Higher maternal random glucose concentrations in the first half of pregnancy are associated with a lower childhood left ventricular mass and left ventricular end-diastolic volume, with the strongest associations for childhood left ventricular mass. These associations were not explained by maternal, birth, or childhood characteristics. Further studies are needed to replicate these findings using repeated maternal glucose measurements throughout pregnancy and offspring cardiac outcomes throughout childhood and adulthood.

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.

Celiac Disease Autoimmunity and Emotional and Behavioral Problems in Childhood.

BACKGROUND AND OBJECTIVES: Celiac disease (CeD) is associated with psychopathology in children. It is unknown whether this association is present in children with celiac disease autoimmunity (CDA) identified by screening. We examined the associations between subclinical CDA and emotional and behavioral problems in children without previous CeD diagnosis. METHODS: In a population-based cohort study of 3715 children (median age: 6 years), blood titers of tissue transglutaminase autoantibodies were analyzed. CDA was defined as a measurement of tissue transglutaminase autoantibodies ≥7 U/mL (n = 51). Children with previous CeD diagnosis or children on a gluten-free diet, were excluded. The Child Behavior Checklist (CBCL) was filled in by parents and was used to assess behavioral and emotional problems of children at a median age of 5.9 years. Multiple linear regression models were applied to evaluate the cross-sectional associations between CDA and CBCL scores. Sensitivity analyses were done in a subgroup of children who were seropositive carrying the HLA antigen risk alleles for CeD. RESULTS: In basic models, CDA was not associated with emotional and behavioral problems on the CBCL scales. After adjustment for confounders, CDA was significantly associated with anxiety problems (ß = .29; 95% confidence interval 0.02 to 0.55; P = .02). After exclusion of children who did not carry the HLA-DQ2 and/or HLA-DQ8 risk alleles (n = 4), CDA was additionally associated with oppositional defiant problems (ß = .35; 95% confidence interval 0.02 to 0.69). Associations were not explained by gastrointestinal complaints. CONCLUSIONS: Our results reveal that CDA, especially combined with the HLA-DQ2 and HLA-DQ8 risk alleles, is associated with anxiety problems and oppositional defiant problems. Further research should be used to establish whether behavioral problems are a reflection of subclinical CeD.