Association between prenatal alcohol exposure and children's facial shape: a prospective population-based cohort study.

STUDY QUESTION: Is there an association between low-to-moderate levels of prenatal alcohol exposure (PAE) and children's facial shape? SUMMARY ANSWER: PAE before and during pregnancy, even at low level (<12 g of alcohol per week), was found associated with the facial shape of children, and these associations were found attenuated as children grow older. WHAT IS KNOWN ALREADY: High levels of PAE during pregnancy can have significant adverse associations with a child's health development resulting in recognizably abnormal facial development. STUDY DESIGN, SIZE, DURATION: This study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. We analyzed children 3-dimensional (3D) facial images taken at ages 9 (n = 3149) and 13 years (n = 2477) together with the data of maternal alcohol consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined six levels of PAE based on the frequency and dose of alcohol consumption and defined three tiers based on the timing of alcohol exposure of the unborn child. For the image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 traits representing facial morphology. These 200 traits were used for statistical analysis to search for associations with PAE. Finally, we generated heatmaps to display the facial phenotypes associated with PAE. MAIN RESULTS AND THE ROLE OF CHANCE: The results of the linear regression in the 9-year-old children survived correction for multiple testing with false discovery rate (FDR). In Tier 1 where we examined PAE only before pregnancy (exposed N = 278, unexposed N = 760), we found three traits survived FDR correction. The lowest FDR-P is 1.7e-05 (beta = 0.021, SE = 0.0040) in Trait #29; In Tier 2b where we examine any PAE during first trimester (exposed N = 756; unexposed N = 760), we found eight traits survived FDR correction. The lowest FDR-P is 9.0e-03 (beta = -0.013, SE = 0.0033) in Trait #139. Moreover, more statistically significant facial traits were found in higher levels of PAE. No FDR-significant results were found in the 13-year-old children. We map these significant traits back to the face, and found the most common detected facial phenotypes included turned-up nose tip, shortened nose, turned-out chin, and turned-in lower-eyelid-related regions. LIMITATIONS, REASONS FOR CAUTION: We had no data for alcohol consumption more than three months prior to pregnancy and thus do not know if maternal drinking had chronic effects. The self-reported questionnaire might not reflect accurate alcohol measurements because mothers may have denied their alcohol consumption. WIDER IMPLICATIONS OF THE FINDINGS: Our results imply that facial morphology, such as quantified by the approach we proposed here, can be used as a biomarker in further investigations. Furthermore, our study suggests that for women who are pregnant or want to become pregnant soon, should quit alcohol consumption several months before conception and completely during pregnancy to avoid adverse health outcomes in the offspring. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research. V.W.V.J. reports receipt of funding from the Netherlands Organization for Health Research (ZonMw 90700303). W.J.N. is a founder, a scientific lead, and a shareholder of Quantib BV. TRIAL REGISTRATION NUMBER: N/A.

Novel Genetic Determinants of Dental Maturation in Children.

Dental occlusion requires harmonious development of teeth, jaws, and other elements of the craniofacial complex, which are regulated by environmental and genetic factors. We performed the first genome-wide association study (GWAS) on dental development (DD) using the Demirjian radiographic method. Radiographic assessments from participants of the Generation R Study (primary study population, N1 = 2,793; mean age of 9.8 y) were correlated with ~30 million genetic variants while adjusting for age, sex, and genomic principal components (proxy for population stratification). Variants associated with DD at genome-wide significant level (P < 5 × 10-8) mapped to 16q12.2 (IRX5) (lead variant rs3922616, B = 0.16; P = 2.2 × 10-8). We used Fisher's combined probability tests weighted by sample size to perform a meta-analysis (N = 14,805) combining radiographic DD at a mean age of 9.8 y from Generation R with data from a previous GWAS (N2 = 12,012) on number of teeth (NT) in infants used as proxy of DD at a mean age of 9.8 y (including the ALSPAC and NFBC1966). This GWAS meta-analysis revealed 3 novel loci mapping to 7p15.3 (IGF2BP3: P = 3.2 × 10-8), 14q13.3 (PAX9: P = 1.9 × 10-8), and 16q12.2 (IRX5: P = 1.2 × 10-9) and validated 8 previously reported NT loci. A polygenic allele score constructed from these 11 loci was associated with radiographic DD in an independent Generation R set of children (N = 703; B = 0.05, P = 0.004). Furthermore, profiling of the identified genes across an atlas of murine and human stem cells observed expression in the cells involved in the formation of bone and/or dental tissues (>0.3 frequency per kilobase of transcript per million mapped reads), likely reflecting functional specialization. Our findings provide biological insight into the polygenic architecture of the pediatric dental maturation process.

Household income and maternal education in early childhood and risk of overweight and obesity in late childhood: Findings from seven birth cohort studies in six high-income countries.

BACKGROUND/OBJECTIVES: This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity. SUBJECTS/METHODS: Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total of N = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8-11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income. RESULTS: Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts. CONCLUSIONS: There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals.

Fetal-placental blood flow and neurodevelopment in childhood: population-based neuroimaging study.

OBJECTIVE: Antenatal Doppler measurements of the fetal umbilical and cerebral circulations can predict perinatal complications; however, it is unclear if subtle variations in antenatal Doppler measurements are associated with long-term neurodevelopmental outcome. In this study, we examined whether antenatal Doppler measurements of the fetal-placental circulation are associated with cognitive and motor abilities and brain morphology in childhood. METHODS: To evaluate differences in long-term sequelae across the continuum of the umbilical and cerebral artery circulations in the general population, we utilized a population-based longitudinal cohort study approach. In women from the Generation R study, we measured second- and third-trimester umbilical artery pulsatility index (UA-PI). Children underwent non-verbal intelligence testing at 4-8 years of age, and at 8-12 years they underwent finger-tapping tests to measure fine motor skills, balance beam tests to measure gross motor skills and brain magnetic resonance imaging. We assessed the relationships between prenatal UA-PI and neurodevelopmental outcome using linear regression. We adjusted for child age and sex, maternal age, education, parity and smoking status. RESULTS: The study sample included 2803 pregnancies. Higher third-trimester UA-PI was associated with poorer fine motor performance (0.41 (95% CI, 0.11-0.70) fewer taps on the finger-tapping test per 1 SD higher UA-PI) and gross motor performance (0.64 (95% CI, 0.20-1.08) fewer steps on the balance beam test per 1 SD higher UA-PI). One SD higher third-trimester UA-PI was also associated with 0.65 (95% CI, 0.04-1.25) points lower intelligence quotient; however, unlike the associations with motor abilities, this finding did not persist after correction for multiple testing. Higher second-trimester UA-PI was associated with smaller brain volume (6.1 (95% CI, 1.0-11.3) cm3 reduction per 1 SD higher UA-PI), but the association did not persist after correction for multiple testing. CONCLUSION: Higher placental vascular resistance may have mild adverse effects on neurodevelopmental outcome at school age. While these effects are subtle at population level, we encourage future research into the role of early circulation in brain development. This information could be used to develop targeted interventions. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Maternal psychological distress during pregnancy and childhood cardio-metabolic risk factors.

BACKGROUND AND AIMS: Previous studies suggest that psychological distress during pregnancy may lead to fetal developmental adaptations, which programme cardio-metabolic disease of the offspring. We examined the associations of maternal overall psychological distress, depression and anxiety during pregnancy with cardio-metabolic risk factors in 10-year-old children and explore potential sex-specific differences. METHODS AND RESULTS: In a population-based prospective cohort study among 4,088 mothers and their children, information about overall psychological distress, including depression and anxiety was obtained through the Brief Symptom Inventory during pregnancy. We measured child blood pressure and heart rate and insulin, glucose, serum lipids and C-reactive protein blood concentrations at 10 years. Analyses were performed in the total group and in boys and girls separately. Psychological distress during pregnancy was associated with higher childhood heart rate among boys only (differences 0.34 (95% Confidence Interval (CI) 0.18, 0.50) standard deviation scores (SDS), 0.22 (95% CI 0.06, 0.38) SDS, 0.33 (95% CI 0.19, 0.48) SDS, for overall psychological distress, depression and anxiety, respectively). Maternal anxiety during pregnancy was associated with higher childhood triglycerides among girls (difference 0.35 (95% CI 0.17, 0.53) SDS). Maternal psychological distress was not associated with childhood blood pressure, cholesterol, insulin, glucose and C-reactive protein concentrations. CONCLUSIONS: Maternal psychological distress may influence their offspring heart rate and triglycerides concentrations. Further studies are needed to replicate these findings and assess the long-term cardio-metabolic consequences of maternal psychological distress.

Human chorionic gonadotropin and risk of pre-eclampsia: prospective population-based cohort study.

OBJECTIVES: Abnormal placentation in early pregnancy may play a role in the pathogenesis of pre-eclampsia. Human chorionic gonadotropin (hCG) regulates placental development and angiogenesis and may affect the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in the serum. The aims of this study were to investigate the association of total hCG with the risk of pre-eclampsia and to examine the potential effect of pro- and anti-angiogenic factors on this association. METHODS: This was a population-based prospective cohort study of 7754 women with a singleton pregnancy. Total hCG was measured in the first available sample (median gestational age, 14.4 weeks; 95% range, 10.1-26.1 weeks) and sFlt-1 and PlGF concentrations in early (< 18 weeks; median, 13.2 weeks; 95% range, 9.6-17.6 weeks) and in mid- (18-25 weeks; median, 20.4 weeks; 95% range, 18.5-23.5 weeks) pregnancy. We tested the association of hCG concentration and risk of pre-eclampsia using regression analysis, adjusting for maternal age, ethnicity, body mass index, parity, education level, smoking status and fetal sex. Additionally, we assessed whether this association was affected by the sFlt-1/PlGF ratio. RESULTS: High hCG concentration was associated with a 1.5-2.7-fold increased risk of pre-eclampsia (P = 0.0001), depending on the cut-off used, and with increased sFlt-1/PlGF ratio during early pregnancy (P < 0.0001). The association between high hCG and pre-eclampsia attenuated by roughly 40% after adjustment for early-pregnancy sFlt-1/PlGF ratio (ß-estimate change from 0.19 ± 0.10 (P = 0.052) to 0.12 ± 0.10 (P = 0.22)). CONCLUSIONS: High total hCG concentration in early pregnancy is associated with an increased risk of pre-eclampsia. The effect of high hCG concentration on the balance between pro- and anti-angiogenic factors during pregnancy may have a role in the pathophysiology of pre-eclampsia. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Ethnic background and children's oral health-related quality of life.

PURPOSE: Ethnic background is known to be related to oral health and socioeconomic position (SEP). In the context of patient-centered oral health care, and the growing number of migrant children, it is important to understand the influence of ethnic background on oral health-related quality of life (OHRQoL). Therefore, we aimed to identify the differences in children's OHRQoL between ethnic groups, and the contribution of oral health status, SEP, and immigration characteristics. METHODS: This study was part of the Generation R Study, a prospective cohort study conducted in Rotterdam, the Netherlands. In total, 3121 9-year-old children with a native Dutch (n = 2510), Indonesian (n = 143), Moroccan (n = 104), Surinamese (n = 195), or Turkish (n = 169) background participated in the present study. These ethnicities comprise the most common ethnic groups in the Netherlands. OHRQoL was assessed using a validated short form of the child oral health impact profile. Several regression models were used to study an association between ethnic background and OHRQoL, and to identify potential mediating factors. RESULTS: Turkish and Surinamese ethnic background were significantly associated with lower OHRQoL. After adjusting for mediating factors, only Surinamese children had a significantly lower OHRQoL than Dutch children (ß:- 0.61; 95% CI- 1.18 to -0.04). CONCLUSIONS: Our results show that Turkish and Surinamese children have a significantly lower OHRQoL than native Dutch children. The association was partly explained by oral health status and SEP, and future studies are needed to understand (cultural) the determinants of ethnic disparities in OHRQoL, in order to develop effective oral health programs targeting children of different ethnic groups.

Cavum Septum Pellucidum in the General Pediatric Population and Its Relation to Surrounding Brain Structure Volumes, Cognitive Function, and Emotional or Behavioral Problems.

BACKGROUND AND PURPOSE: The cavum septum pellucidum, a cavity filled with CSF, is localized between the 2 lateral ventricles of the brain. The cavum is present in all neonates, but it typically closes within 5 months after birth. In some cases, this closure does not occur and a persistent or enlarged cavum septum pellucidum has been linked, in some studies, to psychiatric disorders. However, the clinical relevance in the general population is unknown. In this study, we examined the relationship between the cavum septum pellucidum and volumes of brain structures, cognitive function, and emotional and behavioral problems in children. MATERIALS AND METHODS: This study was embedded in the Generation R Study, a prospective cohort in Rotterdam, the Netherlands. MR imaging studies of 1070 children, 6-10 years of age, were systematically evaluated for the presence and length of a persistent cavum septum pellucidum. An enlarged cavum septum pellucidum was defined as a cavum length of ≥6 mm. Groups without, with persistent, and with enlarged cavum septi pellucidi were compared for brain structure volumes, nonverbal intelligence, and emotional and behavioral problems. RESULTS: The prevalence of cavum septi pellucidi in our sample was 4.6%. Children with an enlarged cavum septum pellucidum had a larger corpus callosum, greater thalamic and total white matter-to-total brain volume ratio, and smaller lateral ventricle volumes. We did not find a relationship between cavum septi pellucidi and cognitive function or emotional and behavioral problems. CONCLUSIONS: The cavum septum pellucidum is a normal structural brain variation without clinical implications in this population-based sample of school-aged children.

Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children.

Up to 13% of women may experience symptoms of depression during pregnancy or in the postpartum period. Depression during pregnancy has been associated with an increased risk of adverse neurodevelopmental outcomes in the child and epigenetic mechanisms could be one of the biological pathways to explain this association. In 844 mother-child pairs from the Avon Longitudinal Study of Parents and Children, we carried out an epigenome-wide association study (EWAS) to investigate associations between prospectively collected data on maternal depression ascertained by the Edinburgh Postnatal Depression Scale in pregnancy and DNA methylation in the cord blood of newborn offspring. In individual site analysis, we identified two CpG sites associated with maternal depression in the middle part of pregnancy. In our regional analysis, we identified 39 differentially methylated regions (DMRs). Seven DMRs were associated with depression at any time point during pregnancy, 7 associated with depression in mid-pregnancy, 23 were associated with depression in late pregnancy, and 2 DMRs were associated with depression throughout pregnancy. Several of these map to genes associated with psychiatric disease and brain development. We attempted replication in The Generation R Study and could not replicate our results. Although our findings in ALSPAC suggest that maternal depression could be associated with cord blood DNA methylation the results should be viewed as preliminary and hypothesis generating until further replicated in a larger sample.

ADHD symptoms and body composition changes in childhood: a longitudinal study evaluating directionality of associations.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is linked to increased risk of overweight/obesity among children and adults. Studies have also implicated obesity as a risk factor for ADHD. However, no studies have evaluated bidirectional, longitudinal associations between childhood fat mass and ADHD symptom severity. OBJECTIVES: We investigate bidirectional associations between ADHD symptoms and measures of body composition between ages 1.5 and 9. We further examine effects of specific eating patterns linked to ADHD on associations between symptom severity and body composition. METHODS: The study utilized data from children (N = 3903) participating in the Generation R cohort (Netherlands). Children were enrolled at birth and retained regardless of ADHD symptoms over time. Cross-lagged and change models examined bidirectional associations between body composition (body mass index/dual-energy X-ray absorptiometry) and ADHD symptoms at four time points in childhood. RESULTS: A child with a clinically concerning ADHD symptom z-score two standard deviations above the mean at age 6 would be expected to experience about 0.22 kg greater fat mass gain measured via dual-energy x-ray absorptiometry between ages 6 and 9, even if they displayed healthy eating patterns (95% CI: 0.11 - 0.28, p < 0.001). Conversely, fat mass at any age did not predict worse ADHD symptoms later. CONCLUSIONS: Beginning in early childhood, more ADHD symptoms predict higher fat mass at later ages. We did not find evidence of a reverse association. Based on these and prior findings, lifestyle counselling during treatment for children with a diagnosis of ADHD should be considered, even if they are diagnosed in early childhood and do not yet have a body mass index of clinical concern.

Psychotic-like experiences in pre-adolescence: what precedes the antecedent symptoms of severe mental illness?

OBJECTIVE: Adolescent psychotic-like experiences predict the onset of psychosis, but also predict subsequent non-psychotic disorders. Therefore, it is crucial to better understand the aetiology of psychotic-like experiences. This study examined whether (a) child emotional and behavioural problems at 3 and 6 years, or (b) childhood adversities were associated with psychotic-like experiences at age 10 years. METHOD: This prospective study was embedded in the Generation R Study; 3984 children (mean age 10 years) completed a psychotic-like experiences questionnaire. Mothers reported problems of their child at ages 3, 6 and 10 years. Additionally, mothers were interviewed about their child's adversities. RESULTS: Psychotic-like experiences were endorsed by ~20% of children and predicted by both emotional and behavioural problems at 3 years (e.g. emotional-reactive problems: ORadjusted = 1.10, 95% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.03, 95% CI: 1.02-1.05) and 6 years (e.g. anxious/depressed problems: ORadjusted = 1.11, 95% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.04, 95% CI: 1.04-1.05). Childhood adversities were associated with psychotic-like experiences (>2 adversities: ORadjusted = 2.24, 95% CI: 1.72-2.92), which remained significant after adjustment for comorbid psychiatric problems. CONCLUSION: This study demonstrated associations between early adversities, childhood emotional and behavioural problems and pre-adolescent psychotic-like experiences, which will improve the understanding of children at increased risk of severe mental illness.

Associations of adult genetic risk scores for adiposity with childhood abdominal, liver and pericardial fat assessed by magnetic resonance imaging.

BACKGROUND: Genome-wide association studies (GWASs) identified single-nucleotide polymorphisms (SNPs) involved in adult fat distribution. Whether these SNPs also affect abdominal and organ-specific fat accumulation in children is unknown. METHODS: In a population-based prospective cohort study among 1995 children (median age: 9.8 years, 95% range 9.4-10.8), we tested the associations of six genetic risk scores based on previously identified SNPs for childhood body mass index (BMI), adult BMI, liver fat, waist-hip ratio, pericardial fat mass, visceral and subcutaneous adipose tissue ratio (VAT/SAT ratio) and four individual SAT- and VAT-associated SNPs for association with SAT (N=1746), VAT (N=1742), VAT/SAT ratio (N=1738), liver fat fraction (N=1950) and pericardial fat mass (N=1803) measured by magnetic resonance imaging. RESULTS: Per additional risk allele in the childhood BMI genetic risk score, SAT increased 0.020 s.d. scores (SDS) (95% confidence interval (CI): 0.009 to 0.031, P-value: 3.28 × 10-4) and VAT increased 0.021 SDS (95% CI: 0.009 to 0.032, P-value: 4.68 × 10-4). The adult BMI risk score was positively associated with SAT (0.022 SDS increase, CI: 0.015 to 0.029, P-value: 1.33 × 10-9) and VAT (0.017 SDS increase, CI: 0.010 to 0.025, P-value: 7.00 × 10-6) and negatively with VAT/SAT ratio (-0.012 SDS decrease, CI: -0.019 to -0.006, P-value: 2.88 × 10-4). The liver fat risk score was associated with liver fat fraction (0.121 SDS, CI: 0.086 to 0.157, P-value: 2.65 × 10-11). Rs7185735 (SAT) was associated with SAT (0.151 SDS, CI: 0.087 to 0.214, P-value: 3.00 × 10-6) and VAT/SAT ratio (-0.126 SDS, CI: -0.186 to -0.065, P-value: 4.70 × 10-5). After stratification by sex the associations of the adult BMI risk score with SAT and VAT and of the liver fat risk score with liver fat fraction remained in both sexes. Associations of the childhood BMI risk score with SAT, and the adult BMI risk score with VAT/SAT ratio, were present among boys only, whereas the association of the pericardial fat risk score with pericardial fat was present among girls only. CONCLUSION: Genetic variants associated with BMI, body fat distribution, liver and pericardial fat already affect body fat distribution in childhood.

Maternal and fetal genetic contribution to gestational weight gain.

BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Maternal folic acid use during pregnancy, methylenetetrahydrofolate reductase gene polymorphism, and child's lung function and asthma.

BACKGROUND: Folic acid supplement use during pregnancy might affect childhood respiratory health, potentially mediated by methylenetetrahydrofolate reductase polymorphism C677T (MTHFR-C677T) carriership. OBJECTIVES: We examined the associations of maternal folic acid supplement use and folate, vitamin B12 and homocysteine concentrations during pregnancy with childhood lung function and asthma. METHODS: This study was embedded in a population-based prospective cohort study among 5653 children. Folic acid supplement use was assessed by questionnaires. Folate, vitamin B12 and homocysteine plasma concentrations were measured in early pregnancy and at birth. At age 10 years, forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), FEV1 /FVC, forced expiratory flow between 25% and 75% (FEF25-75 ), at 75% of FVC (FEF75 ), and asthma were examined. RESULTS: Maternal folic acid supplement use during pregnancy was associated with higher childhood FEV1 and FVC and with a lower FEV1 /FVC, compared with no folic acid supplement use. Among mothers carrying MTHFR-C677T variants, preconceptional start of folic acid supplement use was associated with lower FEV1 /FVC (-0.17 [-0.32, -0.02]) and FEF25-75 (-0.24 [-0.40, -0.07]). Among children carrying MTHFR-C677T wild-type, a higher vitamin B12 level at birth was associated with a lower FEV1 (-0.07 [-0.12, -0.01]) and FVC (-0.09 [-0.15, -0.04]). Folate and homocysteine concentrations were not consistently associated with lower childhood lung function or asthma. CONCLUSIONS: Preconceptional start of maternal folic acid supplement use and higher vitamin B12 concentrations at birth might adversely affect childhood lung function depending on MTHFR-C677T carriership. The clinical implications need to be evaluated.

The concordance between self-reported medication use and pharmacy records in pregnant women.

PURPOSE: Several studies have been conducted to assess determinants affecting the performance or accuracy of self-reports. These studies are often not focused on pregnant women, or medical records were used as a data source where it is unclear if medications have been dispensed. Therefore, our objective was to evaluate the concordance between self-reported medication data and pharmacy records among pregnant women and its determinants. METHODS: We conducted a population-based cohort study within the Generation R study, in 2637 pregnant women. The concordance between self-reported medication data and pharmacy records was calculated for different therapeutic classes using Yule's Y. We evaluated a number of variables as determinant of discordance between both sources through univariate and multivariate logistic regression analysis. RESULTS: The concordance between self-reports and pharmacy records was moderate to good for medications used for chronic conditions, such as selective serotonin reuptake inhibitors or anti-asthmatic medications (0.88 and 0.68, respectively). Medications that are used occasionally, such as antibiotics, had a lower concordance (0.51). Women with a Turkish or other non-Western background were more likely to demonstrate discordance between pharmacy records and self-reported data compared with women with a Dutch background (Turkish: odds ratio, 1.63; 95% confidence interval, 1.16-2.29; other non-Western: odds ratio, 1.33; 95% confidence interval, 1.03-1.71). CONCLUSIONS: Further research is needed to assess how the cultural or ethnic differences may affect the concordance or discordance between both medication sources. The results of this study showed that the use of multiple sources is needed to have a good estimation of the medication use during pregnancy.

Thyroid Function during Early Life and Dental Development.

Children with low levels of thyroid hormones (hypothyroidism) have delayed tooth eruption, enamel hypoplasia, micrognathia, and anterior open bite, whereas children with hyperthyroidism may suffer from accelerated tooth eruption, maxillary, and mandibular osteoporosis. However, it is still unknown whether thyroid function variations within the normal or subclinical range also have an impact on hard dental tissues in healthy children. The objective of this study was, therefore, to investigate the association between thyroid function from the fetal period until early childhood and dental development at school age. This study is embedded in the Generation R Study, a population-based cohort study established in Rotterdam, the Netherlands. Maternal thyroid function (thyroid-stimulating hormone [TSH], free thyroxine [FT4], and thyroid peroxidase antibody [TPOAb] concentrations) was measured during early pregnancy, and thyroid function of the offspring (TSH and FT4) was measured in cord blood at birth and in early childhood (6 y). Dental development was assessed from panoramic radiographs of children of school-going age (9 y). In total, 2,387 to 2,706 subjects were available for the multivariable linear regression analysis, depending on the point in time of thyroid function measurement. There was an inverse association between cord blood and early childhood TSH concentrations with dental development, with a -0.06 lower standard deviation (SD) per 1 mU/L of TSH (95% confidence interval [CI], -0.11 to -0.01) and a -0.06 lower SD per 1 mU/L of TSH (95% CI, -0.11 to 0.00), respectively. There was no association between the maternal thyroid function during pregnancy and the dental development score of the child. However, TPOAb-positive mothers had children with a -0.20 SD (adjusted 95% CI, -0.35 to -0.04) lower dental development score compared with TPOAb-negative mothers. The findings of this study suggest that the thyroid hormone is involved in the maturation of teeth from the early stages of life onward.

Abnormalities in CD57+ cytotoxic T cells and Vδ1+ γδT cells in subclinical celiac disease in childhood are affected by cytomegalovirus. The Generation R Study.

Celiac disease (CD) is a digestive and autoimmune disorder driven by an immune response to modified gluten peptides. Affected intestines show infiltrates of various T-cell and NK-cell subsets. It is currently unclear if individuals with subclinical CD have systemic abnormalities in immune cells. We here studied whether subclinical CD is associated with changes in blood CD57-expressing and Vδ1-expressing lymphocytes in children, and whether cytomegalovirus (CMV) infection modifies this association. Included were 1068 children from the Generation R Study. Serum Immunoglobulin G (IgG) levels against CMV were measured by ELISA; Tissue transglutaminase type 2 antibody (TG2A) levels with fluorescence enzyme immunoassay (FEIA). Duodenal biopsies, additional Human Leukocyte Antigen (HLA) DQ 2.2, 2.5 and 8 and endomysial antibody (EMA) typing were performed in TG2A positive children. Subclinical CD cases (n=12) had 1.8 fold (95% CI 1.06; 3.1) fewer Vδ1+ T cells which was predominantly observed in CMV seronegative children (p-interaction 0.02), and 2.7 fold (95% CI 1.25; 5.99) more CD57+ T cells than HLA DQ2/-DQ8 positive controls (n=339). Hence, children with subclinical CD have alterations in specific blood T cell subsets that are linked to viral pathology. The observed interaction effect between subclinical CD and CMV may contribute to the understanding of disease pathogenesis.

Duration and exclusiveness of breastfeeding and risk of childhood atopic diseases.

BACKGROUND: Breastfeeding may have immune modulatory effects that influence the development of childhood allergic sensitization and atopic diseases. We aimed to examine the associations of breastfeeding with childhood allergic sensitization, inhalant or food allergy and eczema, and whether any association was affected by disease-related modification of the exposure or modified by maternal history of allergy, eczema, or asthma. METHODS: This study among 5828 children was performed in a population-based prospective cohort from fetal life onwards. We collected information on duration (<2 months, 2-4 months, 4-6 months, and ≥6 months) and exclusiveness (nonexclusive vs exclusive for 4 months) of breastfeeding in infancy by postal questionnaires. At age 10 years, inhalant allergic sensitization and food-allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy by a postal questionnaire. Data on parental-reported eczema were available from birth until age 10 years. RESULTS: We observed no association of breastfeeding with any allergic sensitization, physician-diagnosed allergy, or combination of these outcomes. Shorter breastfeeding duration was associated with an overall increased risk of eczema (P-value for trend <.05). Nonexclusively breastfed children had an overall increased risk of eczema (adjusted odds ratio [95% confidence interval]: 1.11 [1.01, 1.23]), compared with children exclusively breastfed for 4 months. Risk period-specific sensitivity analyses, additional adjustment for ointment use for eczema at age 2 months, and cross-lagged modeling showed no consistent results for disease-related modification of the exposure. Results were not modified by maternal history of allergy, eczema, or asthma (lowest P-value for interaction=.13). CONCLUSION: Shorter duration or nonexclusiveness of breastfeeding is associated with a weak overall increased risk of eczema but not allergic sensitization or physician-diagnosed allergy at age 10 years.

Maternal psychiatric symptoms during pregnancy and risk of childhood atopic diseases.

BACKGROUND: Maternal psychiatric symptoms during pregnancy might affect the developing immune system and subsequent risk of childhood atopic diseases. OBJECTIVE: Our aim was to examine the associations of maternal psychiatric symptoms during pregnancy with allergic sensitization, allergy and eczema in children until age 10 years. METHODS: This study among 5205 children was performed in a population-based prospective cohort from foetal life onwards. We assessed maternal and paternal psychiatric symptoms (overall, depressive, anxiety) during pregnancy and at 36 months after delivery, and maternal psychiatric symptoms at 2 and 6 months after delivery using the Brief Symptom Inventory. Inhalant and food allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy or eczema by questionnaires from birth until age 10 years. We used multivariate logistic regression, multinomial logistic regression or generalized estimating equation models where appropriate. RESULTS: We observed no association of maternal psychiatric symptoms during pregnancy with allergic sensitization. Maternal overall psychiatric, depressive and anxiety symptoms during pregnancy were associated with an increased risk of inhalant allergy only (adjusted odds ratio (95% confidence interval) 1.96 (1.44, 2.65), 1.58 (1.25, 1.98) and 1.61 (1.27, 2.03), respectively, per 1-unit increase). Maternal overall psychiatric and anxiety symptoms during pregnancy were associated with an increased risk of eczema (1.21 (1.05, 1.39) and 1.15 (1.02, 1.29), respectively, per 1-unit increase). Effect estimates did not materially change when maternal psychiatric symptoms after delivery, or paternal psychiatric symptoms during pregnancy and after delivery were taken into account. CONCLUSIONS AND CLINICAL RELEVANCE: Maternal psychiatric symptoms during pregnancy were associated with increased risks of childhood inhalant allergy and eczema, independent of maternal psychiatric symptoms after delivery and of paternal psychiatric symptoms.

The association of maternal thyroid function with placental hemodynamics.

STUDY QUESTION: What is the clinical association of maternal thyroid function with placental hemodynamic function? SUMMARY ANSWER: A higher free thyroxine (FT4) concentration in early pregnancy is associated with higher placental vascular resistance. WHAT IS KNOWN ALREADY: Suboptimal placental function is associated with preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs the fetal blood supply), fetal growth restriction and premature delivery. Studies have suggested that thyroid hormone (TH) has a role in placental development through effects on trophoblast proliferation and invasion. STUDY DESIGN, SIZE, DURATION: This study was embedded in The Generation R cohort, a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands. In total, 7069 mothers with expected delivery date between April 2002 and January 2006 were enrolled during early pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHOD: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured during early pregnancy (median 13.4 weeks, 95% range 9.7-17.6 weeks). Placental function was assessed by Doppler ultrasound via measurement of arterial vascular resistance, i.e. umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) (both measured twice, between 18-25th and after 25th gestational weeks) and the presence of uterine artery notching (once after the 25th gestational week) in 5184 pregnant women. MAIN RESULTS AND THE ROLE OF CHANCE: FT4 was positively linearly associated with umbilical artery PI in the second and third trimesters as well as with uterine artery RI in the second trimester and the risk of uterine artery notching in the third trimester (P < 0.05 for all). The association of thyroid function with preeclampsia and birth weight was partially mediated through changes in placental function, with the percentages of mediated effects being 10.4% and 12.5%, respectively. LIMITATIONS, REASONS FOR CAUTION: A potential limitation is the availability of only a single time point for TH measurements and different numbers of missing placental ultrasound measurements for the adverse outcomes. WIDER IMPLICATIONS OF THE FINDINGS: A higher FT4 concentration in early pregnancy is associated with higher vascular resistance in the second and third trimesters in both the maternal and fetal placental compartment. These effects on placental function might explain the association of FT4 with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a fellowship from ERAWEB, a project funded by the European Commission (to M.B.) and by clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw), Project 90700412 (to R.P.P.). The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.