Our findings confirm a large adverse effect of maternal hypothyroxinemia on children's nonverbal IQ at school age. However, we found no evidence that maternal hypothyroxinemia is associated with differences in brain morphology in school-age children.

Previous studies have suggested that prenatal maternal folate deficiency is associated with reduced prenatal brain growth and psychological problems in offspring. However, little is known about the longer-term impact. The aims of this study were to investigate whether prenatal maternal folate insufficiency, high total homocysteine levels and low vitamin B12 levels are associated with altered brain morphology, cognitive and/or psychological problems in school-aged children. This study was embedded in Generation R, a prospective population-based cohort study. The study sample consisted of 256 Dutch children aged between 6 and 8 years from whom structural brain scans were collected using MRI. The mothers of sixty-two children had insufficient (9·1 µmol/l) predicted poorer performance on the language (B -0·31; 95 % CI -0·56, -0·06; P=0·014) and visuo-spatial domains (B -0·36; 95 % CI -0·60, -0·11; P=0·004). No associations with psychological problems were found. Our findings suggest that folate insufficiency in early pregnancy has a long-lasting, global effect on brain development and is, together with homocysteine levels, associated with poorer cognitive performance.

IMPORTANCEMaternal tobacco use during pregnancy has been associated with various health consequences, including suboptimal neurodevelopment in offspring. However, the effect of prenatal exposure to maternal smoking on child brain development has yet to be elucidated. OBJECTIVE To investigate the association between maternal smoking during pregnancy and offspring brain development in preadolescence as well as the mediating pathways. DESIGN, SETTING, AND PARTICIPANTS This prospective, population-based cohort study was embedded in the Generation R Study, Rotterdam, the Netherlands. The Generation R Study was launched in 2002, with follow-up ongoing. Child brain morphology was assessed at 9 to 11 years of age (ie, 10-12 years between exposure and outcome assessment). Data analysis was performed from March 1, 2021, to February 28, 2022, and at the time of manuscript revision. Participants included the singleton children of pregnant women residing in the study area with an expected date of delivery between April 1, 2002, and January 31, 2006; 2704 children with information on maternal smoking during pregnancy and structural neuroimaging at 9 to 11 years of age were included. A subsample of 784 children with data on DNA methylation at birth was examined in the mediation analysis. EXPOSURES Information on maternal smoking during pregnancy was collected via a questionnaire in each trimester. As a contrast, paternal smoking was assessed at recruitment. MAIN OUTCOMES AND MEASURES Brain morphology, including brain volumes and surface-based cortical measures (thickness, surface area, and gyrification), was assessed with magnetic resonance imaging. For mediation analysis, DNA methylation at birth was quantified by a weighted methylation risk score. RESULTS The 2704 participating children (1370 [50.7%] girls and 1334 [49.3%] boys) underwent brain imaging assessment at a mean (SD) age of 10.1 (0.6) years. Compared with nonexposed children (n = 2102), exposure to continued maternal smoking during pregnancy (n = 364) was associated with smaller total brain volume (volumetric difference [b] = −14.5 [95% CI, −25.1 to −4.0] cm 3 ), cerebral gray matter volume (b = −7.8 [95% CI, −13.4 to −2.3] cm 3 ), cerebral white matter volume (b = −5.9 [95% CI, −10.7 to −1.0] cm 3 ), and surface area and less gyrification. These associations were not explained by paternal smoking nor mediated by smoking-associated DNA methylation patterns at birth. Children exposed to maternal smoking only in the first trimester (n = 238) showed no differences in brain morphology compared with nonexposed children. CONCLUSIONS AND RELEVANCEThe findings of this cohort study suggest that continued maternal tobacco use during pregnancy was associated with lower brain volumes and suboptimal cortical traits of offspring in preadolescence, which seemed to be independent of shared family (continued) Key Points Question Is maternal tobacco use during pregnancy associated with preadolescent brain morphology among offspring? Findings In this cohort study of 2704 children in ...

Background Emerging evidence suggests an association of maternal PUFA concentrations during pregnancy with child cognitive and neuropsychiatric outcomes such as intelligence and autistic traits. However, little is known about prenatal maternal PUFAs in relation to child brain development, which may underlie these associations. Objectives We aimed to investigate the association of maternal PUFA status during pregnancy with child brain morphology, including volumetric and white matter microstructure measures. Methods This study was embedded in a prospective population-based study. In total, 1553 mother–child dyads of Dutch origin were included. Maternal plasma glycerophospholipid PUFAs were assessed in midpregnancy. Child brain morphologic outcomes, including total gray and white matter volumes, as well as white matter microstructure quantified by global fractional anisotropy and mean diffusivity, were measured using MRI (including diffusion tensor imaging) at age 9–11 y. Results Maternal ω-3 (n–3) long-chain PUFA (LC-PUFA) concentrations during pregnancy had an inverted U-shaped relation with child total gray volume (linear term: β: 16.7; 95% CI: 2.0, 31.5; quadratic term: β: –1.1; 95% CI: –2.1, –0.07) and total white matter volume (linear term: β: 15.7; 95% CI: 3.6, 27.8; quadratic term: β: –1.0; 95% CI: –1.8, –0.16). Maternal gestational ω-6 LC-PUFA concentrations did not predict brain volumetric differences in children, albeit the linolenic acid concentration was inversely associated with child total white matter volume. Maternal PUFA status during pregnancy was not related to child white matter microstructure. Conclusions Sufficient maternal ω-3 PUFAs during pregnancy may be related to more optimal child brain development in the long term. In particular, exposure to lower ω-3 PUFA concentrations in fetal life was associated with less brain volume in childhood. Maternal ω-6 LC-PUFAs were not related to child brain morphology.