Inflammatory markers in pregnancy - surprisingly stable. Mapping trajectories and drivers in four large cohorts.

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. To translate findings from mechanistic preclinical studies to human pregnancies, studies of serum immune markers are the mainstay. The design and interpretation of human biomarker studies require additional insights in the trajectories and drivers of peripheral immune markers. The current study mapped maternal inflammatory markers (C-reactive protein (CRP), interleukin (IL)-1ß, IL-6, IL-17A, IL-23, interferon- γ ) during pregnancy and investigated the impact of demographic, environmental and genetic drivers on maternal inflammatory marker levels in four multi-ethnic and socio-economically diverse population-based cohorts with more than 12,000 pregnant participants. Additionally, pregnancy inflammatory markers were compared to pre-pregnancy levels. Cytokines showed a high correlation with each other, but not with CRP. Inflammatory marker levels showed high variability between individuals, yet high concordance within an individual over time during and pre-pregnancy. Pre-pregnancy body mass index (BMI) explained more than 9.6% of the variance in CRP, but less than 1% of the variance in cytokines. The polygenic score of CRP was the best predictor of variance in CRP (>14.1%). Gestational age and previously identified inflammation drivers, including tobacco use and parity, explained less than 1% of variance in both cytokines and CRP. Our findings corroborate differential underlying regulatory mechanisms of CRP and cytokines and are suggestive of an individual inflammatory marker baseline which is, in part, genetically driven. While prior research has mainly focused on immune marker changes throughout pregnancy, our study suggests that this field could benefit from a focus on intra-individual factors, including metabolic and genetic components.

Adolescent substance use initiation and long-term neurobiological outcomes: insights, challenges and opportunities.

The increased frequency of risk taking behavior combined with marked neuromaturation has positioned adolescence as a focal point of research into the neural causes and consequences of substance use. However, little work has provided a summary of the links between adolescent initiated substance use and longer-term brain outcomes. Here we review studies exploring the long-term effects of adolescent-initiated substance use with structural and microstructural neuroimaging. A quarter of all studies reviewed conducted repeated neuroimaging assessments. Long-term alcohol use, as well as tobacco use were consistently associated with smaller frontal cortices and altered white matter microstructure. This association was mostly observed in the ACC, insula and subcortical regions in alcohol users, and for the OFC in tobacco users. Long-term cannabis use was mostly related to altered frontal cortices and hippocampal volumes. Interestingly, cannabis users scanned more years after use initiation tended to show smaller measures of these regions, whereas those with fewer years since initiation showed larger measures. Long-term stimulant use tended to show a similar trend as cannabis in terms of years since initiation in measures of the putamen, insula and frontal cortex. Long-term opioid use was mostly associated with smaller subcortical and insular volumes. Of note, null findings were reported in all substance use categories, most often in cannabis use studies. In the context of the large variety in study designs, substance use assessment, methods, and sample characteristics, we provide recommendations on how to interpret these findings, and considerations for future studies.

Prenatal maternal and cord blood vitamin D concentrations and negative affectivity in infancy.

Higher maternal vitamin D concentration during pregnancy is associated with better child mental health. Negative affectivity, an early-emerging temperamental trait, indicates an increased risk of psychopathology. We investigated if maternal early/mid-pregnancy 25-hydroxyvitamin D (25(OH)D) and neonatal cord blood 25(OH)D concentrations are associated with Negative affectivity in infancy. We studied term-born infants from the vitamin D Intervention in Infants study (VIDI, n = 777, follow-up rate 80%, Finland), and the Generation R Study (n = 1505, follow-up rate 40%, Netherlands). We measured maternal serum 25(OH)D at 6-27 weeks (VIDI) or 18-25 weeks (Generation R) of pregnancy, and cord blood 25(OH)D at birth (both cohorts). Caregivers rated infant Negative affectivity at 11.7 months (VIDI) or 6.5 months (Generation R) using the Revised Infant Behavior Questionnaire. Using linear regression, we tested associations between 25(OH)D and Negative affectivity adjusted for infant age, sex, season of 25(OH)D measurement, maternal age, education, smoking, and body-mass-index. Per 10 nmol/l increase in maternal early/mid-pregnancy 25(OH)D, infant Negative affectivity decreased by 0.02 standard deviations (95% confidence interval [CI] - 0.06, - 0.004) in VIDI, and 0.03 standard deviations (95% CI - 0.03, - 0.01) in Generation R. Cord blood 25(OH)D was associated with Negative affectivity in Generation R (- 0.03, 95% CI - 0.05, - 0.01), but not VIDI (0.00, 95% CI - 0.02, 0.02). Lower maternal 25(OH)D concentrations were consistently associated with higher infant Negative affectivity, while associations between cord blood 25(OH)D concentrations and Negative affectivity were less clear. Maternal vitamin D status during early- and mid-pregnancy may be linked with early-emerging differences in offspring behavior.

Fetal Exposure to Maternal Smoking and Neonatal Metabolite Profiles.

Fetal tobacco exposure has persistent effects on growth and metabolism. The underlying mechanisms of these relationships are yet unknown. We investigated the associations of fetal exposure to maternal smoking with neonatal metabolite profiles. In a population-based cohort study among 828 mother-infant pairs, we assessed maternal tobacco use by questionnaire. Metabolite concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines were determined by using LC-MS/MS in cord blood samples. Metabolite ratios reflecting metabolic pathways were computed. Compared to non-exposed neonates, those exposed to first trimester only tobacco smoking had lower neonatal mono-unsaturated acyl-alkyl-phosphatidylcholines (PC.ae) and alkyl-lysophosphatidylcholines (Lyso.PC.e) 18:0 concentrations. Neonates exposed to continued tobacco smoking during pregnancy had lower neonatal mono-unsaturated acyl-lysophosphatidylcholines (Lyso.PC.a), Lyso.PC.e.16:0 and Lyso.PC.e.18:1 concentration (False discovery rate (FDR) p-values < 0.05). Dose-response associations showed the strongest effect estimates in neonates whose mothers continued smoking ≥5 cigarettes per day (FDR p-values < 0.05). Furthermore, smoking during the first trimester only was associated with altered neonatal metabolite ratios involved in the Krebs cycle and oxidative stress, whereas continued smoking during pregnancy was associated with inflammatory, transsulfuration, and insulin resistance markers (p-value < 0.05). Thus, fetal tobacco exposure seems associated with neonatal metabolite profile adaptations. Whether these changes relate to later life metabolic health should be studied further.

Association of Maternal Tobacco Use During Pregnancy With Preadolescent Brain Morphology Among Offspring.

Importance: Maternal 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] cm3), cerebral gray matter volume (b = -7.8 [95% CI, -13.4 to -2.3] cm3), cerebral white matter volume (b = -5.9 [95% CI, -10.7 to -1.0] cm3), 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 Relevance: The 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 factors. Tobacco cessation before pregnancy, or as soon as pregnancy is known, should be recommended to women for optimal brain development of their offspring.

Brain morphology predictors of alcohol, tobacco, and cannabis use in adolescence: A systematic review.

In the last decade, extensive research has emerged on the predictive value of brain morphology for substance use initiation and related problems during adolescence. This systematic review provides an overview of longitudinal studies on pre-existing brain variations and later initiation of alcohol, tobacco, and cannabis use (N = 18). Adolescent structural neuroimaging studies that started before substance use initiation suggest that a smaller anterior cingulate cortex (ACC) volume, thicker or smaller superior frontal gyrus, and larger nucleus accumbens (NAcc) volume are associated with future alcohol use. Also, both smaller and larger orbitofrontal cortex (OFC) volumes were associated with future cannabis and combined alcohol/cannabis use. Smaller amygdala volumes were related to future daily tobacco smoking. These findings could point to specific vulnerabilities for adolescent substance use, as these brain areas are involved in cognitive control (ACC), reward (NAcc), motivation (OFC), and emotional memory (amygdala). However, the reported findings were inconsistent in directionality and laterality, and the largest study on alcohol use predictors reported null findings. Therefore, large population-based longitudinal studies should investigate the robustness and mechanisms of these associations. We suggested future research directions regarding sample selection, timing of baseline and follow-up measurements, and a harmonization approach of study methods.

Neonatal Pain, Opioid, and Anesthetic Exposure; What Remains in the Human Brain After the Wheels of Time?

Objective: To evaluate possible negative long-term effects of neonatal exposure to pain, opioids and anesthetics in children and adolescents. Study Design: We studied five unique groups of children recruited from well-documented neonatal cohorts with a history of neonatal exposure to pain, opioids or anesthetics at different points along the continuum from no pain to intense pain and from no opioid exposure to very high opioid exposure in the presence or absence of anesthetics. We evaluated children who underwent major surgery (group 1 and 2), extracorporeal membrane oxygenation (group 3), preterm birth (group 4) and prenatal opioid exposure (group 5) in comparison to healthy controls. Neuropsychological functioning, thermal detection and pain thresholds and high-resolution structural and task-based functional magnetic resonance imaging during pain were assessed. In total 94 cases were included and compared to their own control groups. Results: Children and adolescents in groups 3 and 5 showed worse neuropsychological functioning after high opioid exposure. A thicker cortex was found in group 1 (pain, opioid and anesthetic exposure) in only the left rostral-middle-frontal-cortex compared to controls. We found no differences in other brain volumes, pain thresholds or brain activity during pain in pain related brain regions between the other groups and their controls. Conclusions: No major effects of neonatal pain, opioid or anesthetic exposure were observed in humans 8-19 years after exposure in early life, apart from neuropsychological effects in the groups with the highest opioid exposure that warrants further investigation. Studies with larger sample sizes are needed to confirm our findings and test for less pronounced differences between exposed and unexposed children.

Maternal preconception and pregnancy tobacco and cannabis use in relation to placental developmental markers: A population-based study.

Maternal tobacco and cannabis use during pregnancy are associated with adverse perinatal outcomes. We hypothesized that maternal tobacco and cannabis use are associated with placental adaptations, which subsequently lead to adverse perinatal outcomes. In a population-based prospective cohort study of 8008 pregnant women, we assessed maternal tobacco and cannabis use by questionnaires. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the first and second trimester and at delivery from blood samples. Placental weight and pregnancy complications were obtained from medical records. We observed that tobacco use before and during first-trimester only was not associated with any angiogenic factors. As compared to no tobacco use, continued use during pregnancy was associated with higher PlGF, lower sFlt-1 concentrations, and lower sFlt-1/PlGF ratio in second trimester (all p-values <0.05). Also, compared to no cannabis use, use before and during pregnancy was associated with higher PlGF concentrations and lower sFlt-1/PlGF ratio in first and second trimester (all p-values <0.05). First trimester only cannabis use was associated with higher sFlt-1 concentrations and higher sFlt-1/PlGF ratio at delivery (all p-values <0.05). Compared to non-use, tobacco use before pregnancy was associated with a higher placental weight, whereas continued tobacco use during pregnancy was associated with a lower placental weight. Continued tobacco or cannabis use was related to higher placental weight to birth weight ratio and higher risk of pregnancy complications (all p-values <0.05). These results suggest that maternal tobacco and cannabis use lead to placental vascular maladaptation predisposing to adverse pregnancy outcomes.

Maternal early-pregnancy ferritin and offspring neurodevelopment: A prospective cohort study from gestation to school age.

BACKGROUND: Iron plays a role in many key processes in the developing brain. During pregnancy, iron supplementation is widely recommended to prevent and treat iron deficiency; however, the prevalence of iron deficiency and the risk of iron overload vary greatly between populations. Evidence on the role of high levels of maternal ferritin, a storage iron marker during pregnancy in relation to offspring neurodevelopment is lacking. OBJECTIVE: Our main objective was to examine if maternal ferritin levels during pregnancy are associated with child cognitive and motor abilities. METHODS: We included Dutch mother-child dyads from the prospective population-based Generation R Study, born in 2002-2006. We compared children whose mothers had high (standard deviation score >+1) or low (standard deviation score <-1) early-pregnancy ferritin to children whose mothers had intermediate ferritin (reference group) using linear regression. Children underwent non-verbal intelligence and language tests at 4-9 years (cognitive abilities), finger-tapping and balancing tests at 8-12 years (motor abilities), and structural magnetic resonance imaging at 8-12 years (brain morphology). Covariates were child age, sex, maternal intelligence quotient estimate, age, body-mass-index, education, parity, smoking and alcohol use. RESULTS: Of the 2479 mother-child dyads with data on maternal ferritin and at least one child neurodevelopmental outcome, 387 mothers had low (mean = 20.6 µg/L), 1700 intermediate (mean = 64.6 µg/L) and 392 high (mean = 170.3 µg/L) early-pregnancy ferritin. High maternal ferritin was associated with 2.54 points (95% confidence interval -4.16, -0.92) lower child intelligence quotient and 16.02 cm3 (95% confidence interval -30.57, -1.48) smaller brain volume. Results remained similar after excluding mothers with high C-reactive protein. Low maternal ferritin was not associated with child cognitive abilities. Maternal ferritin was unrelated to child motor outcomes. CONCLUSION: High maternal ferritin during pregnancy was associated with poorer child cognitive abilities and smaller brain volume. Maternal iron status during pregnancy may be associated with offspring neurodevelopment.

Foetal tobacco and cannabis exposure, body fat and cardio-metabolic health in childhood.

BACKGROUND: Foetal tobacco and cannabis exposure may have persistent cardio-metabolic consequences in the offspring. OBJECTIVE: We examined the associations of maternal and paternal tobacco and cannabis use during pregnancy with offspring body fat and cardio-metabolic outcomes. METHODS: In a population-based prospective cohort study among 4792 mothers, fathers, and children, we assessed parental substance use by questionnaires. Childhood outcomes included body mass index (BMI), body fat, blood pressure, and lipid, glucose and insulin concentrations at 10 years. RESULTS: Children exposed to maternal tobacco use during pregnancy had a higher android/gynoid fat mass ratio (difference 0.22 SDS, 95% confidence interval [CI]: 0.13, 0.30), fat mass index (difference 0.20 SDS, 95% CI: 0.12, 0.28), triglyceride concentrations (difference 0.15 SDS, 95% CI: 0.04, 0.26), and a higher risk of overweight (odds ratio [OR] 1.35, 95% CI: 1.07, 1.71), compared to non-exposed. Children exposed to maternal cannabis during pregnancy had a higher BMI (difference 0.26 SDS, 95% CI: 0.08, 0.44), android/gynoid fat mass ratio (difference 0.21 SDS, 95% CI: 0.04, 0.39), and fat-free mass index (difference 0.24 SDS, 95% CI: 0.06, 0.41), compared to non-exposed. The associations for paternal substance use with child cardio-metabolic health outcomes were similar as those for maternal use. CONCLUSIONS: Similar associations for maternal and paternal substance use during pregnancy suggest that these findings may be explained by shared family-based social and lifestyle factors, rather than by direct foetal programming.

Parental cannabis and tobacco use during pregnancy and childhood hair cortisol concentrations.

BACKGROUND: Fetal exposure to cannabis and tobacco during pregnancy leads to adverse fetal and childhood outcomes. We hypothesized that fetal exposure to cannabis and tobacco have persistent programming effects on hypothalamic pituitary adrenal (HPA) axis functioning in childhood. Therefore, we examined the associations of parental cannabis and tobacco use during pregnancy with childhood hair cortisol and cortisone concentrations at 6 years, as biomarkers of long-term HPA-axis functioning. METHOD: In a population-based prospective birth cohort among 2577 mothers and their children, information of parental cannabis and tobacco use was collected by questionnaires, and maternal urine samples were additionally analyzed to detect cannabis metabolite concentrations. Cortisol and cortisone were measured in hair samples at 6 years. Linear regression analysis with adjustment for several confounders was used to test our hypothesis. RESULTS: As compared to non-exposed children, offspring exposed to cannabis during pregnancy (in combination with tobacco) had higher childhood cortisol concentrations (log-10 transformed difference 0.16, 95 % Confidence Interval 0.04 to 0.28). This association was not mediated by birth weight. No differences in cortisone concentrations among cannabis-exposed children were observed. Maternal tobacco use during pregnancy was not associated with childhood cortisol or cortisone concentrations. Further, paternal cannabis or tobacco use was not associated with childhood cortisol or cortisone concentrations. CONCLUSIONS: Our findings suggest that maternal cannabis use, combined with tobacco, during pregnancy is associated with alterations in offspring HPA-axis functioning. Further studies need to replicate these findings, and assess the causality and long-term consequences of these associations.

Radiofrequency electromagnetic fields from mobile communication: Description of modeled dose in brain regions and the body in European children and adolescents.

BACKGROUND: Little is known about radiofrequency electromagnetic fields (RF) from mobile technology and resulting dose in young people. We describe modeled integrated RF dose in European children and adolescents combining own mobile device use and surrounding sources. METHODS: Using an integrated RF model, we estimated the daily RF dose in the brain (whole-brain, cerebellum, frontal lobe, midbrain, occipital lobe, parietal lobe, temporal lobes) and the whole-body in 8358 children (ages 8-12) and adolescents (ages 14-18) from the Netherlands, Spain, and Switzerland during 2012-2016. The integrated model estimated RF dose from near-field sources (digital enhanced communication technology (DECT) phone, mobile phone, tablet, and laptop) and far-field sources (mobile phone base stations via 3D-radiowave modeling or RF measurements). RESULTS: Adolescents were more frequent mobile phone users and experienced higher modeled RF doses in the whole-brain (median 330.4 mJ/kg/day) compared to children (median 81.8 mJ/kg/day). Children spent more time using tablets or laptops compared to adolescents, resulting in higher RF doses in the whole-body (median whole-body dose of 81.8 mJ/kg/day) compared to adolescents (41.9 mJ/kg/day). Among brain regions, temporal lobes received the highest RF dose (medians of 274.9 and 1786.5 mJ/kg/day in children and adolescents, respectively) followed by the frontal lobe. In most children and adolescents, calling on 2G networks was the main contributor to RF dose in the whole-brain (medians of 31.1 and 273.7 mJ/kg/day, respectively). CONCLUSION: This first large study of RF dose to the brain and body of children and adolescents shows that mobile phone calls on 2G networks are the main determinants of brain dose, especially in temporal and frontal lobes, whereas whole-body doses were mostly determined by tablet and laptop use. The modeling of RF doses provides valuable input to epidemiological research and to potential risk management regarding RF exposure in young people.

Prenatal exposure to organophosphate pesticides and brain morphology and white matter microstructure in preadolescents.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9-12 years. METHOD: Data came from 518 mother-child pairs participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child's age 9-12 years, magnetic resonance imaging was performed to obtain T1-weighted images for brain volumes and surface-based cortical thickness and cortical surface area, and diffusion tensor imaging was used to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy. RESULTS: DM and DE metabolite concentrations were not associated with brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B = -1.00, 95%CI = -1.80, -0.20) and higher MD (B = 0.13, 95%CI = 0.04, 0.21). Similar associations were observed for DE concentrations. CONCLUSIONS: This study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including brain volumes, cortical thickness, and cortical surface area.

Organophosphate pesticide metabolite concentrations in urine during pregnancy and offspring attention-deficit hyperactivity disorder and autistic traits.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides has been associated with altered neuronal cell development and behavioral changes in animal offspring. However, the few studies investigating the association between prenatal OP pesticide exposure and neurodevelopmental outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD) and autistic traits in children produced mixed findings. OBJECTIVE: The objective of the present study was to examine whether maternal urinary concentrations of OP pesticide metabolites are associated with ADHD and autistic traits in children participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. METHOD: Maternal concentrations of 6 dialkylphosphates (DAPs) were measured using gas chromatography coupled with tandem mass spectrometry in urine samples collected at <18 weeks, 18-25 weeks, and > 25 weeks of gestation in 784 mother-child pairs. DAP metabolite concentrations were expressed as molar concentrations divided by creatinine levels and log10 transformed. ADHD traits were measured at ages 3, 6, and 10 years using the Child Behavior Checklist (CBCL) (n = 781) and autistic traits were measured at age 6 years using the Social Responsiveness Scale (SRS) (n = 622). First, regression models were fit for the averaged prenatal exposure across pregnancy. Second, we investigated associations for each collection phase separately, and applied a mutually adjusted model in which the effect of prenatal DAP concentrations from each time period on ADHD and autistic traits were jointly estimated. All associations were adjusted for relevant confounders. RESULTS: Median DAP metabolite concentration was 309 nmol/g creatinine at <18 weeks, 316 nmol/g creatinine at 18-25 weeks, and 308 nmol/g creatinine at >25 weeks of gestation. Overall, DAP metabolite concentrations were not associated with ADHD traits. For instance, a log10 increase in averaged total DAP concentrations across gestation was not associated with a lower ADHD score (-0.03 per SD 95 CI: -0.28 to 0.23). Similarly, no associations between maternal DAP concentrations and autistic traits were detected. CONCLUSIONS: In this study of maternal urinary DAP metabolite concentrations during pregnancy, we did not observe associations with ADHD and autistic traits in children. These are important null observations because of the relatively high background DAP concentrations across pregnancy, the relatively large sample size, and the 10-year follow-up of the offspring. Given the measurement error inherent in our OP pesticide exposure biomarkers, future studies using more urine samples are needed to accurately measure OP pesticide exposure over pregnancy in relation to ADHD and autistic traits.

Maternal prepregnancy body mass index and offspring white matter microstructure: results from three birth cohorts.

BACKGROUND AND AIMS: Prepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts. SUBJECTS AND METHODS: The study used data from three European birth cohorts (n = 116 children aged 6 years, n = 2466 children aged 10 years, and n = 437 young adults aged 26 years). Information on maternal prepregnancy BMI was obtained before or during pregnancy and offspring brain white matter microstructure was measured at age 6, 10, or 26 years. We used magnetic resonance imaging-derived fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter microstructure in the brainstem, callosal, limbic, association, and projection tracts. Linear regressions were fitted to examine the association of maternal BMI and offspring white matter microstructure, adjusting for several socioeconomic and lifestyle-related confounders, including education, smoking, and alcohol use. RESULTS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts, for example, association and projection fibers, in offspring aged 10 and 26 years, but not at 6 years. In each cohort maternal BMI was related to different white matter tract and thus no common associations across the cohorts were found. CONCLUSIONS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings.

Preconception and prenatal cannabis use and the risk of behavioural and emotional problems in the offspring; a multi-informant prospective longitudinal study.

BACKGROUND: Studies of the long-term consequences of maternal cannabis use on child development beyond the neonatal period are sparse. In the current study, we use a multi-information approach to assess the association of prenatal cannabis exposure and child behavioural and emotional functioning. To explore the possible causal nature of the association, we investigated whether maternal tobacco and paternal cannabis use during pregnancy were also associated with child problems. METHODS: The study population included children of a population-based birth cohort in The Netherlands (n = 5903). Information on parental cannabis use was collected using questionnaires; urine of mothers was analysed for the presence of cannabis metabolites. Child behavioural and emotional problems at approximately 7-10 years were measured using validated teacher-, child- and mother-reports. RESULTS: Our findings show associations of maternal cannabis use during pregnancy with offspring externalising problems (B = 0.53; 95% CI: 0.29-0.77), but not with internalising problems (B = -0.10; 95% CI: -0.31-0.11). However, maternal cannabis use before pregnancy was also associated with offspring externalising problems (B = 0.27; 95% CI: 0.02-0.52). Further, cannabis use by the father was associated with child externalising problems (B = 0.36; 95% CI: 0.22-0.49) but not internalising problems. CONCLUSIONS: Prenatal exposure to maternal cannabis use is specifically associated with offspring behavioural problems, but not emotional problems. This association is probably not due to an effect of intrauterine cannabis exposure on fetal development, because both maternal and paternal cannabis exposure during pregnancy were related to offspring externalising problems. Our findings suggest that the association can be explained through residual confounding, most likely through shared genetic vulnerabilities for parental cannabis use and offspring behavioural problems.

An epidemiological, developmental and clinical overview of cannabis use during pregnancy.

The objective of the current narrative literature review is to provide an epidemiological, developmental and clinical overview on cannabis use during pregnancy. Cannabis use in pregnancy poses major health concerns for pregnant mothers and their developing children. Although studies on the short- and long-term consequences of prenatal cannabis exposure are increasing, findings have been inconsistent or difficult to interpret due to methodological issues. Thus, consolidating these findings into clinical recommendations based on the mixed studies in the literature remains a challenge. Synthesizing the available observational studies is also difficult, because some of the published studies have substantial methodological weaknesses. Improving observational studies will be an important step toward understanding the extent to which prenatal exposure to cannabis influences neurodevelopment in the offspring. Therefore, further research on prenatal cannabis exposure and the long-term consequences to offspring health in representative samples are needed to guide and improve clinical care for pregnant women and their children. Future research should also investigate the role of policies on prenatal cannabis use.

Prenatal Cannabis and Tobacco Exposure in Relation to Brain Morphology: A Prospective Neuroimaging Study in Young Children.

BACKGROUND: Cannabis use during pregnancy has been associated with negative behavioral outcomes and psychopathology in offspring. However, there has been little research evaluating alterations in brain structure as a result of maternal cannabis use. In this prospective study, we investigated the association between prenatal cannabis exposure and brain morphology in young children. METHODS: We matched 96 children prenatally exposed to tobacco only (without cannabis) with 113 unexposed control subjects on the basis of age and gender and subsequently selected 54 children exposed to prenatal cannabis (mostly combined with tobacco exposure). These children (aged 6 to 8 years) were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. We assessed brain volumetric measures and cortical thickness in magnetic resonance imaging scans using FreeSurfer. We performed vertexwise analyses in FreeSurfer and linear regression analyses adjusting for relevant covariates using Statistical Package for the Social Sciences. RESULTS: Prenatal cannabis exposure was not associated with global brain volumes, such as total brain volume, gray matter volume, or white matter volume. However, prenatal cannabis exposure was associated with differences in cortical thickness: compared with nonexposed control subjects, cannabis-exposed children had thicker frontal cortices. Prenatal tobacco exposure compared with nonexposed control subjects was associated with cortical thinning, primarily in the superior frontal and superior parietal cortices. CONCLUSIONS: Our findings suggest an association between prenatal cannabis exposure and cortical thickness in children. Further research is needed to explore the causal nature of this association.

Prenatal tobacco exposure and brain morphology: a prospective study in young children.

It is well known that smoking during pregnancy can affect offspring health. Prenatal tobacco exposure has been associated with negative behavioral and cognitive outcomes in childhood, adolescence, and young adulthood. These associations between prenatal tobacco exposure and psychopathology in offspring could possibly be explained by the influence of prenatal tobacco exposure on brain development. In this prospective study, we investigated the association between prenatal tobacco exposure, behavioral and emotional functioning and brain morphology in young children. On the basis of age and gender, we matched 113 children prenatally exposed to tobacco with 113 unexposed controls. These children were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. Behavioral and emotional functioning was assessed at age 6 with the Child Behavior Checklist. We assessed brain morphology using magnetic resonance imaging techniques in children aged 6-8 years. Children exposed to tobacco throughout pregnancy have smaller total brain volumes and smaller cortical gray matter volumes. Continued prenatal tobacco exposure was associated with cortical thinning, primarily in the superior frontal, superior parietal, and precentral cortices. These children also demonstrated increased scores of affective problems. In addition, thickness of the precentral and superior frontal cortices was associated with affective problems. Importantly, brain development in offspring of mothers who quit smoking during pregnancy resembled that of nonexposed controls (no smaller brain volumes and no thinning of the cortex). Our findings suggest an association between continued prenatal tobacco exposure and brain structure and function in school-aged children.

Is maternal use of medicines during pregnancy associated with deciduous molar hypomineralisation in the offspring? A prospective, population-based study.

BACKGROUND: The effects of maternal use of medicines during pregnancy on tooth development has scarcely been studied; only negative effects of tetracycline on tooth germs are known (irreversible tooth discoloration and enamel hypoplasia). OBJECTIVE: The aim of this study was to investigate whether antibacterials and anti-allergic and anti-asthma medicines, being the most frequently used medicines during pregnancy, are associated with deciduous molar hypomineralisation (DMH) and, if so, which specific medicines. MATERIALS AND METHODS: To clarify this possible association, the participants of the Generation R Study, a population-based prospective cohort study from fetal life until young adulthood, were studied. Data on medicine use during pregnancy were retrieved from pharmacies. Clinical photographs of the second primary molars, which were scored for DMH, were taken with an intra-oral camera in 6,690 children (mean age 6.2 years, standard deviation [SD] ± 0.53; 49.9 % girls). RESULTS: During pregnancy, 20.3 % of the mothers used antibacterials, 12.3 % anti-asthma medicines and 5.4 % anti-allergic medicines. The prevalence of DMH was 9.0 % in the study group. There was no association between the use of anti-asthma medicines, anti-allergic medicines (odds ratio [OR]: 0.97 [95 % CI 0.61-1.54]; OR: 1.04 [0.54-2.03]) or antibacterials (OR: 0.73 [0.49-1.09]) during pregnancy and DMH (all p-values >0.05). The study had sufficient power (80 %) to detect significant associations. CONCLUSION: Maternal use of antibacterials, anti-allergic medicines or anti-asthma medicines during pregnancy is not associated with the development of DMH in the offspring.