Prenatal Cannabis Exposure and Infant Development: “A Tolerated Matter”

Since centuries, cannabis is used for recreational, spiritual and medicinal purposes. Today, cannabis is one of the most commonly used illicit substances, also among pregnant women. In the last decades, levels of Δ9-tetrahydrocannabinol in cannabis products have increased, and these higher levels contributed to our interest for investigating the effects of cannabis during pregnancy. The study described in this thesis was embedded within the Generation R Study, a prospective cohort study from foetal life onwards in a multiethnic urban population. In this study, we examined the associations of maternal cannabis use during pregnancy and several offspring outcomes. In order to determine whether cannabis use affects children because of intrauterine exposure, the possible influence of confounding factors should be considered. Moreover, the direct biological effect of intrauterine exposure was addressed by comparing the strength of the associations between maternal and paternal cannabis use during pregnancy and foetal growth using ultrasound measures. Additionally, to determine whether exposure to cannabis has an intrauterine influence or not, the timing of exposure was considered as well, i.e. the comparison between maternal cannabis use only before pregnancy and during pregnancy was made. This manuscript described the determinants of maternal cannabis use during pregnancy. Additionally, it discussed the agreement between maternal self-report of cannabis use during pregnancy and the presence of cannabis metabolites in urine. We addressed the association between maternal and paternal cannabis use and foetal growth and foetal redistribution observed using ultrasound measurements. Finally, this thesis focuses on the relation between parental cannabis use and child behavioural development and verbal and non-verbal cognitive development

Intrauterine Exposure to Antidepressants or Maternal Depressive Symptoms and Offspring Brain White Matter Trajectories From Late Childhood to Adolescence

Background: During pregnancy, both selective serotonin reuptake inhibitor (SSRI) exposure and maternal depression have been associated with poor offspring neurodevelopmental outcomes. In a population-based cohort, we investigated the association between intrauterine exposure to SSRIs and depressive symptoms and offspring white matter development from childhood to adolescence. Methods: Self-reported SSRI use was verified by pharmacy records. In midpregnancy, women reported on depressive symptoms using the Brief Symptom Inventory. Using diffusion tensor imaging, offspring white matter microstructure, including whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity, was measured at 3 assessments between ages 7 to 15 years. The participants were divided into 4 groups: prenatal SSRI exposure (n = 37 with 60 scans), prenatal depression exposure (n = 229 with 367 scans), SSRI use before pregnancy (n = 72 with 95 scans), and reference (n = 2640 with 4030 scans). Results: Intrauterine exposure to SSRIs and depressive symptoms were associated with lower FA in the whole-brain and the forceps minor at 7 years. Exposure to higher prenatal depressive symptom scores was associated with lower FA in the uncinate fasciculus, cingulum bundle, superior and inferior longitudinal fasciculi, and corticospinal tracts. From ages 7 to 15 years, children exposed to prenatal depressive symptoms showed a faster increase in FA in these white matter tracts. Prenatal SSRI exposure was not related to white matter microstructure growth over and above exposure to depressive symptoms.Conclusions: These results suggest that prenatal exposure to maternal depressive symptoms was negatively associated with white matter microstructure in childhood, but these differences attenuated during development, suggesting catch-up growth.</p

Intrauterine Exposure to Antidepressants or Maternal Depressive Symptoms and Offspring Brain White Matter Trajectories From Late Childhood to Adolescence

Background: During pregnancy, both selective serotonin reuptake inhibitor (SSRI) exposure and maternal depression have been associated with poor offspring neurodevelopmental outcomes. In a population-based cohort, we investigated the association between intrauterine exposure to SSRIs and depressive symptoms and offspring white matter development from childhood to adolescence. Methods: Self-reported SSRI use was verified by pharmacy records. In midpregnancy, women reported on depressive symptoms using the Brief Symptom Inventory. Using diffusion tensor imaging, offspring white matter microstructure, including whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity, was measured at 3 assessments between ages 7 to 15 years. The participants were divided into 4 groups: prenatal SSRI exposure (n = 37 with 60 scans), prenatal depression exposure (n = 229 with 367 scans), SSRI use before pregnancy (n = 72 with 95 scans), and reference (n = 2640 with 4030 scans). Results: Intrauterine exposure to SSRIs and depressive symptoms were associated with lower FA in the whole-brain and the forceps minor at 7 years. Exposure to higher prenatal depressive symptom scores was associated with lower FA in the uncinate fasciculus, cingulum bundle, superior and inferior longitudinal fasciculi, and corticospinal tracts. From ages 7 to 15 years, children exposed to prenatal depressive symptoms showed a faster increase in FA in these white matter tracts. Prenatal SSRI exposure was not related to white matter microstructure growth over and above exposure to depressive symptoms.Conclusions: These results suggest that prenatal exposure to maternal depressive symptoms was negatively associated with white matter microstructure in childhood, but these differences attenuated during development, suggesting catch-up growth.</p

Examining associations between brain morphology in late childhood and early alcohol or tobacco use initiation in adolescence:findings from a large prospective cohort

A prominent challenge in understanding neural consequences of substance use involves disentangling predispositional risk factors from resulting consequences of substance use. Existing literature has identified pre-existing brain variations as vulnerability markers for substance use throughout adolescence. As early initiation of use is an important predictor for later substance use problems, we examined whether pre-existing brain variations are associated with early initiation of use. In the Generation R Study, a prospective population-based cohort, brain morphology (gray matter volume, cortical thickness and surface area) was assessed at ages 10 and 14 using neuroimaging. In the second wave, participants reported on alcohol and tobacco use initiation. From a base study population (N = 3019), we examined the longitudinal (N = 2218) and cross-sectional (N = 1817) association between brain morphology of frontolimbic regions of interest known to be associated with substance use risk, and very early (age &lt; 13) alcohol/tobacco use initiation. Additionally, longitudinal and cross-sectional associations were examined with a brain surface-based approach. Models were adjusted for age at neuroimaging, sex and relevant sociodemographic factors. No associations were found between brain morphology (ages 10 and 14) and early alcohol/tobacco use initiation (&lt;13 years). Sex-specific analyses suggested a cross-sectional association between smaller brain volume and early initiated tobacco use in girls. Our findings are important for interpreting studies examining neural consequences of substance use in the general population. Future longitudinal studies are needed to specify whether these findings can be extended to initiation and continuation of alcohol/tobacco use in later stages of adolescence.</p

Psychological Distress and Weight Gain in Pregnancy: a Population-Based Study.

Background Psychological distress and inappropriate or excessive weight gain are common in pregnancy and are associated with adverse maternal and offspring outcomes. Psychological well-being and weight status of women during pregnancy might be interrelated. We aimed to examine whether psychological distress during pregnancy is associated with gestational weight gain. Method In a population-based cohort of 3393 pregnant women, information about psychological distress, depressive and anxiety symptoms was assessed at 20 weeks of gestation using the Brief Symptom Inventory questionnaire. Weight was repeatedly measured during pregnancy and obtained by questionnaire before and after pregnancy. Linear regression and multinomial logistic regression models were used. Weight gain in the second half of pregnancy, total weight gain, and the risks of inadequate and excessive total weight gain were the main outcome measures. Results In total, 7.0% of all women experienced psychological distress. Overall psychological distress and anxiety were associated with lower weight gain in the second half of pregnancy (differences − 1.00 kg (95% confidence interval (CI) − 1.62, − 0.37) and − 0.68 kg (95% CI - 1.24, -0.11), respectively). These associations fully attenuated into non-significance after taking account for socio-demographic variables. Similar results were observed for total weight gain. Only women with anxiety symptoms had, independently of potential confounders, a lower risk of excessive weight gain (odds ratio (OR) 0.61 (95% CI 0.48, 0.91)). Conclusions In this large prospective cohort study, the observed associations of psychological distress with weight gain during pregnancy seem to be largely explained by common socio-demographic factors

A prospective population-based study of gestational vitamin D status and brain morphology in preadolescents

Low vitamin D level during pregnancy has been associated with adverse neurodevelopmental outcomes such as autism spectrum disorders (ASD) in children. However, the underlying neurobiological mechanism remains largely unknown. This study investigated the association between gestational 25-hydroxyvitamin D [25(OH)D] concentration and brain morphology in 2597 children at the age of 10 years in the population-based Generation R Study. We studied both 25(OH)D in maternal venous blood in mid-gestation and in umbilical cord blood at delivery, in relation to brain volumetric measures and surface-based cortical metrics including cortical thickness, surface area, and gyrification using linear regression. We found exposure to higher maternal 25(OH)D concentrations in mid-gestation was associated with a larger cerebellar volume in children (b ​= ​0.02, 95%CI 0.001 to 0.04), however this association did not remain after co

Maternal Sociodemographic Factors Are Associated With Methylphenidate Initiation in Children in the Netherlands: A Population-Based Study

Multiple factors may contribute to the decision to initiate methylphenidate treatment in children such as maternal sociodemographic factors of which relatively little is known. The objective was to investigate the association between these factors and methylphenidate initiation. The study population included 4243 children from the Generation R Study in the Netherlands. Maternal sociodemographic characteristics were tested as determinants of methylphenidate initiation through a timedependent Cox regression analysis. Subsequently, we stratifed by mother-reported ADHD symptoms (present in 4.2% of the study population). When ADHD symptoms were absent, we found that girls (adjusted HR 0.25, 95%CI 0.16–0.39) and children born to a mother with a non-western ethnicity (compared to Dutch-Caucasian) (adjusted HR 0.42, 95%CI 015–0.68) were less likely to receive methylphenidate. They were more likely to receive methylphenidate when their mother completed a low (adjusted HR 2.29, 95%CI 1.10–4.77) or secondary (adjusted HR 1.71, 95%CI 1.16–2.54) education. In conclusion, boys and children born to a mother of Dutch-Caucasian ethnicity were more likely to receive methylphenidate, irrespective of the presence of ADHD symptoms

Neural Profile of Callous Traits in Children: A Population-Based Neuroimaging Study

BACKGROUND: Callous traits during childhood, e.g., lack of remorse and shallow affect, are a key risk marker for antisocial behavior. Although callous traits have been found to be associated with structural and functional brain alterations, evidence to date has been almost exclusively limited to small, high-risk samples of boys. We characterized gray and white matter brain correlates of callous traits in over 2000 children from the general population. METHODS: Data on mother-reported callous traits and brain imaging were collected at age 10 years from participants of the Generation R Study. Structural magnetic resonance imaging was used to investigate brain morphology using volumetric indices and whole-brain analyses (n = 2146); diffusion tensor imaging was used to assess global and specific white matter microstructure (n = 2059). RESULTS: Callous traits were associated with lower global brain (e.g., total brain) volumes as well as decreased cortical surface area in frontal and temporal regions. Global mean diffusivity was negatively associated with callous traits, suggesting higher white matter microstructural integrity in children with elevated callous traits. Multiple individual tracts, including the uncinate and cingulum, contributed to this global association. Whereas no gender differences were observed for global volumetric indices, white matter associations were present only in girls. CONCLUSIONS: This is the first study to provide a systematic characterization of the structural neural profile of callous traits in the general pediatric population. These findings extend previous work based on selected samples by demonstrating that childhood callous traits in the general population are characterized by widespread macrostructural and microstructural differences across the brain

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