Hanan El Marroun

Maternal Use of Selective Serotonin Reuptake Inhibitors, Fetal Growth, and Risk of Adverse Birth Outcomes

CONTEXT Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed to pregnant women, but knowledge about their unintended effects on child health is scarce. OBJECTIVE To examine the effects of maternal SSRI use during pregnancy on fetal growth and birth outcomes. DESIGN The study was embedded in the Generation R Study, a prospective population-based study from fetal life onward. PARTICIPANTS Seven thousand six hundred ninety-six pregnant women were included. Selective serotonin reuptake inhibitor use was assessed by questionnaires in each trimester and verified by pharmacy records. Using depressive symptom scores from the Brief Symptom Inventory, 7027 pregnant mothers (91.3%) had no or low depressive symptoms, 570 pregnant mothers (7.4%) had clinically relevant depressive symptoms and used no SSRIs, and 99 pregnant mothers (1.3%) used SSRIs. MAIN OUTCOME MEASURES Fetal ultrasonography was performed in each trimester. We determined fetal body and head growth with repeated assessments of body and head size. The birth outcomes studied were preterm birth, small for gestational age, and low birth weight. RESULTS Fetuses from mothers with prenatal depressive symptoms showed reduced body growth (β=-4.4 g/wk; 95% CI: -6.3 to -2.4; P<.001) and head growth (β=-0.08 mm/wk; 95% CI: -0.14 to -0.03; P=.003). Mothers using SSRIs during pregnancy had fewer depressive symptoms than mothers in the clinical symptom range. Prenatal SSRI use was not associated with reduced body growth but was associated with reduced fetal head growth (β=-0.18 mm/wk; 95% CI: -0.32 to -0.07; P=.003). The SSRI-exposed children were at higher risk for preterm birth (odds ratio=2.14; 95% CI: 1.08 to 4.25; P=.03). CONCLUSIONS Untreated maternal depression was associated with slower rates of fetal body and head growth. Pregnant mothers treated with SSRIs had fewer depressive symptoms and their fetuses had no delay in body growth but had delayed head growth and were at increased risk for preterm birth. Further research on the implications of these findings is needed.

Intrauterine Cannabis Exposure Affects Fetal Growth Trajectories: The Generation R Study

OBJECTIVE Cannabis is the most commonly consumed illicit drug among pregnant women. Intrauterine exposure to cannabis may result in risks for the developing fetus. The importance of intrauterine growth on subsequent psychological and behavioral child development has been demonstrated. This study examined the relation between maternal cannabis use and fetal growth until birth in a population-based sample. METHOD Approximately 7,452 mothers enrolled during pregnancy and provided information on substance use and fetal growth. Fetal growth was determined using ultrasound measures in early, mid-, and late pregnancy. Additionally, birth weight was assessed. RESULTS Maternal cannabis use during pregnancy was associated with growth restriction in mid-and late pregnancy and with lower birth weight. This growth reduction was most pronounced for fetuses exposed to continued maternal cannabis use during pregnancy. Fetal weight in cannabis-exposed fetuses showed a growth reduction of -14.44 g/week (95% confidence interval -22.94 to -5.94, p = .001) and head circumference (-0.21 mm/week, 95% confidence interval -0.42 to 0.02, p = .07), compared with nonexposed fetuses. Maternal cannabis use during pregnancy resulted in more pronounced growth restriction than maternal tobacco use. Paternal cannabis use was not associated with fetal growth restriction. CONCLUSIONS Maternal cannabis use, even for a short period, may be associated with several adverse fetal growth trajectories.

Downstream Effects of Maternal Hypothyroxinemia in Early Pregnancy: Nonverbal IQ and Brain Morphology in School-Age Children

CONTEXT Although maternal hypothyroxinemia is suggested to be related to various adverse consequences in a childs neurodevelopment, the underlying neurobiology is largely unknown. OBJECTIVE The objective of the study was to examine the relationship between maternal hypothyroxinemia in early pregnancy and childrens nonverbal intelligence quotient (IQ). Furthermore, we explored whether global brain volumes, cortical thickness, and brain surface area differed between children exposed prenatally to hypothyroxinemia and healthy controls. DESIGN AND SETTING The study included a large population-based prospective birth cohort in The Netherlands. PARTICIPANTS A total of 3727 mother-child pairs with data on prenatal thyroid function at less than 18 weeks of gestation and nonverbal IQ at 6 years participated in the study. In 652 children, brain imaging was performed at 8 years of age. MAIN MEASURES Maternal hypothyroxinemia was defined as free T4 in the lowest 5% of the sample, whereas TSH was in the normal range. At 6 years, childrens IQ was assessed using a Dutch test battery. Global brain volumetric measures, cortical thickness, and surface area were assessed using high-resolution structural magnetic resonance imaging. RESULTS The children of mothers with hypothyroxinemia in early pregnancy scored 4.3 points IQ lower than the children of mothers with normal thyroid status (95% confidence interval -6.68, -1.81; P = .001). After adjustment for multiple testing, we did not find any differences in brain volumetric measures, cortical thickness, and surface area between children exposed prenatally to hypothyroxinemia and controls. CONCLUSIONS Our findings confirm a large adverse effect of maternal hypothyroxinemia on childrens nonverbal IQ at school age. However, we found no evidence that maternal hypothyroxinemia is associated with differences in brain morphology in school-age children.

Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are considered safe and are frequently used during pregnancy. However, two case-control studies suggested an association between prenatal SSRI exposure with childhood autism. AIMS To prospectively determine whether intra-uterine SSSRI exposure is associated with childhood autistic symptoms in a population-based study. METHOD A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included. Child pervasive developmental and affective problems were assessed by parental report with the Child Behavior Checklist at ages 1.5, 3 and 6. At age 6, we assessed autistic traits using the Social Responsiveness Scale (n = 4264). RESULTS Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81). Compared with unexposed children, those prenatally exposed to SSRIs also were at higher risk for developing pervasive developmental problems (OR = 1.91, 95% CI 1.13-3.47), but not for affective problems. Children prenatally exposed to SSRIs also had more autistic traits (B = 0.15, 95% CI 0.08-0.22) compared with those exposed to depressive symptoms only. CONCLUSIONS Our results suggest an association between prenatal SSRI exposure and autistic traits in children. Prenatal depressive symptoms without SSRI use were also associated with autistic traits, albeit this was weaker and less specific. Long-term drug safety trials are needed before evidence-based recommendations are possible.

Demographic, emotional and social determinants of cannabis use in early pregnancy: The Generation R study

AIMS To ascertain demographic, emotional and social determinants of cannabis use in early pregnancy. DESIGN This study was embedded in the Generation R study, a multiethnic population-based cohort of parents and their children, followed from pregnancy to childhood. SETTING Rotterdam, The Netherlands. PARTICIPANTS Mothers enrolled in pregnancy who answered questions about their own and their partners substance use before and during pregnancy (n=7610). MEASUREMENTS Using self-report questionnaires, information was collected on maternal demographics, psychopathology, delinquency, childhood trauma, social stress, family functioning, and parental alcohol, tobacco and substance use. Multinomial logistic regression analysis was used, with non-using women as reference. FINDINGS 246 (3.2%) women used cannabis before pregnancy and 220 (2.9%) women used cannabis both before and during pregnancy. The strongest determinant for maternal cannabis use during pregnancy was cannabis use by the biological father of the child (OR=38.56; 95%CI=26.14-58.88). Maternal cannabis use during pregnancy was also independently associated with being single (OR=4.25; 95%CI=2.33-7.75) or having a partner without being married (OR=2.75; 95%CI=1.56-4.85), childhood trauma (OR=1.39; 95%CI=1.22-1.57) and delinquency (OR=3.37; 95%CI=1.90-5.98), but not with maternal age, ethnicity, psychopathology, family functioning and perceived stress. Being religious was protective (Islam: OR=0.25; 95%CI=0.09-0.65) for maternal cannabis use during pregnancy. Additionally, lower educational level determined continued cannabis use in ever-users (OR=3.22; 95%CI=1.54-6.74). CONCLUSIONS Our results showed that multiple demographic, emotional and social characteristics were associated with maternal cannabis use. These characteristics should be considered when investigating offspring exposed to cannabis in utero, as they may play an important role in mother-child interaction and child development.

Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls

BACKGROUND The development of the fetal endocannabinoid receptor system may be vulnerable to maternal cannabis use during pregnancy and may produce long-term consequences in children. In this study, we aimed to determine the relationship between gestational cannabis use and childhood attention problems and aggressive behavior. METHODS Using a large general population birth cohort, we examined the associations between parental prenatal cannabis and tobacco use and childhood behavior problems at 18 months measured using the Child Behavior Checklist in N=4077 children. Substance use was measured in early pregnancy. RESULTS Linear regression analyses demonstrated that gestational exposure to cannabis is associated with behavioral problems in early childhood but only in girls and only in the area of increased aggressive behavior (B=2.02; 95% CI: 0.30-3.73; p=0.02) and attention problems (B=1.04; 95% CI: 0.46-1.62; p<0.001). Furthermore, this study showed that long-term (but not short term) tobacco exposure was associated with behavioral problems in girls (B=1.16; 95% CI: 0.20-2.12; p=0.02). There was no association between cannabis use of the father and child behavior problems. CONCLUSIONS Our results suggest that intrauterine exposure to cannabis is associated with an increased risk for aggressive behavior and attention problems as early as 18 months of age in girls, but not boys. Further research is needed to explore the association between prenatal cannabis exposure and child behavior at later ages. Our data support educating future mothers about the risk to their babies should they smoke cannabis during pregnancy.

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.

Maternal use of antidepressant or anxiolytic medication during pregnancy and childhood neurodevelopmental outcomes: a systematic review.

Antidepressant and anxiolytic medications are widely prescribed and used by pregnant women for acute and maintenance therapy. These drugs are able to pass the placental barrier, and may potentially influence fetal and brain development. It is possible that exposure to prenatal antidepressants or anxiolytic medication may disturb neurotransmitter systems in the brain and have long-lasting consequences on neurodevelopment in the offspring. As all medication during pregnancy may pose a certain risk to the developing fetus, the potential benefits of the medication must be weighed against the risks for both mother and her unborn child. Therefore, information to guide patients and physicians to make a well-balanced decision for the appropriate treatment during pregnancy is needed. In this systematic review, an overview of maternal use of antidepressant or anxiolytic medication during pregnancy and childhood neurodevelopmental outcomes is provided. Some studies indicate a relation between prenatal exposure to antidepressants and adverse neurodevelopmental outcomes such as delayed motor development/motor control, social difficulties, internalizing problems and autism, but cannot rule out confounding by indication. Overall, the results of the observational studies have been inconsistent, which makes translation of the findings into clinical recommendations difficult. More well-designed observational studies and also randomized controlled trials (e.g., maintenance treatment vs. cessation) are needed to move forward and provide a comprehensive evaluation of the risks and benefits of antidepressant and anxiolytic use during pregnancy.

Post-term birth and the risk of behavioural and emotional problems in early childhood

BACKGROUND Post-term birth, defined as birth after pregnancy duration of 42 weeks, is associated with increased neonatal morbidity and mortality. The long-term consequences of post-term birth are unknown. We assessed the association of post-term birth with problem behaviour in early childhood. METHODS The study was performed in a large population-based prospective cohort study in Rotterdam, The Netherlands. Pregnant mothers enrolled between 2001 and 2005. Of a cohort of 5145 children, 382 (7%) were born post-term, and 226 (4%) were born preterm. Parents completed a standardized and validated behavioural checklist (Child Behavior Checklist, CBCL/1.5-5) when their children were 1.5 and 3 years old. We examined the relation between gestational age (GA) at birth, based on early fetal ultrasound examination, and problem behaviour with regression analyses, adjusting for socio-economic and pregnancy-related confounders. RESULTS A quadratic relationship between GA at birth and problem behaviour indicates that both preterm and post-term children have higher behavioural and emotional problem scores than the term born children. Compared with term born children, post-term born children had a higher risk for overall problem behaviour [odds ratio (OR) = 2.10, 95% confidence interval (CI) = 1.32-3.36] and were almost two and a half times as likely to have attention deficit / hyperactivity problem behaviour (OR = 2.44, 95% CI = 1.38-4.32). CONCLUSIONS Post-term birth was associated with more behavioural and emotional problems in early childhood, especially attention deficit / hyperactivity problem behaviour. When considering expectant management, this aspect of post-term pregnancy should be taken into account.

Cortical Morphology in 6- to 10-Year Old Children With Autistic Traits : A Population-Based Neuroimaging Study

OBJECTIVE Recent evidence suggests that symptoms of social impairment in autism spectrum disorder (ASD) form a spectrum that extends into the general population. However, it is unclear whether the neuroanatomy of ASD also shows a similar continuum in the general population. Therefore, the goal of the present study was to investigate the relationship between cortical morphology and autistic traits along a continuum in a large population-based sample of young children. METHOD The study included 717 children, aged 6-10 years, who are participants in the Generation R Study, a large population-based cohort. Autistic traits were measured using the Social Responsiveness Scale when the children were approximately 6 years old. High-resolution MRI was obtained, and morphological measures of the cortex, including cortical thickness and gyrification, were quantified brain-wide. RESULTS Children with more autistic traits showed widespread areas of decreased gyrification. After excluding children with the highest autistic traits and confirmed ASD, the association remained present in a large cluster involving the left hemisphere temporal and precuneus regions. Comparable, but nonsignificant, effects when comparing a small sample of confirmed ASD case subjects with age- and gender-matched control subjects were observed. CONCLUSIONS Differences in cortical morphology related to autistic traits along a continuum in a large population-based sample of school-aged children were found. Part of these differences remained after excluding the most severely affected children. These findings lend support to an extension of the neurobiology of autistic traits to the general population.