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Impact of prenatal exposure to benzodiazepines and z-hypnotics on behavioral problems at 5 years of age: A study from the Norwegian Mother and Child Cohort Study.

ABSTRACT: Many women experience anxiety or sleep disorders during pregnancy and require pharmacological treatment with benzodiazepines (BZDs) or z-hypnotics. Limited information is currently available on how prenatal exposure to these medications affects behavioral problems in children over the long term. Therefore, from a public health perspective, this issue is highly important. The present study aimed to determine whether prenatal exposure to BZDs and z-hypnotics affected externalizing and internalizing behavior problems in children at age 5 years. This study was based on The Norwegian Mother and Child Cohort Study and The Medical Birth Registry of Norway. The final study population included data for 36 401 children, from questionnaires completed by the mothers throughout the 5-year follow up. Children's behaviors were measured at age 5, based on parental responses to The Child Behavior Checklist. Children T-scores of 63 or above were considered to indicate clinically relevant behavior problems. We applied inverse probability of treatment weighting (IPTW) and log-binomial regression models to estimate risk ratios (RRs) and bootstrapped 95% confidence intervals (CIs) with censoring weights to account for loss during follow-up. Several sensitivity analyses were performed to assess the robustness of the main results. The final sample included 273 (0.75%) children that were exposed to BZDs and/or z-hypnotics during pregnancy. The main, IPTW and censoring weighted analyses showed that prenatal exposure to BZD and/or z-hypnotics increased the risks of internalizing behavioral problems (RR: 1.35, 95% CI: 0.73-2.49) and externalizing behavioral problems (RR: 1.51, 95% CI: 0.86-2.64). However, based on sensitivity analyses, we concluded that the risks of displaying externalizing and internalizing problems at 5 years of age did not significantly increase after prenatal exposure to BZDs and/or z-hypnotics. Instead, the sensitivity analyses suggested that residual confounding and selection bias might explain the increased risks observed in the main analyses.

SUBMITTER: Sundbakk LM

PROVIDER: S-EPMC6553737 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Impact of prenatal exposure to benzodiazepines and z-hypnotics on behavioral problems at 5 years of age: A study from the Norwegian Mother and Child Cohort Study.

Sundbakk Lene Maria LM Wood Mollie M Gran Jon Michael JM Nordeng Hedvig H

PloS one 20190606 6

Many women experience anxiety or sleep disorders during pregnancy and require pharmacological treatment with benzodiazepines (BZDs) or z-hypnotics. Limited information is currently available on how prenatal exposure to these medications affects behavioral problems in children over the long term. Therefore, from a public health perspective, this issue is highly important. The present study aimed to determine whether prenatal exposure to BZDs and z-hypnotics affected externalizing and internalizin ...[more]

PMID: 31170221

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Project description:During pregnancy, many women experience sleep problems and anxiety that require treatment. The long-term safety for the child of maternal benzodiazepine (BZD) and z-hypnotic use during pregnancy remains controversial.We conducted a cohort and a sibling control study using data from the Norwegian Mother and Child Cohort Study. Data on use of BZD and z-hypnotics, internalizing and externalizing outcomes, and covariates were collected from mothers at gestational weeks 17 and 30 and when children were 0.5, 1.5, and 3 years of age. The total sample consisted of 71,996 children (19,297 siblings) at 1.5 years and 55,081 children (13,779 siblings) at 3 years. Short-term use was defined as use in one pregnancy period only. Long-term use was defined as use in two or more pregnancy periods. Linear full cohort random-effect and sibling-matched fixed-effect regression models were used to compare internalizing and externalizing behavior in children prenatally exposed compared to those unexposed in the full cohort of pregnancies accounting for family clusters, as well as within sibling clusters comparing pregnancies with discordant exposures. Propensity score (PS) adjustment included variables on indication for use (sleep problems, symptoms of anxiety and depression) and other potential confounding factors.Long-term prenatal exposure to BZD or z-hypnotics was associated with increased internalizing behavior in crude cohort analyses and at age 1.5 years after PS adjustment in sibling-matched fixed-effect models [β 0.60, 95% confidence interval 0.17-0.95]. Analyses on specific drug groups showed that prenatal exposure to BZD-anxiolytics was associated with increased internalizing problems at both 1.5 years [β 0.25, 0.01-0.49] and 3 years [β 0.26, 0.002-0.52] while exposure to z-hypnotics was not associated with any adverse outcomes after adjustment.The findings suggest a moderate association between BZD-anxiolytic exposure and child internalizing problems that is not likely due to stable familial confounding factors.

Project description:BackgroundNumerous intrauterine factors may affect the offspring's growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent.MethodsThis parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age).ResultsHigher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ Pinteraction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ Pinteraction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ Pinteraction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ Pinteraction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ Pinteraction ≤ 0.99).ConclusionsMaternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.

Project description:BackgroundLow educational attainment in parents is associated with child psychopathology. It is not clear whether the associations are due to risk factors that family members share or due to effects of maternal or paternal education on the offspring. We investigate whether associations between maternal and paternal educational attainment and child symptoms of attention deficit/hyperactivity disorder (ADHD), depression, and academic problems are due to shared genetic factors, shared family environmental factors, or effects of the parental phenotype educational attainment itself.MethodsThis study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). The sample comprised 34,958 children (17,128 girls) in 28,372 extended-family units. We used data from related nuclear families linked by siblings in the parent generation. We applied a quasi-experimental extended children-of-twins design that included siblings in both generations and took account of nonrandom mating by including partners. Educational attainment was self-reported by mothers and fathers. Mothers reported children's symptoms of ADHD, symptoms of depression, and academic problems by questionnaire when the children were 8 years old.ResultsChildren of lowly educated parents scored higher on all outcomes and had an approximate doubling of the risk of high symptom levels. The association between maternal and paternal educational attainment and child symptoms of ADHD and academic problems persisted after controlling for shared genetic and family environmental factors. Phenotypic transmission to depression was weaker and in the best fitting model fully explained by genetic factors shared by the two generations.ConclusionsAssociations between educational attainment of mothers and fathers and child symptoms of ADHD and academic problems could not be ascribed to shared familial risk factors, whereas associations with symptoms of depression could. Parental education or resources and behaviors resulting from low education might be targets of interventions aimed at reducing symptoms of ADHD and academic problems.

Project description:IntroductionPrenatal exposure to organophosphorus pesticides (OPPs) has been associated with neurodevelopmental deficits in children, however evidence linking OPPs with specific cognitive mechanisms, such as executive function (EF), is limited.ObjectiveThis study aims to evaluate the association between prenatal exposure to OPPs with multiple measures of EF in preschool-aged children, while considering the role of variant alleles in OPP metabolism genes.MethodsWe included 262 children with preschool attention-deficit/hyperactivity disorder (ADHD), and 78 typically developing children, from the Preschool ADHD substudy of the Norwegian, Mother, Father, and Child Cohort Study. Participants who gave birth between 2004 and 2008 were invited to participate in an on-site clinical assessment when the child was approximately 3.5 years; measurements of EF included parent and teacher rating on Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P), and three performance-based assessments. We measured OPP metabolites in maternal urines collected at ∼17 weeks' gestation to calculate total dimethyl- (ΣDMP) and diethyl phosphate (ΣDEP) metabolite concentrations. We estimated multivariable adjusted β's and 95% confidence intervals (CIs) corresponding to a change in z-score per unit increase in log-ΣDMP/DEP. We further characterized gene-OPP interactions for maternal variants in PON1 (Q192R, M55L), CYP1A2 (1548T > C), CYP1A1 (IntG > A) and CYP2A6 (-47A > C).ResultsPrenatal OPP metabolite concentrations were associated with worse parent and teacher ratings of emotional control, inhibition, and working memory. A one log-∑DMP increase was associated with poorer teacher ratings of EF on the BRIEF-P (e.g. emotional control domain: β = 0.55, 95% CI: 0.35, 0.74), when weighted to account for sampling procedures. We found less consistent associations with performance-based EF assessments. We found some evidence of modification for PON1 Q192R and CYP2A6 -47A > C. Association with other variants were inconsistent.ConclusionsBiomarkers of prenatal OPP exposure were associated with more adverse teacher and parent ratings of EF in preschool-aged children.

Dataset Information

Impact of prenatal exposure to benzodiazepines and z-hypnotics on behavioral problems at 5 years of age: A study from the Norwegian Mother and Child Cohort Study.

Publications

Impact of prenatal exposure to benzodiazepines and z-hypnotics on behavioral problems at 5 years of age: A study from the Norwegian Mother and Child Cohort Study.

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