Dataset Information

Association of Prenatal Exposure to Benzodiazepines With Development of Autism Spectrum and Attention-Deficit/Hyperactivity Disorders.

ABSTRACT:

Importance

Prenatal exposure to benzodiazepines is reported to be associated with neurodevelopmental disorders among children, but associations of maternal genetic confounding with neurodevelopmental disorders among children have not been taken into consideration.

Objective

To ascertain whether prenatal benzodiazepine exposure was associated with development of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).

Design, setting, and participants

This cohort study used linked data from birth certificate registration and the Taiwan National Health Insurance Research Database from January 1, 2004, to December 31, 2017, on 1 138 732 mothers with 1 516 846 live births between January 1, 2004, and December 31, 2017. Data were analyzed between February 20, 2021, and September 19, 2022.

Exposure

Benzodiazepine exposure during pregnancy (first trimester to third trimester) was defined as having at least one benzodiazepine prescription dispensed.

Main outcomes and measures

The main outcomes were ADHD and ASD.

Results

There were 1 516 846 children (mean [SD] gestational age, 38.5 [1.8] years; 789 455 boys [52.0%]) born full term who were younger than 14 years of age and followed up to 2017; 5.0% of the children (n = 76 411) were exposed to a benzodiazepine during pregnancy. Benzodiazepine exposure during pregnancy was associated with increased risks of ADHD (first trimester exposure: hazard ratio [HR], 1.24 [95% CI, 1.20-1.28]; second trimester exposure: HR, 1.27 [95% CI, 1.21-1.34]; third trimester exposure: HR, 1.25 [95% CI, 1.14-1.37]) and ASD (first trimester exposure: HR, 1.13 [95% CI, 1.05-1.21]; second trimester exposure: HR, 1.10 [95% CI, 0.98-1.22]; third trimester exposure: HR, 1.21 [95% CI, 1.00-1.47]). However, no differences were found with unexposed sibling controls during the same time frame for ADHD (first trimester exposure: HR, 0.91 [95% CI, 0.83-1.00]; second trimester exposure: HR, 0.89 [95% CI, 0.78-1.01]; third trimester exposure: HR, 1.08 [95% CI, 0.83-1.41]) or ASD (first trimester exposure: HR, 0.92 [95% CI, 0.75-1.14]; second trimester exposure: HR, 0.97 [95% CI, 0.71-1.33]; third trimester exposure: HR, 1.07 [95% CI, 0.53-2.16]). Similar findings were also noted in the stratification analysis of short-acting and long-acting benzodiazepines.

Conclusions and relevance

This cohort study suggests that previously described adverse neurodevelopmental outcomes associated with benzodiazepine exposure during pregnancy were likely to be accounted for by maternal genetic confounding.

SUBMITTER: Chen VC

PROVIDER: S-EPMC9682429 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association of Prenatal Exposure to Benzodiazepines With Development of Autism Spectrum and Attention-Deficit/Hyperactivity Disorders.

Chen Vincent Chin-Hung VC Wu Shu-I SI Lin Chiao-Fan CF Lu Mong-Liang ML Chen Yi-Lung YL Stewart Robert R

JAMA network open 20221101 11

<h4>Importance</h4>Prenatal exposure to benzodiazepines is reported to be associated with neurodevelopmental disorders among children, but associations of maternal genetic confounding with neurodevelopmental disorders among children have not been taken into consideration.<h4>Objective</h4>To ascertain whether prenatal benzodiazepine exposure was associated with development of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).<h4>Design, setting, and participants< ...[more]

PMID: 36413366

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Project description:ImportanceEvidence is limited regarding the safety of prenatal benzodiazepine and z-hypnotic exposure and its association with long-term neurodevelopment in childhood.ObjectiveTo quantify the associations of the timing and number of intervals of prenatal exposure to benzodiazepines and/or z-hypnotics with the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood.Design, setting, and participantsThis cohort study used data from the 1999 to 2008 population-based Norwegian Mother, Father and Child Cohort Study, which are linked to the Medical Birth Registry of Norway, Norwegian Patient Registry, and Norwegian Prescription Database. Two populations of participants were created: a full sample and a mental health sample. The full sample included mothers and their live-born singletons, whereas the mental health sample was restricted to offspring of mothers who reported anxiety, depression, or sleeping problems during pregnancy or 6 months before pregnancy. Data were analyzed from September 2021 to February 2022.ExposuresMaternal self-report of benzodiazepine and/or z-hypnotic use during pregnancy was grouped into early pregnancy exposure and middle and/or late pregnancy exposure for analysis of the association with timing of exposure, and number of 4-week intervals of exposure was classified (single [1] vs multiple [≥2]) for analysis of the association with number of exposed intervals.Main outcome and measuresThe outcome was ADHD, defined as time to ADHD diagnosis or filled prescription for ADHD medication. To control for confounding, inverse probability of treatment-weighted Cox proportional hazards regression models were used. Hazard ratios and 95% CIs were estimated. The weights were derived from propensity score modeling of the probability of benzodiazepine and/or z-hypnotic exposure as a function of potential confounders between the exposure and the outcome, including maternal symptoms of depression and anxiety.ResultsThe full sample comprised 82 201 pregnancies, and the mental health sample included 19 585 pregnancies. In total, 681 offspring (0.8%) in the full sample and 468 offspring (2.4%) in the mental health sample were prenatally exposed to benzodiazepines and/or z-hypnotics. After weighting, exposure in early (hazard ratio, 0.74; 95% CI, 0.39-1.94) and middle and/or late (hazard ratio, 0.76; 95% CI, 0.35-1.61) pregnancy was not associated with increased risk of childhood ADHD. There was no evidence of substantial association between the number of exposed intervals during pregnancy and childhood ADHD.Conclusions and relevanceResults of this study suggest that there may be no increased risk of childhood ADHD associated with prenatal exposure to benzodiazepines and/or z-hypnotics, regardless of timing of exposure and number of exposed intervals. However, these findings should be interpreted with caution due to low study power.

Project description:BackgroundMaternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics).MethodsThis population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures.ResultsOverall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03-1.84), ID (2.09, 1.53-2.87) and ADHD (1.43, 1.16-1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID.ConclusionThe association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.

Project description:ImportanceThe risk of birth and neurodevelopmental complications with prenatal exposure to antipsychotics is unclear.ObjectiveTo evaluate the association between prenatal antipsychotics exposure and the risk of birth and neurodevelopmental problems.Design, setting, and participantsThis population-based cohort study included children born between January 2001 and January 2015 with follow-up to December 2019 who were identified by the Hong Kong Clinical Data Analysis and Reporting System. Pregnancies with maternal antidepressant/lithium exposure were removed. Primary analyses compared gestationally exposed and gestationally nonexposed individuals with propensity score fine stratification. Additional analyses included gestationally exposed individuals vs those with past exposure and a sibling-matched analysis to evaluate the effect of confounding by indication.ExposuresPrenatal antipsychotic exposure.Main outcomes and measuresPreterm birth (<37 gestational weeks), small for gestational age (birth weight <2 standard deviations below the mean for gestational age), and first diagnosis of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children.ResultsThe cohorts included 333 749 mother-child pairs for ADHD (mean [SD] maternal age at delivery, 31.46 [5.03] years) and 411 251 pairs for ASD, preterm birth, and small for gestational age analyses (mean [SD] maternal age at delivery, 31.56 [5.01] years). There were 13 196 children (3.95%) with a diagnosis of ADHD, 8715 (2.12%) with ASD, 33 891 (8.24%) preterm, and 7009 (1.70%) who were small for gestational age. The weighted hazard ratio (wHR) was 1.16 (95% CI, 0.83-1.61) for ADHD and 1.06 (95% CI, 0.70-1.60) for ASD, while the weighted odds ratio (wOR) was 1.40 (95% CI, 1.13-1.75) for preterm birth and 1.36 (95% CI, 0.86-2.14) for small for gestational age when comparing gestationally exposed with gestationally nonexposed individuals. Additional analyses showed no association when comparing gestationally exposed individuals with those with past exposure (ADHD: wHR, 0.99; 95% CI, 0.60-1.61; ASD: wHR, 1.10; 95% CI, 0.58-2.08; preterm birth: wOR, 0.93; 95% CI, 0.70-1.24; small for gestational age: wOR, 1.21; 95% CI, 0.66-2.20) and in a sibling-matched analysis (ADHD: wHR, 0.41; 95% CI, 0.04-4.93; ASD: wHR, 0.90; 95% CI, 0.40-2.01; preterm birth: wOR, 1.25; 95% CI, 0.85-1.82; small for gestational age: wOR, 0.86, 95% CI, 0.32-2.31).Conclusions and relevanceIn this cohort study, the findings did not suggest that prenatal antipsychotics exposure increased the risk of ADHD, ASD, or small for gestational age. In the primary analysis, there was a small increased risk of preterm birth, but additional analyses comparing gestationally exposed individuals with those with past exposure and comparing gestationally exposed with gestationally nonexposed siblings did not support an increased risk. Given the benefits of treating psychosis during pregnancy, our findings do not support a recommendation for women to discontinue receipt of their regular antipsychotic treatment during pregnancy.

Project description:Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD) are two of the most represented neurodevelopmental conditions in childhood. The diagnostic shift introduced by the DSM-5, allowing a combined diagnosis of ADHD and ASD, poses different clinical challenges related to diagnostic overshadowing, accuracy of clinical judgment and potential delay in an ASD diagnosis in children presenting with ADHD. Here we tried to disentangle the clinical phenotype and specificity of the two co-occurring conditions in relation to autism traits and empathy, by comparing children with ASD with and without comorbid ADHD with children presenting ADHD only and children with typical development. The child versions of the Autism Quotient (C-AQ) and Empathy Quotient (C-EQ) were administered to a total sample of 198 male children between 6 and 14 years old with age appropriate language skills and normal intelligence. Univariate analysis demonstrated no significant differences in the C-AQ total and subscale scores as well as the C-EQ between children with ASD and children with ASD + ADHD, while children with ADHD alone presented an intermediate phenotype between ASD and TD. Furthermore, a receiver operating characteristic (ROC) analysis was applied to discriminate among the different phenotypes. We found that the C-AQ and C-EQ were accurate at distinguishing with satisfactory reliability between: (a) ASD vs. non- ASD (N-ASD) groups comprising both ADHD and TD children (Area Under the Curve AUC 88% for C-AQ and 81% for C-EQ); (b) ASD and TD (AUC 92% for C-AQ and 95% for C-EQ); (c) ASD and ADHD (AUC 80% for C-AQ and 68% for C-EQ). Our data confirm the reliability of the C-AQ and C-EQ as behavioral markers to differentiate ASD (regardless of comorbid ADHD) from an ADHD condition and TD. Interestingly, in our sample an ADHD condition does not increase the severity of the clinical phenotype in terms of autism traits distribution and empathy, suggesting that the psychological measures detected by the two quantitative instruments are independent of ADHD traits. This evidence will contribute to the translational efforts in developing better tailored treatments and preventive strategies.

Project description:ImportanceClinical overlap between autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is increasingly appreciated, but the underlying brain mechanisms remain unknown to date.ObjectiveTo examine associations between white matter organization and 2 commonly co-occurring neurodevelopmental conditions, ASD and ADHD, through both categorical and dimensional approaches.Design, setting, and participantsThis investigation was a cross-sectional diffusion tensor imaging (DTI) study at an outpatient academic clinical and research center, the Department of Child and Adolescent Psychiatry at New York University Langone Medical Center. Participants were children with ASD, children with ADHD, or typically developing children. Data collection was ongoing from December 2008 to October 2015.Main outcomes and measuresThe primary measure was voxelwise fractional anisotropy (FA) analyzed via tract-based spatial statistics. Additional voxelwise DTI metrics included radial diffusivity (RD), mean diffusivity (MD), axial diffusivity (AD), and mode of anisotropy (MA).ResultsThis cross-sectional DTI study analyzed data from 174 children (age range, 6.0-12.9 years), selected from a larger sample after quality assurance to be group matched on age and sex. After quality control, the study analyzed data from 69 children with ASD (mean [SD] age, 8.9 [1.7] years; 62 male), 55 children with ADHD (mean [SD] age, 9.5 [1.5] years; 41 male), and 50 typically developing children (mean [SD] age, 9.4 [1.5] years; 38 male). Categorical analyses revealed a significant influence of ASD diagnosis on several DTI metrics (FA, MD, RD, and AD), primarily in the corpus callosum. For example, FA analyses identified a cluster of 4179 voxels (TFCE FEW corrected P < .05) in posterior portions of the corpus callosum. Dimensional analyses revealed associations between ASD severity and FA, RD, and MD in more extended portions of the corpus callosum and beyond (eg, corona radiata and inferior longitudinal fasciculus) across all individuals, regardless of diagnosis. For example, FA analyses revealed clusters overall encompassing 12121 voxels (TFCE FWE corrected P < .05) with a significant association with parent ratings in the social responsiveness scale. Similar results were evident using an independent measure of ASD traits (ie, children communication checklist, second edition). Total severity of ADHD-traits was not significantly related to DTI metrics but inattention scores were related to AD in corpus callosum in a cluster sized 716 voxels. All these findings were robust to algorithmic correction of motion artifacts with the DTIPrep software.Conclusions and relevanceDimensional analyses provided a more complete picture of associations between ASD traits and inattention and indexes of white matter organization, particularly in the corpus callosum. This transdiagnostic approach can reveal dimensional relationships linking white matter structure to neurodevelopmental symptoms.

Dataset Information

Association of Prenatal Exposure to Benzodiazepines With Development of Autism Spectrum and Attention-Deficit/Hyperactivity Disorders.

Importance

Objective

Design, setting, and participants

Exposure

Main outcomes and measures

Results

Conclusions and relevance

Publications

Association of Prenatal Exposure to Benzodiazepines With Development of Autism Spectrum and Attention-Deficit/Hyperactivity Disorders.

Similar Datasets

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