Maternal Benzodiazepines and Z-Drugs Use during Pregnancy and Adverse Birth and Neurodevelopmental Outcomes in Offspring: A Population-Based Cohort Study

Abstract

<b><i>Introduction:</i></b> The use of benzodiazepines and/or z-drugs in women of childbearing age has increased. <b><i>Objective:</i></b> The aim of the study was to evaluate whether gestational benzodiazepine and/or z-drug exposure is associated with adverse birth and neurodevelopmental outcomes. <b><i>Methods:</i></b> A population-based cohort including mother-child pairs from 2001 to 2018 in Hong Kong was analysed to compare gestationally exposed and nonexposed children on the risk of preterm birth, small for gestational age, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) through logistic/Cox proportional hazards regression with a 95% confidence interval (CI). Sibling-matched analyses and negative control analyses were applied. <b><i>Results:</i></b> When comparing gestationally exposed with gestationally nonexposed children, the weighted odds ratio (wOR) was 1.10 (95% CI = 0.97–1.25) for preterm birth and 1.03 (95% CI = 0.76–1.39) for small for gestational age, while the weighted hazard ratio (wHR) was 1.40 (95% CI = 1.13–1.73) for ASD and 1.15 (95% CI = 0.94–1.40) for ADHD. Sibling-matched analyses showed no association between gestationally exposed children and their gestationally nonexposed siblings for all outcomes (preterm birth: wOR = 0.84, 95% CI = 0.66–1.06; small for gestational age: wOR = 1.02, 95% CI = 0.50–2.09; ASD: wHR = 1.10, 95% CI = 0.70–1.72; ADHD: wHR = 1.04, 95% CI = 0.57–1.90). Similarly, no significant differences were observed when comparing children whose mothers took benzodiazepines and/or z-drugs during pregnancy to children whose mothers took benzodiazepines and/or z-drugs before but not during pregnancy for all outcomes. <b><i>Conclusions:</i></b> The findings do not support a causal relationship between gestational benzodiazepines and/or z-drugs exposure and preterm birth, small for gestational age, ASD, or ADHD. Clinicians and pregnant women should carefully balance the known risks of benzodiazepines and/or z-drugs use against those of untreated anxiety and sleep problems.

Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother–child pairs

“…ADHD was defined by each site using specific diagnosis and medication codes as reported in previous studies and detailed in Supplementary Table 1 (refs. 30 , 31 ). In Hong Kong, New Zealand and Taiwan, children with either one ADHD diagnosis or one ADHD medication prescription were regarded as having the outcome.…”

“…First, most data originated from reimbursement or other administrative purposes rather than research purposes, which represent a variety of data sources, healthcare settings, coding practices, diagnostics criteria, and treatment approaches. Nevertheless, data sources included in this study are all based on high-quality territory-wide electronic health records with robust mother–child linkage and comprehensive information on maternal and child medical records that have been used extensively for pregnancy-related studies 30 , 34 – 36 . Moreover, we applied data source-specific identification criteria for not only the exposure and outcome but also the covariates to maximize the comparability of variables included in the study.…”

“…Covariates were selected based on known confounders for the study association and risk factors for the study outcomes 30 , 42 – 50 , including demographic factors such as maternal age 47 , 51 – 53 , infant sex (as directly recorded by clinicians) 54 , socioeconomic status 55 , 56 , birth year, multifetal pregnancies 57 and other maternal factors including smoking 44 , 47 , 58 , 59 , alcohol consumption 47 , 60 , 61 , psychiatric and neurological conditions 47 , 48 , 62 – 64 , other chronic medical conditions (hypertension 51 , 65 , renal disease, inflammatory bowel disease 66 , 67 , autoimmune disease 46 , 68 , 69 , thyroid disorders 43 , 47 , 70 , 71 and polycystic ovary syndrome 45 , 72 , 73 ), BMI 44 , 47 , 51 , 74 and use of psychotropic medication 42 , 47 , 49 , antihypertensives, ADHD medication and known or suspected teratogenic medication. Various measures were applied as the proxy of socioeconomic status for each data source according to their respective practice (namely, median household income in Hong Kong, education level in Nordic countries, insurance fees in Taiwan and deprivation quintile in New Zealand).…”

Benzodiazepine Use During Pregnancy and Risk of Miscarriage

“…31,32 The negative control design in our study, which redefined different risk periods before the last menstrual period, yielded null results, and further strengthened the accuracy of the approach we used to determine the last menstrual period. While an increasing number of studies have shown that benzodiazepines used during pregnancy do not appear to be associated with an elevated risk of adverse pregnancy outcomes, 27,33,34 concerns regarding teratogenicity and fetal developmental impairments persist. In our study, an increased risk of miscarriage associated with benzodiazepine use during early pregnancy was observed after accounting for measurable confounders, and the results were unlikely to be due to unmeasured confounding.…”

“…While an increasing number of studies have shown that benzodiazepines used during pregnancy do not appear to be associated with an elevated risk of adverse pregnancy outcomes, 27,33,34 concerns regarding teratogenicity and fetal developmental impairments persist. In our study, an increased risk of miscarriage associated with benzodiazepine use during early pregnancy was observed after accounting for measurable confounders, and the results were unlikely to be due to unmeasured confounding.…”