Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.
Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
Acta Psychiatr Scand. 2024 Aug;150(2):65-77. doi: 10.1111/acps.13696. Epub 2024 May 15.
Benzodiazepine (BDZP) and/or z-hypnotic dispensing during pregnancy has increased globally, as have rates of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aimed to estimate the association between gestational exposure to BDZP and/or z-hypnotics and diagnosis of ASD or ADHD in offspring.
We searched MEDLINE, EMBASE, and SCOPUS from inception till December 2023 for relevant English-language articles. Outcomes of interest were risk of ASD and ADHD, two independent primary outcomes, in children exposed anytime during pregnancy to BDZP and/or z-hypnotics versus those unexposed. Secondary outcomes were trimester-wise analyses. Using a random effects model, we pooled the overall and trimester-wise hazard ratios (HRs), with 95% confidence intervals (CIs), separately for risk of ASD and ADHD.
We found six eligible retrospective cohort studies and no case-control studies. There was no increased risk of ASD associated with anytime gestational BDZP and/or z-hypnotic exposure (primary outcome, HR, 1.10; 95% CI, 0.81-1.50; 4 studies; n = 3,783,417; 80,270 exposed, 3,703,147 unexposed) nor after first trimester exposure (HR, 1.15; 95% CI, 0.83-1.58; 3 studies; n = 1,539,335; 70,737 exposed, 1,468,598 unexposed) or later trimester exposures. A very small but significantly increased risk of ADHD was noted with anytime gestational exposure to these drugs (primary outcome, HR, 1.07; 95% CI, 1.03-1.12; 4 studies; n = 2,000,777; 78,912 exposed, 1,921,865 unexposed) and also with (only) second trimester exposure (HR, 1.07; 95% CI, 1.03-1.12; 3 studies; n = 1,539,281; 33,355 exposed, 1,505,926 unexposed). Findings were consistent in sensitivity analyses.
Gestational exposure to benzodiazepines or z-hypnotics was not associated with an increased risk of ASD and with only a marginally increased risk of ADHD in offspring. Given the likelihood of confounding by indication and by unmeasured variables in the original studies, our findings should reassure women who need these medications for severe anxiety or insomnia during pregnancy.
苯二氮䓬类药物（BDZP）和/或 Z 类催眠药在全球范围内的使用量增加，自闭症谱系障碍（ASD）和注意缺陷多动障碍（ADHD）的发病率也有所增加。本系统评价和荟萃分析旨在评估妊娠期暴露于 BDZP 和/或 Z 类催眠药与后代 ASD 或 ADHD 诊断之间的关联。
我们从成立到 2023 年 12 月在 MEDLINE、EMBASE 和 SCOPUS 中搜索了相关的英文文章。感兴趣的结局是在怀孕期间任何时候暴露于 BDZP 和/或 Z 类催眠药的儿童与未暴露于这些药物的儿童相比，患 ASD 或 ADHD 的风险。次要结局是按孕期时间进行的分析。使用随机效应模型，我们分别汇总了 ASD 和 ADHD 的总体和孕期时间风险比（HR）及其 95%置信区间（CI）。
我们发现了 6 项符合条件的回顾性队列研究，没有病例对照研究。与任何时候妊娠期 BDZP 和/或 Z 类催眠药暴露相关的 ASD 风险没有增加（主要结局，HR，1.10；95%CI，0.81-1.50；4 项研究；n=3783417；80270 例暴露，3703147 例未暴露），也没有在首次孕期暴露后增加（HR，1.15；95%CI，0.83-1.58；3 项研究；n=1539335；70737 例暴露，1468598 例未暴露）或后期孕期暴露后增加。与这些药物在任何时候的妊娠期暴露相关的 ADHD 风险很小但有显著增加（主要结局，HR，1.07；95%CI，1.03-1.12；4 项研究；n=2000777；78912 例暴露，1921865 例未暴露），而且仅在第二个孕期暴露时增加（HR，1.07；95%CI，1.03-1.12；3 项研究；n=1539281；33355 例暴露，1505926 例未暴露）。敏感性分析结果一致。
妊娠期暴露于苯二氮䓬类药物或 Z 类催眠药与 ASD 风险增加无关，与后代 ADHD 风险仅略有增加相关。鉴于原始研究中存在的混杂因素和未测量变量的可能性，我们的发现应该让那些在怀孕期间需要这些药物治疗严重焦虑或失眠的女性感到放心。
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