PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, and PharmaTox Strategic Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Oslo, Norway.
JAMA Netw Open. 2022 Dec 1;5(12):e2246889. doi: 10.1001/jamanetworkopen.2022.46889.
Evidence is limited regarding the safety of prenatal benzodiazepine and z-hypnotic exposure and its association with long-term neurodevelopment in childhood.
To 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 PARTICIPANTS: This 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.
Maternal 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.
The 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.
The 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.
Results 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.
关于产前苯二氮䓬类药物和 Z-催眠药暴露及其与儿童期长期神经发育的关系的安全性证据有限。
量化产前暴露于苯二氮䓬类药物和/或 Z-催眠药的时间和次数与儿童期注意缺陷/多动障碍（ADHD）风险之间的关联。
设计、设置和参与者：这项队列研究使用了 1999 年至 2008 年基于人群的挪威母婴儿童队列研究的数据，这些数据与挪威母婴登记处、挪威患者登记处和挪威处方数据库相关联。创建了两个参与者群体：一个完整的样本和一个心理健康样本。完整的样本包括母亲及其活产的单胎，而心理健康样本仅限于在怀孕期间或怀孕前 6 个月报告焦虑、抑郁或睡眠问题的母亲的后代。数据于 2021 年 9 月至 2022 年 2 月进行分析。
母亲在怀孕期间自我报告使用苯二氮䓬类药物和/或 Z-催眠药的情况被分为妊娠早期暴露和妊娠中期和/或晚期暴露，以分析暴露时间的相关性，并且将暴露的 4 周间隔次数（单[1]与多[≥2]）分类以分析暴露间隔次数的相关性。
结果是 ADHD，定义为 ADHD 诊断或 ADHD 药物处方的时间。为了控制混杂因素，使用了逆概率治疗加权 Cox 比例风险回归模型。估计了风险比和 95%置信区间。权重是通过苯二氮䓬类药物和/或 Z-催眠药暴露概率的倾向评分模型得出的，该模型是作为暴露和结果之间潜在混杂因素的函数，包括母亲抑郁和焦虑的症状。
完整的样本包括 82201 例妊娠，心理健康样本包括 19585 例妊娠。共有 681 名（0.8%）的婴儿在完整样本中，468 名（2.4%）的婴儿在心理健康样本中在产前暴露于苯二氮䓬类药物和/或 Z-催眠药。在加权后，妊娠早期（风险比，0.74；95%置信区间，0.39-1.94）和妊娠中期和/或晚期（风险比，0.76；95%置信区间，0.35-1.61）暴露与儿童 ADHD 风险增加无关。在怀孕期间暴露的间隔次数与儿童 ADHD 之间没有明显的关联。
这项研究的结果表明，产前暴露于苯二氮䓬类药物和/或 Z-催眠药可能不会增加儿童 ADHD 的风险，无论暴露时间和暴露间隔次数如何。然而，由于研究力度不足，这些发现应谨慎解释。
