School of Psychological Science, University of Bristol, Bristol, UK.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Addiction. 2022 May;117(5):1458-1471. doi: 10.1111/add.15746. Epub 2021 Dec 5.
BACKGROUND AND AIMS: Studies have indicated that maternal prenatal substance use may be associated with offspring attention deficit hyperactivity disorder (ADHD) via intrauterine effects. We measured associations between prenatal smoking, alcohol and caffeine consumption with childhood ADHD symptoms accounting for shared familial factors. DESIGN: First, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders), adjusted (including confounders) and mutually adjusted (including confounders and partner's substance use). The results were meta-analysed across the cohorts. Secondly, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for smoking, alcohol and coffee consumption were regressed against ADHD symptoms. We triangulated the results across the two approaches to infer causality. SETTING: We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway. PARTICIPANTS: Phenotype data available for children were: N = 5455-7751; N = 1537-3119; N = 28 053-42 206. Genotype data available for mothers was: N = 7074; N = 14 583. MEASUREMENTS: A measure of offspring ADHD symptoms at age 7-8 years was derived by dichotomizing scores from questionnaires and parental self-reported prenatal substance use was measured at the second pregnancy trimester. FINDINGS: The pooled estimate for maternal prenatal substance use showed an association with total ADHD symptoms [odds ratio (OR) = 1.11, 95% confidence interval (CI) = 1.00-1.23; OR = 1.27, 95% CI = 1.08-1.49; OR = 1.05, 95% CI = 1.00-1.11], while not for fathers (OR = 1.03, 95% CI = 0.95-1.13; OR = 0.83, 95% CI = 0.47-1.48; OR = 1.02, 95% CI = 0.97-1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD symptoms in MoBa). The PRS analyses were inconclusive for an association in ALSPAC or MoBa. CONCLUSIONS: There appears to be no causal intrauterine effect of maternal prenatal substance use on offspring attention deficit hyperactivity disorder symptoms.
背景与目的：研究表明，母体产前物质使用可能通过宫内效应与后代注意缺陷多动障碍（ADHD）有关。我们测量了产前吸烟、饮酒和咖啡因摄入与儿童 ADHD 症状之间的关联，同时考虑了共同的家族因素。
设计：首先，我们使用了阴性对照设计来比较母亲和父亲的物质使用情况。我们使用了三种模型进行阴性对照分析：未调整（无混杂因素）、调整（包括混杂因素）和相互调整（包括混杂因素和伴侣的物质使用）。结果在队列之间进行了荟萃分析。其次，我们使用多基因风险评分（PRS）作为暴露的替代物。将母亲的吸烟、饮酒和咖啡消费 PRS 与 ADHD 症状进行回归分析。我们通过两种方法的结果相互印证来推断因果关系。
设置：我们使用了来自三个纵向妊娠队列的数据：英国阿冯纵向研究父母和儿童（ALSPAC）、荷兰世代研究（GenR）和挪威母亲、父亲和儿童队列研究（MoBa）。
参与者：可用于儿童的表型数据为：N=5455-7751；N=1537-3119；N=28053-42206。可用于母亲的基因型数据为：N=7074；N=14583。
测量：通过将问卷评分二分类来获得 7-8 岁儿童 ADHD 症状的指标，并在妊娠中期第二阶段测量母亲产前物质使用的自我报告。
结果：母体产前物质使用的汇总估计值与总 ADHD 症状呈正相关[比值比（OR）=1.11，95%置信区间（CI）=1.00-1.23；OR=1.27，95%CI=1.08-1.49；OR=1.05，95%CI=1.00-1.11]，而父亲则没有（OR=1.03，95%CI=0.95-1.13；OR=0.83，95%CI=0.47-1.48；OR=1.02，95%CI=0.97-1.07）。然而，在敏感性分析中，母亲的相关性并不持续（怀孕前的物质使用，在 MoBa 中调整母亲的 ADHD 症状）。PRS 分析对于 ALSPAC 或 MoBa 中的关联没有结论。
结论：似乎母体产前物质使用对后代注意缺陷多动障碍症状没有宫内的因果效应。
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