Quinn Patrick D, Rickert Martin E, Weibull Caroline E, Johansson Anna L V, Lichtenstein Paul, Almqvist Catarina, Larsson Henrik, Iliadou Anastasia N, D'Onofrio Brian M
Department of Psychological and Brain Sciences, Indiana University, Bloomington.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
JAMA Psychiatry. 2017 Jun 1;74(6):589-596. doi: 10.1001/jamapsychiatry.2017.0456.
Several recent population-based studies have linked exposure to maternal smoking during pregnancy to increased risk of severe mental illness in offspring (eg, bipolar disorder, schizophrenia). It is not yet clear, however, whether this association results from causal teratogenic effects or from confounding influences shared by smoking and severe mental illness.
To examine the association between smoking during pregnancy and severe mental illness in offspring, adjusting for measured covariates and unmeasured confounding using family-based designs.
DESIGN, SETTING, AND PARTICIPANTS: This study analyzed population register data through December 31, 2013, for a cohort of 1 680 219 individuals born in Sweden from January 1, 1983, to December 31, 2001. Associations between smoking during pregnancy and severe mental illness in offspring were estimated with adjustment for measured covariates. Cousins and siblings who were discordant on smoking during pregnancy and severe mental illness were then compared, which helped to account for unmeasured genetic and environmental confounding by design.
Maternal self-reported smoking during pregnancy, obtained from antenatal visits.
Severe mental illness, with clinical diagnosis obtained from inpatient and outpatient visits and defined using International Classification of Diseases codes for bipolar disorder and schizophrenia spectrum disorders.
Of the 1 680 219 offspring included in the analysis, 816 775 (48.61%) were female. At the population level, offspring exposed to moderate and high levels of smoking during pregnancy had greater severe mental illness rates than did unexposed offspring (moderate smoking during pregnancy: hazard ratio [HR], 1.25; 95% CI, 1.19-1.30; high smoking during pregnancy: HR, 1.51; 95% CI, 1.44-1.59). These associations decreased in strength with increasing statistical and methodologic controls for familial confounding. In sibling comparisons with within-family covariates, associations were substantially weaker and nonsignificant (moderate smoking during pregnancy: HR, 1.09; 95% CI, 0.94-1.26; high smoking during pregnancy: HR, 1.14; 95% CI, 0.96-1.35). The pattern of associations was consistent across subsets of severe mental illness disorders and was supported by further sensitivity analyses.
This population- and family-based study failed to find support for a causal effect of smoking during pregnancy on risk of severe mental illness in offspring. Rather, these results suggest that much of the observed population-level association can be explained by measured and unmeasured factors shared by siblings.
最近几项基于人群的研究将孕期母亲吸烟与后代患严重精神疾病（如双相情感障碍、精神分裂症）的风险增加联系起来。然而，这种关联是由因果致畸效应导致，还是由吸烟和严重精神疾病共有的混杂因素引起，目前尚不清楚。
通过基于家庭的设计，在调整测量的协变量和未测量的混杂因素后，研究孕期吸烟与后代严重精神疾病之间的关联。
设计、地点和参与者：本研究分析了截至2013年12月31日的人口登记数据，该队列包括1983年1月1日至2001年12月31日在瑞典出生的1680219人。在调整测量的协变量后，估计孕期吸烟与后代严重精神疾病之间的关联。然后比较孕期吸烟和严重精神疾病不一致的表亲和兄弟姐妹，这有助于通过设计来解释未测量的遗传和环境混杂因素。
通过产前检查获得的母亲自我报告的孕期吸烟情况。
严重精神疾病，临床诊断来自住院和门诊就诊，并使用国际疾病分类代码定义双相情感障碍和精神分裂症谱系障碍。
在纳入分析的1680219名后代中，816775名（48.61%）为女性。在人群水平上，孕期暴露于中度和高度吸烟的后代患严重精神疾病的比率高于未暴露的后代（孕期中度吸烟：风险比[HR]，1.25；95%置信区间，1.19 - 1.30；孕期高度吸烟：HR，1.51；95%置信区间，1.44 - 1.59）。随着对家族混杂因素的统计和方法学控制增加，这些关联的强度减弱。在对家庭内协变量进行比较的兄弟姐妹中，关联明显较弱且无统计学意义（孕期中度吸烟：HR，1.09；95%置信区间，0.94 - 1.26；孕期高度吸烟：HR，1.14；95%置信区间，0.96 - 1.35）。这种关联模式在严重精神疾病亚型中是一致的，并得到了进一步敏感性分析的支持。
这项基于人群和家庭的研究未能找到证据支持孕期吸烟对后代患严重精神疾病风险有因果效应。相反，这些结果表明，观察到的人群水平关联很大程度上可以由兄弟姐妹共有的测量和未测量因素来解释。
