Association Between Maternal Smoking During Pregnancy and Severe Mental Illness in Offspring

Abstract

Importance: 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.

Objective: 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.

Exposures: Maternal self-reported smoking during pregnancy, obtained from antenatal visits.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Figure 1.. Risk of Any Severe Mental Illness (SMI) by Smoking During Pregnancy (SDP) Exposure Status

Estimates of cumulative risk of (ie, proportion diagnosed with) any SMI by age among those with and without any SDP exposure in the full cohort (A) and in siblings discordant for SDP exposure only (B). Shaded areas are pointwise 95% CIs.

Figure 2.. Associations Between Maternal Smoking During Pregnancy and Offspring Severe Mental Illness (SMI)

Hazard ratios from Cox proportional hazards regression models for any SMI (A), bipolar disorder (B), schizophrenia spectrum disorders (C), and SMI with substance use disorder (D). Population models (model 1) were adjusted only for offspring sex and parity. Adjusted models (model 2) additionally included maternal and paternal covariates. Cousin fixed-effects models (model 3) compared discordant cousins and included all covariates. Sibling fixed-effects models (model 4) compared discordant siblings and included offspring and paternal covariates and maternal age at childbirth; maternal covariates that could not differ among siblings were excluded. Error bars indicate 95% CIs. Moderate smoking during pregnancy: 1-9 cigarettes per day; high smoking during pregnancy: ≥10 cigarettes per day. Y-axes are natural log-scaled.