The association between maternal smoking during pregnancy and bipolar disorder in the offspring: alternative interpretations.

Maternal tobacco smoking during pregnancy has been found to be associated with several adverse pregnancy outcomes in prospective and case-control epidemiological studies. In particular, the association between maternal smoking during pregnancy and small-for-gestational-age births is consistently reported in the literature, shows a clear dose-response effect, and is regarded as causal (1). A large, although less consistent, body of evidence also supports the association of maternal smoking during pregnancy with cognitive and behavioral problems in the offspring, including a higher frequency of attention, learning, and memory deficits and an increased risk of developing externalizing mental disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, and substance use disorders (2). In this issue, Talati et al. (3) report on a case-control observational study showing, for the first time, that maternal smoking during pregnancy is associated with a nearly twofold greater risk for bipolar disorder in the offspring after adjusting for several potential confounders, includingmaternal alcohol use and psychiatric history as well as offspring birth weight. The study has several methodological strengths, such as the prospective assessment of maternal smoking, the outcome evaluation carried out many years after the exposure assessment, the use of a population-based birth cohort, and the diagnoses of bipolar disordermade on the basis of direct structured interviews. Pending replication, how do we interpret this finding? There are two main alternative interpretations. The first is that the association betweenmaternal tobacco smoking during pregnancy and the offspring’s risk for bipolar disorder as well as externalizing disorders is explained by the neurotoxic effects of the prenatal exposure to constituents of tobacco smoke (primarily nicotine but also carbon monoxide and possibly others). The second is that the association is spurious, that is, totally explained by environmental and genetic factors related to maternal smoking. A third intermediate possibility is that, although the association is partially confounded, smoking during pregnancy is still one of the environmental factors thatmay combine, either additively or interactively, with genetic vulnerability, contributing to the risk for bipolar as well as externalizing disorders. Let’s briefly review the evidence supporting each of these hypotheses. The toxic effects of prenatal exposure to nicotine and carbon monoxide are well documented. Both substances readily cross the placenta and reach higher concentrations in the fetal than in the maternal compartment. Nicotine disrupts the function of the placenta and exerts an anorexigenic effect leading to maternal and fetal undernutrition. Carbon monoxide, binding to hemoglobin, forms carboxyhemoglobin, which results in fetal hypoxia. Furthermore, the direct action of nicotine on the fetal brain has been found in animal studies to produce disturbances in neuronal migration, abnormalities in cell proliferation and differentiation,