Prenatal Smoking Might Not Cause Attention-Deficit/Hyperactivity Disorder: Evidence from a Novel Design

Background: It is widely considered that exposure to maternal cigarette smoking in pregnancy has risk effects on offspring attention-deficit/hyperactivity disorder (ADHD). This view is supported by consistent observations of association. It is, however, impossible to be certain of adequate control for confounding factors with observational designs. We use a novel "natural experiment" design that separates prenatal environmental from alternative inherited effects. Methods: The design is based on offspring conceived with Assisted Reproductive Technologies recruited from 20 fertility clinics in the United Kingdom and United States who were: 1) genetically unrelated, and 2) related to the woman who underwent the pregnancy. If maternal smoking in pregnancy has true risk effects, association will be observed with ADHD regardless of whether mother and offspring are related or unrelated. Data were obtained from 815 families of children ages 4 years-11 years with parent questionnaires and antenatal records. Birth weight was used as a comparison outcome. The key outcome considered was child ADHD symptoms. Results: Association between smoking in pregnancy and lower birth weight was found in unrelated and related mother-offspring pairs, consistent with a true risk effect. However, for ADHD symptoms, the magnitude of association was significantly higher in the related pairs (beta=.102, p<.02) than in the unrelated pairs (beta=-.052, p>.10), suggesting inherited effects. Conclusions: Our findings highlight the need to test causal hypotheses with genetically sensitive designs. Inherited confounds are not necessarily removed by statistical controls. The previously observed association between maternal smoking in pregnancy and ADHD might represent an inherited effect.