Maternal smoking during pregnancy and type 1 diabetes in the offspring: A nationwide register-based study with family-based designs

Objectives: Maternal smoking during pregnancy is associated with a reduced risk of type 1 diabetes (T1D) in the offspring. We investigated whether this association is consistent with a causal interpretation by accounting for familial (shared genetic and environmental) factors using family-based, quasi-experimental designs. Design: A nationwide, prospective cohort study and a nested case-control study (quasi-experiment) comparing children with T1D to their age-matched siblings (or cousins). Setting: Swedish national registers. Participants: We included 2,995,321 children born in Sweden between 1983 and 2014. Exposure: Information on maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. Main outcome measures: Children were followed for a diagnosis of T1D until 2020 through the National Patient, Diabetes and Prescribed Drug Registers. Results: A total of 18,617 children developed T1D, with a median age at diagnosis of 9.4 years. The sibling and cousin comparison design included 14,284 and 7,988 of these children, respectively. Maternal smoking during pregnancy was associated with a 22% lower risk of offspring T1D in the full cohort (hazard ratio: 0.78, 95% confidence interval [CI]: 0.75 to 0.82) in the multivariable-adjusted model. The corresponding odds ratio was 0.78 (95% CI: 0.69 to 0.88) in the sibling and 0.72 (95% CI: 0.66 to 0.79) in the cousin comparison analysis. Conclusions: This nationwide, family-based study provides support for a protective effect of maternal smoking on offspring T1D. Mechanistic studies are needed to elucidate the underlying pathways behind this link.