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.