Multigenerational smoking during pregnancy and risk of stillbirth: a population-based 3-generation cohort study

Maternal smoking during pregnancy increases risk of stillbirth. Emerging evidence suggests that smoking in pregnancy may be related to health outcomes of a second generation, but the role of grandmaternal smoking on fetal survival of grandoffspring has not been studied.

We investigated the association between maternal grandmaternal cigarette smoking in early pregnancy and grandoffspring risk of stillbirth.

In a countrywide 3-generation Swedish cohort of 176,908 grandmothers (F0), 197,579 mothers (F1), and 316,459 grandoffspring (F2), we compared risk of F2 stillbirth between first trimester smoking and nonsmoking grandmothers using relative risks with 95% confidence intervals. To address unmeasured confounding by shared familial factors, we used the maternal full sisters' smoking status during pregnancy as a negative control exposure. We corrected the relative risk for potential selection survival via inverse probability weighting. We also examined F2 offspring sex-specific associations and interactions between grandmaternal and maternal smoking.

Grandoffspring stillbirth risk (per 1000 deliveries) increased from 3.0 in nonsmoking maternal grandmothers to 3.5 and 3.9 in those smoking 1 to 9 and ≥10 cigarettes/day, respectively. Adjusted relative risk (95% confidence interval) for any smoking vs no smoking was 1.15 (1.01, 1.31). The association was apparent only for male grandoffspring (adjusted relative risk=1.23; 95% confidence interval, 1.01, 1.48). Maternal (F1) smoking was also related to increased stillbirth risk, while maternal (F1) sisters' was not. There was an antagonistic interaction between grandmaternal and maternal smoking in pregnancy; the excess risk of F2 stillbirth associated with maternal (F1) smoking was greater among F2 births with nonsmoking grandmothers (F0) compared to those with smoking grandmothers.

Maternal grandmaternal smoking in early pregnancy is related to an increased risk of grandoffspring stillbirth, independent of unmeasured shared familial factors.