Multigenerational smoking during pregnancy and risk of stillbirth: a population-based 3-generation cohort study - 18/12/25

Doi : 10.1016/j.ajog.2025.11.033

Eduardo Villamor, MD, DrPH ^a,^⁎ , Amanda K. Miglin, BS ^a, Sven Cnattingius, MD, PhD ^b
^a Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
^b Section of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden

^∗Corresponding author: Eduardo Villamor, MD, DrPH.

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 18 December 2025

Abstract

Background

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.

Objective

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

Study Design

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.

Results

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.

Conclusion

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

Le texte complet de cet article est disponible en PDF.

Video

(6.5 Mo)

Le texte complet de cet article est disponible en PDF.

Key words : grandmother, grandoffspring, intergenerational, smoking, stillbirth

Plan

Introduction

Materials and methods

Study design

Ethics approval and consent to participate

Results in the context of what is known

Clinical implications

Strengths and limitations

Conclusion

	The paper has not been presented or accepted for presentation at scientific meetings.
	The authors report no conflict of interest.
	This work was supported by the Eunice Kennedy ShriverNational Institute of Child Health and Human Development ( HD106203 ).
	We sought and obtained approval from the Regional Ethical Review Board in Stockholm, Sweden (No. 2018/5:2). Informed consent was not required because all data were anonymous, and the NRNs were replaced with other unique nontraceable numbers. All methods were performed in accordance with the World Medical Association Declaration of Helsinki.
	The data that support the findings of this study are available from the Swedish National Board of Health and Welfare and Statistics Sweden but restrictions apply to the availability of these data, which were used under license for the present study, and so are not publicly available.