Grandmaternal body mass index in early pregnancy and risk of infant mortality in grandoffspring: a population-based multigeneration cohort study.

Background: Maternal obesity increases risk of infant mortality. Because obesity is highly inheritable, grandmaternal obesity could also play a role. However, it is unknown whether grandmaternal obesity is related to grandoffspring infant mortality risk.

Objectives: We investigated the associations of grandmaternal early pregnancy body mass index [BMI (in kg/m)] and grandoffspring infant mortality risk.

Methods: Using Swedish nationwide registers, we estimated infant mortality hazard ratios (HRs) by levels of maternal grandmaternal early pregnancy BMI among 315,461 singleton live-born grandoffspring. We examined whether the association was mediated through maternal body size. In a subset of 164,095 grandsoffspring we evaluated the role of paternal grandmaternal BMI. To explore whether factors shared within families explained these associations, we studied the relations of maternal or paternal full sisters' BMI and infant mortality.

Results: Maternal grandmaternal overweight or obesity (BMI ≥ 25.0) was associated with increased grandoffspring infant mortality risk. Compared with the population median BMI (21.7), estimated adjusted hazard ratios [HRs (95% confidence interval [CI])] of grandoffspring mortality for BMI 25.0 and 30.0 were, respectively, 1.60 (1.14, 2.23) and 1.61 (1.13, 2.27). Maternal high birth weight-for-gestational age and early pregnancy obesity (BMI ≥ 30.0) were also associated with increased infant mortality risk. The association between maternal grandmaternal overweight or obesity and grandoffspring infant mortality was mostly (62%) mediated through maternal overweight or obesity. Maternal sisters' BMI was unrelated to infant mortality. Paternal grandmaternal obesity was associated with increased infant mortality risk (HR [95% CI] for BMI 30.0 compared with 21.7: 1.65 [1.02, 2.67]); associations with paternal sisters' BMI were not statistically significant.

Conclusions: Maternal grandmaternal overweight or obesity is associated with increased risk of grandoffspring infant mortality; factors shared within families may not play a major role. The association is mediated through the maternal early pregnancy BMI. Whether the association with paternal grandmaternal BMI is explained by shared familial factors warrants future confirmation.