Grandmaternal obesity in early pregnancy and risk of grandoffspring preterm birth: a nationwide three-generation study

Abstract

Obesity in pregnancy increases risk of preterm birth (PTB), a leading cause of infant mortality and morbidity. The heritability of obesity suggests associations of grandmaternal obesity with grandoffspring outcomes, but a potential effect on PTB has not been interrogated. We studied whether grandmaternal (F0 generation) body mass index (BMI) in early pregnancy was related to grandoffspring (F2 generation) PTB risk by type, and to maternal (F1 generation) preeclampsia risk. Among 315,240 singleton live-born infants from a countrywide three-generation Swedish cohort, we compared risks of spontaneous and medically indicated PTB, defined as gestational age <37 completed gestation weeks, between categories of maternal grandmaternal BMI in early pregnancy. We also interrogated associations of grandmaternal BMI categories with risk of maternal preeclampsia, a major cause of medically indicated PTB. We assessed whether the associations were mediated through consequences of obesity. In a subset, we examined associations with paternal grandmaternal BMI. To address unmeasured confounding by shared familial factors, we assessed the associations of parental full sisters’ BMI with PTB. Maternal grandmaternal obesity (BMI ≥ 30.0) was related to increased risks of grandoffspring medically indicated PTB and maternal preeclampsia, compared with normal BMI. Adjusted hazard and risk ratios (95% confidence intervals) were, respectively, 1.54 (1.28, 1.86) and 1.32 (1.16, 1.49). Maternal sisters’ BMI was unrelated to PTB or preeclampsia risks. Maternal obesity or preeclampsia mediated most (85%) of the maternal grandmaternal obesity-grandoffspring medically indicated PTB association, whereas the association with maternal preeclampsia was primarily mediated (61%) through maternal obesity. There were no associations with spontaneous PTB. Paternal grandmaternal obesity was unrelated to grandoffspring’s PTB risk. Medically indicated PTB in grandoffspring is associated with maternal grandmaternal obesity.