Cardiovascular mortality in relation to birth weight of children and grandchildren in 500 000 Norwegian families

Cardiovascular diseases (CVDs) have been related to low birth weight, suggesting the foetal environment may program future risk. Alternatively, common genetic factors for both low birth weight and CVD could explain such associations. We investigated associations between offspring birth weight and paternal and maternal cardiovascular mortality and offspring birth weight and cardiovascular mortality among all four grandparents, and further assessed the mediating role of maternal smoking during pregnancy. All births from 1967 to 2008 that could be linked to parents and grandparents comprised the population (n 1 004 255). The mortality follow-up among parents was from 1970 to 2008 and among grandparents from 1960 to 2008. The association of grandparental mortality with maternal smoking during pregnancy was analysed in a subpopulation of those born after 1997 (n 345 624). Per quintile higher in birth weight was related to 0.82 (0.750.89) hazard ratio from coronary heart disease in mothers and 0.94 (0.920.97) in fathers. For stroke, these were 0.85 (0.780.92) and 0.94 (0.891.00), respectively. In grandparents for cardiovascular causes, the effects were 0.95 (0.930.96) (maternal grandmother), 0.97 (0.960.98) (maternal grandfather), 0.96 (0.940.98) (paternal grandmother), and 0.98 (0.981.00) (paternal grandfather). Adjusting for maternal smoking in pregnancy in the subpopulation accounted for much of the effect on grandparental cardiovascular mortality in all categories of birth weight. For grandparental diabetes mortality, U-shaped associations were seen with grandchild birth weight for the maternal grandmother and inverse associations for all other grandparents. Associations between CVD mortality in all four grandparents and grandchild birth weight exist, and while genetic and environmental factors may contribute to these, it appears that there is an important role for maternal smoking during pregnancy (and associated paternal smoking) in generating these associations. For diabetes, however, it appears that intrauterine environmental influences and genetic factors contribute to the transgenerational associations.