Background: The developmental origins of ischemic heart disease (IHD) have been widely documented but little is known about their persistence across more than one generation. This study aimed to investigate whether the effects of early life disadvantages on adult IHD have changed between generations and are mediated by adult socioeconomic circumstances, and further explore the transgenerational effects of grandparental and parental exposures to disadvantaged circumstances on adult offspring’s IHD.

Methods: We used register-based data from the Uppsala Multigenerational Study, Sweden. The study populations were the  parents born 1915–1929 and  their offspring born 1932–1972 with available obstetric data. The offspring were further linked to grandparents who had their socioeconomic and demographic data recorded. The outcome was incident IHD assessed at ages 32–75 during a follow-up from January 1, 1964 till December 31, 2008. The exposures included birthweight standardized-for-gestational age, ponderal index, gestational length, and parental socioeconomic position (SEP). Education and income were analyzed as  mediators. Potential transgenerational associations were explored by linking offspring IHD to parents’ standardized birthweight and gestational length, grandparental SEP, and to grandmothers’ age, parity, and marital status at parental birth. All associations were examined in Cox proportional hazard regression models.

Results: Lower standardized birthweight and lower parental SEP were found to be associated with higher IHD rates in both generations, with no evidence of effect modification by generation. Education and income did not mediate the association between standardized birthweight and IHD. Disadvantaged grandparental SEP, younger and older childbearing ages of grandmothers, and paternal preterm birth affected offspring’s IHD independent of parental education, income, or IHD history.

Conclusions: The findings point to similar magnitudes of IHD inequalities by early life disadvantages across two historical periods and the existence of transgenerational effects on IHD. Epigenetic dysregulation involving the germline is a plausible candidate mechanism underlying the transgenerational associations that warrant further research.