Introduction Association between individual birth measures and chronic disease morbidity or mortality in their adult relatives contributes to evidence of developmental origins of disease. Internationally, only three studies to date have explored this intergenerational risk association with grandparents. We prospectively examine the relationship between infants' birth-weights and all-cause mortality of their grandparents.

Methods In 2001–2003 the cross-generation cohort study was established at antenatal stage with 1082 participating families, including 1184 grandparents (455 maternal-grandmothers, 271 maternal-grandfathers, 277 paternal-grandmothers and 181 paternal-grandfathers). Grandparents' morbidity and mortality was followed through cohort management. In 2010, the computerised death registry at the General Registrar's Office was searched for any grandparental deaths. HRs were calculated with Cox regression models, adjusted as appropriate for child's gestational age and gender, grandparent's age, mother's age, maternal smoking and height at pregnancy.

Results A total of 85 deaths were registered. An association between lower birth-weight infants (both <2500 g and <3000 g) and grandparental mortality was seen only in maternal line families. A U shaped association with maternal-grandmother's mortality was also consistently observed, but did not reach statistical significance, whether adjusted or not for maternal characteristics [LBW: adjusted-HR (95% CI)=4.2 (0.5 to 37.6); HBW: adjusted-HR (95% CI)=1.3 (0.4 to 4.0)]. Conversely, a significant direct relationship emerged between paternal-grandfather's mortality and higher birth-weight infants (≥4000 g) [HR (95% CI)=3.9 (1.2 to 12.0)]. Controlling for maternal characteristics at pregnancy did not attenuate the relationship, but rather strengthened the risk [adjusted-HR (95% CI)=4.5 (1.4 to 14.9)].

Conclusion These findings are consistent with other studies in showing that maternal and paternal lines of transmission of risk differ, meriting further genetic and possible nutrigenomic investigation.