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Background Diethylstilbestrol (DES) is an endocrine-disrupting pharmaceutical prescribed to pregnant women to prevent pregnancy complications between the 1940s and 1970s. Although DES has been shown in animal studies to have multigenerational effects, only two studies have investigated potential multigenerational effects in humans on preterm birth (PTB), and none on low birthweight (LBW)—major determinants of later life health. Methods Nurses’ Health Study (NHS) II participants (G1; born 1946–64) reported their mothers’ (G0) use of DES while pregnant with them. We used cluster-weighted generalized estimating equations to estimate odds ratios (OR) and 95% confidence intervals (CI) for risk of LBW and PTB among the grandchildren by grandmother use of DES. G1 birthweight and gestational age were considered to explore confounding by indication. Results Among 54 334 G0-G1/grandmother-mother pairs, 973 (1.8%) G0 used DES during pregnancy with G1. Of the 128 275 G2 children, 4369 (3.4%) were LBW and 7976 (6.2%) premature. Grandmother (G0) use of DES during pregnancy was associated with an increased risk of G2 LBW [adjusted OR (aOR) = 3.09; 95% CI: 2.57, 3.72], that was reduced when restricted to term births (aOR = 1.59; 95% CI: 1.08, 2.36). The aOR for PTB was 2.88 (95% CI: 2.46, 3.37). Results were essentially unchanged when G1 birthweight and gestational age were included in the model, as well as after adjusting for other potential intermediate variables, such as G2 pregnancy-related factors. Conclusions Grandmother use of DES during pregnancy is associated with an increased risk of LBW, predominantly through an increased risk of PTB. Results when considering G1 birth outcomes suggest this does not result from confounding by indication.

Grandmothers’ endocrine disruption during pregnancy, low birth weight, and preterm birth in third generation