Association Between Periconceptional Weight of Maternal Grandmothers and Attention-Deficit/Hyperactivity Disorder in Grandchildren.

Importance: Neurodevelopmental disorders have been proposed to involve alterations to epigenetic regulation, and epigenetic effects may extend to germline cells to affect later generations. Weight status may affect DNA methylation, and maternal weight before and during pregnancy has been associated with offspring DNA methylation as well as attention-deficit/hyperactivity disorder (ADHD). Objective: To assess whether a woman's weight before and during pregnancy is associated with ADHD in her grandchild. Design, Setting, and Participants: This cohort study analyzed data from 19 835 grandmother-mother dyads and 44 720 grandchildren in the Nurses' Health Study II (NHS-II) cohort (2001-2013), a population-based prospective cohort study. Cluster-weighted generalized estimating equations were modeled to estimate the association of grandmother's prepregnancy body mass index (BMI) and gestational weight gain with grandchild risk of ADHD. Data analyses were conducted from May 2018 to April 2021. Grandmothers reported their height and weight before, and weight gain during, their pregnancy with the NHS-II participants. Mothers self-reported height and weight prior to pregnancy. From those data, grandmother BMI and mother BMI were calculated as weight in kilograms divided by height in meters squared and categorized as underweight (<18.5), healthy/normal (18.5-24.9), overweight (25.0-29.9), or obese (≥30). Main Outcomes and Measures: Cases of ADHD identified by maternal report of having a child with a diagnosis of ADHD. Results: In total, 19 835 grandmothers (97.6% White race/ethnicity; 2113 [10.7%] prepregnancy underweight and 1391 [7.0%] prepregnancy overweight or obese) were included in this cohort study. Of 44 720 grandchildren, 3593 (8%) received a diagnosis of ADHD. Higher odds of ADHD among grandchildren were found for those whose grandmother was underweight compared with healthy weight prior to pregnancy with the NHS-II participant (adjusted odds ratio, 1.25; 95% CI, 1.10-1.42). By contrast, grandmother gestational weight gain was not significantly associated with risk of grandchild ADHD (adjusted odds ratio for <20 lbs [9.1 kg], 1.06; 95% CI, 0.96-1.16; adjusted odds ratio for >29 lbs [13.2 kg], 1.01; 95% CI, 0.91-1.13). Mother prepregnancy BMI showed an association with ADHD among offspring, with a stronger association detected for obese status (adjusted odds ratio, 1.27; 95% CI, 1.07-1.49) than for overweight status (adjusted odds ratio, 1.13; 95% CI, 1.02-1.26) compared with normal weight as a reference group. The positive association between grandmother prepregnancy underweight and ADHD risk among the grandchildren remained unchanged after further adjustment for potential mediators, including maternal prepregnancy BMI. Conclusions and Relevance: The results of this cohort study indicate that grandmother underweight prior to pregnancy is associated with an increased risk of ADHD among grandchildren, independent of grandmother gestational weight gain and independent of maternal prepregnancy weight status.