Journal of Developmental Origins of Health and Disease

Original Articles

Sex-specific impact of maternal–fetal risk factors on depression and cardiovascular risk 40 years later

J. M. Goldsteina1a2a3 c1, S. Cherkerziana1a2, S. L. Bukaa4, G. Fitzmauricea5, M. Horniga6a7, M. Gillmana8, S. O'Toolea1 and R. P. Sloana9

a1 Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA

a2 Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA

a3 Division of Psychiatric Neuroscience, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

a4 Department of Epidemiology, Brown University, Providence, RI, USA

a5 Department of Psychiatry, Harvard Medical School at McLean Hospital, Belmont, MA, USA

a6 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

a7 Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA

a8 Department of Population Health, Harvard Medical School, Harvard Pilgrim Community Health

a9 Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York, NY, USA


Major depressive disorder (MDD) and cardiovascular disease (CVD) represent leading causes of morbidity and mortality worldwide. We tested the hypothesis that growth restriction and preeclampsia (referred to as fetal risk) are significant predictors of these conditions, with women at higher risk in adulthood. Adult offspring exposed to fetal risk factors and their discordant siblings were from two prenatal cohorts, whose mothers were followed through pregnancy and whom we recruited as adults 40 years later (n = 538; 250 males and 288 females). Subjects were psychiatrically diagnosed and underwent a stress challenge during which parasympathetic regulation was assessed by electrocardiogram, operationalized as high-frequency R-R interval variability (HF-RRV). Linear mixed models and generalized estimating equations were used to examine the relationship of fetal risk on HF-RRV, MDD and comorbidity of low HF-RRV (lowest 25th percentile) and MDD, including interactions with sex and socioeconomic status (SES). Fetal risk was significantly associated with low HF-RRV response (F = 3.64, P = 0.05), particularly among low SES (interaction: F = 4.31, P < 0.04). When stratified by MDD, the fetal risk impact was three times greater among MDD compared with non-MDD subjects (effect size: 0.21 v. 0.06). Females had a significantly higher risk for the comorbidity of MDD and low HF-RRV than males (relative risk (RR) = 1.36, 95% CI: 1.07–1.73), an association only seen among those exposed to fetal risk (RR = 1.38, 95% CI: 1.04–1.83). Findings suggest that these are shared fetal antecedents to the comorbidity of MDD and CVD risk 40 years later, an association stronger in females than in males.

(Online publication November 04 2011)


c1 Address for correspondence: Dr J. M. Goldstein, Division of Women's Health, Brigham and Women's Hospital, One Brigham Circle, 3rd Floor, 1620 Tremont St., Boston, MA 02120, USA. (Email