Prenatal maternal stress is associated with alterations in the structural integrity of the hypothalamic-pituitary-gonadal axis 20 years later: Project Ice Storm.

study questionIs prenatal maternal stress (PNMS) in humans associated with alterations in the sexually differentiated reproductive axis structures in the offspring? SUMMARY ANSWER: PNMS, experienced by pregnant mothers exposed to a natural disaster in 1998, was associated with structural changes in hypothalamic-pituitary-axis (HPG) structures of 18.5-year-old offspring. WHAT IS KNOWN ALREADY: In a human prospective study, PNMS was associated with higher childhood BMI, which in turn predicted earlier menarche. Epidemiological studies have shown that maternal life event stress is associated with changes in gonadal morphology and function. STUDY DESIGN, SIZE, DURATION: A prospective study of mothers exposed to a severe ice storm in 1998 (N = 224) collected measures of PNMS (objective hardship and subjective distress). Offspring reproductive structures were assessed in early adulthood. PARTICIPANTS/MATERIALS, SETTING,

methodsPNMS-exposed offspring (ICE; n = 39, 21 F, 18 M) and a control group (n = 31, 14 F, 17 M; born in 1997) were assessed at age 18.5 years. Participants underwent MRI. Using a novel approach, the structural integrity of the entire HPG axis was assessed using gold-standard manual delineation from their MRI scans. Ovarian antral follicles (2-10 mm) were also counted from MRI images. Salivary estradiol and testosterone were measured with ELISA. Data were analyzed with ANOVA and multiple regression. MAIN RESULTS AND THE ROLE OF CHANCE: The expected sex difference in hypothalamic volume (M > F) was detected in controls. Within ICE, the sex difference was observed at low, but not at high, levels of PNMS (objective and subjective). Greater objective hardship was associated with smaller hypothalamic volume in men. Similarly, pituitary volume was smaller in ICE men compared to control men. Within ICE, greater objective hardship was associated with smaller left testicular volume. Finally, compared to controls, the left ovary had more antral follicles and tended to be larger in ICE women. The group differences and associations between PNMS and HPG morphology were generally medium to large. LIMITATIONS, REASONS FOR CAUTION: The relatively small sample size may have limited our ability to detect small differences and to test interactions with gestational timing of prenatal stress exposure. In addition, the majority of women were taking oral contraceptives, and thus results must be interpreted with caution. WIDER IMPLICATIONS OF THE

findingsPNMS from a natural disaster may lead to functional changes in the human reproductive axis in adulthood. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by a grant from the Canadian Institutes of Health Research (CIHR, FRN 125892; to S.K., D.P.L., and J.C.P., and CIHR MOP 125892 to co-investigators S.K. S.L.J. was funded by a postdoctoral fellowship provided by the Fonds de Québec-Santé (FRQ-S). The funding sources were not involved in the collection, analyses, or interpretation of the data, or writing of the report. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.