Original Article Prenatal stress and affective disorders in a population birth cohort There is increasing interest in whether the timing of maternal stress during pregnancy determines vul- nerability to specific psychiatric diseases in off- spring (1–4), but it is unclear which periods in pregnancy confer vulnerability. It is also not known whether psychosocial stress alone can increase it. Some have suggested that prenatal stress is associated with a higher risk of affective disorders, and that the timing of the stress may influence the risk for this outcome (2, 4–7). The second and third trimesters and the 10 weeks prior to conception have all been reported to be the critical periods (2, 4–7). To address the question of the relevant timing during gestation, we analyzed data from a large birth cohort to ascertain whether women who were at a specific stage of pregnancy during a war of six daysÕ duration had offspring with unique incidences of hospitalization for affective disorders. We analyzed data by month of pregnancy to study the precise timing of potential disruption of fetal development. We also analyzed data by trimester so as to augment the power of our analyses by increasing the numbers of offspring exposed during each period Kleinhaus K, Harlap S, Perrin M, Manor O, Margalit-Calderon R, Opler M, Friedlander Y, Malaspina D. Prenatal stress and affective disorders in a population birth cohort. Bipolar Disord 2013: 15: 92–99. Ó 2012 John Wiley & Sons A ⁄ S. Published by Blackwell Publishing Ltd. Objectives: Pregnant women exposed to an acute traumatic event are thought to produce offspring with an increased incidence of affective disorders. It is not known whether there are specific times in pregnancy which confer increased vulnerability, or if psychosocial stress alone can increase the incidence of affective disorders in offspring. We examined the relationship of the timing of an acute psychosocial threat during pregnancy to the incidence of affective disorders in offspring using data from a large birth cohort. Methods: Using data on 90079 offspring born in Jerusalem in 1964–1976 and linked to IsraelÕs psychiatric registry, we constructed proportional hazards models to evaluate the link between gestational age during the Arab–Israeli war of June 1967 and incidence of mood disorders. Results: Those in their first trimester of fetal development during the war were more likely to be admitted to hospitals for any mood disorders [relative risk (RR) = 3.01, 95% confidence interval (CI): 1.68–5.39, p = 0.0002]; for bipolar disorder the risk was doubled (RR = 2.44, 95% CI: 0.996–5.99, p = 0.054) and for all ÔotherÕ mood disorders the risk was tripled (RR = 3.61, 95% CI: 1.68–7.80, p = 0.001). Mood disorders were also increased in offspring whose mothers had been in the third month of pregnancy in June of 1967 (RR = 5.54, 95% CI: 2.73–11.24, p < 0.0001). Conclusions: A time-limited exposure to a severe threat during early gestation may be associated with an increased incidence of affective disorders in offspring. The third month of fetal development was a moment of special vulnerability. Karine Kleinhaus a,b , Susan Harlap a,b , Mary Perrin a , Orly Manor c , Ronit Margalit-Calderon c , Mark Opler a , Yehiel Friedlander c and Dolores Malaspina a Departments of a Psychiatry, b Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA, c Hebrew University-Hadassah Braun School of Public Health, Jerusalem, Israel doi: 10.1111/bdi.12015 Key words: cohort study – mood disorders – prenatal stress Received 8 March 2012, revised and accepted for publication 1 September 2012 Corresponding author: Karine Kleinhaus, M.D., M.P.H. Department of Psychiatry New York University School of Medicine 550 First Avenue New York, NY 10016 USA Fax: 212-263-2935 E-mail: kkleinhaus@gmail.com Bipolar Disorders 2013: 15: 92–99 Ó 2012 John Wiley and Sons A/S Published by Blackwell Publishing Ltd. BIPOLAR DISORDERS 92