Abstract
Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offspring's sex.In a pilot study linking birth records to Israel's Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964–76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for father's age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison.There was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1–4.7), seen more in females (4.3, 1.7–10.7) than in males (1.2, 0.4–3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2–5.2), also seen more in females (3.6, 1.3–9.7) than males (1.8, 0.6–5.2).These findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia.
Highlights
Stress has become frequent in developed countries, as terrorist threats, actions and their aftermaths are experienced in otherwise stable populations
Maternal age was less strongly associated with schizophrenia; compared to age < 30, the RRs associated with ages 30–34 and 35+ were 1.2 (0.94–1.5) and 1.5 (1.1–2.1, p = .0066)
We considered whether there were secular or seasonal trends in incidence that might confound the interpretation of findings for any one year
Summary
Stress has become frequent in developed countries, as terrorist threats, actions and their aftermaths are experienced in otherwise stable populations. Concern about consequences for offspring whose mothers were stressed during pregnancy derives from strong evidence, from experimental biology, that intrauterine stress can affect neurodevelopment, altering behaviors in animals that are thought relevant to models of cognition, aggression, anxiety and depression [1]. By modifying the fetal hypothalamic-adrenal axis (HPA) and other systems, stress in pregnancy perturbs endocrine function in animal models of diabetes, cardiovascular disease and metabolic syndrome. Too, there is strong evidence that maternal stress in pregnancy can lead to type 2 diabetes, hypertension and metabolic syndrome in the offspring [1]. There is some evidence in humans for unequal responses of males and females to stress at different stages of intrauterine life [8]
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