Objectives: To estimate the risk of schizophrenia in offspring of
women exposed to severe life events periconceptionally or during
pregnancy. The study focuses on the effect of timing of exposure,
and individual, rather than population level exposure, on subsequent
risk of schizophrenia. Methods: All women delivering live births in
Denmark between 1 January 1973 and 30 June 1995 (N=1.38m) were
linked to information about their partners/spouses, their parents, siblings
and their older children. Exposure was defined as death of one
or more of these relatives. Exposure was further classified by timing:
6 months before pregnancy, first 12 weeks’ gestation, 13 to 24 weeks’
gestation, 25 weeks’ gestation until birth. Offspring were followed
until 30 June 2005. Relative risks (RRs) were modelled using log-linear
Poisson regression adjusted for maternal age, offspring age and
sex, unknown spouse (legal father of the child), family history of
mental illness, place of birth and calendar year. Results: The risk of
schizophrenia was significantly elevated in offspring of women
exposed to death of a relative during the first trimester (n=16, adjusted
RR 1.67 [95% CI 1.02-2.73]). Death of a relative during the second,
or third trimesters, or before pregnancy, was not associated with elevated risk of schizophrenia. Relative risks by death of specific relatives
did not reach significance, but the observed risk of schizophrenia
associated with death of a child was greatest (2.02[95% CI
0.65-6.26]) although small numbers (n=3) precluded significance.
Conclusions: The offspring of mothers experiencing an incontrovertibly
severe stressfull event early in pregnancy appear to have a
nearly twofold increased risk of the neurodevelopmental disorder,
schizophrenia. This risk is confined to the first trimester, coinciding
in magnitude and timing with other adverse pregnancy exposures
conferring increased risk, such as famine. The mechanisms of stressrelated
effects on risk of neurodevelopmental disorder may include
gene mutation in specific genes associated with neurodevelopment
or effects on fetal programming of somatic and fetal growth.