The offspring of women who experience the death of a close relative during the first trimester of pregnancy had an increased risk of developing schizophrenia, according to a report in the February Archives of General Psychiatry.

The study suggests that "severe stress" to a mother during the first trimester of pregnancy may increase the chances of her offspring later developing schizophrenia.

Experiencing the death of a relative during the other trimesters or up to six months before pregnancy was not linked with a higher risk of schizophrenia in the offspring. And having a close relative diagnosed with a potentially life-threatening illness did not raise the risk of schizophrenia in offspring, researchers found.

Ali Khashan, M.Sc., and colleagues at the University of Manchester in England examined the records of all women who gave birth in Denmark between January 1973 and June 1995 using the Medical Birth Registry and linked them to close relatives (including older children, spouses, parents, and siblings) using their unique Civil Registration Number, which enables linkage to all national registries in Denmark.

These relatives were then tracked to identify the date of death, if any, and diagnosis of cancer, acute myocardial infarction, or stroke.

Between 1973 and 1995, researchers found that there were more than 1.38 million births in Denmark, and of those, the mothers of 36,193 offspring were exposed to the illness or death of a close relative. More specifically, the mothers of 21,987 children experienced the death of a close family member, and 14,206 experienced serious illness in close relatives.

The records of the offspring were then linked to the Danish Psychiatric Central Register, which includes records of inpatient and outpatient treatment.

When Kashan and colleagues examined the association between mothers' exposure to the death of a close relative or the serious illness of a close relative before and during pregnancy, only one statistically significant finding emerged—children of mothers exposed to the death of a close relative during the first trimester of pregnancy were almost 70 percent more likely than those who were not exposed to the death of a close relative six months prior to or during pregnancy to develop schizophrenia later in life.

In total, 16 mothers who had been exposed to the death of a close relative during the first trimester of pregnancy had offspring who later developed schizophrenia.

When the researchers explored whether a family history of mental illness may have confounded the findings regarding the effect of exposure to death in the first trimester of pregnancy, they found that among women without a family history of mental illness, exposure to death in the first trimester was a significant risk factor for schizophrenia in the eight existing cases [RR=2.64, 95 percent CI, 1.31-5.29].

However, for mothers with a history of mental illness in the family, there was no evidence that exposure to death in the first trimester increased the risk of schizophrenia, according to the researchers—although this finding had limited statistical power due to the small number of cases examined.

The authors noted that all relatives of mothers could not be traced for the study. Researchers were unable to trace mothers to their parents if the mothers had left home before 1968, and as a result, 49 percent of the mothers in the sample had missing links to at least one relative, mainly one of their parents.

Another limitation of the study was that the researchers could not analyze gender differences in schizophrenia risk due to the small numbers of exposed mothers and offspring who developed schizophrenia.

According to the report, a number of biological mechanisms stem from the stress response after a close relative dies that could elevate the risk of developing schizophrenia in the offspring of mothers exposed to the death of a close relative in early pregnancy.

For instance, a number of systems work together to form a" feto-placental" barrier to protect the developing brain of the fetus against the effects of maternal stress. During pregnancy, these include 11ß-hydroxysteroid hydrogenase, an enzyme that breaks down maternal glucocorticoids and increasing levels of maternal corticotrophin-releasing hormone binding protein, which inactivates the maternal corticotrophin-releasing hormone, for instance. Other evidence shows that during late pregnancy, maternal hypothalamic pituitary-adrenal axis responses are blunted.

"These factors suggest that very early in pregnancy, during a most critical phase of neurodevelopment, the fetal brain may be more vulnerable to the physiological effects of stress than later in pregnancy," the report stated.

Kathryn Abel, M.D., a co-author of the report, told Psychiatric News that even though the team controlled for gender, maternal age, family history, and whether the mother gave birth in an urban or rural setting, there may be other factors not measured that may confound the results, such as socioeconomic status of the mother.

Abel is an associate professor of psychiatry at the University of Manchester and director of research at the Centre for Women's Mental Health Research at the university.

Abel said she plans to replicate the study in Sweden, which has a larger population.

In the follow-up study, she and her colleagues plan on controlling for socioeconomic status, protective factors, and "possible mechanisms between maternal stress and fetal growth restrictions," Abel said.

The study was funded by the Tommy the Baby's Charity and the Stanley Medical Research Institute.

An abstract of "Higher Risk of Offspring Schizophrenia Following Antenatal Maternal Exposure to Severe Adverse Life Events" is posted at<archpsyc.ama-assn.org/cgi/content/abstract/65/2/146>.▪