The first-trimester death of a mother's close relative may be associated with the child's eventual development of schizophrenia, according to a national registry.

The adjusted relative risk that a child would develop schizophrenia after age 10 was 1.67 (95% CI 1.02 to 2.73) when the mother's husband, parent, or other close relative of the mother died during the first trimester, found Preben Bo Mortensen, M.D., of the University of Aarhus, and colleagues.

But family members' deaths at other times did not increase the relative risk; nor did illness in the family at any point in pregnancy, the investigators reported in the February issue of the Archives of General Psychiatry.

They calculated that about 0.3% of all schizophrenia cases could be attributed to deaths of mothers' family members in early pregnancy. The researchers said theirs is the largest such study ever done with data on clearly defined and specifically timed severe maternal stress events.

Dr. Mortensen and colleagues examined records associated with 1.38 million Danish births from 1973 to 1995.

The country's national health registry allowed the researchers to check maternal records against those of close relatives, as well as tracking later diagnoses of schizophrenia among the offspring.

A total of 7,331 cases of schizophrenia developed in this population.

The researchers identified 21,987 mothers who lost a husband, parent, sibling, or another child from six months before conception through pregnancy. Another 14,206 mothers had close relatives diagnosed with cancer, heart attack, or stroke during this period.

Relative risks were calculated with the rate of schizophrenia in people whose mothers did not experience a family death or illness during the study period serving as the baseline. They were adjusted for calendar year, age, gender, place of birth, and maternal age.

Serious illness in the family did not significantly increase the risk that the unborn child would later develop schizophrenia.

Nor did a relative's death increase the risk when it occurred up to six months before conception or in the second or third trimester.

Family history of mental illness did not put offspring at greater risk of schizophrenia associated with severe maternal stress.

In fact, the risk of schizophrenia in offspring was higher when a mother suffering a close relative's death during the first trimester had no family history of mental illness (RR 2.64, 95% CI 1.31 to 5.29).

There was no significant increase in risk when women with a family history of mental illness had a close relative die during the first trimester (RR 1.87, 95% CI 0.70 to 4.99). But the researchers noted that only four cases fell into this category.

In sum, the researchers said, the effect of severe first-trimester maternal stress on schizophrenia in offspring "is independent of a range of factors known to influence risk of schizophrenia, such as offspring sex, age, family history of mental illness, place of birth, and maternal age."

They noted that their data on maternal family members were incomplete for mothers who left their parents' homes before 1968, about 49% of their sample. These women were different in some demographic respects from the other mothers in the study. But Dr. Mortensen and colleagues said sensitivity analyses indicated that the potential confounding effects were small or negligible.

Their study did not examine potential mechanisms directly. Dr. Mortensen and colleagues said that stress-induced increases in maternal corticotrophin-releasing hormone may affect neuronal development early in fetal gestation. They cited earlier research suggesting that a feto-placental barrier protects the fetus's developing brain from maternal stresses, but it is not fully functional until later in pregnancy.

The researchers pointed out that other maternal stressors might also have an impact on schizophrenia.

"Less catastrophic, more common events may also increase the risk of schizophrenia in offspring and that maternal stress in a broader sense may have a greater population impact," they wrote.