April 16, 1999

While a history of schizophrenia in a person's family is the strongest link to the risk of developing that disorder, a large new study of the Danish population has uncovered evidence that the month and location of a person's birth may also be risk factors.

Preben Bo Mortensen, D.M.Sc., and colleagues at the Institute for Basic Psychiatric Research at Aarhus University Hospital in Risskov, Denmark, and the Statens Serum Institut in Copenhagen studied 1.75 million persons whose mothers were born from 1935 to 1978.

Denmark's Civil Registration System, which assigns everyone born in or immigrating to Denmark a unique identification number, allows researchers to have access to data on the entire Danish population as does the Danish Psychiatric Central Register, both of which served as the data sources for this study. The latter contains data on about 340,000 persons who have been admitted to Danish psychiatric hospitals.

The results of the study, reported in the February 25 New England Journal of Medicine, show that individuals born in highly urbanized areas and those born in February and March were at greater risk of developing schizophrenia. An urban place of birth contributed greater risk than did late winter birth.

Both of these factors still contributed less risk than did having a parent or sibling with schizophrenia; having a mother with the disorder conferring more risk than having a father so diagnosed.

Having an urban place of birth was the strongest risk factor after familial links. Compared with Danes born in rural areas, the researchers found that individuals born in Copenhagen had a greater relative risk of developing schizophrenia than did persons born in provincial cities with more than 100,000 inhabitants or in Copenhagen suburbs. Again compared with persons of rural birth, the group from cities with more than 100,000 inhabitants was in turn at greater risk than those born in towns with populations of 10,000 or more.

Mortensen and his colleagues suggested that one possible explanation for the finding lies in "increased exposure to infections during pregnancy and childhood because of more crowded living conditions or more perinatal complications in urban areas." They hypothesized as well that perhaps people with an "unexpressed genetic predisposition for schizophrenia are more likely to migrate to urban areas," but they added that "a family history of schizophrenia does not explain or affect the urban-rural differences we observed."

Though less strongly associated with schizophrenia than was urbanization, birth month also conferred modestly increased risk in this study. Children born in early March had a schizophrenia risk that was 1.1 times the risk for those born in early June or early December, the researchers found. Overall, being born in August or September contributed the least degree of risk. There was no interaction between birth month and family history of schizophrenia.

The researchers suggested that "place and season of birth must be seen as proxy variables for factors that contribute more directly to the risk of schizophrenia." Their attributable risk estimates for location and birth month "do not exclude the possibility that genetic factors are necessary causes of schizophrenia in most or all cases. They do, however, suggest that such factors are not sufficient and that environmental factors are major determinants of schizophrenia."

In an accompanying editorial, psychiatric researcher Nancy Andreasen, M.D., Ph.D., points out that "schizophrenia probably occurs as a consequence of multiple 'hits,' which include some combination of inherited genetic factors and external, nongenetic factors that affect the regulation and expression of genes governing brain function or that injure the brain directly." She noted that in some individuals with a genetic predisposition to schizophrenia, the presence of additional factors might be necessary to trigger the onset of the disorder.

In addition to the consequences of urbanization suggested by the Danish researchers, "possible nongenetic factors contributing to increased risk include the effects of poor nutrition on fetal and childhood brain development, exposure to toxins that damage neurons or affect neurotransmitter systems (e.g., alcohol, amphetamines, and retinoids), and exposure to radiation that might induce mutations," explained Andreasen, who is editor of the American Journal of Psychiatry.

She pointed out that as researchers "identify more precisely the cascade of events leading to schizophrenia-neurodevelopmental abnormalities that lead to neural misconnections that lead, in turn, to impaired cognitive processing-we will also identify better and more specific targets for future treatment."