In a small 64-family sample, researchers found the risk of developing the major mental disorder in adult offspring rose seven-fold if the expectant mother had the flu during the first trimester.

If the virus struck between the midpoint of the pregnancy´s first trimester and the midpoint of the second, the risk rose three-fold. There was no increased risk if the flu occurred in the second half of the pregnancy.

"These findings represent the strongest evidence thus far that prenatal exposure to influenza plays a role in schizophrenia," said the study´s lead author, Ezra Susser of the New York State Psychiatric Institute.

In previous studies establishing a connection between flu in pregnant mothers and schizophrenia in their children, the link was seen in the second and third trimesters, the study said.

Unlike those studies, which used estimates of the peaks of flu outbreaks and mothers´ memories, this research examined preserved blood samples taken between 1959 and 1966. The research is part of a larger study of schizophrenia examining prenatal infection, nutrition, chemical exposure, paternal age and other factors.

Among the people in the study with schizophrenia, one quarter of their mothers had been exposed to influenza compared to one in 10 of the control subjects.

Schizophrenia is a general term referring to psychotic disorders that produce delusional or illogical thinking. Initial signs of the disease typically emerge in people in their teens or 20s.

The study suggested factors that could damage the fetal brain including the mother´s antibodies crossing the placenta and reacting with the fetus´ developing immune system, the presence of genetic material from the strain of influenza, and the mother´s elevated body temperature.

Over-the-counter flu remedies also might cause central nervous system problems, it said.

The study´s findings may raise questions about routine vaccinations of women because the antibodies generated could damage a fetus.

The study was published in the Archives of General Psychiatry.