During my first prenatal-care appointment, my obstetrician cautioned me to avoid the flu at all costs. Influenza has long been linked to severe illness and respiratory complications during pregnancy. But a recent animal study published in the Jan. 15 issue of Biological Psychiatry suggests that the flu also may indirectly lead to increased risk of schizophrenia in offspring.
Looking at environmental factors
Researchers are diligently searching for the gene or genes underlying schizophrenia, but despite having identified several “genes of interest” in the disorder, they haven’t yet found a genetic “smoking gun.”
“We know schizophrenia runs in families, and there are some genes that seem to increase risk. But most of those genes actually contribute only a very small percentages to the overall risk for the disorder,” says John Gilmore, director of the Center for Excellence in Community Mental Health at the University of North Carolina at Chapel Hill. “So we know that environmental factors also play an important role, and we’re trying to understand how genes and environment interact to increase the risk for schizophrenia.”
In 2004, Alan Brown, a psychiatrist and epidemiologist at the Columbia University Medical Center, examined archived blood sera, which documents exposure to the flu, from a large group of pregnant mothers. He and his colleagues found that the risk of schizophrenia increased threefold (from 1 in 100 to 3 in 100 births) if exposure occurred in the middle of pregnancy and seven times (from 1 in 100 to 7 in 100 births) if the mother was exposed in the first trimester.
“We hypothesize that having a flu infection with a related immune response can damage fetal development,” says Brown. “The idea is that the fetal brain is in a critical period of development and the mother’s immune response to the flu may alter that development in such a way to increase the risk of schizophrenia.”
Paul Patterson, a researcher at the California Institute of Technology, has found similar results in mice. His work suggests that a cytokine, or immune protein, called Interleukin-6 may be promoting altered fetal brain development. Cytokines also appear to play a role in the development of neurons.
“Interleukin-6 seems to be required and sufficient” to cause a chage, says Patterson. “We’re looking now to see whether it’s working on the placenta or in the brain itself—and how it’s working to cause the damage.”
Flu-related changes to the Rhesus brain
Gilmore, post-doctoral fellow Sarah Short and colleagues decided to look at potential changes in the brains of young Rhesus monkeys, an animal model closer to human than the mouse model. The group examined the brain scans of offspring when mothers were exposed to influenza one month prior to their expected due dates versus a group of animals whose mothers were not exposed to the virus. At one year of age, roughly equivalent to the toddler years in humans, brains of the offspring with exposed mothers showed significant differences, the group found.
“We used functional magnetic resonance imaging (fMRI) and saw that the flu-exposed offspring had smaller overall brain volume, specifically related to gray matter, and increased volume in the lateral ventricles,” says Short. “In humans with schizophrenia, you see very similar brain characteristics.”
This and other evidence suggests that a mother’s immune response to the flu can result in permanent alterations to fetal brain development leading to schizophrenia. And it is possible that this effect could be related to any significant immune response—including one from a vaccine. But Brown, Patterson, and Gilmore all caution that there is still a lot more to learn about the maternal immune response and its effects to the fetal brain. Until those studies can be completed, Brown offers pregnant women practical advice.
“Moms shouldn’t be alarmed. Even if you get the flu or some other infection, the chances are far greater that your child won’t develop schizophrenia,” he says. “But if you are worried, just remember to follow hygienic precautions during pregnancy. Wash your hands, avoid individuals you know who have the flu, and so on. It sounds obvious and trivial, but most people don’t follow those basic rules.”