Herpes simplex virus type 2 (HSV-2), the primary cause of the blistering genital disease that infects roughly one in five U.S. women of childbearing age, may play a role in autism, according to a new study. Active infection with the virus in early pregnancy doubles the chance that a male fetus will develop autism spectrum disorder (ASD) early in life, researchers have found in studying one large Norwegian population. The finding does not mean that all pregnant women with an active HSV-2 infection will give birth to autistic children, but that—in a subset of women thought to be genetically predisposed—the infection may be one of an unknown number of triggers for the condition.
“It’s a very important paper,” says Karen Jones, a behavioral neuroimmunologist at the University of California, Davis, who was not involved with study. “It’s also really important to remember that not every mom who has HSV-2 is going to have a kid with autism.”
Population studies in the United States and other high-income countries put the prevalence of ASD at 1% to 2%, with higher rates for men; the prevalence in U.S. boys is one in 42, or 2.4%. Using data from the Norway Autism Birth Cohort, the scientists—led by a team at Columbia University—identified 442 mothers of children with ASD and matched them with 464 mothers who gave birth to unaffected children of the same sex, in the same month and year, from 1999 to 2008. For all the women, blood samples were available from midpregnancy and the time of birth. The researchers tested the samples for antibodies to five microbes that are known to damage fetuses: Cytomegalovirus, Toxoplasma gondii, rubella, HSV-1, and HSV-2.
High levels of antibodies against HSV-2 from the blood drawn at midpregnancy—indicating an active maternal infection several weeks earlier—were associated with a doubled risk that a male baby would be diagnosed with ASD, the team reports today in mSphere. (There were too few female babies in the study to draw similar conclusions for girls.) The other four microbes did not have a similar effect.
Research increasingly suggests that ASD arises from a combination of genetic susceptibility and environmental triggers. It also suggests that this interaction happens in many cases during fetal life.
In the new paper, the researchers posit that a subgroup of women is genetically predisposed to develop intense immune responses to certain disease-causing organisms—like HSV-2—and that the inflammatory molecules and antibodies generated by the mother’s vigorous immune response cross the placenta and damage the fetal brain.
“We’re not saying that HSV-2 is responsible for infecting the [fetal] brain and causing autism,” stresses senior author Ian Lipkin, an infectious disease expert and epidemiologist at Columbia. Indeed, fetal infection with HSV-2 is so serious that it frequently leads to miscarriages or stillbirths. Rather, Lipkin suspects that HSV-2 is just one among many environmental insults that, when they arrive at a vulnerable point in fetal development in women predisposed to damaging reactions, may trigger ASD in the fetus. That idea comports with a body of previous work, like this Swedish study that found that the hospitalization of a woman for any kind of infection during pregnancy increased the risk of the baby developing ASD by 30%.
Some scientists are skeptical that inflammatory molecules alone could be responsible, in part because of the big changes in brain structure that arise in autistic children in the first 2 years of life, just as symptoms of ASD emerge. For instance, a study published in Nature last week documents abnormal overgrowth of the surface of the brain in 6- to 12-month-old babies who go on to be diagnosed with ASD.
“The changes in the architecture of the neocortex in the brains of kids with autism are so profound that it’s hard to imagine how an inflammatory response, even in utero, is going to cause that,” says Peter Hotez, a vaccine scientist and pediatrician at Baylor College of Medicine in Houston, Texas, who was not involved in the new study and who is the father of an autistic 24-year-old daughter.
Why exposure to the other four microbes during pregnancy didn’t trigger the same increased risk of ASD is one of the many mysteries that future studies will need to address. So is the question of whether female fetuses are similarly put at risk by HSV-2; answering that question will require studies on larger populations.