Summary: Researchers discover a link between genital herpes infections during pregnancy and an increased risk of autism in the offspring.
Source: Columbia University.
Women with signs of active genital herpes had twice the odds of giving birth to offspring with autism spectrum disorder.
Women actively infected with genital herpes during early pregnancy had twice the odds of giving birth to a child later diagnosed with autism spectrum disorder (ASD), according to a study by scientists at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health and the Norwegian Institute of Public Health.
The study is the first to provide immunological evidence on the role of gestational infection in autism, reporting an association between maternal anti-herpes simplex virus-2 (HSV-2) antibodies and risk for ASD in offspring. Results appear in mSphere, a journal of the American Society for Microbiology.
“We believe the mother’s immune response to HSV-2 could be disrupting fetal central nervous system development, raising risk for autism,” says lead author Milada Mahic, a post-doctoral research scientist with the Center for Infection and Immunity and the Norwegian Institute of Public Health.
The authors do not believe that the risk is due to direct infection of the fetus because such infections are typically fatal. Instead, they suggest that neurodevelopmental outcomes are due to primary or reactivation of infection in mothers with inflammation in close proximity to the womb.
About one in five American women carries HSV-2, also known as genital herpes, a highly contagious and lifelong infection usually spread through sex. After an initial outbreak, HSV-2 virus lives in nerve cells and is often inactive, with flare-ups occurring with diminishing frequency as the body builds up immunity to the virus.
The researchers sought to explore the link between maternal infection and risk for autism, focusing on five pathogens known collectively as ToRCH agents–Toxoplasma gondii, rubella virus, cytomegalovirus, and herpes simplex viruses type 1 and 2–to which exposure during pregnancy can lead to miscarriage and birth defects. They examined blood samples from 412 mothers of children diagnosed with ASD and 463 mothers of children without ASD enrolled in the Autism Birth Cohort (ABC) Study overseen by the Norwegian Institute of Public Health. Samples were taken at two time points–at around week 18 of pregnancy and at birth–and analyzed for levels of antibodies to each of the ToRCH agents.
They found high levels of antibodies to HSV-2, not any of the other agents, correlated with risk for ASD. This link was only evident in blood samples taken at a time point reflecting exposure during early pregnancy when the fetal nervous system undergoes rapid development, not at birth. The finding mirrors earlier epidemiological data indicating that activation of the maternal immune system during early-to-mid-pregnancy is associated with long-term developmental and behavioral problems in offspring.
In all, 13 percent of mothers in the study tested positive for anti-HSV-2 antibodies at mid-pregnancy. Of these, only 12 percent reported having HSV lesions before pregnancy or during the first trimester, a likely indication that most infections were asymptomatic.
The effect of anti-HSV-2 antibodies on risk for ASD was only seen in males, not females. But because the number of females with ASD in the ABC Study is small, the researchers say there is not enough evidence to conclude that the effect is sex-specific, although generally, autism is more common in males.
According to the authors, further study is needed to determine if screening and suppression of HSV-2 infection during pregnancy is needed.
“The cause or causes of most cases of autism are unknown,” says senior author W. Ian Lipkin, director of the Center for Infection and Immunity. “But evidence suggests a role for both genetic and environmental factors. Our work suggests that inflammation and immune activation may contribute to risk. Herpes simplex virus-2 could be one of any number of infectious agents involved.”
Co-authors include Siri Mjaaland at the Center for Infection and Immunity and Norwegian Institute of Public Health; Mady Hornig, Ezra Susser, Michaeline Bresnahan, Bruce Levin, and Xiaoyu Che at Columbia’s Mailman School; and Hege Marie Bøvelstad, Nina Gunnes, Anne-Siri Øyen, Ted Reichborn-Kjennerud, Synnve Scholberg, Per Magnus, Christine Roth, Camilla Stoltenberg, and Pål Surén at the Norwegian Institute of Public Health; and Deborah Hirtz at the U.S. National Institute of Neurological Disorders and Stroke.
Funding: The study was supported by grants from the National Institutes of Health (NS47537, NS086122), the Jane Botsford Johnson Foundation, Simons Foundation Autism Research Initiative, Norwegian Ministry of Health and Care Services, Norwegian Ministry of Education and Research, and the Research Council of Norway. The authors report no conflicts of interest.
Source: Tim Paul – Columbia University
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research “Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring” by Milada Mahic, Siri Mjaaland, Hege Marie Bøvelstad, Nina Gunnes, Ezra Susser, Michaeline Bresnahan, Anne-Siri Øyen, Bruce Levin, Xiaoyu Che, Deborah Hirtz, Ted Reichborn-Kjennerud, Synnve Schjølberg, Christine Roth, Per Magnus, Camilla Stoltenberg, Pål Surén, Mady Hornig, and W. Ian Lipkin in mSphere. Published online February 2017 doi:10.1128/mSphere.00016-17
Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring
Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; P = 0.03) when adjusted for parity and child’s birth year. No association was found between ASD and the presence of IgG antibodies to Toxoplasma gondii, rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections.
IMPORTANCE The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy.
“Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring” by Milada Mahic, Siri Mjaaland, Hege Marie Bøvelstad, Nina Gunnes, Ezra Susser, Michaeline Bresnahan, Anne-Siri Øyen, Bruce Levin, Xiaoyu Che, Deborah Hirtz, Ted Reichborn-Kjennerud, Synnve Schjølberg, Christine Roth, Per Magnus, Camilla Stoltenberg, Pål Surén, Mady Hornig, and W. Ian Lipkin in mSphere. Published online February 2017 doi:10.1128/mSphere.00016-17