title: Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring.
abstract: 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 toToxoplasma 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 toToxoplasma 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.IMPORTANCEThe 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.
authors.affiliation: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA; Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Milada
authors.initials: M
authors.lastname: Mahic
authors.affiliation: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA; Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Siri
authors.initials: S
authors.lastname: Mjaaland
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Hege Marie
authors.initials: HM
authors.lastname: Bøvelstad
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Nina
authors.initials: N
authors.lastname: Gunnes
authors.affiliation: Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA; New York State Psychiatric Institute, Columbia University, New York, New York, USA.
authors.forename: Ezra
authors.initials: E
authors.lastname: Susser
authors.affiliation: Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA; New York State Psychiatric Institute, Columbia University, New York, New York, USA.
authors.forename: Michaeline
authors.initials: M
authors.lastname: Bresnahan
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway; Nic Waals Institute, Lovisenberg Hospital, Oslo, Norway.
authors.forename: Anne-Siri
authors.initials: AS
authors.lastname: Øyen
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Levin
authors.affiliation: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Che
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hirtz
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ted
authors.initials: T
authors.lastname: Reichborn-Kjennerud
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Synnve
authors.initials: S
authors.lastname: Schjølberg
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway; Nic Waals Institute, Lovisenberg Hospital, Oslo, Norway.
authors.forename: Christine
authors.initials: C
authors.lastname: Roth
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Per
authors.initials: P
authors.lastname: Magnus
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway; Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Stoltenberg
authors.affiliation: Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Surén
authors.affiliation: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
authors.forename: Mady
authors.initials: M
authors.lastname: Hornig
authors.affiliation: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
authors.forename: W Ian
authors.initials: WI
authors.lastname: Lipkin
keywords: autism; birth cohort; herpes simplex virus; infection; prenatal; serology