HSV-2 gestational infection and offspring autism risk

"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."

That was the conclusion reached in the paper published by Milada Mahic and colleagues [1] including the research tag-team that is Mady Hornig and Ian 'virus hunter' Lipkin in the list of contributing authors. Having already received some media attention (see here), it doesn't need much more from me but I do want to include a few details and relevant points in this blog entry.

So, the Autism Birth Cohort was the starting point, and "442 mothers of children with ASD... and 464 frequency-matched controls" who all provided plasma samples "(903 samples acquired at midpregnancy and 878 acquired after delivery)." Said samples were analysed for IgG antibodies to ToRCH agents: "Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses 1 (HSV-1) and 2 (HSV-2)." Some of those viruses and parasites have previously been mentioned with [some] autism in mind (see here and see here and see here).

Results: well, an important detail first: "Because rubella vaccination is part of the routine child vaccination schedule in Norway, almost all individuals had IgG antibodies to rubella virus." Indeed, other authors have speculated that rubella vaccination has actually "prevented substantial numbers" of autism as a knock-on effect of reducing the numbers of cases of congenital rubella syndrome [2]. Vaccination doing more than just saving lives eh?

Next: "Our data suggest that the presence of high levels of anti-HSV-2 antibodies at midpregnancy increases the risk of ASD [autism spectrum disorder] in boys." The authors complemented this finding by some rather neat statistical wizardry whereby odds ratios were calculated based on "four different anti-HSV-2 reference levels (60, 120, 180, and 240 arbitrary units [AU]/ml)." Having said that: "High levels of antibodies, which are typically indicative of recent infection, were found in only a small number of subjects." They also reported "no statistically significant association with risk was found with high levels of HSV-2 antibodies at delivery" and saw nothing significant when it came to the other infections examined. These important points have been picked up in the NHS Choices entry on this study (see here).

These are interesting findings and, as far as I can see, represent something quite novel to the quite vast autism research landscape (assuming you count maternal HSV-2 levels and not antibody levels in actual people diagnosed with autism). The reliance on data from an initiative like the Autism Birth Cohort ensured some rigour in terms of the diagnosis of autism [3] and with the reputations following Drs Hornig and Lipkin, one would have to be pretty brave to question their virus-hunting credentials also with autism in mind [4].

Then to the million-dollar question: how might elevated HSV-2 antibodies during pregnancy affect offspring risk of autism? There is a familiar theme offered by the authors to this question as per statements like: "ASD risk associated with high levels of antibodies to HSV-2 is not specific to HSV-2 but instead reflects the impact of immune activation and inflammation on a vulnerable developing nervous system." I know some people still have a bit of a problem with the idea that something like maternal immune activation (MIA) might up the risk for various offspring outcomes [hint: if an article contains the word 'truth' in the title, step away] but please, stop with the 'it can never happen' generalisations and instead look to the existing peer-reviewed evidence on the topic [5]. Yes, science needs to do more on the topic of MIA and autism but clues are emerging all the time...

Oh, and I'll be coming to research talking about another member of the herpesviruses in relation to autism quite soon on this blog.

To close, operation hardtack and other videos (best viewed in full-screen mode).

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[1] Mahic M. et al. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere. 2017. Feb 22.

[2] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination - United States, 2001-2010. BMC Public Health. 2011; 11: 340.

[3] Stoltenberg C. et al. The Autism Birth Cohort (ABC): A Paradigm For Gene-Environment-Timing Research. Molecular Psychiatry. 2010;15(7):676-680.

[4] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.

[5] Careaga M. et al.  Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry. 2017 Mar 1;81(5):391-401.

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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, & W. Ian Lipkin (2017). Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere : 10.1128/mSphere.00016-17