Link between herpes in pregnancy and autism is unconfirmed

"'WOMEN infected with herpes while they are pregnant are twice as likely to have a child with autism', " The Sun reports.

The headline is prompted by a study looking at whether maternal infections during pregnancy are associated with the risk of neurological developmental disorders such as autism spectrum disorders (ASDs).

However, The Sun has focused on only one result of a much larger set of findings – none of which were able to confirm the association between maternal infections and autism in children.

The Norwegian study looked at levels of antibodies to several viruses in pregnant women, collecting samples at 18 weeks during pregnancy and after delivery. These antibodies would indicate current or previous infection or immunity following vaccination. They then followed up whether any of the women had children later diagnosed with autism.

It looked at levels of antibodies to the herpes "family" of viruses (HSV-1 and HSV-2), as well as rubella, toxoplasma gondii and cytomegalovirus (a common virus related to chickenpox).

The study initially found no association between any of the levels of antibodies during pregnancy or after delivery, and the development of ASD in boys or girls. When they performed numerous additional analyses, they found that high levels of antibodies to the HSV-2 virus during mid-pregnancy were associated with the development of ASD in boys. However, this was based on just 14 women so it not reliable.

While it is recommended to avoid the herpes virus during pregnancy due to the risks of complications, based on this evidence, autism is not one of these.

Where did the story come from?

The study was carried out by researchers from the US and Norway including Columbia University and the University of Oslo. It was funded by grants from the National Institutes of Health, the Jane Botsford Johnson Foundation, the Simons Foundation Autism Research Initiative, the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research and the Research Council of Norway.

The study was published in the peer-reviewed journal mSphere on an open-access basis, so the study is free to read online.

Both The Sun and the Mail Online are arguably guilty of scaremongering and inaccuracy in their reporting of the study. They did not point out any of the limitations of the study, in particular that the results are based on such a small number of women that they could have been down to chance.

In contrast, CNN provides useful contrasting opinions from independent experts. Its coverage includes a quote from Dr David Winston Kimberlin, a professor of paediatric infectious diseases, who says "pregnant women should not be worried about HSV-2 (genital herpes) as a cause of autism based upon the findings of this single exploratory research study".

What kind of research was this?

This was a case-control study that wanted to look at whether maternal infections during pregnancy are associated with the risk of neurological developmental disorders such as autism spectrum disorders (ASDs).

Autism spectrum disorders are characterised by various degrees of social impairment and deficits in language and communication. The development of the condition is not well understood, but both genetic and environmental factors are thought to play a role.

Infections during pregnancy have been suggested to be a risk factor for the development of several neurological disorders such as ASD in the offspring and this study wanted to explore this hypothesis further. It hoped to understand more about disease severity and whether that was dependent on the time of infection during pregnancy.

Case-control studies are a useful way of better understanding potential links between exposure and outcome for uncommon conditions. However, the study design means that they are more prone to bias so it's important to bear in mind that other factors may have a role to play in the suspected causal relationship.

What did the research involve?

This study used data collected as part of the Norwegian Mother and Child Cohort Study, which recruited pregnant mothers, fathers and their children in Norway from 1999 to 2008. The study collected maternal blood samples during week 18 of pregnancy and after delivery. Questionnaires on a variety of health outcomes and conditions were sent to the mothers when their children were three, five and seven.

This Autism Birth Cohort study used data on 442 mothers of children who reported in the questionnaires that their child had been diagnosed with ASD and 464 matched controls (mothers of children without ASD). The controls were matched based on sex, birth month and birth year.

Maternal blood samples had been analysed for levels of immunoglobulin G (IgG) antibodies to Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1) and HSV-2. If the IgG antibodies were present, this would indicate that the mother had been infected with the virus at some point in her life. Higher levels or rising levels would suggest current infection or reactivation of the virus. The researchers were able to assess this by comparing the test taken mid-pregnancy with post-pregnancy.

The data was then analysed to see whether there were any links between high levels of infection and the development of ASD in the children. External confounding factors were controlled for including: maternal age at delivery, maternal smoking during pregnancy, parity (number of births) and maternal education.

What were the basic results?

Mothers of children with ASD were more likely to be first-time mothers. Most women in each group had antibodies to rubella because of the vaccination programme. Around half of women in each group had antibodies to HSV-1 and CMV. Fewer had antibodies to Toxoplasma (10% of mothers in each group) or HSV-2 (12% in the control group and 13% in the ASD group).

The planned series of tests found no significant differences in the presence of any of the antibodies either during mid-pregnancy or after delivery and subsequent diagnosis of ASD in boys or girls.

The researchers then performed a number of additional unplanned analyses looking at the levels of antibodies to HSV-2 and risk of ASD. When they used a high cut-off level to suggest current infection during mid-pregnancy, they found that boys were more likely to get ASD (odds ratio 2.07, 95% confidence interval 1.06 to 4.06). However, this was based on around 10 women in the ASD group and four in the control group who had "high" levels of 640AU/ml or more (precise figures not provided, our estimates are based on graphs).

With such a small sample group any association could well have been the result of chance.

How did the researchers interpret the results?

The researchers concluded: "This is the first study to report an association between maternal anti-HSV-2 antibody levels and risk of ASD in offspring. Our data suggest that the presence of high levels of anti-HSV-2 antibodies at mid-pregnancy increases the risk of ASD in boys.

"We speculate that 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."

Conclusion

This was a Norwegian case-control study that looked at whether maternal infections during pregnancy are associated with the risk of neurological developmental disorders such as autism spectrum disorders (ASDs) in their children.

The study initially found no association between any of the pathogens during pregnancy or after delivery, and the development of ASD in boys or girls.

Further investigations suggested that high levels of HSV-2 virus antibodies during mid-pregnancy were associated with increased risk of the development of ASD in boys.

The researchers suggest that the suspected risk of ASD associated with high levels of virus is not down to the HSV-2 virus itself but the impact of inflammation and the subsequent activation of the immune system on child development during pregnancy

However, while this finding has been widely reported in the media, it is based on just 14 women so is not reliable. Performing repeated unplanned analyses is bound to come up with some association in the end through sheer chance.

It is important that pregnant women do take precautions to prevent herpes infection during pregnancy, especially the third trimester, as there is a risk of passing the virus on to the baby.

More research would be needed to confirm the speculations that herpes infection during pregnancy can increase the risk of autistic spectrum disorder.