Second Trimester Fevers Increase Autism Risks 40%

A new study finds that fevers in pregnant women during the second trimester increase the risk of a child with autism by 40%. The magnitude of this effect closely matches estimates from previous independent studies. The sample size is 95,000 (which is just barely big enough to measure these effects), while most other fevers are not as definitvely associated with autism risk.

The link is strongest in the second trimester, when a single fever is associated with a 40 percent increase in autism risk. Three or more fevers after the first trimester triples the risk of having a child with autism, according to the study, which appeared 13 June in Molecular Psychiatry. 

The findings support the idea that a pregnant woman’s immune response, which often includes fever, can disrupt brain development in the fetus, says lead researcher Mady Hornig, associate professor epidemiology at the Columbia University. 

The study is inconclusive on whether drugs that lower fever mitigate the risk, but the results hint that they might, says Sarkis Mazmanian, professor of biology at the 

California Institute of Technology. . . .

15,701 of the mothers reported on a health questionnaire that they’d had one or more fevers while pregnant. The team followed all of the participants’ children until they reached age 9, on average, and found that 583 received an autism diagnosis.

The timing of the fever matters for autism risk, the researchers found. Compared with the 40 percent increase in the second trimester, having a fever in the first trimester carries a 34 percent increase in the risk of autism, but that result is not statistically significant. Having a fever in the third semester has no effect on autism risk.

The researchers also found a dose-response relationship for fever: The increase in risk ranges from 30 percent throughout pregnancy for one or two episodes of fever, to more than threefold for three or more episodes in the second trimester and beyond.

Still, the vast majority of women who have a fever during pregnancy do not have a child with autism and the absolute increase in risk is small. Even among mothers who had three or more fevers, only 5 out of 308 children (about 1.6 percent) have autism, compared with 376 of 65,502 children (about 0.6 percent) whose mothers reported no fevers. . . .

Hornig’s team examined whether medications that lower body temperature would reduce the risk. More than 5,600 women took acetaminophen for fever during their second trimester. The team found an association between acetaminophen use and a decrease in autism risk, but it was not statistically significant. Only 161 women took ibuprofen during the second trimester, and none of them have a child with autism. (About half of pregnant women use acetaminophen at least once, but doctors generally advise against ibuprofen use during pregnancy.) . . .

A 2013 study led by Hertz-Picciotto found that drugs that lower fever mitigate the increase in autism risk associated with fever. 

The mechanism for fevers to cause autism in a fetus might include autoimmune responses and/or inflammation (which aren't mutually exclusive - inflammation is one type of autoimmune response).

Autism has a strong genetic component, although it appears that a lot of the risk comes from de novo mutations that were not present in either of the parents when they were born. It also appears that women have protective genes that are absent in men that mitigate autism symptoms or prevent them from arising.

Baseline autism spectrum disorder risk is on the order of 1% of all births (comprising a large share of symptoms previously classified as cognitive developmental disorders not otherwise classified), so it is closer to 1.4% percent for pregnant women who have fevers in the second trimester (a scenario consistent with the notion that the anatomical systems that develop in this time period during gestation are the ones that are associated with autism).

But, if the 40% figure is to be applied on a case by case basis, rather than across the board (which isn't clear from the media report that I link) the concern may be much more of a concern in pregnancies where this is a high risk of autism (e.g. in cases where the father is middle aged or older, where there is a family history of sub-clinical autism-like personality traits, and where the fetus is male), than in pregnancies where no autism risk factors are present. 

On the other hand, if this is an across the board increase in risk, that does not interact with other risk factors, then second trimester fevers may be the main source of risk in otherwise low autism risk pregnancies, while it is a minor consideration relative to other risk factors in high autism risk pregnancies.

This is one of only a handful of well documented environmental causes of autism, which has a strong genetic component. Another is exposure of the parents to agricultural chemicals (before conception in the case of fathers and during gestation in the case of mothers).