Study hints at link between flu in pregnancy, infant autism

Nov 13, 2012 (CIDRAP News) – An epidemiologic study from Denmark has raised the possibility that influenza and fever during pregnancy increase the risk of autism in infants, but the findings are far from conclusive.

The researchers studied the records of more than 96,000 children and interviewed their mothers about infections during pregnancy. About 1% of those children had autism spectrum disorder (ASD) or infantile autism. The researchers found signs that flu during pregnancy doubled the risk of infantile autism and that prolonged fever during pregnancy tripled it.

But because they assessed so many pregnancy-related variables, they said those findings could have shown up merely by chance, and much more research is needed. Their report was published online yesterday by Pediatrics.

Clue from animal studies
Evidence from animal studies suggests that activation of the immune system during pregnancy can cause problems with brain development in fetuses, the report says. Hence the research team set out to assess whether common infections, febrile episodes, or use of antibiotics during pregnancy were associated with a risk of ASD or autism in babies.

Using the Danish national birth cohort and the Danish Psychiatric Central Register, the team examined data on 96,736 children born from 1997 to 2003. In telephone interviews they questioned the children's mothers about infections, febrile episodes, and antibiotic use during pregnancy and the early postpartum period. The questions covered 11 types of infections and symptoms and five classes of antibiotics.

The team found that 976 (1%) of the children had ASD, including 342 (0.4%) with infantile autism.

The researchers found no significant associations between overall ASD and specific types of infections. But when they looked at infantile autism only, they found that flu during pregnancy was associated with a 2.3-fold increase in risk (adjusted hazard ratio, 2.3; 95% confidence interval [CI], 1.0 to 5.3).

Similarly, febrile episodes in general were not associated with any increase in risk of ASD or autism. But febrile episodes longer than 7 days were associated with a 1.6-fold increase in the risk of ASD (95% CI, 1.0 to 2.5) and a 3.2-fold jump in the risk of infantile autism (95% CI, 1.8 to 5.6).

The analysis also linked the use of various antibiotics during pregnancy with a small increase in risk of ASD or infantile autism. The use of sulfonamides or penicillin raised the risk by about 50%, and the use of macrolides increased the risk of infantile autism 2.2-fold (95% CI, 1.1 to 4.4).

A major qualifier
But the researchers take pains to explain that these hints of associations could be pure chance findings rather than evidence of a real connection.

"A great limitation of this study is that we made 106 adjusted comparisons; thus, the few statistically significant associations observed could be chance findings," they state. "The study is explorative, and we thus made no adjustments for multiple testing."

In fact, they add, "None of the statistically significant findings would have survived any correction for multiple comparisons."

Their overall conclusion is that there was little evidence that self-reported common infections during pregnancy are risk factors for ASD in children. On the other hand, the findings alone do not rule out a possible association. "We emphasize the need for further research on this important topic," the report concludes.

Andrew T. Pavia, MD, chief of the Division of Pediatric Infectious Diseases at the University of Utah, agreed with the authors' caveats about their findings.

"This is an interesting study, but at best exploratory," Pavia commented by e-mail. "In addition to being exploratory, the major limitation is statistical. As the authors point out, the associations they found were just marginally statistically significant in the way they approached the analysis, meaning there would be about a 5% chance of finding an association by chance alone when there was in fact no association."

Pavia said the problem of multiple comparisons makes the findings "relatively unreliable," although the topic deserves more research.

"In essence the problem of multiple comparisons is that if you look at 20 random variables (cystitis, penicillin, herpes outbreaks, etc) then on average you will find one association by chance alone with a 'statistically significant' P value of 0.05," he said. "The authors looked at 106 variables, which suggested that on average they would find 5 significant associations that were due to chance alone. They found about that [many]."

He added that the relatively wide confidence intervals noted in the findings, with lower limits as low as 1.0, support the possibility that they could have occurred by chance.

Pavia also commented, "This type of epidemiological study may eventually point us in the right direction, but no single study can be taken alone. This is analogous to some of the studies of heart disease and diet, where depending on the study and the methods, a given food may or may not appear to be associated with disease. Epidemiologists understand this, but when the public hears about each study with a weak effect, it becomes pretty chaotic."

Atladottir HO, Henriksen TB, Schendel DE, et al. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics 2012 December; 130(6) (Early online publication Nov 12) [Abstract]

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