Prolonged Fever During Pregnancy May Increase Autism Risk

Pam Harrison

November 13, 2012

Fever lasting longer than 1 week may increase the risk for infantile autism, a large population-based study suggests.

Hjördis Ósk Atladóttir, MD, PhD, University of Aarhus, Denmark, and colleagues found that children whose mothers had a fever lasting longer than 1 week before gestational week 32 had about a 3-fold increased risk of being diagnosed with infantile autism.

In addition, children whose mothers reported influenza infection during pregnancy had about twice the risk of being diagnosed with infantile autism.

In contrast, influenza infection was not associated with the diagnosis of autism spectrum disorder (ASD).

There also appeared to be a small increased risk for ASD and infantile autism among children whose mothers used certain antibiotics during pregnancy, although this finding might have been due to chance alone.

"We found no association between ASD and mild maternal infections, such as respiratory infection, urinary tract infection, or genital infection," Dr. Atladóttir told Medscape Medical News.

"But we are suggesting that maternal influenza infection and prolonged episodes of fever as well as the use of various antibiotics during pregnancy are potentially weak risk factors for ASD and infantile autism," he added.

The study was published online on November 12 in Pediatrics.

Maternal Immune Activation

Outside of the United States, the term "infantile autism" roughly corresponds to autism spectrum disorder (ASD), the umbrella term used in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, that covers 3 different subtypes of ASD.

In the current study, investigators separated out infants with infantile autism and ASD.

Researchers speculate that maternal immune activation during pregnancy may disrupt fetal neurodevelopment. Infectious disease is the most common path to maternal immune activation during pregnancy.

The study included 96,736 children from the Danish National Birth Cohort (DNBC). Exposure data were collected by telephone interviews with the mother at an average gestational age of 17 weeks and 32 weeks and then 6 months after the birth of the child.

Diagnoses of ASD were identified in the Danish Psychiatric Central Register.

A total of 976 DNBC children were diagnosed with ASD (1%); 342 had infantile autism (0.4%).

Following maternal influenza infection, the hazard ratio (HR) for infantile autism was 2.3. Following a prolonged febrile episode, the HR for infantile autism was 3.2.

There was also a small increased risk for both ASD and infantile autism after the use of both macrolides and sulfonamides anytime during pregnancy, as well as the use of penicillin during the second and third trimesters.

Table. Hazard Ratios of Offspring Being Diagnosed With ASD or Infantile Autism After Febrile Episode During Pregnancy

  First Trimester Second Trimester Third Trimester
  ASD/Infantile Autism ASD/Infantile Autism ASD/Infantile Autism
Febrile episode ≥ 7 days 1.6/2.9 1.8/4.2 Not estimated because of incomplete data



The Childhood Autism Risks from Genetics and Environment (CHARGE) study, which was published earlier this year and reported by Medscape Medical News at that time, also showed that fever during pregnancy was associated with a 2-fold increased risk for ASD or developmental delay in offspring.

However, CHARGE did not identify any association between influenza infection during pregnancy and ASD or developmental delay.

Dr. Atladóttir suggested that his group's findings partially confirm results from CHARGE with respect to fever during pregnancy.

"We really don't know why we only find an association between prolonged fever and ASD," said Dr. Atladóttir. "It could be the effect of accumulated inflammatory response in the mother, but this is still speculative."

He did add, however, that the fact that 2 independent studies have found an association between fever and autism suggests that there might be some truth to the findings.

"This topic is definitely worth further study," he said.

Positive Signal

Ousseny Zerbo, PhD, lead author of the CHARGE study and now a postdoctoral researcher with the Kaiser Permanente Northern California Division of Research, in Oakland, California, agreed that this study supports the finding that fever during pregnancy can increase ASD risk.

"But you have to look at fever in the broader scope of inflammation because inflammation is related to the immune system, so we need to look more closely at immune dysregulation in mothers as it relates to autism," Dr. Zerbo told Medscape Medical News.

Colleen Boyle, PhD, National Center on Birth Defects and Development Disabilities (NCBDDD), as well as Marshalyn Yeargin-Allsopp, MD, also at the NCBDDD, told Medscape Medical News that the important message from this study is how mothers may protect their infants from negative health consequences during pregnancy.

"We know that there are adverse consequences for the mother and the child due to influenza during pregnancy, and women who are pregnant now should get their annual flu shot because it not only protects mothers from getting influenza; studies show that mothers who receive the influenza shot while pregnant also decrease the infant's risk of illness as well."

The study was funded by the Aarhus University Research Foundation, the Aase and Ejnar Danielsen Foundation, and the Augustinus Foundation. The authors have disclosed no relevant financial relationships.

Pediatrics. Published online November 12, 2012. Abstract