Prenatal Exposure to Antiepileptic Linked to Autism

Caroline Cassels

February 01, 2013

Prenatal exposure to valproate (VPA), an antiepileptic drug (AED) that has previously been linked to major congenital malformations and lower IQ in children, has now been linked to an increased risk for autism spectrum disorders (ASD), new research suggests.

The final results of an 11-year longitudinal study conducted by investigators at the University of Liverpool in the United Kingdom showed that in addition to ASD, VPA was linked to an increased risk for other neurodevelopmental disorders when taken as monotherapy or in combination with other drugs.

"The most common neurodevelopmental disorder at 6 years of age for VPA exposed children was ASD," the authors, led by Rebecca Bromley, PhD, write.

The study was published online January 31 in the Journal of Neurology, Neurosurgery and Psychiatry.

First Prospective Look at Autism

It is well established that prenatal exposure to the majority of AEDs is associated with major congenital malformations in a dose-dependent manner. However, results from the well-known Neurodevelopmental Exposure to Antiepileptic Drugs (NEAD) study have shown a robust association between prenatal VPA and reduced cognitive function in children, most recently, reductions in IQ.

Dr. Kimford Meador

In January, Kimford J. Meador, MD, and colleagues published 6-year outcomes of NEAD. As reported by Medscape Medical News at that time, the findings showed that prenatal exposure to VPA was linked to a 7- to 10-point reduction in IQ at age 6 years.

In the current study, Dr. Bromley and colleagues note that results from studies such as NEAD have "increased concern about the longer term influences of prenatal exposure to AEDs."

They add that animal studies, as well as retrospective research in humans, point to an increased risk for ASD with AEDs. However, the researchers note, the current study is the first prospective research to examine this link.

They also point out that previous research in humans suggests that neurodevelopmental disorders are more prevalent in children exposed to VPA. Other research has implicated prenatal exposure to the AED carbamazepine (CBZ) to ASD, although to a lesser extent than VPA. However, they add, the question remains as to whether prenatal exposure to AEDs is associated with an increased likelihood of neurodevelopmental disorders.

To compare the prevalence of diagnosed neurodevelopmental disorders in children prenatally exposed to different AEDs, the investigators conducted a prospective, longitudinal cohort study of pregnant women, both with and without epilepsy. The children of this cohort were followed longitudinally until age 6 years.

Informed Consent

The study included 415 children (214 control participants and 201 children born to women with epilepsy) born between 2000 and 2004 in the northwest of England and followed until age 6 years. The children's physical and intellectual development was assessed at 12 months, 3 years, and 6 years.

Of 528 women included in the study, 243 had epilepsy. Of this group, all but 34 took AEDs during pregnancy. A total of 59 took CBZ; 59 took VPA; 36 took lamotrigine (LTG); 41 took a combination of AEDs; and 15 took other drugs.

At 6 years of age, 19 children in the entire cohort had a diagnosis of a neurodevelopmental disorder. Of these, 12 were diagnosed with ASD, and of these, 1 had a diagnosis of ASD and attention-deficit/hyperactivity disorder (ADHD). Three children had ADHD only, and the 4 remaining children had a diagnosis of dyspraxia.

Among the 19 children with a diagnosis of neurodevelopmental disorders, 3 had physical malformations, and all of these children had been exposed to AEDs in utero.

Neurodevelopmental problems were significantly more common among children born to women with epilepsy compared with control participants — 7.46% vs 1.87%.

Children exposed to VPA in utero, either as monotherapy (6/50 [12.0%]; adjusted odds ratio [aOR], 6.05; 95% confidence interval [CI], 1.65 - 24.53; P = .007) or in combination with other drugs (3/20 [15.0%]; aOR, 9.97; 95% CI, 1.82 - 49.40; P = .005) were significantly more likely to have a diagnosis of a neurodevelopmental disorder compared with control children (4/214 [1.87%]).

ASD was the most frequent diagnosis. Investigators found no significant increase of ASD among children exposed to CBZ (1/50) or LTG (2/30).

"A 6 or 10 times increased prevalence of neurodevelopmental disorders is reported here for children with a history of prenatal VPA exposure respectively for monotherapy and polytherapy exposure. The most common neurodevelopmental disorder at 6 years of age for VPA exposed children was ASD," the authors write.

"If VPA is the treatment of choice, women should be provided with as much information as possible to enable them to make an informed decision. This should take place prior to conception as the evidence suggests that the neuropathology of ASD develops early in gestation," Dr. Bromley and colleagues add.

MDs Not Getting the Message

Asked to comment on the findings by Medscape Medical News, Dr. Meador, from Emory University in Atlanta, Georgia, who was principal investigator of the NEAD study, agreed that women of childbearing potential need to be better educated about the risks for AEDs, particularly VPA.

According to Dr. Meador, one the study's main strengths is its prospective nature, and although it included a relatively small number of participants, Dr. Meador said the findings do indicate a link between autism and VPA, providing clinicians with "another piece of information that fetal valproate exposure is detrimental across a range of cognitive and behavioral outcomes in children."

Although reports of the potential teratogenic effects of AEDs have been in the published literature for more than a decade, Dr. Meador said that in his experience, physician uptake of this information has been slow. The data suggest that outside of tertiary care centers, VPA is still widely prescribed in women of childbearing age.

"Despite all this tremendous evidence for malformations and other neurodevelopmental problems, including cognitive difficulties, and now autism, where the strength of the evidence is increasing, there is still a lot of this drug being used. The findings from this study add to the concerns about prescribing valproate as first-line therapy, especially in women of childbearing potential," said Dr. Meador.

He also pointed out that the majority of AED prescriptions are not for epilepsy. "Less than half of the prescriptions in the United States of antiepileptic drugs are for seizures or epilepsy. The majority are for psychiatric and pain indications."

"VPA is very effective drug for a variety of disorders; it is also a very dangerous drug for the unborn child. If a woman comes out of a doctor's office with a prescription for valproate and she doesn't know about its risks, then someone didn't do their job of providing adequate informed consent. I think we may have to improve the education of women so they can be their own advocates in this regard," he added.

The authors and Dr. Meador have disclosed no relevant financial relationships.

J Neurol Neurosurg Psychiatry. Published online January 31, 2013.Abstract