Prenatal Valproate Exposure Linked to Autism

April 24, 2013

Maternal use of valproate during pregnancy was associated with a significantly increased risk for autism in offspring, even after adjustment for parental psychiatric disease and epilepsy, in a large Danish registry study.

The study, published in the April 24 issue of JAMA, was led by Jakob Christensen, PhD, Aarhus University Hospital, Denmark.

"Valproate is already not recommended in pregnancy because of the risk of malformations," Dr. Christensen told Medscape Medical News. "There has also been a recent study [showing] it may also be associated with low intelligence in children exposed during pregnancy, and now we have shown it may also increase the risk of autism. When you add all these together, it is definitely a drug you would want to avoid in pregnancy."

He added: "There must be a continuous effort to include this information along with all the other risks in discussions with women of childbearing age who are candidates for valproate."

Dr. Christensen noted that there have been case reports of autism associated with valproate use in pregnancy, and a few small studies have suggested a link, as have animal studies. "This is a larger study and we had a large comparator group of unexposed children, so we could adjust for certain risk factors."

3- to 5-Fold Increase in Risk

For the study, the researchers used data on all children born in Denmark between 1996 and 2006 identified from the Danish Civil Registration System. Information on valproate use in their mothers during pregnancy was obtained from the Danish Prescription Register. The Danish Psychiatric Central Register was used to identify children diagnosed for the first time with autism spectrum disorder and with childhood autism, and to identify parents diagnosed with psychiatric disorders before birth of the child.

Gestational age, birth weight, and parity information were obtained from the Danish Birth Register. The National Hospital Register was used to identify children diagnosed with congenital malformations and also to identify parents diagnosed with epilepsy before birth of the child.

Results showed that of 655,615 children born in the study period, 5437 had autism spectrum disorder, including 2067 with childhood autism. There were 2644 children exposed to antiepileptic drugs during pregnancy, 508 of whom were exposed to valproate.

Children exposed to valproate had a 3-fold increased risk for autism spectrum disorder and a 5-fold increased risk for profound childhood autism compared with unexposed children.

Table. Risk of Developing Autism With Valproate Exposure In Utero

Endpoint Valproate Exposure (%) No Valproate Exposure (%) Hazard Ratio (95% Confidence Interval)
Autism spectrum disorder 4.42 1.52 2.9 (1.7 - 4.9)
Childhood autism 2.50 0.48 5.2 (2.7 - 10.0)


Dr. Christensen commented, "We wanted to see if the risk of autism was associated with malformation, but after excluding those children with malformation, the relative risk of autism with valproate did not change. So it appears to not be associated with congenital malformations."

He said it was not fully understood how autism develops. "It is possibly linked to neuronal development and the way neurons connect, so it may be that the drug disrupts this process somehow. The prenatal period, when the brain is developing, is thought to be the most important for autism."

Asked whether valproate would be risky in terms of autism if used in children, Dr. Christensen said they did not look at that but he would not think so because the neuronal connections are already formed by 3 or 4 years age of age.

"While I believe our results are probably true, I would like to see them replicated in another large study in a different setting," he added. "This study is not comparable to a randomized trial. There will always be confounders we didn't account for. We tried to adjust for age of parents, gender of child, and psychiatric history, but women who take valproate may still be different in some way that we have not looked at."

Dr. Christensen believes most physicians are aware of the risk for congenital malformations with valproate but may not be aware of the intelligence and autism links.

"While it is clearly not recommended in pregnancy, there may be no other option for some patients. But usually use in pregnancy occurs because the pregnancy was not planned and the women do not realize until it is too late. They might have been warned not to get pregnant on this drug, but quite often they will still get pregnant, possibly accidentally. Others will not take the advice on board, considering the risk to be low, which it is."

He estimated that congenital malformations may affect about 2% to 3% of the general population, and may increase to 4% to 10% if valproate is taken in pregnancy.

In the JAMA paper, the researchers point out that because autism spectrum disorders are serious conditions with lifelong implications for affected children and their families, even a moderate increase in risk may have major health importance.

"Still, the absolute risk of autism spectrum disorder was less than 5%, which is important to take into account when counseling women about the use of valproate in pregnancy," they add.

Still Used Extensively in Young Women

In an accompanying editorial, Kimford J. Meador, MD, and David W. Loring, PhD, from Emory University, Atlanta, Georgia, report estimates that there are around 8 million annual prescriptions for antiepileptic medications in the United States among girls and women aged 15 to 44 years, including almost 1 million for valproate.

They point out that valproate is an effective treatment, not only for seizures but also for pain and bipolar disorder, as well as other disorders, but other therapeutic options are available for most women with these disorders.

"It appears that it is being prescribed for women of childbearing potential at a rate that does not fully consider the ratio of benefits to risks," they add. "This raises concern as to whether these women are receiving adequate information for informed consent based on a full understanding of the treatment risks and alternative therapies."

The editorialists conclude that use of valproate in women of childbearing potential should be minimized, and that because approximately half of the pregnancies in the United States are unplanned, delaying discussions of treatment risks until a pregnancy is considered will leave a substantial number of children at unnecessary risk.

This study was supported by grants from the European Research Council and the Danish Medical Research Council. Dr. Christensen reported receiving honoraria for serving on the scientific advisory boards of UCB Nordic and Eisai AB; receiving lecture honoraria from UCB Nordic and Eisai AB; and receiving travel funding from UCB Nordic. Another author reported receiving grants from Autism Speaks and the National Institutes of Health. No other study authors have disclosed any relevant financial relationships. Dr. Meador reported receiving research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Patient-Centered Outcomes Research Institute (PCORI), Pfizer, and UCB Pharma; receiving salary support paid to Emory University from the Epilepsy Consortium, which receives funding from NeuroPace, Novartis, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals; receiving travel support from sanofi-aventis; receiving payment as speaker for continuing medical education courses for the American Academy of Neurology and American Epilepsy Society; and serving on the professional advisory board for the Epilepsy Foundation and the editorial boards for Cognitive and Behavioral Neurology, Epilepsy and Behavior, Neurology, and Journal of Clinical Neurophysiology. Dr. Loring reported receiving consulting fees from NeuroPace; grant support from the National Institutes of Health, PCORI, Pfizer, and UCB Pharma; and book royalties from Oxford University Press.

JAMA. 2013;309:1696-1703, 1730-1731. Abstract   Editorial