Autism Linked to Valproate in Pregnancy, Study Shows

Children born to mothers who took the epilepsy drug valproate during pregnancy were 5 times more likely to be born with autism than those whose mothers didn’t take the medication, a Danish study found.

The anti-seizure drug was also associated with a 3-fold increase of autism spectrum disorder, which includes Asperger syndrome and other developmental disorders, according to research published in the April 24th issue of JAMA (Journal of the American Medical Association).  The study was led by Jakob Christensen, PhD, Aarhus University Hospital, Denmark. The new research is based on about 700,000 babies born in Denmark.

Results showed that of 655,615 children born in the study period, 5,437 had autism spectrum disorder, including 2,067 with childhood autism. There were 2,644 children exposed to anti-epileptic drugs during pregnancy, 508 of which were exposed to valproate.

“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 it is now believed that it increases the risk of autism. When you add all these together, it is definitely a drug you would want to avoid in pregnancy.”

Previous studies have found more birth defects and lower intelligence among children of mothers who took valproate, but the new work represents the “strongest evidence to date” of a link between the drug and autism, according to an editorial published this week.

The American Academy of Neurology recommends avoiding valproate in pregnancy whenever possible due to cognitive and physical birth defect problems for children exposed during pregnancy. It is highly recommended that women be informed of the potential risks of fetal valproate exposure before valproate is prescribed. Although the American Academy of Neurology and the American Epilepsy Society have both said that while it is safe for women with epilepsy to become pregnant, particular caution must be taken with valproate.

When looking only at children of mothers with epilepsy (432 of 508), the risk of autism was 2.9 times higher with valproate exposure, with an absolute risk of 2.95 percent vs. 1.02 percent among all others in the cohort not exposed to the drug.

Autism spectrum disorder showed a 70 percent elevation in that analysis, however, not statistically significant.

The risk for children exposed to valproate during pregnancy also appeared elevated if the mother was not taking the drug for treatment of epilepsy, but the numbers were small.

That may not have been very reliable, though, since the timing was based on when the prescription was filled, not when the pills were taken, and because few women took the drug solely in later pregnancy.

Although valproate is a very effective drug, prescribing it to pregnant women should be minimized. Instead, doctors should offer alternative therapies. If no alternative therapies work, then only the lowest effective dose of valproate should be prescribed. Those who have to take it should be fully aware of the risks involved in taking the medication.

Dr. Kimford Meador, a neurologist who wrote an editorial, said that findings show valproate should be avoided and other treatments used instead to control seizures in women of childbearing age to reduce risk of autism in their unborn children. If not, only the lowest dose of the drug should be given. Previous research has linked valproate’s use during pregnancy to heart defects, spinal bifida, cleft palates and cognitive problems including lower intelligence scores.

“This is an important risk factor and one that can be avoided or at least the risk reduced in women who don’t need to take this and can take another drug,” Meador, a professor of neurology at Emory University in Atlanta, said in a telephone interview. “This is the strongest evidence to date that there is a link between fetal exposure and childhood autism or autism spectrum disorder.”

AbbVie Inc. (ABBV), based in North Chicago, Illinois, sells valproate under the brand name Depakote.  The U.S. Food and Drug Administration (FDA) have approved this drug for the treatment of seizures, prevention of migraine headaches and to treat manic episodes associated with bipolar disorder. It is also used off-label by doctors for other (unapproved) conditions, particularly psychiatric disorders, according to the FDA website.

“The risks outweigh the benefits but the caveat is the drug is important to some women,” stated in a telephone interview with Christopher Stodgell, associate professor in the Department of Obstetrics and Gynecology at the University of Rochester Medical Center in New York, who is studying the drug’s connection to autism. “It’s important that these women understand what those risks are.”

The study was one of the largest to show valproate’s link to autism, he said.

Meador said that more studies are needed to better understand how seizure drugs and other treatments affect an unborn child.

Dr. Christensen 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.”

“There’s still a great deal of valproate being used,” Meador said.  “The amount being used in women of childbearing age seems to be excessive given the risk benefit ratio. There’s alternative drugs that have lower risks than valproate.”

“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.”

Both Christensen and Meador said they believe that valproate might increase the risk of autism and autism spectrum disorders by altering the development of nerve cells in the brain. The drug doesn’t necessarily destroy the developing cells, but changes them in a way that makes it harder for the cells to work and communicate with each other the way they’re supposed to.

Since valproate is an effective treatment not only for seizures but also for pain and bipolar disorder, as well as other disorders, it is estimated that approximately 1 million annual prescriptions are written in the U.S. among girls and women aged 15 to 44.

Although the study tied the use of valproate in pregnancy to higher autism risk in children, it did not establish a cause-and-effect relationship.

Women of childbearing potential should be informed of the risks before valproate is prescribed to them.  The risks can affect a child for their lifetime.

Feel free to contact one of our Gacovino Lake attorneys for more information at 1-800-246-HURT (4878).

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