Long-term Negative Impact on Child IQ With Valproate

Intriguing Secondary Finding on Potential Protective Effect of Periconceptual Folate

Caroline Cassels

April 26, 2012

April 26, 2012 (New Orleans, Louisiana) — Prenatal exposure to the antiepileptic drug (AED) valproate appears to have an enduring negative impact on children's IQ compared with 3 other commonly used anticonvulsant medications, new research shows.

Here at the American Academy of Neurology (AAN) 64th Annual Meeting, Kimford Meador, MD, from Emory University in Atlanta, Georgia, presented the final 6-year outcomes from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which showed that compared with carbamazepine, phenytoin, and lamotrigine, valproate had a long-term, dose-dependent, negative impact on child IQ across all intelligence measures.

Dr. Kimford Meador

"The findings at 6 years of age confirm our previous findings at 3 years that children exposed to valproate have lower IQs than the other 3 drug groups. In addition, we found valproate was associated with lower executive function, memory, verbal, and nonverbal abilities, and that these effects were dose dependent, but we didn't see any dose-dependent effects for the other drugs," Dr. Meador told Medscape Medical News.

With the aim of determining the potential impact of prenatal exposure of AEDs on children's cognition, the prospective, observational multicenter study included more than 300 pregnant women with epilepsy who were on AED monotherapy. These patients were enrolled in the study between 1999 and 2004 at 25 centers in the United States and Europe.

Multivariate analyses were conducted on intent-to-treat (n = 311) and completer samples (n = 224) with appropriate follow-up analyses and secondary analyses of other cognitive measures.

Dose-Dependent Effect for Valproate

With an adjusted mean IQ of 99, children exposed to valproate had significantly lower IQ scores than children in each of the other AED groups (carbamazepine, 105; lamotrigine, 108; phenytoin, 106), the investigators report.

Children in the valproate group also had significantly poorer verbal abilities and memory compared with children in each of the other AED groups. Further, compared with lamotrigine, children in the valproate group had poorer scores on measures of nonverbal and executive functions.

Valproate dose was also negatively associated with IQ, verbal, nonverbal, memory, and executive functions, but the other AEDs did not demonstrate a dose-dependent relationship.

According to Dr. Meador, higher maternal IQ was significantly linked to higher IQ in children overall in each AED group, with the exception of valproate.

Maternal IQ, he noted, is the "number one predictor of a child's IQ, but interestingly, valproate appears to disrupt this important association."

In addition to maternal IQ, the investigators controlled for other potential confounders that might explain child IQ. These included major malformations, gestational age, socioeconomic status, race, and maternal seizure type. Although a few of these factors were significant, none explained child IQ, Dr. Meador said.

Not a Good First Choice

On the basis of previous and final NEAD data as well as findings from other studies, Dr. Meador said he "feels strongly" that valproate is "not a good first choice treatment" for women of childbearing potential and that it should be avoided if possible.

He noted that there is a subset of women with primary generalized epilepsy for whom valproate clearly offers the best efficacy. However, even in these women, it may be prudent to try other agents first.

Potential exceptions, he said, may include patients who have failed several other drugs or those whose conditions have been well controlled with valproate and who are concerned about potential breakthrough seizures due to switching.

"I have carried some women through pregnancy on valproate, and what I've tried to do is keep the dose as low as possible while still maintaining seizure control and spread the dose out. There is some animal data that suggest there may be a peak effect rather than a total load effect, and so you can spread it out by administering multiple doses or using extended-release formulations," said Dr. Meador.

Offsetting Effect of Folate

One of the most interesting findings from the study, he said, was the observation that periconceptual folate appeared to mitigate the negative impact of AEDs, including valproate, on children's cognitive function.

"This [mitigating] effect was present for every one of the drug groups. It didn't make up for the drug effect, but in each drug group, the children who were exposed to folate in utero had higher IQs than the ones that were not exposed (108 vs 102).

"However, it's important to note that this is an observational study, and this [perinatal folate] was not our primary focus. But to me this is an extremely interesting observation that needs to be followed up," he said.

Potentially, Dr. Meador added, periconceptual folate may have broad implications beyond what the Centers for Disease Control and Prevention (CDC) has already recommended for the prevention of neural tube defects.

He noted that the recommended folate dose for healthy women is 0.4 mg. However, he said, in women with epilepsy, it may be worthwhile to consider a slightly higher dose, because there is concern that some AEDs may have the potential to interfere with folate levels.

He also pointed out that AEDs are widely prescribed for other neurological conditions, including migraine and chronic pain. In addition, he said, physicians need to keep in mind that 50% of pregnancies are unplanned, and therefore all women of childbearing potential who are on these medications should be counseled about potential teratogenic risk as soon as the drugs are prescribed.

The study's findings, he said, continue to support the FDA's recent safety warning to healthcare professionals about the link between in utero exposure to valproate products and the risk of impaired cognition, which was based primarily on the NEAD study's 3-year results, published in 2009 in the New England Journal of Medicine.

Need for More Research

The major strength of the NEAD study, said Dr. Meador, was that it was prospective and had multiple measurements of potential confounding variables and multiple standardized cognitive assessments in the children.

However, he added, because it is not a randomized trial, a potential concern is that the results may be due to confounding factors related to baseline characteristics that might affect the child's IQ.

"For example, there is a larger proportion of women on valproate that have primary generalized epilepsy, as you might expect, because it works well in that group. However, there's also a sizeable number in the lamotrigine group that also have this type of epilepsy, so I don't believe epilepsy type explains this. Still, it is impossible to completely rule out any potential residual confounding effects," he said.

However, he noted, in analyses adjusted for a large number of baseline characteristics, the link between maternal valproate use and poor cognitive outcomes in children persisted.

"If you take our data and look at it with the other data on valproate, there is a consistent pattern that emerges. However, there is certainly a need for additional research; you have to have more than 1 observational study to make these determinations."

Dr. Meador noted that there are many AEDs in current use among women of childbearing age for which there are no data.

The fact is, he said, the vast majority of women with epilepsy will have normal babies. However, he noted that AEDs are "among the most teratogenic agents used by women of childbearing age" and that clinicians must try to balance the risk to mothers and their unborn babies.

AEDs Not Just for Epilepsy

Commenting on the study for Medscape Medical News, Amy R. Brooks-Kayal, MD, Chief and Ponzio Family Chair in Pediatric Neurology at Children's Hospital Colorado, Denver, and Professor of Pediatrics, Neurology and Pharmaceutical Sciences, University of Colorado School of Medicine, Denver, said that the NEAD study is "one of the most important studies looking at the treatment of women with epilepsy who are of childbearing age."

The 6-year results, said Dr. Brooks-Kayal, extend the 3-year findings in important ways.

"First, 6-year outcomes are far more accurate. You are very limited in the neuropsychological testing you can do at 3 years of age — at 6 years, you can get a much more accurate score that is far more predictive of children's ultimate outcome in adulthood," she said.

In addition, Dr. Brooks-Kayal noted that the fact that the valproate data held up "so consistently" at 6 years suggests that clinicians need to discuss the risks of valproate and other AEDs before their female patients become pregnant.

"These effects occur very early in gestation. It's very important to control seizures during pregnancy, but if there are safer options, then those need to be considered. There are some women where valproate is the only drug that controls seizures, so if it is prescribed, it needs to be done with a great deal of careful monitoring, using the lowest possible dose and adjusting the dose to avoid big peak and drop effects as well as making sure women are on periconceptual folate," she said.

There is a need, she added, for greater education of neurologists as well as other physicians, including general practitioners, psychiatrists, internists, and gynecologists, about the potential teratogenic risks of AEDs.

"There is no specific reason to think that the [teratogenic] effects of valproate [and other AEDs] are unique to women with epilepsy, so I think this is information that all physicians who prescribe these drugs need to be aware of," said Dr. Brooks-Kayal.

Dr. Meador has disclosed no relevant financial relationships. Dr. Brooks-Kayal owns stock and/or stock options in Johnson & Johnson and Myelin Pharmaceuticals.

American Academy of Neurology (AAN) 64th Annual Meeting. IN5-2.003, presented April 23, 2012.

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