ARTICLE IN BRIEF
1. ✓ IQ scores of children whose mothers had taken valproate during their pregnancy were lower than those of children who were exposed to other antiepileptic drugs in utero.
BOSTON—Infants whose mothers take valproic acid, or valproate, for seizure control during pregnancy have an increased risk of cognitive delays, according to a leading epilepsy investigator who reported the findings here at the AAN annual meeting in May.
“The cognitive performance of the children on valproate was lower than children on other commonly used antiepileptic drugs and could not be explained by any other factors,” said principal investigator Kimford J. Meador, MD, in a phone interview after the meeting. “This finding was consistent with two prior retrospective studies and one small prospective study.” Dr. Meador is the Melvin Greer Professor of Neurology at the University of Florida in Gainesville.
In the ongoing prospective study, Neurodevelopmental Effects of Antiepileptic Drugs (NEAD), Dr. Meador and his co-investigators wanted to determine the long-term effects of in utero antiepileptic drug (AED) exposure on cognitive outcomes. They enrolled women with epilepsy who were taking carbamazepine, lamotrigine, phenytoin, or valproate for seizure control. They plan to follow the children until they are six years old.
Data were presented on the IQ results for the 185 children when they were two years old as reflected in the Mental Developmental Index (MDI) scores. The investigators controlled for maternal IQs and blood levels of anticonvulsant medications. Not surprisingly, the children's IQs were significantly correlated to those of their mothers, at a probability of less than 0.0002.
However, the MDIs were significantly lower for those exposed to valproate compared to carbamazepine (p<0.02), lamotrigine (p<0.016), and phenytoin (p<0.012). Thirteen percent of children with an MDI lower than 70, considered to be a significant delay, took carbamazepine; 11 percent, lamotrigine; 12 percent, phenytoin; and 24 percent, valproate. Further, the maternal valproate blood level was significantly inversely correlated with MDI, with a probability of less than 0.005. The children's MDI score was directly correlated with maternal IQ for each drug except for valproate.
The findings add to the earlier research by Dr. Meador and others showing worse anatomical outcomes for children exposed in utero via maternal use of valproate. “Most of the findings showed the effect to be dose-dependent,” Dr. Meador said. “Unfortunately, the risks of adverse effects for the children appear to increase at the point at which the mother is getting a therapeutic level of the drug. We would not recommend valproate as a first choice drug for women of childbearing age. When valproate is used, women should be informed of the risks.”
In some cases using valproate in pregnancy may still be justifiable despite the risks to the fetus, he said, noting that the drug is particularly effective at controlling seizures in primary generalized epilepsy. “It could be that someone is only controlled on valproate, but you need to inform the individual and include the risks as well as the benefits in your decision making,” he said.
Because so many pregnancies are not planned, that conversation should be extended to all women of childbearing age on the medication, whether or not they are planning pregnancies in the near future, he said.
It is not known at this point whether the findings on valproate's impact on infant cognitive development will result in a change in labeling, Dr. Meador said. He noted that the FDA changed the labeling last year but even so, that change does not fully reflect the newest findings regarding the drug's risks. He added that an AAN committee is rewriting the guidelines for pregnancy and epilepsy and that this issue will be addressed in the new guidelines.
“This is an important study, because there has been increasing evidence over time regarding problems with valproate in pregnancy,” said Jacqueline French, MD, in a phone interview. “Everyone knew about teratogenicity, but nobody knew about the risks of delayed cognitive development in babies exposed to valproate that appeared normal at birth.” Dr. French, who was not involved in the study, is a professor of neurology at the University of Pennsylvania in Philadelphia, where she is an assistant dean for clinical trials.
Dr. French added: “We think that just getting by the first trimester is important, but with brains and central nervous system development, it's the last trimester that is also critical, as it is in fetal alcohol syndrome. If a woman has a seizure mid-pregnancy, people may have thought it was acceptable to use valproate. This study shows that this is not so.”
She applauded the investigator for considering all of the potential confounders that could underlay the results. “Typically, the higher the IQ of the mother, the higher that of the baby, and this correlation was wiped out with valproate,” she said. “In addition, Dr. Meador demonstrated a dose-response relationship. Other studies have also shown that fathers on valproate don't have children with delayed development.”
WHAT ARE THE ALTERNATIVES?
Dr. French noted that the decision to switch women with epilepsy off valproate is not so simple. She noted that in a 3,000-person study — comparing old and new AEDs — valproate was more effective than new drugs (Lancet 2007;369:1016–1026). “When a woman wants to switch drugs, we can't assure her that the alternative drugs will be as effective,” she said.
There is also a risk of seizure break-through with switching drugs, Dr. French said. “The switch may, for example, require temporary cessation of driving. I always think of the mom with a toddler who has been seizure-free for a year and who wants to get pregnant. We want to take into consideration the health of the mom, the toddler, and the fetus.”
The challenge in treatment decisions is compounded by the fact that seizures are not universally harmful to fetuses, she added. “We see some decelerations [slowed heart beat] with some seizures, but that is not an incontrovertible truth,” Dr. French said. “We do worry about the consequence of seizures, though, particularly with driving.”
CONTRACEPTIVES AND LIMITATIONS
Neurologists should have a clear understanding of today's contraceptive methods and their limitations, including low-dose hormonal modalities, and talk frankly to women of childbearing age about their plans and about the impact valproate could have on a pregnancy, she said. Women should know, for example, that if they are taking a low-dose oral contraceptive and have a gastrointestinal illness that involves nausea or vomiting, their contraceptive may not have been absorbed, and they may need to use a back-up method for the duration of that menstrual cycle.
“We definitely need to have that talk,” she said. “For example, certain types of generalized epilepsy are treated with valproate in adolescence.” Physicians cannot assume that adolescent patients are abstaining from sexual activity, she said. For more information on valproate and pregnancy, as well as other concerns, she recommended that neurologists refer patients to the Web site of the Epilepsy Foundation: www.epilepsy.com.
Neurologists also need to know that some anti-epileptic drugs interfere with oral contraceptives. “Valproate does not, but many patients are on combination therapy,” she said.
• Adab N, Kini U, Vinten J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry
• Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology
• Wyszynski DF, Nambisan M, Holmes LB, et al. Antiepileptic Drug Pregnancy Registry: Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005;64(6):961–965.
• Vajda FJ, Eadie MJ. Maternal valproate dosage and fetal malformations. Acta Neurol Scand
• Wide K, Winbladh B, Källén B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: A nation-wide population-based register study. Acta Paediatr 2004;93:174–176.
• Artama M, Auvinen A, Raudaskoski T, Isojärvi I, Isojärvi J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology
• Morrow JI, Russell A, Craig J, et al. Malformation risks of anti-epileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77(2):193–198.
• Cunnington M, Tennis P, et al., for the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology
• Meador KJ, Baker GA, Wolff MC, et al., for the NEAD Study Group. In utero antiepileptic drug exposure: fetal death and malformations. Neurology
• Marson AG, Al-Kharusi AM, Appleton R, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: An unblinded randomised controlled trial. Lancet