NEJM Study Confirms Exposure to Depakote Lowers Children’s IQ

A study in The New England Journal of Medicine, comparing the intelligence quotient (IQ) levels of children whose epileptic mothers were prescribed one of several antiepileptic drugs during pregnancy, confirms that Depakote (valproate) significantly lowers children’s IQ–regardless of the mother’s intelligent quotient.

The researchers followed pregnant women in the United States and United Kingdom between 1999 and 2004, the results are based on 260 of their children.

Underscoring the indisputable evidence that Depakote is the culprit, the study found that the higher the dosage of valproate a woman had taken, the lower the IQ of the child. For the other drugs, dosage levels made no significant difference.

In the United States, about 25,000 children are born each year to women who have epilepsy, a brain disorder that causes people to have recurring seizures.

The authors note that “women with epilepsy are at increased risk for poor pregnancy outcomes, although most of their children are normal.” Cognitive effects on human fetuses exposed to antiepileptic drugs have not been adequately studied–even though animal studies should have raised concerns about the potential for human harm produced by antiepileptic drugs. The evidence from animal studies shows that fetal exposure to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities in animals.

The new study,by the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group, focused on the effect of antiepileptic drugs on young children whose mothers were prescribed one of the drugs in this class. It was supported by the National Institute of Neurological Disorders and Stroke and the United Kingdom Epilepsy Research Foundation.  The findings are consistent with those of previous investigations: “our interim analysis of the NEAD study indicates that the maternal use of valproate during pregnancy is associated with an increased risk of cognitive impairment in children at 3 years of age. This information is relevant to counseling women of reproductive age regarding this drug class.”

The study is important because it’s the largest to show a connection between Depakote and diminished IQ. Its publication in the prestigious New England Journal of Medicine should alert physicians who until now have ignored the drug’s potential dangers to fetuses.

IQ scores of children exposed to an antiepileptic drug in utero were in the range of 98 to 101 for those whose mothers had taken lamotrigine, phenytoin, and carbamazepine. In contrast, toddlers whose mothers had taken Depakote (valproate) had IQs of 92, on average.

Unfortunately,  the review panel of the US sponsoring agency, NINDS, opposed the inclusion of a control group of children not exposed to any antiepileptic drug.

The NINDS reviewers seem to have completely missed the point that it is the magnitude of the effect of drug exposure to no drug that is an important clinical issue. By limiting the comparison to other drugs–all of which may have had negative cognitive effects on developing children’s brains–conceals the full magnitude of harm produced by these drugs.

Indeed, Dr. Lewis Holmes, director of the North American Antiepileptic Disease Pregnancy Registry, and a professor at Harvard University, who was not involved in the study noted that without such a comparison group, it’s hard to know what the full impact on mental development this class of drugs produces.

We would add, that the omission of a control group also diminishes the scientific authoritativeness of the study results.

Prior studies cited by the authors:

“Retrospective studies in the United Kingdom found poorer outcomes among children exposed to valproate in utero as compared with children who were unexposed and with those exposed to other antiepileptic-drug monotherapies. These poor outcomes for valproate included increased developmental delays in a cohort younger than 6 years of age, increased special education needs in a cohort 5 to 18 years of age, and reduced verbal IQ in a cohort 6 to 16 years of age, as compared with unexposed children (7 points), children exposed to carbamazepine (10 points), and children exposed to phenytoin (15 points).”

 “A prospective Finnish study reported a reduction in verbal IQ among children exposed to valproate as compared with unexposed controls (13 points) and with children exposed to carbamazepine (14 points). This prospective study was limited by a small sample of subjects exposed to valproate monotherapy (13 children) and lack of information on maternal IQ.”

Depakote is also associated with the highest incidence of fetal malformations–10.7%!

Several studies have also shown that valproate is associated with an increased risk of congenital malformations; this association is dose dependent.

“A recent meta-analysis indicated that of various antiepileptic drug monotherapies, valproate was associated with the highest incidence of malformations (10.7%; 95% CI, 8.2 to 13.3). The results of several studies showing an increased incidence of anatomical or behavioral teratogenesis in children exposed to valproate as compared with other antiepileptic drugs raise serious concern that valproate poses a particular risk to the unborn child.”

The authors conclude:

“The present results, together with other data, suggest that valproate should not be used as a first-line antiepileptic drug in pregnant women or — since data indicate that half of pregnancies are unplanned — in women of childbearing potential. Our finding that associations between the use of valproate in pregnancy and lower IQ in the offspring are dose-dependent suggests that lower doses may be safe. However, it should be recognized that there is considerable individual variability among children exposed to similar doses.”

OF RELEVANCE: The majority of women prescribed an antiepileptic are not at risk of seizures.

Fewer than half of antiepileptic-drug prescriptions are written for epilepsy or seizuresthe majority of prescriptions are intended for pain management and psychiatric indications.

Given the significant risks posed by antiepileptic drugs–Depakote in particular, which is associated with a 10.7% risk of malformationsit is hard to justify prescribing this class of drugs in women who may become pregnant.  The use of antiepileptic drugs, Depakote in particular, for indications other than seizure should be banned or contra-indicated.

posted by Vera Hassner Sharav

See:  THE NEW ENGLAND JOURNAL OF MEDICINE
Volume 360:1597-1605    April 16, 2009
Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs
Kimford J. Meador, M.D., Gus A. Baker, Ph.D., Nancy Browning, Ph.D., Jill Clayton-Smith, M.D., Deborah T. Combs-Cantrell, M.D., Morris Cohen, Ed.D., Laura A. Kalayjian, M.D., Andres Kanner, M.D., Joyce D. Liporace, M.D., Page B. Pennell, M.D., Michael Privitera, M.D., David W. Loring, Ph.D., for the NEAD Study Group

ABSTRACT

Background Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain.

Methods Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis i a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in uteroO This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age.

Results At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children’s IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate.

Conclusions In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.

Source Information

From Emory University, Atlanta (K.J.M., P.B.P., D.W.L.); the University of Liverpool, Merseyside, United Kingdom (G.A.B.); EMMES Corporation, Rockville, MD (N.B.); St. Mary’s Hospital, Manchester, United Kingdom (J.C.-S.); the University of Texas Southwestern Medical Center, Dallas (D.T.C.-C.); the Medical College of Georgia, Augusta (M.C.); the University of Southern California, Los Angeles (L.A.K.); Rush University Medical Center, Chicago (A.K.); Riddle Health Care, Media, PA (J.D.L.); and the University of Cincinnati, Cincinnati (M.P.).

Address reprint requests to Dr. Meador at the Department of Neurology, Emory University, Woodruff Memorial Research Bldg., 101 Woodruff Cir., Suite 6000, Atlanta, GA 30322, or at kimford.meador@emory.edu.
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Epilepsy drug in pregnancy may lower child’s IQ
By MIKE STOBBE

ATLANTA (AP) — Toddlers of moms who took the epilepsy drug valproate during pregnancy had lower IQs than the children of women who used other anti-seizure medicines, according to a new study.

The valproate children had IQ scores six to nine points lower by age 3, said the study’s lead author, Dr. Kimford Meador of Emory University. The drug, also sold in the U.S. under the brand name Depakote, had previously been linked to birth defects, particularly spina bifida. Women of childbearing age have long been advised to avoid it.

“We’ve known this drug is a bad actor for a long time,” said Dr. Lewis Holmes, director of the North American Antiepileptic Disease Pregnancy Registry, based at Massachusetts General Hospital in Boston.

The new study is important because it’s the largest to show a connection between valproate and diminished IQ. Its publication in the prestigious New England Journal of Medicine should alert physicians who until now have ignored the drug’s potential dangers to fetuses, added Holmes, who was not involved with the study.

In the United States, about 25,000 children are born each year to women who have epilepsy, a brain disorder that causes people to have recurring seizures. In the study, researchers followed pregnant women in the United States and United Kingdom between 1999 and 2004. The results are based on about 260 of their children.

Toddlers whose mothers had taken valproate had IQs of 92, on average. In contrast, IQ scores were in the range of 98 to 101 for children of women who had taken lamotrigine, phenytoin, and carbamazepine. IQ tests are designed so a child of average intelligence scores 100.

The higher the dosage of valproate a woman had taken, the lower the IQ of the child, the researchers found. For the other drugs, dosage levels made no significant difference.

The number of children in the study is small, and it’s possible that other factors influenced the results. However, the researchers accounted for differences in a child’s birth weight, the age and IQs of their mothers, the type of epilepsy the mothers had, and other factors that could have influenced the results.

A major drawback is that the study did not include children whose epileptic mothers took no medication during pregnancy, Holmes said.

It’s possible that all four epilepsy medications had some effect on mental development, he said. Without such a comparison group, it’s hard to know, said Holmes, who is also a professor of pediatrics at Harvard Medical School.

Valproate, also given for migraine headaches and mood disorders, continues to be used by some epileptics because it’s the only thing that works, said Meador, the study author.

Doctors say it’s often important for epileptic women to keep taking their medications during pregnancy because seizures can lead to injuries.

Women on the drug who want to get pregnant should plan their pregnancies carefully and consult with a doctor, wrote Swedish researcher Dr. Torbjorn Tomson, in an editorial that accompanied the new study.

Switching drugs after a woman realizes she is pregnant is unlikely to reduce the risk of birth defects. And abruptly stopping the medication may endanger the mother and the fetus, he wrote.  “That could be catastrophic,” Meador agreed.

Copyright © 2009 The Associated Press. All rights reserved.