Valproate Carries Highest Risk for Major Congenital Malformations of All Antiepileptics

Becky McCall

July 06, 2010

July 6, 2010 (Rhodes, Greece) — Sodium valproate exposure during pregnancy more than doubles the risk for a major congenital malformation (MCM) in the fetus compared with carbamazepine or lamotrigine. Polytherapy, especially with regimens that include valproate, is linked to an even greater risk than monotherapy.

The latest results from the UK Epilepsy and Pregnancy Register and preliminary results from the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) were presented here at the 9th European Congress on Epileptology (ECE) to a packed hall of clinicians eager for an update.

Both studies tracked the incidence and risk for MCMs with antiepileptic drugs (AEDs) during pregnancy. The UK-based study analyzed full outcome data for exposures from 1996 through January 2009, whereas EURAP produced a first report, although data are still limited.

The UK study, a 15-year, prospective, observational registration and follow-up study, was presented by Fiona Kennedy, MD, a neurologist from Royal Victoria Hospital, Belfast, Northern Ireland. The most striking results were found with valproate vs carbamazepine and lamotrigine.

Dr. Kennedy reported that the risk for MCMs is higher for women taking AEDs during pregnancy compared with those receiving no treatment and that this risk was statistically significant in the polytherapy group compared with patients receiving monotherapy. "Those exposed to sodium valproate have 2.4 times the risk of a malformation with carbamazepine and 2.7 times the risk [with] lamotrigine. Similar results were found in the polytherapy group with valproate-based combinations conferring twice the risk of those with carbamazepine and lamotrigine," Dr. Kennedy reported.

She added that the lowest risk from available trial data appeared to be with exposure to lamotrigine and carbamazepine; however, levetiracetam looked promising.

Information was collected on pregnant women with epilepsy, whether taking AEDs (either monotherapy or polytherapy) or not. Age of onset, cause of epilepsy, seizure type and frequency, drug history, and changes to use of AED and folic acid were recorded when possible. Details of previous pregnancies, family history of congenital malformations, and any prenatal test results were also logged.

Outcome data were collected 3 months after the expected delivery date. By April 2010, 6513 patients had full outcome data. A total of 463 women had epilepsy without treatment, whereas 4723 had received 1 drug and more than 1000 had received polytherapy while pregnant. Embryonic abnormalities up to 6 weeks after birth were also recorded.

"We found in those patients not exposed to AEDs, that the MCM rate was 2.44%, in the monotherapy group the rate was 3.33%, whilst the rate in the polytherapy group was almost twice that [of patients receiving monotherapy] at 5.02%," reported Dr. Kennedy.

Of the monotherapies, carbamazepine had an MCM rate of 2.56%, and lamotrigine had an MCM rate of 2.25%, which is just above the background rate. Valproate had double the rate of MCMs at 6.16%. There were no cases of MCMs in levetiracetam monotherapy and 9 of 229 cases (3.9%) in levetiracetam polytherapy, although numbers were small.

Carbamazepine and lamotrigine were most commonly associated with cardiac and genitourinary MCMs. Valproate was associated with a high number (1.2%) of neural tube defects, facial cleft defects (1.2%), and genitourinary malformations (1.8%). In comparison, carbamazepine and lamotrigine both had a 0.3% incidence of neural tube defects, facial clefts occurred in 0.4% and 0.1% of the 2 drug groups, and there was an incidence of 0.6% and 0.7% for genitourinary malformations with carbamazepine and lamotrigine, respectively.

AED-Based Polytherapy Sharply Increases Risk for MCMs

Dr. Kennedy reported that the UK Epilepsy and Pregnancy Register has more than 100 polytherapy combinations, categorized as carbamazepine, lamotrigine, or valproate based. "The malformation rate for based-based polytherapy was 3.94%; with lamotrigine this rose to 4.34%. Valproate had double the malformation rate at 7.77%.

"In the topiramate group there was a malformation rate of 5.3% and 7.4% in the polytherapy group. These rates are very similar to valproate thus far, although the numbers to date are small. "

There were 498 informative outcomes available with levetiracetam. Eight malformations were found in total, all in the polytherapy group, with the majority associated with combinations based on valproate, topiramate, or lamotrigine.

In conclusion, Dr. Kennedy told Medscape Medical News that she found the results quite reassuring overall. "For clinical practice, monotherapy is preferable to polytherapy if continuation of drugs in pregnancy is necessary."

The other registry discussed at the ECE was EURAP, which is an international registry that looks at major congenital malformations in infants born to women taking AEDs during pregnancy. Dino Battino, MD, from the Institute of Neurology at Carlo Besta Foundation in Milan, Italy, presented the small amount of data available thus far.

This included rates of MCMs for the 4 most common AEDs at 1 year of age for the registry's first 5750 prospective pregnancies.

MCM rates from exposure to AEDs during the first trimester were lamotrigine at 2.9% (range, 2.1% – 4.1%), carbamazepine at 5.7% (range, 4.6% – 7.1%), valproate at 9.3% (range, 7.6% – 11.3%), and phenobarbital at 7.5% (range, 4.6% – 12.0%).

Treatments were split into 3 dose ranges. However, these results will only be available after a multivariate analysis has been carried out, Dr. Battino noted.

"In conclusion, we observed an overall MCM rate of 6.1% at 1 year. A dose-event relationship was demonstrated for based, phenobarbital, and valproate. Multivariate analysis will be conducted soon," remarked Dr. Battino.

Commenting on the results of both registries, Georgia Montouris, MD, of Boston University School of Medicine, Massachusetts, said she believed valproate is still a valuable drug for some women. "Depakote [divalproex sodium, Abbott] still has a place, but we have to remember that seizures during pregnancy have dire consequences. Depakote is the only answer for some pregnant women."

Furthermore, she added that she was very concerned about assessing teratogenicity based on dose rather than serum levels. "I've had patients on valproic acid at 1500 mg with levels of 39 and others on 1000 mg with levels of 89, so I can't concede that that is equal in terms of teratogenicity."

"So are we doing enough to monitor levels? I monitor [serum levels in] my patients monthly, on the day of delivery and the day after, and I make [dose] adjustments throughout pregnancy if I see levels drop because I don't want to wait for that seizure. I think we need this data in our registry."

In a separate session, James Morrow, MD, consultant neurologist from the Royal Victoria Hospital in Belfast, Ireland, and a coinvestigator for the UK Epilepsy and Pregnancy Register, presented results of an analysis of the effects of folic acid supplementation on risk for MCM.

Dr. Morrow explained that he had compared women who took folic acid before conception with women who did not. "We did not find any protective effect like that seen in the general population, suggesting there may be a different mechanism at work here," he remarked.

Javed Ismail, MD, of Birmingham City Hospital in Birmingham, United Kingdom, commented. "There appears to be a paper saying folic acid does not have a beneficial effect. It might be a good idea from now on to try and look at whether folic acid tends to prevent these malformations."

Dr. Bonetti is an investigator for EURAP. EURAP is supported by educational grants to the CPC from GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi-Synthelabo, UCB Pharma, and Novartis. National networks may also receive support in the form of unrestricted grants from other pharmaceutical companies. Dr. Montouis declared that she conducted drug trials for various pharmaceutical companies and has received speaking fees from Pfizer, UCB, and GlaxoSmithKline. Dr. Ismail has declared no relevant financial relationships.

9th European Congress on Epileptology (ECE): Abstract 274. Presented June 28, 2010.

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