[Research] Newer Generation AEDs and the Risk of Birth Defects

[Bernard]

There is a study conducted in Denmark making the news today claiming that "newer generation" anti-epileptic drugs pose no greater risk of major birth defects. The study was published in JAMA:

...
Design, Setting, and Participants Population-based cohort study of 837,795 live-born infants in Denmark from January 1, 1996, through September 30, 2008. Individual-level information on dispensed antiepileptic drugs to mothers, birth defect diagnoses, and potential confounders were ascertained from nationwide health registries.

Main Outcome Measures Prevalence odds ratios (PORs) of any major birth defect diagnosed within the first year of life by fetal exposure to antiepileptic drugs.

Results Of the 1,532 infants exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam during the first trimester, 49 were diagnosed with a major birth defect compared with 19,911 of the 836,263 who were not exposed to an antiepileptic drug (3.2% vs 2.4%, respectively; adjusted POR [APOR], 0.99; 95% confidence interval [CI], 0.72-1.36). A major birth defect was diagnosed in 38 of 1019 infants (3.7%) exposed to lamotrigine during the first trimester (APOR, 1.18; 95% CI, 0.83-1.68), in 11 of 393 infants (2.8%) exposed to oxcarbazepine (APOR, 0.86; 95% CI, 0.46-1.59), and in 5 of 108 infants (4.6%) exposed to topiramate (APOR, 1.44; 95% CI, 0.58-3.58). Gabapentin (n = 59) and levetiracetam (n = 58) exposure during the first trimester was uncommon, with only 1 (1.7%) and 0 infants diagnosed with birth defects, respectively.

Conclusion Among live-born infants in Denmark, first-trimester exposure to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam compared with no exposure was not associated with an increased risk of major birth defects.

http://jama.ama-assn.org/content/305/19/1996

Unfortunately, I can't see the full article and nowhere in the abstract or media reports based upon it define what is meant by "major birth defects".

A few words of caution before getting too excited over the news:

...
The finding can be seen as reassuring to women of childbearing age who take the newer epilepsy drugs. But it had one major limitation: It did not include many women who took the drug Topamax (topiramate).

Back in March, the FDA warned that use of Topamax early in pregnancy was associated with an increased risk for cleft lip and cleft palate in newborns, citing new drug registry data suggesting a 16-fold increase in risk.

Most of the women in the new study who took an antiseizure drug took Lamictal (lamotrigine), and their birth defect risk was just slightly higher than women who took no antiseizure drugs.
...
The Danish study included data on 837,795 live births occurring in that country between January 1996 and September 2008, including 1,532 women who took a second-generation antiseizure drug during their first trimester.

Just over a thousand women took Lamictal, about 400 took Trileptal (oxcarbazepine), about 100 took Topamax, and close to 60 each took Neurontin (gabapentin) or Keppra (levetiracetam). Some of the women took more than one drug.
...
NYU professor of neurology and epilepsy specialist Jacqueline A. French, MD, calls the study somewhat reassuring, but she adds that studies based on registries of women taking the drugs tell more about their risks.

It was data from this type of study that FDA officials cited when they warned about the Topamax oral birth defect risk earlier this year.

“The findings are reassuring because if the rates of fetal malformation were as high as with Depakote, even with the small sample sizes in this study we would see it,” she tells WebMD. “But the findings are not reassuring enough to say that we are out of the woods with all of these drugs.”
...

http://www.webmd.com/epilepsy/news/2...epilepsy-drugs

... The team cautioned, however, that the results did not include enough women who had taken either gabapentin or levetriacetam to reach any conclusions about risk associated with them. Also, the study did not monitor abortions or miscarriages that might have been associated with use of the drugs. Nonetheless, the team said, the results should provide great confidence for expectant mothers who suffer from epilepsy or any of the other disorders.
...

http://www.latimes.com/health/booste...,5646501.story

Since the study was weighted towards women taking Lamictal, I'd like to see some more study/science explaining the difference between their results and the FDA warning issued back in 2006 about Lamictal and cleft lip/palate. Is that considered a "major" birth defect?

[Nakamova]

Major defects are structural abnormalities that affect the way a person looks and require medical and/or surgical treatment. Minor defects are abnormalities that do not cause serious health or social problems. Cleft lip/palate falls somewhere between the two -- it requires what is now considered routine surgery, but does not cause serious health or social problems -- so perhaps the Danish study downgraded it to "minor". I agree, it would be nice to know more about the criteria and the results.