First-trimester exposure to the newer generation of antiepileptic drugs – lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam – does not appear to raise the risk of major birth defects, according to a report in the May 18 issue of JAMA.
In addition, none of these agents was associated with subgroups of major birth defects categorized by organ system, said Ditte Molgaard-Nielsen and Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen.
Noting that "there is only sparse information on the teratogenic effects of most of the newly licensed antiepileptic drugs," the researchers assessed the issue using data from national Danish registries of births, prescriptions, and major congenital anomalies for 1996 through 2008. They excluded cases of birth defects associated with chromosomal aberrations; genetic disorders; and known causes, such as fetal alcohol syndrome, and assessed a final cohort of 837,795 live births.
Of these, there were 19,960 major birth defects diagnosed within the first year of life, for an overall rate of 2.4%.
There were 1,532 pregnancies in which the fetus was exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at some time during the first trimester. A total of 49 of these infants (3.2%) were diagnosed as having a major birth defect, compared with 19,911 (2.4%) of the 836,263 unexposed pregnancies.
After the data were adjusted to account for potential confounders such as maternal use of older-generation antiepileptic drugs, which are known to raise the risk by two- to threefold, or a history of birth defects in siblings, exposure to these newer agents was no longer associated with an increased risk of major birth defects, Ms. Molgaard-Nielsen and Dr. Hviid said (JAMA 2011;305:1996-2002).
In a further analysis of the data, the risk of birth defects was found to be unrelated to the use of any of the five newer-generation antiepileptic drugs individually. Another analysis showed that there was no dose-response effect of increasing risk with escalating doses of lamotrigine, the most frequently used of the five drugs.
"We conducted a number of sensitivity analyses to evaluate the robustness of our results, including adjusting for exposure to drugs in the U.S. Food and Drug Administration’s pregnancy categories D and X. ... No association with major birth defects was found in any of these analyses," they noted.
An exploratory analysis examined whether exposure to all of the drugs was associated with major birth defects categorized by the affected organ system. No significantly increased risk was found, except for a fourfold increase in eye defects associated with the use of lamotrigine.
However, this association "is likely a chance finding." The subgroup of infants with eye defects included only four infants, and they were affected by "4 etiologically different eye defects, which argues against a causal association."
The question of whether maternal epilepsy itself is associated with an increased risk of birth defects is still debated. In this study, maternal epilepsy was associated with a moderately increased risk of birth defects, the investigators noted.
Their study was limited in that it did not include any information on spontaneous or induced abortions. "This will bias an association ... toward the null if the birth defect itself increases the risk of induced or spontaneous abortion," they added.
Although this was the largest cohort study to date on this issue, further research with larger sample sizes is needed to delineate the risks of specific birth defects. This study could not exclude minor to moderate excesses in risks of overall birth defects or of specific birth defects, they said.
This study was supported by the Danish Medical Research Council and the Lundbeck Foundation. Ms. Molgaard-Nielsen and Dr. Hviid reported no relevant financial disclosures.