Prenatal testing. We also recommend that pregnant women who are taking an AED—particularly those taking a higher-risk drug such as valproate—undergo a detailed first-trimester ultrasonographic study between 16 and 20 weeks’ gestation. Amniocentesis should be avoided, if possible. If needed, however, amniotic alpha-fetoprotein levels may be determined for additional risk assessment.15
Medication changes. Once a woman is pregnant, stopping or switching AEDs requires a higher level of caution and is usually ill-advised. We generally avoid medication switches after conception. But if a patient explicitly requests a change to a “safer” agent, we may attempt a cross-taper, as we would before pregnancy. Evidence suggests, however, that it may be too late to avoid the risk of major congenital malformations, which typically develop very early in pregnancy.1,3
Avoid untried AEDs. We advise against changing a pregnant woman’s seizure medication to an agent she has not tried before, because of the risks of both common adverse effects, such as allergies, and rare idiosyncratic reactions leading to aplastic anemia and Stevens-Johnson syndrome.
INTEGRATING EVIDENCE AND EXPERIENCE
For the developing fetus, newer drugs are safer
For the developing fetus, newer drugs are safer
Newer-generation antiepileptic drugs (AEDs), which include lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam, are not associated with an increased risk of major birth defects in the first year of life when they are used during the first trimester of pregnancy, according to a new cohort study from Denmark. The study, published in the May 18, 2011, issue of JAMA, includes data on 837,795 live-born infants in Denmark from January 1996 through September 2008. Individual-level information on the AEDs dispensed to mothers, the diagnosis of any birth defects, and potential confounders were ascertained from nationwide health registries.
Of the live births included in the study, 19,960 involved infants who had a diagnosis of a major birth defect (2.4%) during the first year of life. Among 1,532 pregnancies exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at any time during the first trimester, 49 infants (3.2%) had a major birth defect. In comparison, 19,911 infants (2.4%) of 836,263 unexposed pregnancies had a major birth defect. After adjustment for various variables, Ditte Molgaard-Nielsen, MSc, and Anders Hviid, MSc, DrMedSci, found no increased risk of major birth defects associated with use of the newer-generation AEDs, though exposure to gabapentin and levetiracetam during the first trimester was uncommon.
“Our study, to our knowledge, is the largest analytic cohort study on this topic and provides comprehensive safety information on a class of drugs commonly used during pregnancy,” write Molgaard-Nielsen and Hviid. “The use of lamotrigine and oxcarbazepine during the first trimester was not associated with moderate or greater risks of major birth defects like the older-generation antiepileptic drugs, but our study cannot exclude a minor excess in risk of major birth defects or risks of specific birth defects. Topiramate, gabapentin, and levetiracetam do not appear to be major teratogens, but our study cannot exclude minor to moderate risks of major birth defects,” the authors conclude.
Topiramate remains a category D drug
The findings of this cohort study do not change the fact that topiramate was recently designated as a Pregnancy Category D drug. The US Food and Drug Administration issued an alert on March 4, 2011, notifying health-care professionals and patients that the drug’s category had changed from C to D because of new evidence of an increased risk of oral clefts in infants exposed to the agent in utero. Pregnancy Category D means that there is positive evidence of human fetal risk based on human data but the potential benefits from use of the drug in pregnant women may be acceptable in certain situations despite its risks.
—Janelle Yates, Senior Editor
Reference
AED dosing throughout pregnancy
When seizures are well controlled prior to conception, they usually remain controlled during pregnancy, although both increases and decreases in seizure frequency have been reported.16 Seizure exacerbations are usually due to decreased AED levels; this may be the result of decreased plasma protein binding, decreased albumin concentration, or increased drug clearance,16 although stress, sleep deprivation, and noncompliance may be contributing factors, as well. The changes in pharmacokinetics make it imperative that seizure frequency as well as AED levels be carefully monitored throughout pregnancy.
Although detailed information about changes in serum levels of the newer AEDs during pregnancy is not available, it can be assumed that they will decline somewhat even if the dose remains the same. Carbamazepine has the least alteration in metabolism during pregnancy,17 whereas a widely disparate effect on lamotrigine metabolism during pregnancy has been noted. In some women, serum levels of lamotrigine have been shown to decrease by as much as 60% to 90% due to induction of UDP-glucuronosyltransferase (UGT) enzymes,18 the drug’s main metabolic enzymes. Increased clearance of lamotrigine typically occurs within the first several weeks of pregnancy and returns to baseline within 2 weeks after birth.