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 for 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.
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 while 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.
As a result, incremental dosing of lamotrigine is usually required early in the pregnancy. In some cases, dramatic increases—several multiples of the preconception dose—may be needed, followed by a rapid decrease after delivery.18
Monitoring drug levels
Our approach to monitoring AED levels in a pregnant woman with epilepsy includes the following:
- Check levels at baseline—prior to conception, whenever possible—and monthly throughout the pregnancy, with more frequent checks for women with recurrent seizures and those taking lamotrigine.
- Use the dose at which the patient was seizure-free prior to conception as a target level during pregnancy.
- Adjust the dose as needed to maintain the preconception serum drug level.
Drug-specific considerations. As phenytoin and valproate are highly protein-bound, we follow free levels during pregnancy rather than total levels alone. (If your facility is not equipped to track free drug levels, it is important to realize that total levels of these AEDs may not accurately reflect the drug level.) If your patient is taking phenytoin and you’re unable to obtain this information, you can use the patient’s albumin level and the total phenytoin level to estimate the free level of the drug with the following formula:
Free phenytoin = measured level/ [(0.2 × albumin level) + 0.1].
Provide vitamin K augmentation late in pregnancy. In addition to routinely prescribing 4 mg/d folic acid for pregnant women with epilepsy, we recommend oral augmentation of vitamin K as another protective measure.
AEDs that induce hepatic CYP enzymes also induce vitamin K metabolism, thereby reducing the effectiveness of vitamin K-dependent clotting factors and predisposing newborns to hemorrhagic disease.13 It remains unclear whether only women who are taking CYP enzyme-inducing AEDs or all women taking AEDs should receive oral vitamin K supplementation in the last few weeks of pregnancy. We recommend oral vitamin K supplementation for all pregnant women with epilepsy (phytonadione 10 mg/d) starting at 36 weeks’ gestation and continuing until delivery despite the lack of a proven benefit because it is safe and carries little, if any, risk.
An intramuscular injection of 1 mg vitamin K is generally given to all newborns—regardless of whether the mother has epilepsy and takes AEDs—to prevent hemorrhagic disease.13
Should women taking AEDs breastfeed?
The advantages of breastfeeding are largely undisputed, but women being treated with AEDs are generally concerned about the possibility of contaminated breast milk. While antiepileptic agents such as gabapentin, lamotrigine, levetiracetam, and topiramate are excreted in breast milk in potentially clinically important amounts, no short-term adverse effects have been observed in nursing infants of women being treated with AEDs.13 Little information is available regarding long-term effects, and the AAN and AES state that further study is needed. Nonetheless, breastfeeding is generally believed to be a relatively safe option for patients with epilepsy who are being treated with AEDs, and is not contra-indicated by the AAN/AES guidelines.13