Drugs, Pregnancy, and Lactation

OB/GYN News, Oct 1, 2001 by Gideon Koren

An estimated 0.5%-2% of pregnant women are on antiepileptic medication. Most experts would agree that medical treatment of seizures cannot be stopped during pregnancy because of the high risks to the fetus if the mother has a seizure. The problem is that most first-line antiepileptic drugs have been associated with some degree of fetal risk, although the vast majority of exposed fetuses are not affected.

Some studies suggest epilepsy itself is associated with a higher risk of fetal malformations. Other research has come to different conclusions. A recent study following a relatively large group of untreated pregnant women with epilepsy suggested the disorder confers no increased fetal risk.

All three of the first-line drugs for treating epilepsy--carbamazepine (Tegretol), valproic acid (Depakote), and phenytoin (Dilantin)--have been associated with some fetal risks.

There are not much data yet on the safety of the new generation antiepileptics, such as lamotrigine (Lamictal) and gabapentin (Neurontin), when used during pregnancy.

When antiepileptics are combined, the rate of fetal malformations increases. Thus, when a woman is on more than one antiepileptic, she should be followed closely with detailed ultrasound. For a patient planning a pregnancy, clinicians should carefully consider whether she can be managed on fewer drugs before she conceives.

Here is a rundown on the risks associated with various antiepileptics:

* Valproic acid. This drug is associated with about a 2% risk of neural tube defects, which can be detected in utero with detailed ultrasound and alpha-fetoprotein measurement. There is a debate over whether valproic acid is associated with other malformations, such as limb deformities, but the evidence for this has not been strong.

* Carbamazepine. This agent is associated with about a 1% risk of neural tube defects in exposed fetuses. Whether in utero exposure affects development or IQ is still debated. One of our studies found that the IQ scores of carbamazepine-exposed babies followed from pregnancy through ages 2-4 were similar to those of controls. But an Israeli study published in 1996 found slightly lower IQs among exposed children, so clearly the verdict is not in. Still, for the most part, carbamazepine is considered the antiepileptic drug of choice during pregnancy by many clinicians.

* Phenytoin. Phenytoin is associated with fetal hydantoin syndrome, typified by changes in the finger tips, hypoplasia of nails, a broad nasal bridge, a wide distance between the eyes, and developmental delay.

Few studies on in utero exposure to phenytoin have been conducted. One of the studies, conducted prospectively by my colleagues and me, found that 7 of the 34 babies born to 34 women treated with phenytoin during pregnancy had severe mental retardation at ages 2-4 years, compared with one case among controls.

* Phenobarbital. Although it does not appear to increase the risk of major malformations, phenobarbital is not used as much as it once was. A compelling study from the Netherlands of children whose mothers were given phenobarbital or placebo late in pregnancy for premature rupture of the membranes to induce bilirubin conjugation found that 18 years later those exposed to phenobarbital had lower IQs and lower levels of school achievement, compared with those exposed to placebo.

Although it hasn't been proven to reduce the risk of neural tube defects in exposed babies, many would agree that women on valproic acid or carbamazepine should take 4 mg of folic acid a day rather than 0.4 mg before conception and during the first trimester.

The tendency during pregnancy is to give the lowest possible dose of medications, which is warranted, but as the pregnancy progresses, a woman may need more of the drug to remain in the therapeutic range. Later in pregnancy, when seizures can also be induced by other causes, such as hypertension, hyponatremia, and hypoalbuminemia, higher doses may be needed. Physicians may want to check blood levels of the antiepileptic drug to see if patients are still in the therapeutic range.

Carbamazepine, valproic acid, and phenytoin are compatible with breastfeeding; a very small amount of these drugs is excreted into breast milk and has no apparent effect on the baby. Phenobarbital, however, is excreted in large amounts into breast milk and is not compatible with breast-feeding, because it may cause sedation and CNS depression in the baby.

DR. GIDEON KOREN is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He is also the director of the Motherisk Program at the Hospital for Sick Children in Toronto, which conducts research and provides information and counseling to women and health care providers on drug therapy during pregnancy. More information is available at www.motherisk.org or by calling 416-813-6780.