Epilepsy is the most frequently encountered neurologic disorder during pregnancy. Approximately one third of women with epilepsy have an increase in seizure frequency during pregnancy. Some women have seizures only during pregnancy. Seizure exacerbation may occur at any time, but it is most frequently encountered at the end of the first and at the beginning of the second trimester. The likelihood of a change in seizure frequency appears to be independent of seizure type and frequency before pregnancy.

Although some pregnant women have an exacerbation of their seizures because of noncompliance or sleep deprivation, in the majority of these women, a number of physiologic changes are responsible for the increase in seizure frequency. During pregnancy, hepatic metabolism of antiepileptic drugs is increased, presumably because of the stimulating effect of progesterone on the liver. During pregnancy, glomerular filtration and renal excretion increase. Antiepileptic drugs cleared by the renal route (gabapentin, lamotrigine, levetiracetam) often have an increase in clearance beginning early in pregnancy and ending abruptly soon after delivery. Body weight, total body water, and intravascular volume gradually increase throughout pregnancy. An increase in the volume into which the drug is distributed (volume of distribution) results in a lower plasma concentration, even if the rate of drug metabolism or renal excretion is not altered. Lower plasma concentrations of antiepileptic drugs during pregnancy, therefore, appear to be related to the combined effects of enhanced hepatic metabolism, increased renal clearance, and an increased volume of distribution. The greatest changes in plasma concentration occur during the first trimester with lamotrigine, phenobarbital, and phenytoin, and during the third trimester with carbamazepine.

Another important physiologic change occurring during pregnancy is the change in protein binding of antiepileptic drugs. Plasma albumin concentration tends to decline during pregnancy, which leads to a proportional reduction in the protein binding of drugs. Although the total plasma concentration of a drug may decrease during pregnancy, the free (non-proteinbound) fraction of highly bound drugs such as phenytoin and valproate may increase, so that the concentration of free drug, which is the pharmacologically active portion, may change very little. To monitor effective drug concentration, measuring concentrations of the free drug is sometimes necessary, especially for phenytoin and valproate.

After delivery, drug pharmacokinetic values often return to prepregnancy values within a few days for renally excreted drugs and a few weeks for drugs metabolized by the liver. Returning antiepileptic dosing rates to their prepregnancy values is usually necessary after delivery.

See Chapter 8.

An association between fetal malformations, maternal epilepsy, and antiepileptic drugs has long been noted. In the late 1960s, phenytoin was claimed to be associated with a number of birth anomalies, and the term fetal hydantoin syndrome was coined. However, many of the birth anomalies associated with phenytoin were observed in infants of mothers with epilepsy who were taking antiepileptic drugs other than phenytoin or who were not taking antiepileptic drugs. Although antiepileptic drugs increase the risk for congenital anomalies, the risk of malformations is
increased in mothers with epilepsy, regardless of whether they are taking antiepileptic drugs.

Major malformations include cleft lip and palate, cardiac defects (ventricular septal defects), neural tube defects, and urogenital defects. Whereas congenital malformations in the general population range from 2% to 3%, the risk for malformations in infants of mothers with epilepsy is significantly higher. The risk if the mother is taking antiepileptic drugs is even higher. The risk of malformations in any individual pregnancy in a woman with epilepsy taking a single antiepileptic drug is estimated to be between 4% and 6% for the older antiepileptic drugs.

This risk of major malformations is also increased in mothers receiving polytherapy taking toxic levels of antiepileptic drugs. All of the antiepileptic drugs have been associated with congenital malformations, although the incidence and type of the malformations may vary with the drug. Trimethadione, which should never be used during pregnancy, results in major malformations or fetal loss in 87% of pregnancies. This figure is far higher than that for any other antiepileptic drugs. The risk of spina bifida appears to be significantly greater in infants exposed to valproate or carbamazepine, but not other antiepileptic drugs.

In addition to major malformations, infants born to mothers taking antiepileptic drugs are at increased risk for minor anomalies, including epicanthal folds, hypertelorism, broad or flat nasal bridges, an upturned nasal tip, prominent lips, and fingernail hypoplasia. These minor anomalies, although more common than in the general population, do not influence general health.

Infants of mothers with epilepsy are approximately twice as likely to have an adverse pregnancy outcome. Stillbirths and neonatal death rates of infants of mothers with epilepsy are approximately twice as high as in the general population. Premature births are more common, and birth weights are also lower. Infants of mothers with epilepsy also have a higher risk of mental retardation, learning disabilities, and epilepsy than the general population. Finally, infants born to mothers with idiopathic generalized epilepsy are at increased risk for developing epilepsy.

Limited available studies indicate a risk for impaired cognitive development in the offspring of women with epilepsy. The relative contributions of heredity, maternal epilepsy, antiepileptic drugs, and socioeconomic factors are not clear.

The concentration of a drug in breast milk is determined by the plasma concentration and the protein binding of the medication. Because antiepileptic drugs do not bind to protein in milk, the concentration of drug in milk is approximately the same as the free plasma concentration. The greater the plasma-protein binding, the lower the amount of drug excreted in the milk. Phenytoin
is very poorly absorbed from the infant gastrointestinal tract and tightly bound to plasma proteins; consequently, no detectable amounts of phenytoin are usually found in the plasma of breast-fed infants whose mothers take phenytoin. The amount of phenobarbital and primidone obtained in breast milk can be significant, and some infants nursing from mothers taking phenobarbital have significant plasma concentrations of phenobarbital. Clinical symptoms such as poor suck, lethargy, and irritability may ensue. Lamotrigine is metabolized slowly in neonates, and blood levels may be higher than anticipated from the breast-milk concentration. Measurements of lamotrigine levels in the newborn may be beneficial if the infant becomes lethargic.

The specifics of breast-feeding for each antiepileptic drug are reviewed in Chapter 11. No absolute contraindications exist to breastfeeding while taking antiepileptic medications. The benefits of breast-feeding, such as reduced risk of infection, must be weighed against the immediate and long-term (unknown) risks of exposure to antiepileptic drugs. Women should make individual, informed choices.

All women of childbearing potential should be told the risks associated with pregnancy. Decisions regarding antiepileptic drug therapy should be made before the woman becomes pregnant. If the woman is receiving polytherapy, attempts should be made to convert to monotherapy before she becomes pregnant. Monotherapy should be reduced to the lowest effective dose. All women contemplating pregnancy should be taking folic acid, 1 to 4 mg per day.

All of the commonly used antiepileptic drugs are associated with both minor and major malformations. The drug of choice, therefore, is whichever antiepileptic drug controls a woman’s seizures without causing side effects. However, women with a family history of neural tube defects should probably avoid valproic acid and carbamazepine. During the pregnancy, toxic and subtherapeutic concentrations must be avoided. Monthly monitoring of antiepileptic drug levels during pregnancy is recommended. Because of the increased clearance of antiepileptic drugs during pregnancy, the dosages of antiepileptic drugs often must be increased. If the patient experiences signs of toxicity in the face of apparent therapeutic drug levels, a free phenytoin or valproate plasma concentration determination may be useful.

An ultrasonographic evaluation should be performed to rule out spina bifida, cardiac anomalies, or a limb defect at 16 to 18 weeks. If ultrasound examination is not conclusive, amniocentesis could be performed, and α-fetoprotein levels obtained.

Good nutrition and adequate sleep are essential. The patient must avoid use of other medications, except as directed by a physician. Smoking and the consumption of alcohol should be avoided, because they have been associated with fetal anomalies. Alcohol may also stimulate hepatic pathways, altering the metabolism of antiepileptic drugs, and, thus altering the risk that malformations may occur.

To prevent hemorrhagic disease of the newborn (possibly due to induction of enzymes degrading vitamin K), vitamin K oral supplementation at 10 mg per day should be carried out from the 36th week of gestation until delivery. This practice does not supplant the recommendation of the American Academy of Pediatrics and the American College of Obstetrics and Gynecology that all infants receive vitamin K at birth.