Treatment of Epilepsy During Pregnancy

Nancy Foldvary-Schaefer

Epilepsy affects nearly 1% of the population, including almost 1 million women of childbearing potential (1). The management of epilepsy during pregnancy can be challenging for neurologists as well as other health care professionals. Nearly 50% of pregnancies in the United States are unplanned, with more than half of all unplanned pregnancies ending in abortion (2). Women rarely consult health care providers for preconception planning or during the first few weeks of pregnancy (3). In a survey by the British Epilepsy Association, 51% of women with epilepsy claimed to have never received advice on contraception or the interaction between oral contraceptives (OCs) and antiepileptic drugs (AEDs) (4). Only 34% had ever discussed pregnancy with their physicians, and less than 10% had received information about the adverse effects of AEDs on fetal development (4). Of obstetricians surveyed in Scotland, 51% were unaware of the need for preconception counseling, 33% did not consider it necessary to monitor AED levels, 56% never administered vitamin K1, and nearly 15% usually or always discouraged breast-feeding (5). A U.S. survey of physician practices revealed that 4% of the neurologists and none of the obstetricians polled were aware of the effects of the six most common AEDs on OC efficacy, despite the fact that approximately 25% had reported unexpected pregnancies among patients in their practice (6). These data illustrate the magnitude of the lack of awareness on the part of health care providers of issues faced by women with epilepsy during the childbearing years. Recent guidelines and reviews on the management of women with epilepsy and numerous recent reviews of the subject are excellent resources for physicians caring for this group of patients (1,7, 8, 9).

CONTRACEPTION

In 1972, Kenyon described the first case of OC failure associated with the use of phenytoin (10). Since then, the increased risk for OC failure among women receiving drugs metabolized by the hepatic cytochrome P450 (CYP450) 3A4 (CYP3A4) enzyme, including phenytoin, primidone, carbamazepine, ethosuximide, barbiturates, and topiramate, has been documented (11, 12, 13). Drugs that induce the CYP3A4 isoenzyme accelerate the metabolism of estrogen and progesterone, reducing their concentrations by up to 50% and increasing the risk for unexpected pregnancy (11,12). Phenobarbital, primidone, phenytoin, and carbamazepine also increase the production of sex hormone-binding globulin (SHBG), to which progesterone is tightly bound (14). This further reduces the concentration of unbound (free) progesterone, increasing the likelihood of OC failure. Unexpected pregnancy has been described in women receiving phenytoin concomitantly with subdermal implants containing the synthetic progestin levonorgestrel (Norplant, Wyeth, Philadelphia, Pennsylvania) (15,16). Despite the absence of significant enzyme-inducing properties, oxcarbazepine increases the production of SHBG and significantly reduces estrogen and progesterone concentrations, suggesting that its use may be associated with an increased incidence of OC failure (17). Valproic acid, lamotrigine, gabapentin, felbamate, tiagabine, and levetiracetam do not significantly alter the metabolism of the female sex steroids (18, 19, 20, 21, 22, 23). Zonisamide was found to produce small, most likely clinically insignificant, effects on ethinyl estradiol and levonorgestrel concentrations (24). The efficacy of the intramuscular progestin medroxyprogesterone (Depo-Provera, Pharmacia, Kalamazoo, Michigan) in women with epilepsy is unknown. This long-acting contraceptive is an attractive option both for noncompliant patients and for women with cognitive impairment or psychiatric disorders. Unplanned pregnancies have not been reported in women using medroxyprogesterone, although the manufacturer recommends shortening the interval between injections in women receiving enzyme-inducing drugs (25).

Less than 1% of women in the general population experience accidental pregnancy within the first year of OC use (26, 27, 28). Of 41 women receiving OCs and AEDs in one study, 3 unplanned pregnancies were reported, representing a 25-fold increase over the expected rate of 0.12 (29). The effects of AEDs on sex steroid metabolism in any given patient are unpredictable. The most reliable indicator of OC failure is midcycle bleeding, which is present in more than two-thirds of women taking AEDs prior to actual OC failure (27). Bleeding occurs more often with the use of phenytoin, phenobarbital, or carbamazepine than with valproic acid or benzodiazepines (30). Increasing the dose of estrogen restores normal bleeding patterns in the majority of cases. Previous guidelines recommend the use of OC formulations containing 50 μg ethinyl estradiol or mestranol (31). However, given the number of new formulations released in recent years, the optimal type and route of administration of hormonal contraception in women with epilepsy has not yet been elucidated. The added risk associated with the use of higher-dose estrogen should be discussed. Barrier methods are recommended if breakthrough bleeding occurs.

The effect of OCs on seizure control has not been extensively studied. Based on several small studies, a minority of women experience more frequent seizures after the initiation of OC therapy (32, 33, 34). In the only placebo-controlled study, a low-dose synthetic combination pill did not adversely affect seizure control in 20 women with epilepsy (33). More frequent laboratory monitoring is recommended at the initiation of OC therapy, because sex steroids may accelerate the metabolism of enzyme-inducing drugs. It was recently discovered that lamotrigine plasma levels were reduced by nearly 50% by OCs leading to an increase in seizures after OCs were started or signs and symptoms of toxicity after withdrawal (34a). This interaction is due to the induction of glucuronide conjugating enzymes by OCs, operative in the metabolism of lamotrigine.

OBSTETRIC COMPLICATIONS

A variety of obstetric complications occur more frequently in women with epilepsy (Table 49.1) (3,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45). The risk for spontaneous abortion is slightly higher in women with epilepsy than in the general population, as well as in treated versus untreated women with epilepsy (35,40,46). In one study, the risk for spontaneous abortion was four times higher among women with epilepsy and more than two times higher in the wives of men with epilepsy than was the rate in the women’s same-sex siblings (41). The rate of elective abortion is also higher in women with epilepsy than in the general population (35,43). Labor and delivery are uncomplicated in the majority of cases, although labor induction and cesarean section are performed at least twice as often in women with epilepsy compared with the general population (36, 37, 38,40,45,47,48). Epilepsy alone is not an indication for these procedures. Cesarean section should be considered in women with neurologic or cognitive impairment that is likely to interfere with maternal cooperation during labor, women with poorly controlled seizures during the third trimester, and women with a history of stress-induced seizures. Emergency cesarean section is warranted when seizures during labor adversely affect the infant or impede maternal cooperation. The incidence of perinatal mortality is increased twofold among infants born to women with epilepsy (36,37,49, 50, 51).

TABLE 49.1 OBSTETRIC COMPLICATIONS IN WOMEN WITH EPILEPSY

Toxemia	Abruptio placentae
Preeclampsia	Premature labor
Hemorrhage	Low Apgar scores
Anemia	Hyperemesis gravidarum
Pregnancy-induced hypertension	Perinatal mortality
Spontaneous abortion	Cesarean section
Forceps-assisted delivery	Labor induction

SEIZURE CONTROL

The fear of more frequent seizures is a major concern among pregnant women with epilepsy. Seizure frequency appears to be unchanged in more than half of cases, whereas approximately one third of women experience more frequent seizures, and a minority are improved (Table 49.2). Seizures may increase during the first trimester (52,53) or toward the end of pregnancy and in the puerperium (47,51,54, 55, 56, 57). Following pregnancy, seizure control reverts back to preconception levels in the majority of cases (53). Poor preconception seizure control appears to be a reliable predictor of seizure control during pregnancy. Women with monthly seizures are significantly more likely to have more frequent seizures during pregnancy than those who are seizure free or have infrequent seizures in the year before conception (43,44,47,53). Other factors leading to breakthrough seizures include declining AED concentrations as a consequence of the physiologic changes of pregnancy, noncompliance, stress, and sleep deprivation. Noncompliance and/or sleep deprivation is present in more than 50% of women with breakthrough or worsening seizures during pregnancy (58,59). Anxiety over fetal AED exposure and fears about breastfeeding are the most common reasons for noncompliance (58). The incidence of status epilepticus is comparable to that of the general epileptic population; however, morbidity and mortality for both mother and fetus are high. Eclampsia, subarachnoid hemorrhage, choriocarcinoma, pheochromocytoma, cerebral venous thrombosis, amniotic fluid embolus, and thrombotic thrombocytopenic
purpura should be considered in women experiencing new seizure types or new onset of seizures during pregnancy.

TABLE 49.2 SEIZURE FREQUENCY DURING PREGNANCY^a

Series	Pregnancies	Unchanged (%)	Increased (%)	Decreased (%)	SE^b (%)
Knight and Rhind (53)	153	51	44	5	1.3
Nakane et al. (46)	227	59	32	9	NA
Remillard et al. (56)	78	50	46	4	NA
Schmidt et al. (59)	136	50	37	13	NA
Otani (58)	125	70	23	7	NA
Bardy (55)	154	54	32	14	0
Gjerde et al. (199)	78	66	17	17	1.3
Wilhelm et al. (44)	93	63	25	6	1.0
Dravet et al. (112)	50	66	22	12	NA
Tanganelli and Regesta (43)	138	80	17	3	NA
Tomson et al. (66)	93	61	15	24	NA
Sabers et al. (51)	143	66	21	7	0
Vidovic and Della Marina (200)	50	54	22	24	0
Total	1518	61	29	10	0.6
Abbreviation: NA, data not available.
^aMinimum of 50 pregnancies reported in the English literature. ^bStandard error for 684 pregnancies.

To avoid the adverse effects of seizures on the fetus, factors leading to more frequent seizure occurrence should be minimized. Isolated, generalized motor seizures during pregnancy can produce fetal bradycardia, decelerations, and decreased variability lasting up to 30 minutes (60,61). Intracranial hemorrhage and death after isolated motor seizures have been described (62). Whether other seizure types directly harm the fetus is less clear. Nei and colleagues (63) recorded fetal decelerations lasting 3.5 minutes and pronounced fetal bradycardia during a 1-minute complex partial seizure, suggesting that nonconvulsive seizures may also be detrimental to the fetus.

PHARMACOKINETICS OF ANTIEPILEPTIC DRUGS

Changes in hepatic, renal, gastrointestinal, and cardiovascular physiology during pregnancy alter the pharmacokinetics of AEDs (64, 65, 66, 67). As pregnancy progresses, AED concentrations tend to decrease because of reduced protein binding, greater volume of distribution, accelerated hepatic metabolism, increased renal clearance, impaired intestinal absorption, and noncompliance. Increased concentrations of estrogen and progesterone accelerate the metabolism of enzyme-inducing drugs. Serum concentrations of AEDs begin to fall in the first trimester, reaching a nadir near term and returning to their preconception levels within 4 to 12 weeks postpartum (67,68). This has been most frequently demonstrated with phenytoin (66,69, 70, 71, 72, 73, 74, 75, 76), valproic acid (70,77), phenobarbital (68,70, 71, 72), and carbamazepine (66,68,72). Alterations in protein binding are most marked in the third trimester, resulting in higher unbound (free) fractions of drugs that are more rapidly eliminated (78). Consequently, for the highly protein-bound drugs phenytoin, valproic acid, and, to a lesser degree, carbamazepine, free levels are more reliable during pregnancy. The percent decline in total concentrations of phenytoin, phenobarbital, carbamazepine, and valproic acid was found to be 56%, 55%, 42%, and 39%, respectively; free levels of phenytoin, phenobarbital, and carbamazepine fell by 31%, 50%, and 11%, respectively, and free valproic acid concentrations increased by 25% (67). The sharpest decline in phenytoin and phenobarbital concentrations occurs in the first trimester, whereas carbamazepine levels decline maximally in the third trimester and valproic acid concentrations appear to decline more steadily throughout pregnancy (67).

With the exception of lamotrigine, little is known of the pharmacokinetics of the newer AEDs in pregnancy. The apparent clearance of lamotrigine increases during pregnancy by as much as 330% above preconception levels, leading to breakthrough seizures and dose escalation in most cases (79,79a,80). Apparent clearance returned to baseline as early as 2 weeks postpartum, requiring dose reduction often in the first few days postpartum to prevent toxicity. Until more is known, women taking the newer AEDs should be monitored closely for breakthrough seizures during pregnancy and for signs of toxicity in the early postpartum period.

Table 49.3 shows neonatal AED pharmacokinetics. Protein binding is reduced in newborns compared with adults because of decreased albumin concentrations and increased bilirubin production. In hyperbilirubinemic states, protein binding is further reduced, resulting in increased
free fractions of such highly bound drugs as phenytoin and valproic acid. Albumin increases rapidly over the first few days of life, reaching adult levels by 5 months of age. Similarly, renal tubular function is reduced in neonates, which may have major implications on the capacity for excretion of drugs such as gabapentin, levetiracetam, and vigabatrin. Because primidone is metabolized in the newborn, levels of phenobarbital and phenylethylmalonamide may increase transiently after birth (81). Placental transfer of valproic acid is more efficient from mother to fetus, and therefore concentrations of valproic acid and its metabolites are higher in umbilical cord blood than in maternal serum (82). Serum concentrations of the other AEDs are generally lower in cord blood than in maternal serum. Drug clearance is reduced in the first few days of life; the half-life of drugs is prolonged in neonates compared with children and adults. Longer drug half-lives and slower clearance rates have been reported in premature infants compared with term infants. The activity
of most enzymes involved in drug metabolism reaches that of adult levels by 2 to 3 months of age.

TABLE 49.3 PHARMACOKINETICS OF NEONATAL ANTIEPILEPTIC DRUGS

Agent	Adult Half-life (h)	Neonate Half-life (h)	Cord-to-Maternal Serum Ratio	Breast Milk-to-Plasma Ratio
Phenobarbital	75-110	42-563	0.6-1.0	0.4-0.6
Primidone	10-15	7-60	0.4-1.2	0.4-1.0
Phenytoin	9-30	9-110	0.5-1.0	0.1-0.6
Ethosuximide	30-60	41	1.0	0.8-1.0
Carbamazepine	9-15	8-36	0.5-0.8	0.2-0.7
Valproic acid	6-18	28-88	0.5-4.6	0.01-0.2
Felbamate	13-22	NA	NA	NA^a
Gabapentin	5-7	NA	NA	0.6
Lamotrigine	12-62	NA	0.6-1.3	0.56-0.61
Topiramate	12-24	24	1.0	0.86
Tiagabine	7-9	NA	NA	NA^b
Oxcarbazepine	8-10^c	17^c	0.21/0.19	0.5
Levetiracetam	6-8	NA	NA	NA
Zonisamide	50-70	61-109	0.92	0.93
Abbreviation: NA, data not available.
^aExcreted in human breast milk; concentration unknown. ^bExcreted in breast milk of lactating rats. ^cFor the active metabolite, 10-monohydroxy (MHD). Data from Bossi L, Assael M, Avanzini G, et al. Plasma levels and clinical effects of antiepileptic drugs in pregnant epileptic patients and their newborns. In: Johannessen S, et al., eds. Antiepileptic therapy: advances in drug monitoring. New York: Raven Press, 1980:9-18; Nau H, Rating D, Koch S, et al. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother’s milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 1981;219:768-777; Bossi L. Neonatal period including drug disposition in newborn: review of the literature. In: Janz D, Dam M, Richens A, et al., eds. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982:327-341; Baughman FA Jr, Randinitis EJ. Passage of diphenylhydantoin across the placenta. JAMA 1970;213:466; Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 1998; Froescher W, Gugler R, Niesen M, et al. Protein binding of valproic acid in maternal and umbilical cord serum. Epilepsia 1984;25:244-249; Kaneko S, Sato T, Suzuki K. The levels of anticonvulsants in breast milk. Br J Clin Pharmacol 1979;7:624-627; Kuhnz W, Jager-Roman E, Rating D, et al. Carbamazepine and carbamazepine-10,11-epoxide during pregnancy and postnatal period in epileptic mother and their nursed infants: pharmacokinetics and clinical effects. Pediatr Pharmacol (New York) 1983;3:199-208; Kuhnz W, Koch S, Jakob S, et al. Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status. Br J Clin Pharmacol 1984;18:671-677; Kuhnz W, Koch S, Helge H, et al. Primidone and phenobarbital during lactation period in epileptic women: total and free drug serum levels in the nursed infants and their effects on neonatal behavior. Dev Pharmacol Ther 1988;11:147-154; Mirkin BL. Placental transfer and neonatal elimination of diphenylhydantoin. Am J Obstet Gynecol 1971;109:930-933; Nau H, Kuhnz W, Egger HJ, et al. Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet 1982;7:508-543; Pynnonen S, Kanto J, Sillanpaa M, et al. Carbamazepine: placental transport, tissue concentrations in foetus and newborn, and level in milk. Acta Pharmacol Toxicol (Copenh) 1977;41:244-253; Rane A, Bertilsson L, Palmer L. Disposition of placentally transferred carbamazepine (Tegretol) in the newborn. Eur J Clin Pharmacol 1975;8:283-284; Bulau P, Paar WD, von Unruh GE. Pharmacokinetics of oxcarbazepine and 10-hydroxy-carbazepine in the newborn child of an oxcar-bazepine-treated mother. Eur J Clin Pharmacol 1988;34:311-313; Kawada K, Itoh S, Kusaka T, et al. Pharmacokinetics of zonisamide in perinatal period. Brain Dev 2002;24:95-97; Myllynen P, Pienimaki P, Jouppila P, et al. Transplacental passage of oxcarbazepine and its metabolites in vivo. Epilepsia 2001;42:1482-1485; Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000;41:709-713; and Shimoyama R, Ohkubo T, Sugawara K. Monitoring of zonisamide in human breast milk and maternal plasma by solid-phase extraction HPLC method. Biomed Chromatogr 1999;13:370-372.

All of the AEDs are detectable in breast milk, usually at concentrations lower than that of maternal serum. Data on the newer AEDs are extremely limited. The primary factors influencing the excretion of drugs into breast milk include plasma protein binding, lipid binding, and ionization characteristics. For agents that are highly protein bound, excretion into breast milk tends to be low. Conversely, because breast milk has a higher triglyceride content than plasma, drugs with high lipid solubility, such as benzodiazepines, tend to accumulate in milk. Because only the un-ionized drug diffuses across biologic membranes, the degree of ionization of an agent affects its concentration in milk. Nevertheless, it is generally believed that breast-feeding need not be discouraged in women with epilepsy, because the advantages seem to outweigh the risks of adverse effects in the newborn (83). In most instances, breast-feeding is accomplished without difficulty. If irritability or sedation after feeding are observed, breast-feeding should be discontinued.

The majority of infants born to women taking AEDs have no significant AED-related adverse effects. However, neonatal sedation, hypotonia, poor sucking, feeding difficulty, and, rarely, respiratory depression have been reported. These difficulties are usually apparent at birth and disappear within 2 to 8 days. An estimated 5% to 10% of exposed infants are affected (84,85). Withdrawal symptoms have been reported in infants exposed to barbiturates, phenytoin, and benzodiazepines (85). Clinical features of neonatal AED withdrawal include hyperactivity, hyperreflexia, hyperventilation, hyperphagia, vomiting, excessive crying, disturbed sleep, seizures, tremors, myoclonus, hypertonia, sneezing, and yawning (85, 86, 87, 88). Symptoms typically begin shortly after birth and last from days to months, although the onset may be delayed for up to 10 to 15 days (89). Transient hepatic dysfunction associated with carbamazepine exposure and paralytic ileus in a fetus exposed to clonazepam and carbamazepine have been reported (90, 91, 92).

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