Introduction

For persons with epilepsy the past 20 years have seen enormous advances in the development of superior diagnostic and treatment techniques. We have also seen a significant improvement in social attitudes towards persons with epilepsy. Marriage and child rearing have in the past been seen as inappropriate activities for women with epilepsy (WWE). These unfortunate and misguided attitudes were often based on the misperception that epilepsy was inherited, or that the behavior of people with epilepsy was unpredictable and hence unsuitable for childrearing.

Nothing could be farther from the truth. Women with epilepsy can and do have normal and healthy children. The risk of epilepsy in the offspring of persons with this disorder are small. More effective antiepileptic drugs (AEDs), the ability to perform therapeutic plasma monitoring of these drugs, and a better understanding of the risk factors for pregnancy have resulted in significantly improved care.

There are however special problems that women with epilepsy face in respect to fertility, contraception, and pregnancy. Women with epilepsy have lower fertility rates than that of the general population. Certain AED can interfere with the effectiveness of hormonal contraceptives, thus increasing the risk of unplanned pregnancies. Pregnancy, labor and delivery present particular risks for women with epilepsy. The post partum period is one in which changes in a woman's metabolism can result in changes in AED concentration, and the importance of seizure control increasing with the new responsibilities of child care. This chapter will review these issues in turn.

Contraception

The ability to conceive is taken for granted by most women. In fact considerable effort is directed to prevent unwanted pregnancy. Women with epilepsy, however, have only 1/4 to 1/3 as many children as women in the general population (Svigos 1984. Yerby et al. 1984). Explanations for this phenomenon have included social and organic hypotheses. Seizures may have an effect on pituitary-hypothalamic action and disrupt ovulation. Electroconvulsive therapy increases prolactin within 15 to 20 minutes, and in premenopausal women there is an acute increase in both LH and FSH. Generalized and in some instances partial complex seizures can also increase prolactin serum concentrations by a factor of 3. This fact has been used to assist physicians in differentiating epileptic from non-epileptic seizures (Trimble et al. 1978).

Strong social pressures on women with epilepsy to refrain from reproducing may also be a factor. In a study of patients at the Montreal Neurological Institute (Dansky et al. 1980), marital rates were lower in men and women whose epilepsy began before the age of 20. Men whose seizures began before age 10 and between the ages 10 and 20 had marital rates of 58% (p<.025) and 89% (p>.05) of the general population, respectively. Among women, those whose seizures began before age 10 and between the ages of 10-20 years had marital rates of 32% (p<.01) and 47% (p<.01) of the general population, respectively. Since most live births occur in the setting of marriage, the lower marriage rates in persons with epilepsy would be expected to correlate with lower reproductive "success" of these individuals.

In a creative approach to this problem Schupf and Ottman (1994), compared the fertility rates of persons with epilepsy with their unaffected siblings. They demonstrated that WWE who are unmarried have fertility rates only 36 % of their siblings. When WWE marry that rate increases to only 42 %. In contrast unmarried men with epilepsy have fertility rates of 35 % which climb to 78 % when they marry. This suggests that organic as opposed to social factors may contribute to the higher rates of infertility in women with epilepsy.

Menstrual irregularity and anovulatory cycles are seen more often in WWE (Backstrom, 1976). Herzog and co-workers (1986) demonstrated reproductive and endocrine disorders (RED) in a cohort of women with temporal lobe epilepsy. Nineteen of 50 women had significant reproductive problems. Seven had polycystic ovarian disease, 7 had hypergonadotropic hypogonadism, and 6 hypogonadotrophic hypogonadism. Women with primary generalized epilepsies have also been shown to have RED. Five of 20 women studied by Bilo and colleagues (1988) had RED, 3 with polycystic ovarian disease, and 2 with hypogonadotropic hypogonadism. Women with epilepsy have been found to have more variation in lutenizing hormone (LH) pulse frequency and lower LH concentrations than controls (Drislane et al. 1994). In addition women with left sided ictal epileptiform foci had polycystic ovarian disease, and those with right sided foci hypogonadotropic hypogonadism.

Ascertainment bias could account for the high proportion of WWE with RED in these studies. When the fertility rates of married women with epilepsy are considered however, it becomes more probable that seizures may contribute to this problem.

The other important variable are AED. Antiepileptic drugs may interfere with the hypothalamic pituitary axis. Amenorrhea, oligomenorrhea, prolonged or irregular cycles were seen in 20 % of 238 WWE ( Isojarvi et al. 1993). Though only 12 % of the 238 women were treated with valproate, 45 % of those on valproate monotherapy and 25 % on valproate polytherapy had menstrual disturbances. Polycystic ovaries were found in 43 % of valproate treated women. Eighty percent of women treated with valproate before the age of 29 had polycystic ovarian disease.

The problem of infertility in WWE is clearly complicated. There are probably multiple factors: both seizure type, frequency and perhaps lateralization; as well as AEDs which may effect an individual patient. Infertility in a couple deserves a careful evaluation of both partners. For WWE ultrasonography to rule out polycystic ovarian disease, serum LH and FSH concentrations, and an evaluation of AED use will help one narrow the focus of treatment. While there is evidence that valproate may adversely impact the fertility of some women, unless polycystic ovarian disease or hypogondaotropic hypogonadism is found, discontinuation of valproate in a well controlled person is not warranted.

Hormonal Contraceptives and AED

The effectiveness of oral and other forms of hormonal contraception can be reduced by enzyme inducing AED (carbamazepine, phenytoin, phenobarbital, felbamate, topiramate). We think of hormonal contraceptives as oral medications. It is important to remember that they come in three formulations: oral (estrogen-progesterone combinations, or progesterone only); implantable subcutaneously (levonorgestrel), or intrauterine (progestasert); and injectable (depoprovera). All three forms can be adversely impacted by AED.

AEDs lower concentrations of estrogens by 40 to 50 %. They also increase sex hormone binding globulin (SHBG) hence increasing binding of progesterone and therefore reducing unbound progesterone. The result is that with enzyme inducing AED hormonal contraception is less reliable.

Kenyon (1972) and others (Hempel et al, 1973; Janz and Schmidt, 1974) have found that oral contraceptives (OC), with lower estrogen-content, breakthrough bleeding occurred in some women on AEDs. Breakthrough bleeding refers to vaginal bleeding during the middle of the cycle, and results from a relative lack of estrogen. In some of these women with breakthrough bleeding, unplanned pregnancies later occurred. The contraceptive failure of the combined (estrogen-progesterone) OC is approximately 0.4 pregnancies per 100 women. In WWE taking enzyme-inducing AEDs, the failure rate is higher, although the exact numbers probably vary with the dose of AED and the specific OC.

Low or mini dose oral contraceptives are to be avoided. Oral contraceptives should have at least 50ug. of estrogens. The more rapid clearance of the estrogens will reduce the likelihood of unwanted side effects from higher dose tablets.

Failure of implantable hormonal contraceptives have also occurred. Midcycle spotting or bleeding is a sign that ovulation is not being prevented and suggests the need to use alternative or supplementary methods of contraception such as barriers. Contraceptive failure may not always be predicable, even when midcycle spotting does not occur. Basal morning temperature charting can document ovulatory suppression. Use of a non enzyme inducing AED may be considered (valproate, lamotrigine, gabapentine).

Pregnancy

Most women with epilepsy can conceive and deliver healthy children. Their pregnancies are however, considered to be high risk due to the fact that these women have more complications of pregnancy, labor and delivery and have a higher risk of adverse pregnancy outcomes.

Seizures

During pregnancy, one-quarter to one-third of women with epilepsy will have an increase in seizure frequency (Sabin and Oxorn 1956), see Table 1. This increase is unrelated to seizure type, duration of epilepsy, or seizure frequency in a previous pregnancy. Knight and Rhind (1975) found an association between seizure frequency prior to pregnancy and increased seizures during gestation. They also found that seizures were most frequent in pregnancies with male (64%) as opposed to female (30%) infants. These observations have not been verified by other investigators (Bardy 1982, Philbert and Dam 1982, Schmidt et al. 1983).

The increase in seizure frequency seen during pregnancy is strongly associated with the changing kinetics of AED in pregnancy. Plasma concentrations of AED decline as pregnancy progresses even in the face of constant and in some instances increasing doses (Nau et al. 1981). Plasma concentrations tend to rise postpartum (Yerby et al. 1990). While reduction of plasma drug concentrations are not always associated with an increase in seizure frequency, virtually all women with increased seizures in pregnancy have subtherapeutic drug levels (Dansky et al. 1982, Janz 1982, Schmidt et al. 1982, Schmidt et al. 1983, Otani 1985).

Several mechanisms have been proposed to explain the decline of anticonvulsant levels during pregnancy. Intestinal malabsorption (Ramsay et al. 1978), decreased plasma protein binding (Perruca and Crema 1981, Yerby, Friel, and Miller 1985), reduced concentration of albumin, and increased drug clearance (Eadie, Lander, and Tyrer 1977, Dam et al. 1979, Nau et al. 1981, Janz 1982, Philbert and Dam 1982) may all play some role. The rate of clearance appears to be greatest during the third trimester.

Falling levels of anticonvulsant drugs appear to be strongly associated with increasing seizure frequency. Some clinical observations are at variance with this. The increase in seizure frequency has been described both in first trimester (Maroni and Markott 1969, Knight and Rhind 1975, Canger et al. 1982, Schmidt et al. 1983) or evenly distributed throughout pregnancy (Huhmar and Jaruinen 1961) and not exclusively in the third trimester when the levels have fallen their lowest.

Other factors particularly compliance issues, may also contribute to the fall in levels. In a prospective study, Schmidt and coworkers (1983) discovered that 50 of 136 (37%) of pregnant women with epilepsy had an increase in seizure frequency. Upon careful questioning, 68% of these women were not compliant or suffering from sleep deprivation. A prospective Japanese study, Otani (1985) described an increase in seizure frequency in 27% of women. One half of these women were deliberately non compliant because of concerns about the effect of anticonvulsants on their children. With all of these factors contributing to the fall of levels during pregnancy, monthly monitoring of anticonvulsant drugs using free levels is advised (Levy and Yerby 1985).

Convulsions are undesirable during pregnancy. First trimester seizures have been found to result in an increased risk of congenital malformations in the offspring 12.3 % vs. 4 % for children exposed to maternal seizure at other times (Lindhout et al 1992). Generalized, tonic-clonic seizures place both mother and fetus at risk for hypoxia and acidosis (Stumpf and Frost 1978). Although rare, stillbirths have occurred following a single generalized convulsion (Burnett 1946, Higgins and Comerford 1974) or series of seizures (Suter and Klingman 1957). Status epilepticus carries a high mortality rate for mother and fetus. In Teramo and Hiilesmaa's review, status epilepticus was an uncommon complication of epileptic pregnancies. Yet of the 29 reported cases, nine of the mothers and 14 of the infants died during or shortly after an episode of status (Teramo and Hiilesmaa 1982). The child of a woman who had three generalized tonic clonic seizures during her pregnancy, (at 19, 28, and 32 weeks gestation), developed an intracerebral hemorrhage (Minkoff et al. 1985).

Generalized (though not partial) convulsions occurring during labor can have a profound effect on fetal heart rate (Teramo et al. 1979). The increased rate of neonatal hypoxia and low Apgar scores may be related to such events (Yerby, Koepsell, and Daling 1985). Though generalized convulsions may have an adverse effect on fetal heart rate, partial seizures do not appear to do so.

Maternal Complications

Women with epilepsy are at greater risk for obstetrical complications during pregnancy. (Bjerkdal and Bahna 1973, Monson, Rosenberg, and Hartz 1973, Montouris, Fenichel, and McLain 1979). Vaginal bleeding has been described significantly more often in women with epilepsy than controls (Bjerkdal and Bahna 1973, Nelson and Ellenberg 1982). Anemia has been described twice as often in women with epilepsy (Svigos 1984). Hyperemesis gravidarum occurs more frequently in these patients (Bjerkdal and Bahna 1973, Nelson and Ellenberg 1982), which may complicate compliance with oral medication. Pre-eclampsia has been described more frequently in these women (Bjerkdal and Bahna 1973, Vert and Deblay 1979, Nelson and Ellenberg 1982).

Labor and delivery also offers more difficulties for women with epilepsy. Abruptio placentae and premature labor have been described more often in these patients (Janz and Fuchs 1964, Hill and Tennyson 1982, Kalter and Warkany 1983). Janz and Fuchs (1964) described weak uterine contractions in women taking anticonvulsant drugs, which may explain why interventions are utilized more frequently in these patients. Induced labor, mechanical rupture of membranes, the use of forceps or vacuum assistance, and cesarean sections are twice as common in these pregnancies (Bjerkdal and Bahna 1973, Egenaes 1982, Hill and Tennyson 1982, Yerby, Koepsell, and Daling 1985). Obstetricians caring for these women must be aware of the higher risks and be prepared to intervene.

Meperidene is frequently used for pain control post partum. It should used with caution due to its propensity for lowering seizure threshold. Serum AED levels tend to rise in the post partum period, plateauing around 8 to 10 weeks. Women whose dosage has been increased during pregnancy may therefore develop clinical toxicity, and need to be carefully monitored in the post partum period (Yerby et al 1990).

Fetal Complications

The infants of mothers with epilepsy (IME) are at greater rsik for a variety of adverse pregnancy outcomes. None of which has received the attention of investigators that congenital malformations have.

The first report of a malformation associated with anti-epileptic drugs (AED) described a child exposed to mephenytoin in utero who developed microcephaly, cleft palate, malrotation of the intestine, a speech defect and an IQ of 60 (Müller–Kuppers 1963). The pregnancy was also complicated by vaginal bleeding. In 1964 Janz and Fuchs performed a retrospective survey to evaluate the problem of AED–associated malformations at the University of Heidelberg. Four hundred and twenty–six pregnancies in 246 mothers with epilepsy were studied. The rates of miscarriages and stillbirths were increased for these patients, but the malformation rate was only 2.2% not significantly different from that of the general population of West Germany. The authors concluded that AED were not associated with an increased risk of malformations.

Pantarotto (1965) described a neonate with aplasia of the bone marrow after phenytoin exposure in utero. Centra and Rasore–Quartino (1965) reported the first case of congenital heart disease with in utero exposure to phenytoin and phenobarbital. Melchior et al (1967) described orofacial clefts with exposure to primidone or phenobarbital. In a 1968 letter published in Lancet, S.R. Meadow reported 6 cases of children with orofacial clefts, 4 of whom had additional abnormalities of the heart and dysmorphic facial features. All of these children had been exposed to AED in utero. He noted that similar abnormalities had been reported following the unsuccessful use of abortifactant folic acid antagonists. Since some AED act as folic acid antagonists he postulated that this might account for AED teratogenicity, and asked for other clinicians to inform him of similar cases. This resulted in the collection of an 30 additional cases and prompted a retrospective survey in which 427 pregnancies in 186 women with epilepsy were reviewed. For the first time, a clear increase in the malformation rates of infants of mothers with epilepsy (IME) was demonstrated. Speidel and Meadow concluded that: 1) congenital malformations are twice as common in IME exposed to AED; 2) no single abnormality was specific for AED exposure; 3) a group of these children would have a characteristic pattern of anomalies which, at its fullest expression, consisted of trigonocephaly, microcephaly, hypertelorism, low set ears, short neck, transverse palmar creases, and minor skeletal abnormalities.

Congenital malformations remain the most commonly reported adverse outcomes in the pregnancies of epileptic mothers. Malformation rates in the general population range from 2 to 3% (Kalter & Warkany 1983, Kelly 1984a). Reports of malformation rates in various populations of IME range from 2.3 to 18.6% (Janz & Fuchs 1964, Meyer 1973, Nakane et al 1980, Meadow 1968, Philbert & Dam 1982). These combined estimates yield a risk of malformations in an individual epileptic pregnancy of 4 to 8%. Evaluation of these studies reveals a wide range of methodologies, and it is questionable whether it is even appropriate to combine data from these studies. Some are matched controls (Koch et al 1992, Tanganelli & Regesta 1992), while others use population registers (Dravet et al 1992, Robert et al 1992), and many have no controls at all (Lindhout et al 1992, Kallen 1986). Despite the variety of approaches a consistent trend is seen with infants of women with epilepsy having roughly 2 to 3 times the number of infants with malformations when compared to the general population (Table 1).

TERATOGENICITY OF ANTIEPILEPTIC DRUGS

Table 1. Malformation rates in the offspring of epileptic and control mothers

	Control		Epileptic Mothers
Authors	Malformation Rate(%)	No. of Pregnancies	Malformation Rate(%)	No. of Pregnancies
Sabin & Oxorn (1956)	5.4	56
Janz & Fuchs (1964)	2.3	225
German et al (1970)	5.3	243
Elshove & Van Eck (1971)	1.9	12,051	15.0	65
Speidel & Meadow (1972)	1.6	483	5.2	427
South (1972)	2.4	7,892	6.4	31
Spellacy (1972)	50	5.8	51
Bjerkedal & Bahna (1973)	2.2	12,530	4.5	311
Fedrick (1973)	5.6	649	13.8	217
Koppe et al (1973)	2.9	12,455	6.6	197
Kuenssber & Knox (1973)	3.0	14,668	10.0	48
Lowe (1973)	2.7	31,877	5.0	245
Meyer (1973)	2.7	110	18.6	593
Millar & Nevin (1973)	3.8	32,227	6.4	110
Monson et al (1973)	2.4	50,591	4.7	306
Miswander & Wertelecki (1973)	2.7	347,097	4.1	13
Biale et al (1975)	16.0	56
Knight & Rhind (1975)	3.65	69,000	4.3	140
Starreveld & Zimmerman (1975)	7.0	372
Visser et al (1976)	2.3	9,869	3.7	54
Weber et al (1977)	2.2	5,011	4.0	731
Annegers et al (1978)	3.5	748	8.1	259
Seino & Miyokosh (1979)	13.7	272
Dieterich et al (1980)	37
Majewshi et al (1980)	16.0	111
Nakane et al (1980)	11.5	700
Hillesmaa et al (1981)	2.0	5,613	7.7	4,795
Lindhout et al (1984)	2.4	151
Stanley et al (1985)	3.4	62,265	3.7	244
Beaussart et al (1986)	7.8	295
Kallen (1986)	4.9	635
Robert et al (1986)	1.4	20,916	6.7	148
Rating et al (1987)	3.7	162	5.3	150
Gaily (1990)	2.9	105	9.1	153
Dravet et al (1992)	1.4	117,183	7.0	281
Kaneko et al (1992)	6.2	145
Koch et al (1992)	4.3	116	6.9	116
Lindhout et al (1992)	7.6	172
Tanganelli & Regesta (1992)	2.6	140	3.6	138

There are a number of potential factors which could account for the increased rates of malformations seen in infants of mothers with epilepsy. Maternal seizures during pregnancy, the epileptic genotype, falls and injuries secondary to the seizures, lower socioeconomic status and its attendant limited access to prenatal care. There are; however, a series of observations which strongly implicate AED as the cause of the increased malformation rate amongst IME. These are: 1) Comparisons of the malformation rates in the offspring of mothers with epilepsy treated with AED as opposed to those with no AED treatment reveal consistently higher rates in the children of the treated group as illustrated in Table 2 (Nakane et al 1980, Speidel & Meadow 1972, Monson et al 1973, Annegers et al 1978, Lowe 1973, South 1972). 2) Mean plasma AED concentrations are higher in mothers with malformed infants than mothers with healthy children (Dansky et al 1980). 3) Infants of mothers on polytherapy have higher malformation rates than those exposed to monotherapy (Nakane 1979, Lindhout et al 1984). 4) Maternal seizures during pregnancy do not appear to increase the risk of congenital malformations (Fedrick 1983).

Although it appears logical to assume that polytherapy carries more inherent risks than monotherapy, high drug levels and multiple drugs may be associated with the severity of epilepsy. Seizure frequency or severity may be a confounding factor, and AED therapy may be only associated with, but not causally responsible for, the increased rate of congenital malformations. Majewski and co–workers (1980) described increased malformation rates and central nervous system injury in IME exposed to maternal seizures. More recently, Lindhout and co-workers (1992) described a marked increase in malformations amongst infants exposed to first trimester seizures (12.3%) compared to fetuses that were not subject to any maternal seizures (4.0%) . Malformations were more often observed in infants exposed to partial seizures than to generalized tonic clonic seizures. Nonetheless, most investigators have found that maternal seizures during pregnancy had no impact on the frequency of malformations, development of epilepsy or febrile convulsions (Nakane et al 1980, Annegers et al 1978).

There are few studies comparing malformation rates among the offspring of treated WWE as opposed to untreated mothers. With the exception for the two most recent studies, all previous investigations reveal a consistently elevated malformation rate for infants exposed in utero to AED (Table 2). This association is further supported by studies comparing malformation rates in two chronological cohorts. In a multi-institutional Japanese study, the malformation rates in 172 IME born between 1978 and 1984 were compared to a second cohort of 145 IME born between 1985 and 1989. The malformation rates fell from 13.5% to 6.2% in these two cohorts. The change was attributed to the fact that between 1978 and 1984, only 16.1% of IME were exposed to AED montherapy, whereas in the second cohort, 63.4% of the women with epilepsy (WWE) received AED monotherapy (Kaneko et al 1992). A joint University of Rotterdam-University of Berlin study compared malformation rates in two cohorts of IME. The first group, born between 1972 and 1979 had an average number of 2.2 AED exposures. Of the malformed infants in that group, only 2% were exposed to monotherapy while 25% were exposed to four AED. In the second cohort, born between 1980 and 1985, the IME were exposed to an average of 1.7 AED. Eight percent were on monotherapy and none of the IME were exposed to more than 3 drugs. Dravet and colleagues (1992) found that IME on polytherapy had higher malformation rates (16%), than monotherapy exposed infants (6%). A prospective study from Genoa of 138 pregnancies of WWE found neither AED monotherapy nor high therapeutic plasma concentrations correlated with increased risk for congenital malformations in the offspring. Polytherapy including phenobarbital and phenytoin appeared to be the only risk factor (Tanganelli & Regesta 1992).

Table 2. Malformation rates in the offspring of treated and non–treated epileptic mothers.

	Malformation Rate(%)
Authors	Anticonvulsants	No anticonvulsants
Janz & Fuchs (1964)	2.2	0
Speidel & Meadow (1972)	5.0	0
South (1972)	9.0	0
Lowe (1973)	6.7	2.7
Monson (1973)	5.3	2.9
Annegers (1974)	7.1	1.8
Annegers (1978)	10.7	2.4
Nakane (1979)	11.5	2.3
Nakane (1980)	13.8	8.5
Robert et al (1986)	7.2	0
Rating et al (1987)	5.3	5.9
Koch et al (1992)	6.9	8.0

Neural Tube Defects

The first reports of neural tube defects (NTD), associated with with exposure to an AED were with valproic acid ( Robert & Guibaud 1982). Subsequent North American reports have also implicated carbamazepine, (Rosa 1991). Further evaluations of these exposures have determined that it is spina bifida apperta (SB), which is specifically associated with the exposure as opposed to other NTD (Lindhout et al. 1992 b). Methodological difficulties make prevalence estimates imprecise, most of the data published is in the form of case reports, case series, or very small cohorts from registries which were not designed to evaluate pregnancy outcomes, (Rosa 1991). It has been estimated that the prevalence of SB with valproate exposure is 1 % to 2 % (Lindhout & Schmidt 1986), and with carbamazepine 0.5 % (Rosa 1991). A recent prospective study in Holland, however, demonstrated a prevalence rate of SB with valproate exposure of 5.4 %. This increased rate was associated with higher average daily doses (1,640 + 136 mg/d) of valproate in the affected than in the unaffected IME (941 + 48 mg/d). The authors therefore suggest that dose reduction be practiced whenever valproate must be used in pregnancy (Omtzigt et al. 1992).

As a result of these observations the Centers for Disease Control (CDC), have recently recommended supplimentation of folate for women of child bearing age. They reviewed 8 studies 4 observational and 4 interventional. The interventional studies randomly assigned women with a previous history of bearing a child with a neural tube defect to folate 0.36, 4.0 or 5.0 mg/dy or placebo. The observational studies compared spina bifida or neural tube defect rates in children with or without in utero folate exposure. In 7 of the 8 studies risk of neural tube defects were reduced from 60 to 100 %. The CDC has therefore recommended that all women of childbearing age take 0.4 mg. of folate per day (MMWR 1992). These recommendations are not specific for WWE, but become increasingly important given the association of the antiepileptic drug valproate and carbamazepine with the development of neural tube defects.

Fetal Anti-epileptic Drug Syndromes

A variety of dysmorphic syndromes consisting of patterns of congenital anomalies associated with AED exposure have been reported. Minor anomalies are structural deviations that do not constitute a threat to health and by definition, occur in less than 4 % of the population (Marden et al. 1964). To date, six clinical AED syndromes have been reported in the medical literature. A Fetal Trimethadione Syndrome was first described by Zachai and colleagues (1975). Children exposed to this drug were more likely to be short in stature, microcephalic, have V-shaped eyebrows, epicanthal folds, low set ears, anteriorally folded helices, and irregular teeth. Inguinal hernias, hypospadias, and simian creases were also frequently observed. A retrospective study of trimethadiaone exposures in 53 pregnancies revealed fetal loss or major malformations in 87 % of the pregnancies (Feldman et al. 1977). Follow-up studies have reported significant rates of mental retardation among the exposed infants (Goldman et al. 1986). Trimethadione, introduced in the 1940's for the treatment of absence epilepsy, has been largely supplanted by less toxic, more effective compounds and is seldom used today in the treatment of epilepsy.

The Fetal Hydantoin Syndrome (FHS) was initially described by Loughnan et al. (1973), and expanded upon including formally naming the syndrome by Hanson and Smith (1975). Among the many dysmorphic findings associated with this syndrome, hypoplasia and irregular ossification of the distal phalanges was originally believed to be the single most characteristic feature. Of the five children described by Hanson and Smith, only one was exposed to phenytoin monotherapy. The infants displayed facial dysmorphism including: epicanthal folds, hypertelorism, broad flat nasal bridges, an upturned nasal tip, wide prominent lips, and in addition distal digital hypoplasia (DDH), intrauterine growth retardation and mental retardation. Subsequently, Hanson et al. (1976), reported a prevalence of FHS of 11%, with an additional 30% of the i exposed children expressing some of the syndrome's features. He also suggested that these children are at greater risk for the development of neural crest tumors, although subseuqent prospective studies have failed to verify this initial observation. A prospective study from the University of Helsinki, examined 121 infants of mothers with epilepsy, 82 exposed to phenytoin, found no cases of FHS. Hypertelorism and distal digital hypoplasia were the only dysmorphic features associated with phenytoin exposure in this study (Gaily et al 1988).

A Primidone Embryopathy has also been described. Affected children present with hirsute foreheads, thick nasal roots, anteverted nostrils, long philtrums, straight thin upper lips, and DDH. These children tend to be small for dates, have an increased risk for psychomotor retardation and heart defects (Rudd and Freedom 1979, Gustavson and Chen 1985). A case report of a family in whom all 4 siblings had clinical features of the FHE demonstrates the complexity involved in evaluating affected children. The first 2 children in this family were exposed to both phenytoin and primidone in utero. In an attempt to prevent dysmorphism in subsequent pregnancies, the phenytoin was discontinued. Unfortunately, the third and fourth children had the same dysmorphic features as their elder siblings having been exposed to primidone monotherapy (Krauss et al 1984).

A syndrome of facial dysmorphism, pre- and post-natal growth deficiency, developmental delay, and minor anomalies has been described in children exposed to phenobarbital. The clinical features were similar to those seen with exposure to both phenytoin and alcohol, hence the author felt that it should not be classified as a separate syndrome (Seip 1976). He also noted that all three of these compounds can result in folate deficiency and hypothesized that such a deficiency could be the common mechanism for the dysmorphism seen.

Dysmorphic features in children exposed to valproic acid in utero were defined as a syndrome by Di Liberti et al (1984). These children have inferior epicanthal folds, flat nasal bridges, upturned nasal tips, thin vermilion borders, a shallow philtrum, and downturned mouths. Long thin overlapping fingers and toes, and hyper-convex nails have also been described. Recently, several cases of fetal valproate exposure and radial ray aplasia have been reported, but the prevalence of these abnormalities cannot be determined from case reports (Bron et al. 1990). Children exposed to valproate also appear to be at greater risk for perinatal distress (43 %) and low Apgar scores (28 %), postnatal growth deficiency and microcephaly (Jager-Roman et al. 1986, Ardinger et al. 1988).

A Fetal Carbamazepine Syndrome has been described by a single group of investigators (Jones et al. 1989). Dysmorphic features include: upslanting palpebral fissures, epicanthal folds, short nose, long philtrum, DDH and microcephaly. Developmental delay was also found in 20 % of exposed children, although the authors used one standard deviation from the mean as the cut-off for abnormality, rather than the customary two standard deviations. Applying the conventional definitions to their data, eliminates any increased risk for developmental delay in the carbamazepine exposed children. Reduction in fetal head circumference has been reported in carbamazepine exposed children (Hiilesmaa et al. 1981). Although smaller than controls, the head sizes were still within the normal range and the differences between the IME and controls disappeared as the children matured.

The question of whether these are drug-specific syndromes is controversial. Facial dysmorphism is difficult to quantify and is ot specific for any one anticonvulsant drug. Infants of mothers with epilepsy with similar dysmorphic features have been described in the pre-anticonvulsant era (Baptisti 1938, Philbert and Dam 1982). The long-term outcome and hence, significance of these anomalies remain unclear. The hypothesized association of dysmorphism with mental retardation (Hanson et al. 1976) has not always been confirmed (Granstrom 1982, Hutch et al 1982). In those few cases which have been followed into early childhood, the dysmorphic features tend to disappear as the child grows older (Janz 1982). In all of these syndromes, the primary abnormalities involve the midface. A retrospective study spanning 10 years of deliveries in Israel found hypertelorism to be the only anomaly seen more often in infants of mothers with epilepsy than controls; this was associated with all anticonvulsant drugs except primidone (Neri et al. 1983). These various anomalies might better be named the Fetal Anti-epileptic Drug Syndrome (FADS), as opposed to a half-dozen overlaping drug specific syndromes.

Other Adverse Pregnancy Outcomes

Epilepsy in the Offspring of Parents with Epilepsy

The risk of epilepsy in children of parents with epilepsy is higher than that in the general population. Interestingly enough, this risk is higher (relative risk of 3.2) for children of mothers with epilepsy (Annegers et al. 1978). Paternal epilepsy appears to have less impact on the development of seizures in children. The presence of maternal seizures during pregnancy, but not AED use, is associated with an increased risk of seizures in the offspring (relative risk 2.4) (Ottman et al. 1988). Evidence to support a genetic component for seizure development in these infants comes from kindling studies in experimental animals. If rats with experimental epilepsy are made to have generalized seizures during pregnancy, their offspring are not more susceptible to kindling than rats with no seizures during parturition (Holmes and Weber 1985).

Infant Mortality

Fetal death (defined as fetal loss greater than 20 weeks gestation) appears to be as common and perhaps as great a problem as congenital malformations and anomalies. Studies comparing stillbirth rates found higher rates in infants of mothers with epilepsy (1.3 - 14.0%) compared to infants of mothers without epilepsy (1.2 - 7.8%). Some reports do not compare rates with general population figures or other controls making it difficult to establish whether children are at increased risk (Annegers et al. 1974, Knight and Rhind 1975). A large Norwegian study failed to demonstrate increased risks of stillbirth in infants of mothers with epilepsy but clearly demonstrated increased neonatal deaths (Bjerkdal and Bahna 1973).

Spontaneous abortions, defined as fetal loss occurring prior to 20 weeks of gestation, do not appear to occur more commonly in infants of mothers with epilepsy. A history of previous spontaneous abortions was not found to be significantly different between women with epilepsy (24%) and controls (17.8%) (odds ratio 1.44, 95% C.I. 1.03 - 2.02) (Yerby, Koepsell, and Daling 1985). In a recent report by Annegers and co-workers, the gestational age adjusted rate ratio for spontaneous abortions was no higher for women with epilepsy than the wives of men with epilepsy. Nor was there any difference in spontaneous abortion rates for treated women with epilepsy (14.6%) compared to untreated women (15.7%) (Annegers et al. 1988). Other studies have, however, demonstrated increased rates of neonatal and perinatal death. Perinatal death rates range from 1.3 - 7.8% compared to 1.0 - 3.9% for controls (Janz and Fuchs 1964, Speidel and Meadow 1972, Bjerkdal and Bahna 1973, Knight and Rhind 1975, Stumpf and Frost 1978, Kalen 1986, Tanganelli & Regesta1992).

Hemorrhagic Disease

A neonatal hemorrhagic phenomenon has been described in the infants of mothers with epilepsy. It differs from other neonatal hemorrhagic disorders in that the bleeding tends to occur internally during the first 24 hours of life. First described by Van Creveld (1957) and delineated as a syndrome by Mountain (1970), it was initially associated with exposure to phenobarbital or primidone but has subsequently also been described in children exposed to phenytoin, carbamazepine, diazepam, mephobarbital, amobarbital, and ethosuximide. Prevalence figures are as high as 30% but appear to average 10%. Mortality is over 30%, because bleeding occurs within internal cavities and is often not noticed until the child is in shock.

The hemorrhage appears to be a result of a deficiency of vitamin K-dependent clotting Factors II, VII, IX, and X. Maternal coagulation parameters are invariably normal. The fetus, however, will demonstrate diminished clotting factors and prolonged prothrombin and partial thromboplastin times. A prothrombin precursor, protein induced by vitamin K absence (PIVKA) has been discovered in the serum of mothers taking anticonvulsants (Davies, Argent, and Staub 1985). Assays for PIVKA may permit prenatal identification of infants at risk for hemorrhage (Walker, Bardlow, and Atkinson 1982, Argent, Rothberg, and Pienaar 1984).

This phenomenon can be prevented by maternal ingestion of oral vitamin K1 in the last month of gestation (Deblay et al. 1982). Anticonvulsants can act like warfarin, and can inhibit vitamin K transport across the placenta. These effects can be overcome by large concentrations of the vitamin. Despite lower levels of coagulation factors, the fetus is generally able to obtain enough maternal vitamin K in utero. After birth it must rely on exogenous sources of vitamin K because the newborn gut is sterile. Routine administration of vitamin K at birth is not adequate to prevent hemorrhage if any two of the coagulation factors fall below 5% of normal values (Srinivasan et al. 1982). Successful treatment requires fresh frozen plasma intravenously.

Low Birth Weight

Low birth weight (less than 2500 gm) and prematurity have been described in infants of epileptic mothers. The average rates range from 7-10% and 4-11% respectively (Bjerkdal and Bahna 1973, Annegers et al. 1974, Teramo et al. 1979, Nakane et al. 1980, Nelson and Ellenberg 1982, Svigos 1984). Microcephaly has been demonstrated in these infants and associated with all anticonvulsants (Nelson and Ellenberg 1982, Neri et al. 1983). A Finnish study found a stronger association between carbamazepine exposure in utero and small head circumference than with other anticonvulsant drugs (Hiilesmaa et al. 1981).

Infants of mothers with epilepsy have been reported to have higher rates of mental retardation than controls. This risk is increased by a factor of 2 to 7 fold according to various authors (Speidel and Meadow 1972, Hill et al. 1974, Nelson and Ellenberg 1982). None of these studies controlled for parental intelligence, and while IQ scores at age 7 between groups of children exposed (FSIQ = 91.7) or not exposed (FSIQ = 96.8) to phenytoin reached statistical significance, the clinical significance of such difference is unknown (Nelson and Ellenberg 1982).

We have found that IME display lower scores in measures of verbal acquisition at both two and three years of age. Though there was no difference in physical growth parameters between IME and controls, IME scored significantly lower in the Bailey Scale of Infant Development's mental developmental index (MDI) at two and three years. They also performed significantly less well on the Bates Bretherton early language inventory (p<0.02), in the Peabody Picture Vocabulary's scales of verbal reasoning (p<0.001) and composite IQ (p<0.01), and displayed significantly shorter mean lengths of utterance (p<0.001), (Leavitt et al. 1992).

Lactation

Perinatal lethargy, irritability, and feeding difficulties have been attributed to intrauterine exposure to anticonvulsants, especially phenobarbital and phenytoin (Bethenod and Frederich 1975, Svigos 1984). Nursing children will often become sleepy and stop feeding prior to satiation. They will then shortly awaken, hungry and irritable, to repeat the process. Some investigators have found no relationship between type of anticonvulsant drug, concentration, or disappearance from plasma despite a twofold increase in sedation and drug withdrawal symptoms in infants of mothers with epilepsy (Koch et al. 1985). Virtually all anticonvulsants are excreted in breast milk. The more highly protein bound the AED the less will be transferred from plasma to milk. With the exception of carbamazepine and ethosuximide, the elimination half-life of anticonvulsants tends to be prolonged in neonates.

NEONATAL PHARMACOKINETICS OF ANTICONVULSANTS

Breast Milk/Plasma		Elimination Half-life (hour)
Anticonvulsan	Concentration Ratio	Adult	Neonate
Carbamazepine	0.4 - 0.6	8 - 25	8 - 28
Ethosuximide	0.9	40 - 60	40
Phenobarbital	0.4 - 0.6	75 - 126	45 - 500
Phenytoin	0.2 - 0.4	12 - 50	15 - 105
Primidone	0.7 - 0.9	4 - 12	7 - 60
Valproic Acid	0.01	6 - 18	30 - 60

New Antiepileptic Drugs

Several novel AED have recently or are soon to be marketed in the United States, While some of these compounds like Vigabatrine and Oxcarbazepine have been available in Europe for some time, our clinical experience with pregnant women is extremely limited.

Felbamate, Gabapentine, and Lomotragine have not been found to be mutagenic, teratogenic or carcinogenic in animal models. Doses of these drugs which yield maternal toxicity demonstrate some secondary embryotoxicty as well: increased resorptions, reduced numbers of implantation scars, reduced number of live fetuses per litter, and reduced fetal weight. I am aware of only three human pregnancies with felbamate exposure, all resulted in healthy children. Neither gabapentine nor lamotrigine have been reported to have caused birth defects in humans when used in montherapy.

Vigabatrine in very high maternal doses 150 to 200 mg/kg has been shown to reduce the mean fetal weight and increase cleft lip and palate rate in rabbits. In rats reduction in mean fetal weight and multiple soft tissue malformations have been reported. In the few reported instances of human fetal exposure in monotherapy no congenital malformations have resulted.

Management Principles for Women with Epilepsy

Ideally we would not use medication even AED during pregnacy. Women with epilepsy represent a subset of the population which cannot realistically discontinue their treatment without the risk of seizures. Seizures, particularly generalized tonic clonic seizures are hazardous in pregnancy. Miscarriages have been associated with generalized seizures. Blunt trauma from falls is a major cause of obstetrical injury. In addition to the medical issues there are practical / social ones. Most women are unwilling to risk the loss of job or drivers license which can occur if they have a seizure without medication. Unless a woman has been seizure free for at least 2 years discontinuing medication is probably ill advised.

It is fairly common for women to seek obstetrical advice after they have conceived. It is also fairly common for their physicians to recommend discontinuation of AED as a result. This does not protect the fetus from the risk of malformations. The major organ systems have formed by late in the first trimester. The posterior neuropore closes by day 27 and the palate by the 47th day of gestation. By the time most women realize they are pregnant, malformations may have already developed. Discontinuing AED at this point only increases their risk for seizures.

Women with epilepsy of childbearing age need to be informed of the risks of pregnancy associated with anticonvulsant use prior to conception if at all possible. They also need to know that seizures can be harmful to mother and fetus, and that risks can be reduced with proper care.

All women with epilepsy should take folic acid supplimentation. The Center for Disease Control recommends 0.4 mg/dy. Women with a positive family history of neural tube defects should probably avoid valproic acid if other AED are as effective for her. When these drugs are used careful ultrasonographic evaluation at 16 - 18 weeks should be performed to rule out spina bifida aperta, cardiac or limb defects. If the ultrasound is inconclusive amniocentesis should be performed with measures of both alpha fetoprotein and acetylcolenesterase obtained. These three tests have an accuracy of 98 %. During the last week of pregnancy vitamin K1 should be prescribed 10 mg/dy until delivery to prevent neonatal hemorrhage.

Free AED levels should be monitored monthly and dosage adjusted as necessary to prevent seizures. Levels will fall in all patients but seizures increase in only one third. I personally like to see patients enter their last month of gestation with therapeutic free AED levels to reduce the risk of seizures during labor and delivery. The patient's neurologist and obstetrician need to work together and establish a plan for treating acute seizures particularly during labor. Short acting benzodiazepines are probably the most effective method of controlled acute seizures in this setting. AED levels will need to be followed through the eight postpartum week, because they tend to rise during this period and may lead to clinical toxicity.

Pediatricians following IME need to be alert for the possibility of hemorrhage and drug withdrawal. Such children also need to be carefully and regularly evaluated so that if any developmental delay occurs early intervention can be instituted. A well informed patient and cooperation between neurologist and obstetrician will reduce most risks. The overwhelming majority of women with epilepsy have normal and healthy children. It is important to educate about the risks, but also important to discuss the positive when counseling women with epilepsy and their families.

Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303

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