Management of Pregnancy in Women with Epilepsy

- The management of women with epilepsy is an area that has received increased attention from neurologists. The discrimination and bias of past eras has gradually given way to an atmosphere in which marriage and child rearing is considered acceptable for women with epilepsy (WWE). We therefore tend to forget that in the not too distant past most States had legislation prohibiting marriage for persons with epilepsy.

?The advent of better neurological training, improved diagnostic techniques, the development of vagal nerve stimulation and a group of new and effective medications have vastly improved the management of epilepsy. The majority of women with this disorder can have healthy children. The management of women however, presents unique issues not present for men. To be effective neurologists need to understand these issues. Fluctuations in sex steroid hormones can have an impact on seizure control. Treatment with some antiepileptic drugs (AED), may have cosmetic consequences which may effect compliance and quality of life. Sexual dysfunction is seen more often in persons with epilepsy. Infertility is more common in women with epilepsy. It is unclear whether this is a function of the treatment or the underlying disorder. Enzyme inducing AED may reduce the effectiveness of hormonal contraceptives. Hormonal contraceptives may impact plasma concentrations of specific AED. Women with epilepsy are at greater risk for complications of pregnancy and adverse pregnancy outcomes. The following is a practical discussion of the management of these problems.

A discussion of pregnancy needs to be preceded by reviewing the problems of contraception. Oral contraceptives have not been associated with exacerbation of epilepsy (Mattson et al., 1986). The effectiveness of hormonal contraceptives can however, be reduced by enzyme inducing AED (carbamazepine, phenytoin, phenobarbital, felbamate, topiramate). Hormonal contraceptives come in three formulations: oral (estrogen-progesterone combinations, or progesterone only); subcutaneous, (levonorgestrel) or intrauterine, (progestasert) implants; and injectable (depoprovera). All three forms can be adversely impacted by enzyme inducing AED.

AEDs may lower concentrations of estrogens by 40 to 50 %. They also increase sex hormone binding globulen (SHBG) which increases the binding of progesterone and reducing the unbound fraction. The result is that hormonal contraception is less reliable with enzyme inducing AED.

The low or mini dose oral contraceptives are therefore to be used with caution. Because it is the progesterone not the estrogen that inhibits ovulation, using higher does estrogens alone may not be effective. The more rapid clearance of the oral contraceptive when used in conjunction with an enzyme inducing AED will reduce the likelihood of unwanted side effects from higher dose tablets.

Failure of implantable hormonal contraceptives have also occurred (Shane-McWhorter et al., 1998). Midcycle spotting or bleeding is a sign that ovulation is not suppressed. If this occurs alternative or supplementary methods of contraception are required. Contraceptive failure may not always be predicable, even when mid-cycle spotting does not occur. Failure of basal body temperature to rise at mid-cycle can be used to document ovulatory suppression.

Medroxyprogesterone injections should be given every 10 instead of 12 weeks to women on enzyme inducing AED. This shorter cycle is less likely to result in unintended pregnancy (Crawford 2002).

For multiparous women with epilepsy, intrauterine devices may be an excellent contraceptive choice. Alternatively non-enzyme inducing AED may need to be considered (valproate, lamotrigine, gabapentine, zonisamide, or leviteracetam).

?A recent report suggests that topiramate at doses of less than 200mg. a day lacks enough enzyme induction to effect hormonal contraceptives. Higher doses however do reduce ethinyl estradiol concentrations by 18% on 200mg., 21% with 400mg. and 30% with 800mg. of topiramate a day. (Doose et al 2002).

The importance of the potential impact of enzyme inducing AED cannot be underestimated. In a survey of 294 general practices in the General Practice Research Database 16.7% of women with epilepsy aged 15 to 45 were taking an oral contraceptive. Two hundred were on an enzyme inducing AED and 56% on low estrogen (<50ug.) hormonal contrceptives (Shorvon et al. 2002).

There has been at least one circumstance in which oral contraceptives effect AED concentration. Sabers and colleagues (2003) have demonstrated a marked reduction in lamotrigine concentrations when oral contraceptives are also taken. The average plasma concentration in 22 women on lamotrigine monotherapy and an oral contraceptive was 13umol/L. In a similar group of women on Lamotrigine monotherapy with no oral contraceptive use the plasma concentrations averaged 28umol/L. a significant reduction in AED concentration of over 50%. It has been suggested that oral contraceptives may induce the metabolism of glucuronidated drugs such as lamotrigine. In addition during the portion of the cycle in which women are taking the non active form of oral contraceptives (days 21-28) lamotrigine concentrations may increase by 60%. These potentially relatively rapid fluctuations in plasma concentrations of lamotrigine when oral contraceptives are used in co-medication need to be understood by physicians.

- The cyclic pattern of sex steroid hormone production develops at puberty. It appears as though the proportion of estrogens and progesterone not the absolute concentrations is what is important in permitting a normal menstrual cycle. Given the fact that sex steroid hormone production is the result of pituitary hormone secretion which depends upon normal hypothalamic function it is not surprising that women with epilepsy whose cortex is producing epileptiform discharges may have reproductive dysfunction.

- Epidemiological studies have demonstrated that women with epilepsy have only 1/4 to 1/3 as many children as women in the general population (Bilo et al. 1988, Isojarvi et al. 1993). A variety of hypotheses have been developed to explain this phenomenon. A direct effect of seizures or epileptiform discharges on pituitary and hypothalamus could disrupt ovulation. Electroconvulsive therapy increase prolactin concentrations over five fold within 15 to 20 minutes, and in premenopausal women there is an acute increase in LH and FSH. Generalized seizures also increase prolactin serum concentrations within 15 to 20 minutes by a factor 3 fold. This fact has been used to assist physicians in differentiating epileptic from non-epileptic seizures (Drislane et al. 1994). Partial seizures however do not increase serum prolactin and they account for the majority ( 60 % ) of the epilepsies.

- Strong social pressures on women with epilepsy to refrain from reproducing could also be a factor, Schupf & Ottman (1994), have demonstrated that unmarried WWE have fertility rates only 36 % of their non-epileptic siblings. When WWE marry however that rate increases to only 42 %. Social pressures may contribute but even among married WWE infertility is common.

Women with epilepsy have higher rates of reproductive and endocrine disorders (RED) than expected. In a large clinical center 50% of women with epilepsy were found to have menstrual abnormalities, 20% amenorrheic and 35% anovulatory (Herzog 1999). Herzog and co-workers (1986) was among the first to demonstrate RED in 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 also have RED. Five of 20 women studied by Bilo and colleagues (1988) had RED, 3 with polycystic ovarian disease, and 2 with hypogonadotropic hypogonadism. Ascertainment bias may account for the high proportion of WWE with RED in these studies, nonetheless clinicians should be aware of these potential problems.

- 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. Furthermore 80 % of women treated with valproate before the age of 29 had polycystic ovarian disease.

Women with epilepsy have more variation in lutienizing 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.

Libido is significantly reduced in 1/3 of men and women with epilepsy (Morrell 1991). Increasing seizure frequency appears to decrease sexual desire, while there is no difference in libido between treated and untreated women with epilepsy. Hyposexuality and orgasmic dysfunction has been reported in between 8 to 68% of women with epilepsy. Survey data have demonstrated that 43% of adults with epilepsy have never had a sexual partner. This compares unfavorably with 3% of adult women without epilepsy (Lambert 2001). Persons with localization related epilepsies appear to have higher rates of sexual dysfunction compared to those with primarily generalized epilepsies. Shukla and colleagues (1979) have demonstrated 64% of women with partial, compared to 8% of generalized epilepsies report hyposexuality and sexual dysfunction.

The problem of infertility in WWE is complex. There are multiple factors: seizure type, frequency and the site of ictal onset; 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. There is evidence that valproate may adversely impact the fertility of some women. If the patient’s seizures are controlled discontinuation of valproate is not warranted unless polycystic ovarian disease or hypogondaotropic hypogonadism is found.

The social and political biases against marriage and childbearing for WWE have largely diminished. The majority of WWE can conceive and bear normal healthy children. The pregnancies of WWE do present a greater risk for complications of pregnancy, they are more likely to have difficulties during labor, and there is a higher risk of adverse pregnancy outcomes (Table 1).

One-quarter to one-third of WWE will have an increase in seizure frequency during pregnancy (Table 2). This increase is unrelated to seizure type, duration of epilepsy, or seizure frequency in a previous pregnancy. While most studies have demonstrated that the increase trends to occur toward the end of pregnancy recent reports find that a substantial number (31%) have their increase in the first trimester. In addition out of the 215 prospectively studied pregnancies one in eight or 12.5% of women had to be hospitalized due to complications from increased seizures during pregnancy (Cahill et al. 2002).

Plasma concentrations of anticonvulsant drugs decline as pregnancy progresses, even in the face of constant and in some instances increasing doses (Nau et al., 1981, Tomson et al. 1994, Rodriguez-Palomares et al. 1995, Tomson et al. 1997). Plasma concentrations tend to rise postpartum (Yerby et al. 1990, Ohman et al. 2000). Although reduction of plasma drug concentration is not always accompanied by an increase in seizure frequency, virtually all women with increased seizures in pregnancy have subtherapeutic drug levels (Dansky et al. 1982, Janz 1982, Schmidt 1982, Schmidt et al. 1983, Otani 1985). The decline of anticonvulsant levels during pregnancy is largely a consequence of decreased plasma protein binding (Perruca 1982, Yerby et al. 1985, Tomson et al. 1994), reduced concentration of albumin, and increased drug clearance (Nau et al. 1981, Janz 1982, Dam et al. 1979, Philbert & Dam M 1982). The clearance rates are greatest during the third trimester. Table 3 summarizes some of the pharmacokinetics of anticonvulsant drugs during pregnancy.

The changes in pharmacokinetics are the most important but not the only factor contributing to the decline in AED levels. In a prospective study, Schmidt and coworkers (1983) found that 37% of pregnant WWE in their clinic had an increase in seizure frequency. Upon careful questioning, 68% of these women were deliberately non-compliant or were 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 also deliberately non-compliant because of concerns about the effect of anticonvulsants on their children. Using hair analysis to measure AED concentrations Williams and colleagues (2002) deomonstrated that 15% of pregnant patients had little or no AED in proximal as opposed to their distal hair samples. This strongly suggests that they discontinued their medication during the pregnancy. It must also be remembered that for some women the elevated estrogen levels in pregnancy coupled with the changes in AED may contribute to increased seizure frequency. With all of these factors contributing to the fall of drug levels during pregnancy, monthly monitoring of anticonvulsant drugs using free levels is advised (Levy & Yerby, 1985), but more importantly women need to be counseled about the importance of protection from seizures.

Seizures during pregnancy increase the risk of adverse pregnancy outcomes. First trimester seizures have been found to increase the risk of congenital malformations in the offspring 12.3 % vs. 4 % for children exposed to maternal seizure at other times (Lindhout et al. 1992). The risks of malformations was found to be greater in infants of mothers with generalized as opposed to localization related epilepsies 15.8% vs. 9% in a small prospective study from India (Thomas et al. 2001).

Generalized, tonic-clonic seizures increase the risk for hypoxia and acidosis (Stumpf & Frost 1978) as well as injury from blunt trauma. Canadian researchers have found that maternal seizures during gestation increase the risk of developmental delay (Leonard et al 1997). Although rare, stillbirths have occurred following a single generalized convulsion (Burnett 1946, Higgins & Commerford 1974), or series of seizures (Suter C, Klingman 1957). 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).

Though thankfully uncommon status epilepticus carries a high mortality rate for mother and fetus. In a series of the 29 reported cases, 9 of the mothers and 14 of the infants died during or shortly after an episode of status (Teramo & Hiilesmaa 1982). There are few additional case reports of status in pregnancy since the Teramo and Hiilesmaa paper. Licht and Sankar reported a successful delivery of twins following myoclonic status epilepticus (Licht & Sankar 1999). Individual reports are few (Fougner at al. 1985, Mendez-Quijada et al. 1990). There is a particularly interesting report of a young woman with pyridoxine dependent seizures who at 14 weeks of gestational age developed status refractory to AED but responsive to IV B6, but these must be very uncommon (Schulze-Bonhage et al. 2004).

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 et al. 1985). Though generalized convulsions may have an adverse effect on fetal heart rate, partial seizures do not appear to do so.

The infants of epileptic mothers are at greater risk for a variety of adverse pregnancy outcomes. These include fetal death, congenital malformations, neo natal hemorrhage, low birth weight, developmental delay, feeding difficulties, and childhood epilepsy (Table 2).

Fetal death (defined as fetal loss after 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%) (Table 5).

??Spontaneous abortions, defined as fetal loss prior to 20 weeks of gestation, do appear to occur more commonly in infants of mothers with epilepsy (Yerby & Cawthon 1996). Women with localization related epilepsies appear to be at greater risk for spontaneous abortions than those with other seizure types (Schupf & Ottman 1997). Other studies have demonstrated increased rates of neonatal and perinatal death. Perinatal death rates range from 1.3 % to 7.8% compared to 1.0 % to 3.9% for controls (Table 4).

Fetal malformations have been associated with in utero exposure to AED. Congenital malformations are defined as a physical defect requiring medical or surgical intervention and resulting in a major functional disturbance. Congenital anomalies in contrast are defined as deviations from normal morphology that do not require intervention. It is uncertain whether these aberrations represent distinct entities or a spectrum of physiological responses to insult to the developing fetus: malformations at one extreme and anomalies at the other. For the purposes of this review, congenital malformations and anomalies will be discussed separately.

Congenital malformations are the most widely reported and dramatic adverse outcome of pregnancy. The first report of a malformation associated with anticonvulsant drugs described a child exposed to mephenytoin in utero who developed microcephaly, cleft palate, a speech defect, and an IQ of 60 (Mullers-Kuppers 1963). Speidel and Meadow (1972), initiated a retrospective survey of 427 pregnancies in 186 WWE, and found increased rates of malformations for infants of mothers with epilepsy (IME). They concluded that:

Infants of mothers with epilepsy, exposed to anticonvulsant drugs in utero, are twice as likely to develop birth defects as infants not exposed to these drugs. Malformation rates in the general population range from 2 to 3%. Reports of malformation rates in various populations of exposed infants range from 1.25 to 12.5% (Fedrick 1973, Kelly 1984, Nakane et al. 1980, Philbert & Dam 1982, Steegers-Theunissen et al. 1994, Jick & Terris 1997, Kaneko et al. 1999, Canger et al. 1999, Thomas et al. 2001, Vajda et al. 2003). These combined estimates yield a risk of malformations in a pregnancy of a WWE of 4 to 6%. Cleft lip, cleft palate, or both, and congenital heart disease account for many of the reported cases. Orofacial clefts are responsible for 30% of the increased risk of malformations in these infants (Kelly 1984, Friis et al. 1986, Abrishamchian et al. 1994).

?A wide variety of congenital malformations have been reported, and every anticonvulsant drug has been implicated as a cause. No anticonvulsant drug can be considered absolutely safe in pregnancy, yet most of these drugs do not produce any specific pattern of major malformations.

?A possible exception to this is the association of sodium valproate and carbamazepine with neural tube defects (NTD). Robert and Guibaud (1982) were the first to make this association. Working in a birth defects registry in the Rhone Alps region of France they reported NTD in IME exposed to valproic acid in utero. Between August 1979 and August 1982, 72 infants with lumbosacral neural tube defects were born in this region. Nine of the 72 or 12.5% had been exposed to valproic acid, though 2 of the 9 had a family history of neural tube defects. The mothers of five of these children took valproate monotherapy, one valproate and phenobarbital and one valproate and clonazepam.

?In an attempt to clarify this observation Roberts and colleagues (1986) collected another 141 pregnancies in women with epilepsy using a combination of questionaries and EEG registries. This unselected cohort had a malformation rate of 17.7% and 4 cases of spina bifida all with intrauterine exposure to valproic acid, though only one with monotherapy.

??More recent studies have revealed an association between carbamazepine exposure in utero and NTD, (Rosa 1991, Little et al. 1993). Subsequent evaluations of these exposures identify spina bifida apperta (SB) as the specific NTD associated with the valproic acid or carbamazepine exposure (Lindhout 1992). Methodologic problems make frequency estimates imprecise since most published data are case reports, case series, or very small cohorts from registries that were not designed to evaluate pregnancy outcomes. The prevalence of SB with valproate exposure is approximately 1% to 2% (Lindhout & Schmidt 1986), and with carbamazepine 0.5 % (Rosa 1991, Hiilesmaa 1992). However, a prospective study in the Netherlands found IME exposed to valproate had a 5.4% prevalence rate of SB. Average daily valproate doses were higher in the IME with SB (1,640 + 136 mg./d) than in the unaffected IME (941 + 48 mg/d). Another group of investigators has found that valproate doses of 1000 mg/day or plasma concentrations of less than 70 ug./ml. or less are unlikely to case malformations (Kaneko et al. 1999). Both groups recommend that valproate dose be reduced whenever valproate must be used in pregnancy (Omtzigt 1992, Kaneko et al. 1999).

Neural tube defects (NTD) are uncommon malformations occurring in 6/10,000 pregnancies. Spina bifida and anencephaly are the most commonly reported NTD and affect approximately 4,000 pregnancies annually resulting in 2,500 to 3,000 births in the United States each year (Mullinare & Erickson 1997, Honein et al. 2001). The types of NTD associated with AED exposure are primarily myelomeningocele and anencephaly which are the result of abnormal neural tube closure between the third and fourth weeks of gestational age.?

? Previous thinking about NTD visualized the fusion of the neural tube as one in which the lateral edges met in the middle and fused both rostrally and caudally similar to a bi-directional zipper. Recent studies have suggested there are multiple sites for neural tube closure (Van Allen et al. 1993, Golden & Chenoff 1995) and that different etiologies may result in different types of abnormality.

There are four separate sites along the neural tube where neuralation develops. The first is midcervical. The second is at the cranial junction of the prosencephalon and mesencephalon. The third at the site of the future mouth or stomadeum. This region fuses in a caudal direction only. The fourth is the region over the rombencephalon between the second and third regions (Van Allen et al. 1993).

There are differences in specific sites and timing of each individual closure region. The majority of human NTD can be explained by failure of one or more closure sites. Anencephaly with frontal and parietal defects is due to failure at closure site two. Holocrania with also involves defects of the posterior cranium to the foramen magnum is due to failure of closure of areas two and four. Lumbar spinal bifida results from failure of closure one. The devlopment of closure sites appears to be under genetic control and also affected by environmental factors. In twins concordance rates are only 56% for anencephaly and 71% for spina bifida. In Great Britain there is a male preponderance of lumbar spina bifida and female preponderance of holocrania and anencephaly. Even valproic acid appears to have species differential effects being associated with spina bifida in humans and exencephaly in mice (Seller et al. 1995)

? A number of risk factors are associated with neural tube defects . A previous pregnancy with NTD is the strongest association with a relative risk (RR) of 10. There are strong ethnic/geographic associations with NTD. Rates per 1,000 are 0.22 for Caucasians, 0.58 for persons of Hispanic descent and 0.08 for persons of African descent. The incidence of NTD in Mexico is 3.26/1000, for Mexican-born persons living in California 1.6/1000 and for U.S. born persons of Mexican descent 0.68/1000 (Harris & Shaw 1995). Diabetic mothers have 7.9 times the rates of NTDs in their offspring (Becerra et al. 1990). Deficiencies of glutathione, folate, vitamin C, riboflavin, zinc, cyancobalamin, selenium and excessive exposure to Vitamin A have been associated with NTD. Higher rates are seen in children of farmers, cleaning women and nurses (Blatter et al. 1996, Matte et al. 1993). Pre-pregnancy weight has also been demonstrated to be a factor. Werler and colleagues (1996) compared RR for NTD in control women weighing 50-59kg. and found the RR increased to 1.9 in women weighing 80-89kg. and 4.0 for those weighing over 110kg. AED may be a necessary but not sufficient risk factor for the development of NTD.

Women with epilepsy as do all women of childbearing age should take folate supplementation. The dose recommended by the Center of Disease Control of 400ug/d may not be high enough for many women who do not metabolize folate effectively. Even with folate supplementation women taking valproate or carbamazepine should avail themselves of prenatal diagnostic ultrasound to rule out NTD.

For many years it has been reported that infants of mothers with epilepsy are at greater risk for a unquie for of neonatal hemorrhage. First described by Van Creveld (1957) who suggested that vitamin K deficency might be the cause. It was first delineated as a syndrome by Mountain (1970), but there have been numerous reports of in utero AED exposure associated with neonatal hemorrhage (Lawerence 1963, Douglas 1966, Kohler 1966, Solomon et al. 1972, Bleyer & Skinner 1976, Griffiths 1981, Srinivasan et al. 1982, Sutor 1995). 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.

It has been differentialted from other hemorrhagic disorders in infancy in that the bleeding occurs internally, during the first 24 hours of life. Accurate prevalence figures are lacking.

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).

The historical demonstration of an increased risk of neonatal hemorrhage coupled with a demonstrated deficiency of vitamin K and the PIVKA led clinicians to believe the relative lack of vitamin K and presence of PIVKA was the cause of this particular neonatal hemorrhage. Four studies demonstrated that oral maternal supplementation increased neonatal vitamin K and reduced hemorrhage (Owen et al. 1967, Deblay et al. 1982, Cornelissen et al. 1993, Anai et al. 1993).

This practice has been challanged. Kaaja and colleagues (2002) found no difference in the rates of neonatal hemorrhage in 667 infants of mothers with epilepsy (0.7%) and 1,334 control infants (0.4%). No mothers in either group were supplimented with vitamin K, but all infants received intramuscular vitamin K at delivery. They felt that on the basis of their experience no evidence of a difference in clinical bleeding could be found, hence supplementation was not recommended. Hey (1999) measured cord blood from 137 infants of mothers with epilepsy taking phenobarbital, phenytoin or carbamazepine and found that 14 of 105 had prolonged prothrombin times but none had any clinical bleeding. He felt that the lack of clinical bleeding in his series made supplementation with vitamin K inappropriate.

Some background may help clarify the apparent differences in conclusions made by these observors. Vitamin K deficiency is common in a neonates. Maternal vitamin levels are not reflected in cord blood. When Shearer and colleagues (1982), measured vitamin K in mothers they found values ranging from 0.13 - 0.29ng/ml but none in the cord blood. Even after IV supplementation raised levels to 45 - 93ng.ml cord values rose only to 0 - 0.14ng./ml. This descrepancy between maternal and neonatal vitamin K levels haas lead researchers to look for PIVKA as a proxy for vitamin K deficency. PIVKA is formed as a result of incomplete carboxylation of protein precursors of vitamin K and so is present when vitamin K is absent or present in very small concentrations.

The problem is in part that there is a confusion between vitamin K deficency, laboratory evidence of abnormal coagulation parameters and clinical bleeding. Vitamin K deficiency is common, the presence of PIVKA less so, but clinical bleeding in neonatal life is rare. Shapiro et al (1986) demonstrated that PIVKA presence is fairly uncommon in the general population of newborns 2.9% and more common in premature infants. We have no good data on prevalence of neonatal hemorrhage in infants of mothers with epilepsy, but we do have reasonably accurate case reports.

We also have reasonable causation. 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 coagulation factor levels, 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.

It is not so much that Kaaja and Hey are incorrect but that it is extremely difficult to measure the effects of infrequent clinical outcomes. Neonatal hemorrhage is also unlikely to be identified unless it is severe and the child clinically ill in those first 24 hours. The marked increase in PIVKA in infants of mother with epilepsy suggests that they are at increased risk for hemorrhage and the increase in developmental delay and need for additional educational assistance seen so often in this population suggests that small degrees of hemorrhage may effect the development of these infants (Leonard et al 1997, Adab et al. 2001, Meador & Yerby 2002).

To make matter more interesting Howe and colleagues (2003) suggests that vitamin K deficiency in a developing embryo results in a failure of vitamin K dependent carboxylation processes and resulting in an accumulation of compounds that effect embryonic cartilaginous development. Such children are at risk for midface hypoplasia. They base this hypothesis on the clinical similarities between the mid face abnormalities seen in warfarin and phenytoin exposed children. Howe suggests that because maternal supplementation with vitasmin K reverses the deficiency perhaps such supplementation should start prior to conception.

Therefore it is clear that one should offer maternal supplementation to pregnant women with epilepsy. The risks of neonatal hemorrahge while low clearly exists as demonstrated by elevated PIVKA levels, particularly with enzyme inducing AED. There is a lack of an effective intervention once a neonate bleeds. There is the additional possibility of small bleeds which while not clinically detectable at birth may have long term effects. There is an hypothesized possibility of an association of decreased carboxylation secondary to decreased vitamin K and the development of some types of malformations. There is a lack of risk with the recommended vitamin K supplimentation (10mg/day). There is also a clear need for better prevalence data on the true risk of clinical bleeding in infants of mothers with epilepsy.

Low birth weight (less than 2500 gm.) and prematurity have been described in infants of epileptic mothers. The average rates range from 7-10% for low birth weight and 4-11% for prematurity (Sivgos 1984, Teramo & Hiilesmaa 1982, Nakane et al. 1980, Annegers et al. 1974, Hvas et al. 2000). These studies do not analyze the effect of specific seizure types, frequency or AED on this aspect of fetal development.

A prospective study which pooled data from three countries (Canada, Japan and Italy) on 870 infants of mothers with epilepsy found that 7.8% were below the 10^th percentile in weight at birth (Battino et al. 1999). The risk was greater with polytherapy.

Body dimensions of infants of mothers with epilepsy have been studied by Wide and colleagues (2000). Infants exposed to polytherapy not surprisingly, were shorter and smaller than those exposed to monotherapy. Exposure to monotherapy with carbamazepine revealed a tendency toward small for gestational age, birth weight and head circumference but it was not statistically significant.

?For some time investigators have demonstrated that 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 & Meadow 1972, Hill et al. 1974). None of these early studies controlled for parental intelligence, although differences in 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 (Hill & Tennyson 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) and in the Peabody Picture Vocabulary's scales of verbal reasoning (p<0.001) and composite IQ (p<0.01), and they displayed significantly shorter mean lengths of utterance (p<0.001), (Leavitt et al. 1990).

?All studies have demonstrated that polytherapy exposed infants have performed significantly less well on neuropsychometric testing than those exposed to monotherapy. Socioeconomic status had the strongest association with poor test scores, but maternal seizures during pregnancy was also a significant risk factor (Losche et al. 1994).

Leonard et al (1997) has in part addressed the question of whether maternal seizures or in utero exposure to AEDs are responsible for the developmental delay seen. A group of children of mothers with epilepsy followed to school age were found to have a rate of intellectual deficiency of 8.6%. The Wechler Intelligence Scale for Children revealed significantly lower scores for children exposed to seizures during gestation (100.3), than for children whose mother's seizures were controlled (104.1) or controls (112.9).

Work by Reinish and colleagues (1995), suggests that AED alone may contribute to developmental delay. Young men whose mothers did not have epilepsy but took phenobarbiatl during pregnancy had significantly lower IQ scores as adults than controls. Full scale IQ scores were 100 for exposed compared to 107 for controls, and VIQ 101 and 108 respectively.

Both maternal epilepsy and AED exposure in utero appear to effect development of offspring in a study by Koch et al. (1999). Severity of outcomes increased from controls, to maternal epilepsy with no AED exposure, to maternal epilepsy with AED exposed children.

Developmental delay was demonstrated in 19% of AED exposed Scottish children compared to just 3% of their non-exposed siblings (Dean et al. 2002). These observations continue to suggest that developmental delay is a significant adverse outcome for IME.

Controlling for socioeconomic status one of the most important variables in terms of cognitive outcome, has been done in a study by Adab et al (2001). Evaluating which children required additional educational needs instead of measuring IQ demonstrated that children of mothers with epilepsy had significantly more educational needs than controls. This was most striking for children exposed to valproic acid monotherapy 30% compared to 11% for children with no AED exposure and 3% for children exposed to carbamazepine monotherapy. In a follow up study by this same group a comparison of infants exposed to various AED in monotherapy lower verbal IQ scores were seen children exposed to valproate than those exposed to carbamazepine or phyentoin (Adab et al 2004).

Developmental delay is a significant adverse outcome for infants of mothers with epilepsy. The magnitude is similar to that for congenital malformations. There are a number of important variables which contribute to cognitive development the most significant is maternal IQ, but gestational seizures, AED exposure are also contributory factors.

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. 1996). 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 & Weber 1985).

Since 1993 a number of effective new AEDs have been introduced in North America. Their diminished side effects profiles have made them increasingly popular. Gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and zonisamide are all now available in the United States. There is some tendency to think that since we know the older AED have hazards the new ones might be acceptable substitutes. Unfortunately there is little information to support their safety. The numbers of reported exposed pregnancies with these drugs is very low, and unfortunately not large enough for one to determine if there is an increased risk of adverse outcome with fetal exposure to these compounds. We know that lamotrigine and levetiracetam concentrations decline during pregnancy and expect that this is also true for the other new AEDs, (Tomson et al. 1997). This is what we know to date.

The paucity of data on newer AED has led to the development of pregnancy registries. These prospective data collection centers can serve as an "early warning system" by looking for either clusters of specific abnormalities or rates of malformation in excess of expected. They are hampered by the fact that not all women with epilepsy who deliver will enroll, and there is poor data on the true number of exposed women. Therefore no denominator exists to permit the estimation of rates. Such a system can only accurately capture major malformations of the type diagnosable at birth. Given these limitations this remains the only method currently available for surveillance and physicians and patients are encouraged to enroll.

There are now two major regional pregnancy registries for AED: European (EURAP), and North American (NAREP). All are prospective and collect information for all AED. They differ in the source of subjects. The NAREP requires patients themselves to report while the other rely on physicians. Most collect a reasonable amount of information on potential confounders such as maternal age, race, previous pregnancy history, seizure type and frequency, and exposure to other medications.

Some pharmaceutical companies have developed their own registries. Glaxo Smith Kline has registries for several of its products including lamotrigine. The International Lamotrigine Pregnancy Registry has been the most effective of all existing registries providing to date the most extensive information on lamotrigine’s effects on pregnancy outcomes (Tennis & Elderidge 2002). There is a Gabapentin Pregnancy Registry organized by Dr. Georgia Montouris and sponsored by Pfizer. There is also a registry for vigabatrin, but this drug has not been approved for use in the United States.

To date the most productive industry registry has been the Lamotrigine Pregnancy Registry with 1081 prospectively registered pregnancies, 908 with known outcomes. There have been 68 retrospectively reported pregnancy outcomes. Their toll free number for case reports is: 800-336-2176.

There is also a toll free number for the North American Pregnancy and Epilepsy Registry: 1-800-232-2334. Established in 1996 it has prospectively enrolled over 3442 women, 1961 of whom were on monotherapy. Higher than expected risk of malformations have been identified with Phenobarbital (6.3%, 95% C.I. 1.9 - 9.6) & Valproic Acid (10.7%, 95% C.I. 4.2 - 13.6%). To date it has been unable to provide information on the newer AED. yy

The European Pregnancy and Epilepsy Registry (EURAP) has been in effect for four years. This Registry now includes collaborators in 37 countries. With a central registry center in Milan it utilizes networks of reporting physicians in participating countries who recruit and enroll women with epilepsy taking AED prior to any knowledge of their pregnancy outcome (before the first ultrasound) and within the first 16 weeks of their pregnancy. The recruiting physician supplies data the registry using a set of 5 subforms A-E. Subform A is completed at the time of enrollment, B at the end of the first trimester, C at the end of the second trimester, D within 3 months of delivery, and the last subform E within 14 months of delivery. Each subform is submitted to a national coordinator who checks it for completeness and accuracy before forwarding it to the Central registry in Milan. Over 6000 women have been enrolled, there are 2601 ongoing pregnancies. One thousand and seven hundred and forty four have been followed up through their first year. There is a 6% malformation rate for all monotherapy subjects.

A Swedish birth registry study has reviewed 1398 AED exposed infants. The odds ratio for malformations in infants exposed to AED was 1.86 (95% C.I. 1.4 — 2.4). Malformation rates for specific AED in monotherapy were: 4.0% for corbamazepine; 4.4% for lamotrigine; 6.8% for phenytoin; and 9.7% for valproic acid (Wide et al. 2004).

An Australian pregnancy registry has combined prospective and retrospective data an unusual approach. They have reported in oral platform sessions at the American Epilepsy Society meeting in 2004 on 565 completed cases. They reported a 15% malformation rate with valproate monotherapy with higher rates seen with doses above 1100mg. a day.

The primary problem with registries is that they rely on self reporting and are not population based. With no true denominator, statistical rates cannot be calculated. Suggestions that all existing registries pool their data in order to increase the sample size have been met with concerns about the different entry criteria and outcome definitions used by the various studies. Ideally comprehensive post marketing surveillance on a national or regional basis would be a preferable method of monitoring medication safety. To date most governments have failed to provide the resources required for such an undertaking.

Vagal nerve stimulation (VNS), is a technique using an implanted generator which produces an electrical stimulation of the left vagal nerve in the neck. It is used to reduce the frequency and severity of seizures in persons with epilepsy. The device is manufactured by the Cyberonics Corporation of Houston, Texas. Approximately 13,000 persons with epilepsy have had VNS implantation. There have been 11 pregnancies in women using the VNS. Eight had normal children. Two women choose to have elective abortions in one of these the fetus was malformed probably from the AED the woman was also taking. One woman had a spontaneous abortion (miscarriage).

Those who care for WWE face a dilemma. Seizures need to be prevented; but fetal exposure to anticonvulsant drugs needs to be minimized. Though it might appear that the ideal situation would be to withdraw the patient from anticonvulsants prior to conception. For most women this is not a realistic option. Women today are more likely to be employed and the potential disruption of their lifestyle by seizures, such as the risk of loss of driver's license, makes elimination of anticonvulsants impractical. More importantly maternal seizures increase the risk of injury, miscarriage, epilepsy in the offspring and developmental delay.

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 already may have developed. WWE of childbearing age need to be informed of the risks of pregnancy associated with anticonvulsant use prior to conception if at all possible (Table 1). They also need to know that seizures can be harmful to mother and fetus, and that risks can be reduced with proper care.

- Many people appear to be unaware that even healthy parents have a 2-3% risk of having a child with a malformation. Given the current state of the art the best we can do is practice risk reduction. In general risks can be minimized by the preconceptual use of multivitamins with folate, and using AED in monotherapy with the lowest effective dose and preventing maternal seizures. Monitoring free drug levels both prior to and during pregnancy will permit accurate assessment of concentrations in a situation where plasma protein binding is in flux. Dose adjustment, however, should be made on a clinical basis. Plasma anticonvulsant drug concentrations will fall in pregnant women, but only a quarter to one-third will have an increase in seizures. We tend to keep dosage as low as possible during conception and organogenesis, but will often raise dosage during the third trimester to reduce the risk of seizures during labor.

- Supplementation with at least 0.4 mg/day of folate is recommended by the Center for Disease Control for all women of childbearing age whether or not they have epilepsy. Recent studies have suggested that perhaps 0.5 or 0.6 mg/day might be more effective. The exception is for those women in which there is a family history of a neural tube defect. For these women 4.0 mg/day is the recommended dose. A number of observational and interventional studies have demonstrated a reduction in the risk of malformations in general and neural tube defects specifically in women taking folate prior to conception (Lawerence et al. 1981, Smithells et al. 1983, Vergel et al. 1990, MRC Study Group 1991, Czeizel & Dudas 1992 ). The doses used in these studies ranged from 0.36 to 5.0 mg/day.?

Vitamin K1, 10 mg per day, should be initiated late in the third trimester to prevent neonatal hemorrhage. We usually prescribe it during the final month of gestation.

Breast-feeding is generally safe in term infants as they have been exposed to the AED for 9 months and have induced their hepatic microsomal enzyme systems. However breast feeding should be done cautiously by women receiving phenobarbital or primidone due to the risk of infant sedation. The known milk/plasma concentration ratios of AEDs are listed in Table 6.

Pregnant women taking valproate and or carbamazepine should avail themselves of prenatal diagnostic techniques ultrasound and alpha fetoprotein measurement. Ultrasonography has become much more accurate and in experienced hands can identify the vast majority of structural defects. Current prenatal testing recommendations are as follows.

When a WWE initially presents to her neurologist, pregnant her gestational age (GA) needs to be established with reasonable accuracy. One cannot rely on last menstrual period (LMP) alone but an early ultrasound should be obtained to date the pregnancy. Once GA is established, a calendar can be planned with dates for monthly AED level checks, prenatal testing and initiating Vitamin K supplementation determined ahead of time.

The management of women with epilepsy presents unique challenges. Confirmation of diagnosis, and verification of most appropriate AED for the individual are the starting points. With effective patient education and careful and consistent management which includes a coordinated treatment plan with both neurologist and obstetrician, these patients can and do have successful pregnancies and healthy offspring. Neural tube defects are serious malformations lacking effective therapeutic interventions. Their risk can be reduced by careful management and theoretically eliminated by prenatal diagnosis and therapeutic abortion. In our role as advisors we need to recognize that all patients may not share our value systems or even begin to perceive what it really means to care for a child with a NTD. . Physicians must be sensitive to their patient’s anxieties and be prepared to manage not simply their seizures but their emotional concerns as well.

PRECONCEPTION	•Patient Education •Start Folic acid supplementation •Determine AED free level at which Pt. is controlled
FIRST POST CONCEPTION VISIT	•Review Education •Measure Free AED level & rbc folate •Determine EDC •Plan pregnancy follow up visits
12^TH WEEK GA	•Anatomic US •AED free level
15^TH WEEK GA	•Maternal serum screen: (AFP)
16^TH WEEK GA	•Anatomic US •AED free level
20^TH WEEK GA	•AED free level
24^TH WEEK GA	•AED free level
28^TH WEEK GA	•AED free level
32^ND WEEK GA	•AED free level
36^TH WEEK GA	•AED free level •Start Vitamin K •Plan for acute Sz. Rx during L&D
DELIVERY	•Examine child for anomalies/defects
4^TH WEEK Post Partum	•AED free level • Watch for AED toxicity
8^TH WEEK Post Partum	•AED free level