Pregnancy and the Mother 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. 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.

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 increases 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).

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. 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.

Antiepileptic drugs may also interfere with the hypothalamic pituitary axis. Amenorrhea, oligomenorrhea, prolonged or irregular cycles have been described in WWE by Isojarvi and colleagues (1993). Women with epilepsy taking valproate were over represented, 45% of those on valproate monotherapy and 25 % on valproate polytherapy had menstrual disturbances. Polycystic ovaries were found in 43 % of valproate treated women and 80 % of women treated with valproate before the age of 29 had polycystic ovaries.

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 (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 therefore 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 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.

One-quarter to one-third of WWE will have an increase in seizure frequency during pregnancy. 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 (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. 1992, 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 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.

Seizures during pregnancy increase the risk of adverse pregnancy outcomes. 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).

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). Partial seizures may also have similar effects if less often (Sahoo et al 2005).

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.

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%).

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.

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.

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, Wide et al. 2004, Morrow et al. 2006). 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.

?An exception to this is the association of sodium valproate with neural tube defects (NTD). 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, Vadja et al. 2003).

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 mothers with epilepsy. 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.

?With a prevalence of 0.6 to 1% it is estimated that there are 24,000 deliveries to women with epilepsy in the United States each year. If 75 to 95% of these persons take AED we can expect 18,000 to 22,800 infants exposed to AED in utero per year. It is estimated that half of all AED prescriptions are used for conditions other than epilepsy. Though these patient populations may have fewer women of child bearing years the numbers of exposed children is substantial.

Most investigators have focused on congenital malformations as the primary adverse outcome for children of mothers with epilepsy. The rates are approximately double those in the general population. I would argue that the magnitude of developmental delay is similar.

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 unclear (Hill & Tennyson 1982). In comparing 76 IME with 71 unexposed control children Wide and colleagues (2002), found no difference in scores on developmental tests, but did find a tendancy for phenytoin exposed children to have a greater reduction in tests of motor coordination.

Leavitt and colleagues 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).

Polytherapy exposed infants 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). All AED are clearly not created equal and Koch and co-workers (1999) have demonstrated that primidone particularly when used in polytherapy is associated with lower Wechler score of intelligence.

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 control to maternal epilepsy no AED exposure to maternal epilepsy AED exposed children.

An intensive retrospective analysis of 100 consecutive pregnancies seen at a tertiary epilepsy center found that 3.9% of the children were premature, 1.1% had congenital malformations and 6.2% developmental delay. This despite the fact that 59% of the mothers were seizure free and 98% took folic acid during their pregnancy (Katz et al. 2001).

Another retrospective study demonstrated that 16% of 594 children of mothers with epilepsy exposed to AED in utero compared to 11% of 176 of children with no AED exposure required additional educational assistance in school. This was felt to be a reasonable marker for developmental delay. In addition differences between AED were found with 30% of children exposed to valproate monotherapy, 24% exposed to valproate polytherapy, but only 3.2% of carbamazepine monotherapy exposed children requiring additional educational assistance (Adab et al. 2001). Monotherapy with other AED had rates of 6% and polytherapy without valproate 16%. Children with no AED exposed had an 11% use of additional educational services.

The same cohort of children were studied to determine their IQ scores. Of 251 children tested the mean IQ for valproate exposed children was 82 compared to 95 for carbamazepine exposed and 92 for AED unexposed children (Vinten et al 2001).

The authors followed up their initial cohort eventually studying 249 children of mothers with epilepsy from ages 6 to 16. The numbers in monotherapy were modest 41 exposed to valproate, 52 to carbamazepine, 21 to phenytoin and 49 to polytherapy compared to 80 unexposed children. They used regression analysis to demonstrate that both exposure to valproate and frequent generalized tonic clonic seizures in pregnancy increased the risk of low verbal IQ scores (Adab et al 2004).

Three other studies have found increased rates of developmental delay in children exposed to carbamazepine ranging from 8 to 20% (Scolnik et al. 1994, Jones at al. 1989, and Ornoy & Cohen 1996). One of these studies only used a single standard deviation from the mean to qualify has developmentally delayed and thus overstates the risk (Jones et al 1989).

A retrospective study of mothers with epilepsy delivering in Scotland between 1976 and 2000 used the non-exposed siblings as controls. Developmental delay was demonstrated in 19% of 293 AED exposed children compared to just 3% of their non-exposed siblings. The rate of delay in valproate exposed children was particularly high 37%. Congenital malformations were found in 14% of exposed and 5% of non-exposed siblings. The investigators also state that facial dysmorphism was present in 52% of exposed and 25% of non-exposed siblings which makes one wonder about the nature of this population (Dean et al. 2002).

Reinisch and colleagues conducted double-blind studies examining intelligence in adult men with in utero exposure to Phenobarbital (1995).Their mothers by and large had not had epilepsy but took the drug for other indications. Unexposed members of the same birth cohort, matched on a large number of variables, were used as controls. The first study used the Wechsler Adult Intelligence Scale (Danish version); the second, the Danish Military Draft Board Intelligence Test. The authors' concluded:

In one of the best designed prospective studies of outcomes of mothers with epilepsy Gaily and colleagues (2004) measured the intelligence of 182 children of mothers with epilepsy and 141 controls. The investigators performing the testing were blinded as to the child’s exposure. The following table is from their report.

Group	N	Mean VIQ	Mean PIQ	Mean FSIQ
Entire Group	182	92.8	100.3	96.0
No AED	45	94.3	98.6	95.6
All Mono Rx	107	94.4	101.9	98.0
CBZ Mono Rx	86	96.2	103.1	99.7
VPA Mono Rx	13	83.5	96.3	89.7
Other Mono Rx	8	91.1	96.9	93.6
All Poly Rx	30	84.9	97.1	89.5
VPA Poly Rx	17	81.5	96.1	86.6
Control	141	94.9	102.4	97.6

This suggests that children exposed to Valproate and polytherapy are at higher risk for developmental delay than children exposed to carbamazepine or unexposed children.

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, pregabalin, 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.

The North American Registry has over 2970 mono therapy prospective subjects and is the only registry with a concurrent control group. It has found an increased risk of malformations for Phenobarbital of 6.3% an odds ratio of 4, and an increased risk for valproate as well 10.7% an OR of 7. In addition it has determined that while lamotrigine has an overall malformation rate of 2.7% it does appear to increase the rate of oral clefts to 8.9/1,000 compared to 0.37/1,000 in the general population (Holmes et al. 2004, Wyszynski et al. 2005, Holmes et al. 2006 in press).

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 carbamazepine; 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 (Vadja et al. 2003).

A registry from the United Kingdom reported on 3607 pregnancies. The malformation rate was 3.7% for those exposed to monotherapy and 6.1% exposed to polytherpy. There were higher rates of malformations in polytherapy with valproate than without (OR 2.49). Carbamazepine monotherapy exposures resulted in the lowest malformation rates of 2.1%followed by gabapentine 3.7%, lamotrigine 3.5%, phenytoin 4.1% and valproate 6.1% (Morrow et al 2005).

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. 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.

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.

Pregnant women taking valproate 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.