Management of Epilepsy and PregnancySanjeev V Thomas
Indian Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum. 695011, India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 16534170
Source of Support: None, Conflict of Interest: None
Epilepsy is recognized as the commonest serious neurological disorder in the world. Women with epilepsy (WWE) experience several gender-related physical and social problems. They constitute high obstetric risk because of reduced fertility, risk of seizures during pregnancy, and complications of pregnancy. Hormonal and other factors can alter the pharmacokinetics of antiepileptic drugs (AED) during pregnancy and puerperium. Antenatal exposure to AEDs, particularly at higher dosage and in polytherapy, increases the risk of fetal malformation. Recent reports raise the possibility of selective developmental language deficits and neurocognitive deficits with antenatal exposure to AEDs. There are concerns regarding the effect of traces of AEDs that pass to the infant during breast-feeding. The pre conception management is the cornerstone for epilepsy care in WWE. A careful reappraisal of each case should ascertain the diagnosis, the need for continued AED therapy, selection of appropriate AEDs, optimization of the dosage, and prescription of folic acid. During pregnancy, the fetal status needs to be monitored with estimation of serum a-feto-protein and ultrasound screening for malformations. The dosage of AEDs can be adjusted according to clinical requirement and blood levels of AEDs. Several institutions recommend oral vitamin K toward the end of pregnancy when enzyme-inducing AEDs are prescribed because the latter may potentially predispose the new born to hemorrhagic disease, but recent reports indicate that such a risk is practically negligible. WWE who are using enzyme-inducing AEDs (phenobarbitone, primidone, phenytoin, carbamazepine, and oxcarbazepine) need to know that these AEDs may lead to failure of oral contraception.
Keywords: Antenatal ultrasonography, antiepileptic drug, congenital malformation, epilepsy, gender issues, pregnancy, prevention, reproductive dysfunction, teratogenesis, treatment
Epilepsy is a common neurological disorder with a prevalence rate of approximately 0.5% in most communities. It is estimated that there are over 2.5 million women with epilepsy (WWE) in India, with up to 52% of them being in the reproductive age group. People with epilepsy, especially women, experience tremendous social stigma and alienation in life. Despite progress in medical and surgical therapy, better social acceptance, and favorable legal stand, WWEs are less, often married (59%), when compared with others in the community (65%)., Neurologists and obstetricians are increasingly faced with WWE during pregnancy, but apparently are not adequately informed about their optimal management., Several important aspects need to be attended to, which manage pregnancy in WWE: Pregnancy influences the natural history of epilepsy and seizures are likely to worsen in about one-third of them; the bioavailability of antiepileptic drugs (AEDs) may change considerably owing to alterations in its pharmacodynamics and kinetics and most AEDs are potentially teratogenic and hence may increase the risk of fetal malformations.
Hormonal aspects of epilepsy
Experimental and clinical studies have shown that seizures are influenced by the female sex hormones estrogen and progesterone., In general, estrogen lowers the seizure threshold and progesterone elevates it. In most experimental animal models, estrogen lowers the threshold for seizures induced by electroshock, kindling, pentylenetetrazol, and other agents. Topical brain application or intravenous administration of estradiol in rabbits increases spontaneous paroxysmal spike discharges, especially when there is a pre-existing cortical lesion. Progesterone, on the other hand, reduces spontaneous and induced epileptiform discharges. Similar observations have been made in human beings also. Conjugated estrogen, when administered intravenously, activated epileptiform discharges in 11 of 16 women with clinical seizures. In another study, four of seven women with partial epilepsy showed significant reduction in interictal spike frequency when progesterone was infused intravenously.
Epileptic syndromes during pregnancy
Several mechanisms, including syndromes such as metabolic derangement, eclampsia, and cerebral venous sinus thrombosis, can induce seizures during pregnancy and postpartum period, epilepsy being the commonest amongst them. Majority of WWE have had seizures even before pregnancy. Rarely, some WWE may experience seizures only during pregnancy, which is termed gestational epilepsy . Such women would be seizure-free between pregnancies. Another subgroup (gestational onset epilepsy) may have their first seizure during pregnancy and thereafter may continue to get spontaneous recurrent seizures. Approximately 1-2% of WWE may experience status epilepticus (SE) during pregnancy, which is associated with high morbidity and mortality.
Effect of pregnancy on seizure frequency
Pregnancy has a variable effect on seizure frequency. Seizure frequency may remain unchanged or decreases in two-third of WWE, whereas it may increase in others. Seizure frequency may also vary between pregnancies in the same woman. There can be diverse patterns of seizure frequency during pregnancy. WWE may have a stable pattern with seizure frequency remaining more, less, or unchanged throughout the entire period of pregnancy. Others may have an unstable pattern wherein the seizure frequency may vary widely and often unpredictably during different months of pregnancy. In a recent study it was observed that nearly 61% patients had a stable pattern and 39% women had an unstable pattern. Approximately 1% of them had SE. Diverse mechanisms have been put forward to explain the change in seizure frequency during pregnancy. Apart from the reproductive hormones, several other factors such as noncompliance and decrease in blood levels of free form of AED, influence seizures during pregnancy [Table - 1].
Effect of epilepsy on pregnancy
It is generally considered that WWE have reduced fertility rate.,, The proportion of women who get married and the age at marriage can influence the fertility rate. The demographic, social, economic, and medical factors that influence marriage in WWE need further examination. Polycystic ovarian disease (PCOD), an important cause for infertility, may occur in approximately 10% of women in the community. It should be distinguished from polycystic ovaries that may be seen in as much as 20% of women in the community. The European-American consensus workshop requires two of the three criteria (oligo/anovulaton, clinical, or biochemical signs of hyperandrogenism and polycystic ovaries) to be present in order to diagnose PCOD. It appears that WWE have an increased tendency for PCOD. Use of sodium valproate (VPA) had been shown to correlate with the presence of PCOD, which reverses when VPA is substituted by another AED. A recent consensus report has recommended that if a reproductive endocrine disorder is found in WWE, AED treatment should be reviewed to ensure that it is correct for the particular seizure type and that it is not contributing to the endocrine problem. The possible benefits of a change in treatment must be balanced against seizure control and the cumulative side effect of alternative agents.
Complications of pregnancy
It is uncertain whether WWE have more complications of pregnancy. A recent prospective study of 643 pregnancies in WWE showed that the frequencies of several complications of pregnancy in WWE were comparable with those without epilepsy, except for spontaneous abortions, anemia, ovarian cyst, and fibroid uterus. Nevertheless, several other studies have not demonstrated an excess risk of abortion in WWE.,, There are conflicting reports regarding the increased risk of nonpreteinuric hypertension, pre-eclampsia, eclampsia, and abruptio placenta in WWE. Frequency of cesarean section may be increased for WWE, although most of them can have normal vaginal delivery. Uterine inertia, seizures, and failure of progression of labor are usual causes of cesarian section [Table - 2]. A generalized seizure at term can cause transient fetal asphyxia, as evidenced by cardiotocography. Fetal bradycardia, reduced variability, and decelerations are seen for approximately 15 min after grand mal seizure. In general, most WWEs can expect an uneventful pregnancy and delivery.
Effect of epilepsy and AED on fetus
Effects on fetal and neonatal anthropometric parameters
Minor variations in anthropometric features have been observed in infants of mothers with epilepsy. Low birth weight and reduced length and head circumference have been observed in certain studies. A recent study has shown that infants exposed to AEDs may have increased tendency for minor facial anthropometric variations when compared to normal babies. However, this variation was not correlated with any specific AED or with polytherapy compared with monotherapy. Physiological impairments that were noticed in the newborns include low Apgar score and failure to thrive. Babies born to mothers taking phenobarbitone may experience mild irritability owing to the withdrawal effect of phenobarbitone, but it is likely to disappear in a few days' time. Rarely, withdrawal seizures have been noticed in exposed neonates.
The risk of malformation in the baby is one of the major concerns for WWE. Deviations from normal development can be classified into major malformations and minor anomalies. Malformations refer to major abnormalities that require surgical intervention within the first year of life or are likely to result in significant impairment and disability, e.g., neural tube defects (NTDs), congenital heart disease, or cleft palate. Anomalies are minor deviations from normal development that may not cause significant impairment or disability, e.g., Hypertelorism, acral hypoplasia of nails.
In 1964, Janz first drew attention to the possible teratogenic effects of AEDs. The first systematic study in English language was by Meadow in 1968. Since then several fetal syndromes such as fetal hydantoin syndrome, fetal ethosuximide syndrome and fetal phenobarbitone syndrome have been described. The commonly observed malformations may affect cardiovascular system, gastrointestinal system, skeletal and connective tissues, and central nervous system [Table - 3]. It had been observed that the malformations observed with different AEDs share much in common and are often indistinguishable. Hence, they are often referred to as fetal AED syndromes.
A joint European prospective study of human teratogenesis associated with maternal epilepsy has recently shown that most of the commonly used AEDs carry a relative risk of malformations when used in mono- or polytherapy [Table - 4]. Several groups of medical professionals have been examining this issue over many decades through registries of epilepsy and pregnancy in several countries. None of the commonly used AEDs are free of teratogenic effects. A community-based study of 1398 AED-exposed infants from Sweden (90% as monotherapy) had shown that odds ratio for neonatal malformations was 2.52 (95% CI: 1.43-4.68) for those exposed to VPA monotherapy compared with carbamazepine (CBZ) monotherapy. The North American Registry of Pregnancy and AED usage had recently demonstrated that antenatal use of phenobarbitone (PB) increases the relative risk of major malformations to 4.2 compared with a background risk of 1.62%. The same group has also shown that the relative risk of having an affected offspring for VPA-exposed women was 7.3 (95% CI: 4.4-12.2; P < 0.001). They had identified 16 affected cases among 149 VPA-exposed women (proportion: 10.7%; 95% CI: 6.3-16.9%). The prevalence in the internal comparison group was 2.9% (95% CI: 2-4.1%; odds ratio: 4.0, 95% CI: 2.1-7.4; P < 0.001) and external comparison group was 1.62%.
Several new AEDs have come in to the market in the last decade. The scope of newer AEDs in the management of epilepsy and pregnancy [Figure - 1] needs careful evaluation [Table - 5]. It is important to remember that currently we have only meager data on the safety of newer AEDs with regard to human pregnancy and great caution should be exercised while interpreting them. Oxcarbazepine (OXB) has several pharmacological properties favorable for pregnancy. According to a recent report on 55 pregnancies with OXB (35 monotherapy), one malformation (cardiac) was observed in the offspring of a patient receiving the combination of OXB and PB and none with OXB monotherapy. In a series of 309 infants (from six countries) exposed to OXB (248 as monotherapy), the malformation rates were 2.4% for monotherapy and 6.6% for the adjunctive therapy group. The relative risk of malformation for OXB monotherapy appeared to be comparable with that in community.
Clinical trials of lamotrigine (LTG) started in 1984 and by turn of the next decade several thousand patients had been prescribed this drug. It is a broad spectrum AED with clinical indications similar to VPA. The U.K. registry reported a higher malformation rate with VPA, 5.9% (4.3-8.2%; 95% CI), than with CBZ (2.3% [1.4-3.7%]) or LTG (2.1% [1.0-4.0%]). International Lamotrigine Registry had published their results re cently. Among 414 first-trimester exposures to LTG monotherapy, 12 outcomes with major birth defects were reported (2.9% CI: 1.6-5.1%). The risk of malformations after first-trimester exposure to LTG monotherapy was similar to that observed in general population. Nevertheless, the risk of major birth defects was much higher (12.5%, 95% CI: 6.7-21.7%) when LTG was combined with VPA in the first trimester. These preliminary results indicate that LTG may have a lesser teratogenic potential than VPA. Nevertheless, several other factors also need to be taken in to consideration. It appears that LTG and topiramate (TPM) have lower efficacy against idiopathic generalized epilepsy, when compared with VPA. In a series of 962 persons with idiopathic generalized epilepsy, one year remission was highest (52.1%) for of persons using VPA monotherapy and lower for those using TPM (34.6%) and LTG (16.7%) monotherapy. Persons on LTG may experience increase in seizure frequency during pregnancy because LTG is eliminated much faster than during nonpregnant state. The concentration of LTG in breast milk is higher than that for other AEDs., Breast-fed infants may occasionally have blood levels in the therapeutic range. Most of the recent studies indicate that the risk of NTD in the offspring seems to be much less with LTG, when compared with VPA, but this needs further validation.
There is only limited information available regarding safety of vigabatrin during pregnancy. Fewer pregnancies have been prospectively identified among women receiving gabapentin, tiagabine, TPM, and levetiracetam. Efforts are being made to systematically collect such data through registries., If one of the newer AEDs is the most efficacious and best tolerated AED for a woman, the general principles for pregnancy care should be followed as for the established AEDs. TPM passes freely across placenta and appears to a limited extent (60-80%) in breast milk. Breast-fed infants had only negligible concentrations of TPM in their blood samples. Preliminary data from phase-IV studies indicate that levetiracetam has no unfavorable effects on the fetus.,
Neurocognitive development and AED exposure in-utero
Most babies born to WWE are normal. Recent reports suggest that these babies may have an increased risk of developmental delay or specific learning disabilities.,, Most of the studies are retrospective in design and do not control for all other variables. When 249 mother-child pairs were evaluated with a series of neuropsychological tests (children were 6-16 years old), those exposed to VPA had a significantly lower verbal IQ when compared with those with exposure to other AEDs or those not exposed to any AED.
Preconception evaluation is the most important phase in the management of epilepsy and pregnancy. WWE need to have a neurological review at this stage, in order to ascertain the diagnosis and the need for continued treatment with AEDs. Several professional groups have examined this aspect in great detail and have come out with evidence based practice guidelines.,,,,,62 Most studies have shown that the risk of malformations in fetus is likely to be low with monotherapy, use of relatively lower dose, spacing of daily dose into multiple aliquots, and preconception use of folic acid. The controlled or extended release formulations of AEDs are likely to maintain a steady blood levels without much fluctuations. There is considerable variation in the risk of malformations with different AEDs even when used as monotherapy. Different AEDs carry different therapeutic efficacies against different seizure types. Physicians need to discuss these aspects with WWE and their partners and explain the rationale of AED selection. It may be possible to withdraw AED if the patient had remained seizure-free for more than 2 years. The general guidelines for AED withdrawal as for patients in remission are followed in WWE also. Persons with juvenile myoclonic epilepsy may have to continue therapy, even when they had been seizure-free for quite some time and the EEG was normal. In the case of high-risk pregnancies (with family history of NTDs or previous pregnancies with birth defects), the option of an alternate AED needs to be discussed with the patients although the second AED may also carry the potential risk. There is much debate regarding the choice of AED for women with juvenile myoclonic epilepsy who are contemplating pregnancy. The risk and benefits of VPA vs LTG or TPM needs to be discussed with them so that the patients would be able to make an informed choice. High-dosage VPA and combination of VPA and LTG may be avoided, if possible, in preconception period and early pregnancy, since it carries a higher risk of fetal malformations.
Scientific opinions differ with regard to the role of periodic monitoring of blood levels of AEDs during pregnancy. Blood levels of several AEDs tend to decrease during the latter part of pregnancy (largely owing to drop in the protein-bound fraction). Nevertheless, the patients may not experience aggravation of seizures because the free drug level is not much reduced and because of the favorable hormonal effects. It is important to estimate the free drug levels if the patient experiences unexpected increase in seizures.
A universal recommendation for antenatal care includes prescription of 0.4 mg of folic acid daily. The dosage of folic acid recommended for women with higher risk varies from 1-4 mg daily in several countries. Women in developing countries may be at higher risk of folic acid deficiency owing to dietary inadequacy, infections, or concomitant use of other drugs. In India, 4-mg tablets of folic acid are not readily available. We therefore recommend that all women planning pregnancy should receive 5 mg daily of folic acid. The general protocol for preconception management of WWE that is followed in the Indian Registry of Epilepsy and Pregnancy (IREP) is depicted in [Figure - 1].
Seizures tend to improve or remain unchanged in nearly two-thirds of WWE. The risk of seizures is higher in the first trimester of pregnancy and around delivery time. The policy of the IREP is to avoid any change in AEDs once pregnancy had been confirmed in a WWE. Nevertheless, in cases of polytherapy with multiple drugs, it may be possible to eliminate the third, and occasionally the second, AED after retaining the AED(s) appropriate for the seizure. It is preferable to keep the total daily dose of VPA below 1000 mg as higher doses have been implicated with an increased risk of NTD. Care should be taken to split the daily dose in to three or four divided aliquots in order to avoid high peak levels in the blood. It is important to ensure good compliance with AEDs throughout pregnancy in order to avoid relapse of seizures. The dosage may have to be increased in some patients in the third trimester, especially if the blood levels (preferably free drug levels) are low. The risk of seizure relapse around the time of delivery is three times more than during the rest of the pregnancy. The increased risk of seizure relapse is probably related to the lack of compliance, dehydration, prolonged fasting, or effect of concomitant medications. Care should be taken to avoid such provoking factors at the time of delivery.
Status epilepticus can occur rarely during pregnancy (less than one percent). General guidelines for managing SE can be followed in such instances. The fetal outcome had been poor when it took a long time to control seizures.
The general schedule of antenatal check-up should be followed in all WWE. Folic acid supplementation should be initiated as soon as pregnancy is confirmed, if it had not been started in the preconception period.
Monitoring for fetal malformations
Monitoring for fetal malformations should be carried out towards the end of first trimester. The first line screening procedure would be estimation of serum a-feto-protein (AFP), which tends to be elevated in cases of open NTD. Serum levels of AFP increase gradually during the first trimester and drop toward the fourth month of pregnancy. Hence, the levels should be correlated with the period of pregnancy preferably with conceptual age, calculated with the help of ultrasonography. Each laboratory needs to establish the normative values of AFP for different periods of pregnancy, because there can be wide variations in the values among various laboratories. A recent trend is to express the AFP level as multiples of medians for that period of pregnancy. This makes interlaboratory comparisons easier. AFP levels could be elevated for other reasons such as twin pregnancy, placental hemorrhage, etc. If the AFP levels are abnormally elevated, the trend needs to be ascertained by repeating the test after 1 or 2 weeks. The result also needs to be correlated with a detailed ultrasonography targeting fetal organogenesis. The management protocol that is followed in the IREP63 is given in [Figure - 2].
Of late, ultrasonography that can detect several fetal malformations has become an integral part of antenatal check. Early detection of malformations such as spina bifida and meningomyelocele require careful ultrasonography by experienced persons. Amniocentesis and cord blood analysis may have to be resorted to in selected cases where fetal karyotyping also may be required.
It is very important to offer counseling to the patient and the family prior to and after undergoing screening procedures. The family would require delicate and detailed counseling if a serious malformation had been detected. The sensitivity and specificity of the findings are also required to be explained to the family. Care should be taken to explain in simple terms the type of malformation that is identified and its possible impact on the fetal survival and quality of life. The various options available to the family, such as termination of pregnancy, continuation of pregnancy, and the scope of fetal surgery can be explained to the couple.
AEDs that induce hepatic C450 enzyme system appear to be associated with vitamin K deficiency in the newborn. Their use can result in hemorrhagic disease of the newborn, leading to intraparanchymal and intracerebral hemorrhage. Such babies may show elevated levels of protein induced by vitamin K absence (PIVKA). Administration of vitamin K 1 to the mother can help prevent hemorrhagic disease of the newborn. It is generally recommended that pregnant WWE on enzyme-inducing AEDs should be prescribed vitamin K 1 (10 mg/day) during the last month of pregnancy. These neonates should receive the customary dose of injection vitamin K 1 mg on day 1. The obstetrician should plan the type of delivery based on the obstetrical indications. Nearly one-third of our patients required caesarian section.
The AEDs used in the third trimester should not be continued in the first three months postpartum without any alterations in the dosages. Some patients would experience exacerbation of seizures during this period, which was attributable to sleep deprivation and physical exhaustion. It is helpful to arrange with the family members to share some aspects of caring for the newborn to avoid undue physical and emotional stress.
Most of the AEDs tend to cross in to the breast milk in inverse relation to their protein binding [Table - 6]. Newer AEDs tend to pass in to breast milk in greater concentration than older drugs., The benefits of breast-feeding probably far outweigh the potential risk to the infant. Nevertheless, infants need to be carefully monitored for any untoward effects attributable to AED exposure through breast milk. Monitoring of infant serum drug concentrations is advisable but not mandatory. The general recommendation is to continue breastfeeding, but the feeds may be given before the woman takes her AED doses.
Spacing and contraception
The family needs to be counseled about the need for proper spacing of childbirth from the interest of the mother and baby. Oral contraceptives, especially low estrogen preparations and progesterone implants, may have reduced efficacy when used along with enzyme-inducing AEDs (PHT, CBZ, OXB, and PB). TPM may reduce the ethinyl estradiol level by a different mechanism. In presence of such AEDs, it may be necessary to use oral pills with more than 50 µg of estrogen. Non-enzyme-inducing AEDs such as VPA, LTG, and GBT may not interfere with oral contraceptive pills. Medroxyprogesterone depot injections taken once in 3 months or intrauterine devices can be used as alternate methods of contraception.
WWE have several special problems related with pregnancy, which need careful attention from the attending neurologists and obstetricians. It is comforting to know that majority of WWE can have safe pregnancy and childbirth. Fetal malformations attributable to exposure to AEDs occur in a small proportion of instances only and appropriate preconception management can probably reduce this risk.
[Figure - 1], [Figure - 2][Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]