Shubha Niranjan et al. / Journal of Pharmacy Research 2011,4(11),4181-4183
Review Article ISSN: 0974-6943
Available online through www.jpronline.info
Management of Epilepsy During Pregnancy Shubha Niranjan *, Pramod Kumar Sharma, Vipin Kumar Garg, Sambhu Charan Mondal, Avnesh Kumar Singh Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Baghpat Bypass, NH-58, Meerut-250005, Uttar Pradesh, India.
Received on: 19-05-2011; Revised on: 08-06-2011; Accepted on:01-07-2011 ABSTRACT Pregnant women with epilepsy are at serious risk of various complications. These may constitute high obstetric risk because of reduced fertility, risk of seizures during pregnancy, perinatal death, fetal malformation, miscarriage and increased seizure frequency. Preconception counselling and coordination of care is what can help to reduce these risks. A careful reappraisal of each case should ascertain the diagnosis, the need for continued Anti-epileptic drugs (AED) therapy, selection of appropriate AEDs, optimization of the dosage form and folic acid supplementation. Pregnancy has been found to influence the natural history of epilepsy and seizures and is often found likely to worsen seizure frequency in about one-third of them. The bioavailability of AEDs may change considerably owing to alterations in its pharmacodynamics and kinetics. Most of the AEDs are potentially teratogenic. Hence they may increase the risk of fetal malformations. During pregnancy, the fetal status needs to be monitored with estimation of serum a-fetoprotein and ultrasound screening for malformations. The dosage of AEDs can be adjusted according to clinical requirement and blood levels of AEDs. Key words: malformation, pregnancy, teratogenic, seizures, anti-epileptic drugs.
INTRODUCTION Although not common among pregnant women, epilepsy is one of the most common neurological disorders during gestation. [1] Approximately every one in 200 pregnancies occurs in woman with epilepsy taking antiepileptic drugs. Though in the majority of these women, pregnancy may proceed without any apparent difficulty, there is evidence of increased risks for both mother and child. [2] Use of anti-epileptic drugs is associated with a number of side-effects. The outcome of an epileptic women’s pregnancy may range from epilepsy, genetic predisposition, AED induced teratogenicity and severity of convulsive disorder. Management of epilepsy during pregnancy requires a balance of maternal and foetal risks associated with uncontrolled seizures against the potential teratogenic effects associated with the use of anti-epileptic drugs. [3] A rational approach should be adopted for treatment in these cases which requires knowledge of risks as well as understanding of the effects of pregnancy on seizure control and of gestational effects on anti-epileptic drug disposition. During pregnancy, the monitoring of AED levels can help to provide seizure control. The physiological changes of pregnancy may alter AED pharmacokinetics. During pregnancy, as a function of increased cardiac output and plasma volume, renal blood flow and glomerular filtration are found to increase and extra vascular fluid and adipose tissue increase to create a larger volume of distribution. The level of serum albumin decreases, which reduces drug binding, increases the free fraction and increases drug clearance. Uncontrolled tonic-clonic seizures are potentially hazardous to the mother and are generally assumed to be more harmful to the foetus. Infants who have been exposed to AEDs in utero run an increased risk of congenital malformations, approximately twice the rate reported in the general population. [4] The common treatment strategy has been to use the appropriate AED for the woman’s seizure disorder as monotherapy in the lowest effective dosage throughout pregnancy, the objective being to use AEDs in such a way that generalised tonic-clonic seizures are avoided with minimal risks to the foetus, the newborn and the breast-fed infant. Valproic acid should be avoided if possible. [5] Any major change in the treatment of a woman with epilepsy should be made before conception. Regular monitoring of drug concentrations is recommended during pregnancy, in particular for drugs with proved teratogenic potential. [3] Proper seizure control is the primary goal in treating pregnant women’s with epilepsy. With appropriate selection of treatment and prudent preconceptional, antenatal and postpartum management favorable results can be obtained in almost 95% of such cases. Often, the evaluation of the risk and safety of pregnancy in such women is complicated by a variety of factors. Women with epilepsy are at greater risk of menstrual abnormalities, reproductive endocrine disorders, and reduced fertility. Polycystic ovaries as
*Corresponding author. Shubha Niranjan Meerut Institute of Engineering and Technology, Baghpat Bypass, NH-58, Meerut- 250005, Uttar Pradesh, India. Tel.: +91 9410853439 E-mail:
[email protected]
well as hypo or hyper gonadotrophic hypogonadism are more common in women with epilepsy than in general population. These abnormalities have been related to the effects of seizures on the hypothalamic –pituitary gonadal axis and to the possible side effects of AEDs. When compared to the general population, infants of mother with epilepsy have higher rates of major and minor malformations even when they have not been exposed to medication in utero. [1] Prevalence of epilepsy It is estimated that there are about 2.5 million women with epilepsy (WWE) in India and about two-third of them are in the childbearing age group.[ 6 ] Epilepsy complicates about 0.15% of all pregnancies. [7] General principles of treatment Following are some general principles of treatment of epilepsy though these also apply to treatment of epilepsy in pregnant women. 1.Choice of drug and dose should be according to seizure type and need of individual patient. 2.Early treatment should be initiated-because each seizure episode increases propensity to further attacks. Drugs with different mechanism of action must therefore be combined. 3.The therapy should be kept as simple as possible. A seizure diary should be maintained to keep a track of frequency/propensity of seizures. 4.Drug withdrawal should be gradual except in case of toxicity. 5.Dose adjustment should be done through therapeutic drug monitoring of plasma levels and patient compliance should be considered. 6.Therapy should be initiated with single drug preferably at low dose and the dose should be increased gradually till full control of seizure /side effects appear. Another drug should be substituted if full control is not obtained at maximum tolerated dose of one drug. With one AED risk is double (4%-6%), with two AEDs the risk is threefold (6%-9%) for women taking several AEDs (three or more) the risk may be even higher (upto 15%). [8,9] Preconception counselling and coordination of care among members of the health care team is key for treating women with epilepsy. Safety considerations in pregnancy Evidences available conclude definite risk of malformations of infants of mothers treated with anti-epileptic drugs. No doubt if tonic –clonic convulsions are not controlled risk to unborn child is evident in the form of temporary lack of oxygen. Concerns during these pregnancies include the risk of fetal malformation, perinatal death, miscarriage, and increased seizure frequency. More than 90 % of women with epilepsy will have normal, healthy infants. However, they are at greater risk for complications of pregnancy, labor and adverse pregnancy outcomes as compared to women without epilepsy. Additional risks associated with uncontrolled epilepsy during pregnancy •Birth defects •Impaired postnatal cognitive development •Neural tube defects such as spina bifida ( Carbamazepine, Valproate)
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Shubha Niranjan et al. / Journal of Pharmacy Research 2011,4(11),4181-4183 •Orofacial cleft (Lamotrigine) •Cardiac abnormalities •Low IQ (Valproate, Phenobarbital) mental retardation and/or microcephaly •Developmentally delayed children •Miscarriage in early pregnancy •Premature labour in more advanced pregnancy •Injury to foetus •Increased risk of haemorrhage in child •Fetal loss and congenital malformations (trimethadione) •Minor abnormalities include hypertelorism, epicanthal folds, shallow philtrum, distal digital hypoplasia, and simian creases. Malformations/abnormalities are 2-3 times more common in infants of mothers who received antiepileptic drugs during pregnancy. The main risk antiepileptic drug may pose is by interfering with formation of nervous system. Brain and spinal cord develop from cells which must first arrange themselves into tube like structure. This process of neural tube formation may be interfered with. Defects of neural tube may range from trivial abnormalities of vertebrae to major abnormalities in which there is maldevelopment of spinal cord with weakness of legs and loss of bladder control. Neural tube defects also includes group of malformations known as spina bifida. There is an obvious increased risk of such malformations in infants of mothers who received antiepileptic drugs during pregnancy. Risk is increased if more than one anti-epileptic drug is taken. Some seizure medication can lead to failure of oral birth control pills. Contraceptives containing ethinylestradiol reduce concentrations of Lamotrigine and Valproate. [10] Factors that may affect seizure control during pregnancy •Non –compliance/withdrawl of drug which is mostly due to the fear of teratogenic effects. •Hormonal changes that occur in pregnancy. •Alteration in pharmacokinetics of antiepileptic drugs during gestation. •Sleep deprivation in pregnancy. •Mental and physical stress in labour. [11] Mechanism for altered drug concentration in pregnancy •Increased elimination through enzyme induction (AEDs such as Phenobarbital, Primidone, Phenytoin, Carbamazepine induce cytochrome P450 enzyme system may induce foetal microsomal enzymes). •Impaired absorption( e.g. hyperemesis gravidarum) •Increased plasma volume (during pregnancy renal blood flow and glomerular filtration increases as a function of increased cardiac output this results in increase in plasma volume, extracellular fluid –increase in volume of distribution-decrease in plasma concentration of drug) •Decrease in drug binding to plasma proteins (The level of serum albumin decreases, which reduces drug binding, increases the free fraction and increases drug clearance) •Increased elimination (Lamotrigine metabolism and clearance increases during pregnancy) Diagnosis of neural tube defects Major neural tube defects in foetus can be detected by checking the levels of alpha-fetoprotein in amniotic fluid surrounding foetus, and by ultrasound examination. [12] Unfortunately these diagnostic tests are not reliable until pregnancy is fairly advanced (i.e. 16 weeks for amniocentesis and 18 weeks for ultrasound). These tests can prove to be beneficial in deciding the need of terminating pregnancy. If there is a family history of neural tube defects Phenytoin sodium has been found to be safer than Sodium Valproate and Carbamazepine. If a woman taking anti-epileptic drugs becomes pregnant the need of continuing the therapy must be determined. If the seizures are minor or if last major seizure occurred years previously therapy may be discontinued. If it’s decided that there is a risk of major seizures which requires continuing treatment it is preferable to use single drug. Normally drugs may be taken twice daily, blood levels should be prevented from peaking too high by administering drugs more frequently in smaller doses. The total daily dose should be increased if mother’s size increases. Blood levels must be checked regularly. At least when pregnancy is diagnosed, at monthly intervals from 5 th month onwards and weeks after delivery Evidences suggest that folic acid supplements given during pregnancy decrease risk of neural tube defects such as spina bifida, the risk of which is increased during pregnancy. Women with epilepsy are recommended to take 4mg of folic acid daily, compared to 400 µg recommended for women generally. [13] Counselling of pregnant epileptic women’s
Women with epilepsy should be counselled on various issues. Some of the important issues include: vRisk of inheriting epilepsy vCourse of pregnancy and delivery. vMaternal and foetal risks associated with seizures vExpected course and risk of seizures vPotential foetal risks associated with use of antiepileptic drugs. vPossibilities and limitations of diagnostic tests (prenatal) vPrinciple of drug treatment of epilepsy vFolate prophylaxis [14,15] Anti-epileptic drugs Phenytoin A substantial increase in 8-hydroxylation during pregnancy may be responsible for its increased clearance rate and the consequent decrease in serum concentration. Generally a fall in total serum phenytoin concentration may cause lack of seizure control and may require increase in dose. Phenytoin is found to cause fetal hydantoin syndrome which consists of anomalies including craniofacial anomalies, distal digital hypoplasia, epicanthal folds, hypertelorism, low-set ears and developmental delay. Of infants born to women who used phenytoin during pregnancy, 10-30% were reported to exhibit some of the syndromes, most commonly distal digital hypoplasia. However, few infants exposed to monotherapy have the entire constellation of findings. Of note, in a long-term neurodevelopmental study, 16 patients whose mothers received phenytoin monotherapy during pregnancy demonstrated slightly delayed locomotor development compared with children whose mothers took carbamazepine and with normal controls. Phenobarbital It is less frequently prescribed now days because of its tendency to produce sedation and impaired cognitive function. Neonates exposed prenatally to Phenobarbital should be monitored for withdrawl symptoms for 2-6 weeks starting t1/2 to 7 of life due to its long elimination half life(100 hrs). A drug registry reported 5 (6.5%) of 77 patients who had received phenobarbital monotherapy had fetuses with major malformations, compared with a background rate of 1.6%. Primidone Primidone is metabolized to Phenobarbital hence many of the effects on the fetus are similar. Use of primidone has been reported to cause primidone embryopathy, which includes a hirsute forehead, thick nasal roots, a long philtrum, and anteverted nostrils. However, many of these findings were similar to those found in association with phenobarbital and phenytoin exposure. Valproic acid It is rapidly absorbed and highly bound to protein albumin. Dose adjustment in pregnancy are made by clinical observation in combination with therapeutic drug monitoring. Divided doses are preferred to avoid high peaks of valproic acid serum concentration. A syndrome of specific craniofacial abnormalities and long, thin digits with hyperconvex nails has been described in infants exposed to valproic acid during pregnancy. Furthermore, an association between valproic acid and neural tube defects was noted at a rate of 1-2% .In recent studies comparing valproic acid with carbamazepine, valproic acid appears to be associated with a higher risk for major congenital malformations as well as developmental delay and decreased verbal intelligence. [16, 17] Carbamazepine Carbamazepine is 60-70% bound to protein albumin and hepatic metabolism being the main route of elimination. As a consequence of auto induction of metabolism there may be a decrease in serum concentration during the first months of therapy. As drug levels tend to be lower in pregnancy and bioavailability may be lower than with conventional carbamazepine higher dose may be required when controlled release medication is used. The concentration of the active metabolite (carbamazepine-10,11 epoxide) was reported to increase during pregnancy. This increase is of particular importance as the metabolite is believed to have comparable pharmacological activity to the parent drug. In 1989, a syndrome that included craniofacial abnormalities and hypoplastic nails was described in infants exposed to carbamazepine monotherapy in utero. In a cohort study in 1996, 6 of 47 infants demonstrated this syndrome. These infants also had lower IQ scores than controls. Carbamazepine is also associated with an increased risk of neural tube defects in as many as 0.5-1% of births (i.e. 10 times the baseline risk), cardiac anomalies. Thus, a fetal echocardiogram is recommended at 20-22 weeks’ gestation for patients taking this drug.
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Shubha Niranjan et al. / Journal of Pharmacy Research 2011,4(11),4181-4183 Table: Foetal abnormalities associated with use of various Anti-epileptics Foetal Abnormality Neural tube defects Distal digital hypoplasia Low IQ Microcephaly Intrauterine growth restriction Lip abnormalities Developmental delay Low-set ears Epicanthal fold Long philtrum Short nose Hypertelorism Others
Phenobarbital
Phenytoin
V
V V
V V V V
Valproate
Carbamazepine
V
V
Trimethadione
Primidone V V
V V
V V
V V
V V
V
V V
V V
Ptosis
Ptosis
V V V
V -
Hypoplastic phalanges
Oxcarbazepine Oxcarbazepine does not produce the active 10, 11 epoxide metabolites which may play a role in pharmacokinetics, drug interactions and teratogenicity. Trimethadione In 1975, a cluster of findings including epicanthal folds, low-set ears, microcephaly, short stature, and irregular teeth was ascribed to trimethadione. Currently, trimethadione is rarely used in the treatment of epilepsy and should certainly be discontinued during pregnancy. Gabapentin, Lamotrigine, Felbamate, Topiramate These newer anticonvulsants have not been studied extensively in pregnancy. Several studies of in utero exposure reported either case reports of anomalies or no effects on the fetus. None of the existing studies revealed a rate of congenital malformations greater than that for a woman with epilepsy who is not taking AEDs. However, randomized trials have demonstrated that Valproate use leads to better seizure control than several of these newer AEDs. Thus, the benefits and risks between congenital anomalies and seizure control needs to be considered when preparing the women with epilepsy for pregnancy. The new anticonvulsants generally have a better pharmacokinetic profile and are not metabolized to known teratogens. All of these anticonvulsants are considered US Food and Drug Administration pregnancy category C. Although, they are still known to cross both the placenta and into breast milk. The newer anti-epileptic drugs which are low (topiramate, felbamate,oxcarbazepine) or non-protein bound (gabapentin, vigabatrin) are eliminated from the body through increased clearance (vigabatrin, gabapentin) have no effect on cytochrome P-450 enzyme system(gabapentin, vigabatrin, lamotrigine), no anti folate effect, no arene oxide metabolites, and if given in monotherapy may be considered for use for women with epilepsy. [18] CONCLUSION A range of complications may occur during pregnancy in women with seizure disorder. The foetus is likely to be at greater risk of congenital abnormalities that may include facial clefts, cardiac abnormalities and neural tube defects and other complications in the form of low IQ and developmental delay. During pregnancy women need special care and medical attention so that the risks of seizure and AEDs administration can be balanced. In most of the cases, AED monotherapy and folate supplementation are recommended. Moreover, AED levels should be monitored and the foetus should be screened for abnormalities through serum testing, ultasonography and amniocentesis if possible. Appropriate preconceptional management can prove to be beneficial in reducing the associated risk. The general strategy for treatment of epilepsy during pregnancy should be: all the major changes in treatment should be accomplished before conception. Appropriate drug should be administered and
V V V V
Cardiac abnormality
Hirsute forehead
valproic acid should be avoided, monotherapy should be followed at minimum concentration. REFERENCES : 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18.
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Journal of Pharmacy Research Vol.4.Issue 11.November 2011
4181-4183
