THE CLINICAL MANAGEMENT OF EPILEPSY IN PREGNANT WOMEN

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1 WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Bhargavi et al. SJIF Impact Factor Volume 7, Issue 3, Review Article ISSN THE CLINICAL MANAGEMENT OF EPILEPSY IN PREGNANT WOMEN L. Divya Bhargavi*, K. Rishitha, Dr. G. Sushmitha, Dr. V. Tejaswi, Dr. G. Ramesh and P. Srinivasa Babu Vignan Pharmacy College, Vadlamudi Article Received on 27 Jan. 2018, Revised on 17 Feb. 2018, Accepted on 01 Mar DOI: /wjpps *Corresponding Author L. Divya Bhargavi Vignan Pharmacy College, Vadlamudi ABSTRACT Epilepsy is a neurological disorder characterised by seizures. The antiepileptic drugs prescribed for management of women with epilepsy during pregnancy have to face different challenges. The goal of treatment is to control seizures in women and minimise foetal exposure to AEDs so as to reduce the risk of structural and neuro developmental teratogenic effects on the foetus. Seizure threshold may be lowered with a number of pregnancy associated changes such as physiological, endocrine, and psychological. As seizures can harm both mother and foetus, these women need antiepileptic drug treatment. The pharmacokinetics of antiepileptic drugs during pregnancy can altered by hormonal and other factors. Higher dosage and polytherapy of AEDs can increase the risk of fetal malformation during antenatal exposure. Clinicians have to balance potential foetal adverse effects against the risks of uncontrolled maternal disease while treating with antiepileptic drugs in pregnant women. The treatment goal in pregnancy is to maintain a balance between the harmful effects of seizures and an effective but low dose of a single antiepileptic drug. KEYWORDS: epilepsy, anti-epileptic drugs, foetal abnormalities, neural tube defects. INTRODUCTION: Epilepsy is a neurological disorder characterised by seizures. Approximately, 0.5-1% of the population have active epilepsy, where one third of them are pregnant women. [7] Women with epilepsy face multiple issues in antenatal, intrapartum, and postpartum period. It is a situation where it can be confused with non-proteinuric hypertension. Pregnant women with epilepsy (WWE) are advised to take anti-epileptic drugs (AEDs) to reduce maternal and fetal risks associated with seizures. The goal is to control seizures in mother and to minimise the Vol 7, Issue 3,

2 fetal exposure to AEDs. AEDs exposure during prenatal stage may be associated with complications such as major congenital malformations, intrauterine growth retardation, dysmorphic syndromes, and deficits in neurocognitive developments. [1,8,7] EFFECTS OF PREGNANCY ON EPILEPSY HORMONAL ASPECT IN PREGNANCY Studies have shown that the seizure frequency is influenced by the female sex hormones estrogen and progesterone. Generally, estrogen lowers the seizure threshold, while progesterone elevates it. [4,9,10] SEIZURE FREQUENCY DURING PREGNANCY Seizure frequency may increase or decrease in WWE, which may have a stable pattern with more, less or unchanged seizure frequency throughout the period of pregnancy. Several factors influencing seizures during pregnancy are hormones, noncompliance and decrease in blood levels of free form of AEDs. [1,4] INFERTILITY WWE are generally considered to have reduced fertility. PCOD is an important cause for infertility and those women with epilepsy have increased tendency to develop PCOD. [5,11,12] EPILEPTIC SYNDROME DURING PREGNANCY Seizures during pregnancy can be induced by several mechanisms such as metabolic derangement, eclampsia, and cerebral venous sinus thrombosis. WWE may have seizures before pregnancy or may experience seizures only during pregnancies, which is termed as gestational epilepsy. Gestational onset epilepsy is another subgroup, where women may experience their first seizure and thereafter may continue to get spontaneous recurrent seizures. About 1-2% of WWE may experience status epilepticus during pregnancy. [4] COMPLICATIONS OF PREGNANCY A recent prospective of 643 pregnancies showed that the frequency of complications in pregnancy were comparable with those without epilepsy except for spontaneous abortions, anaemia, ovarian cyst and fibroid uterus. Reports show the increased risk of non-proteinuric hypertension, pre-eclampsia, eclampsia and abruptio placenta in WWE. Specifically, abdominal trauma can result in ruptured foetal membranes, subsequent infection, and premature labour, although the risk is low. [4,14] Generalised tonic-clonic seizures can cause Vol 7, Issue 3,

3 foetal hypoxia and acidosis. WWE may have increased frequency of caesarean section although most of them have normal vaginal delivery. Usual causes of caesarean section are uterine inertia, seizures and failure of progression of labour. Fetal bradycardia, reduced variability, and decelerations are seen. [4,13] The adverse effects of seizures may be associated with ischemia, maternal stress, which cause foetal suffering, intrauterine growth delay, altered protein synthesis, changes in expression of apoptotic proteins and long term disturbances in brain function. [13,15] EFFECTS OF PREGNANCY ON AEDs The pregnancy induced physiological changes influence the distribution, availability and metabolism of AEDs. [3] Drug absorption may be altered due to decreased gastric tone and motility. Drug ingestion may be affected by nausea and vomitings during first trimester. Studies have shown an increase in renal blood flow and glomerular filtration rate causing overall reduction in total plasma concentration and also the unbound fraction of AEDs. This effect starts after conception and reduces in last few weeks of pregnancy. [3,6,16] Hormonal changes increase estrogen levels, which leads to the accelerated drug glucoronidation. This effect increases gradually throughout the first and second trimester. The activity of CYP450 enzymes is also increased which may alter the hepatic clearance is noticed. AED protein binding may be affected by reduced serum albumin concentration. Increased plasma volume or increased total body water may increase the volume of distribution with increase in weight, and thus leads to the reduced AED serum concentrations. Inter-individual differences both in drug disposition and seizure control, may affect the serum concentrations of AEDs, example, frequent vomiting may impair intake and intestinal absorption of AEDs. Co-administration with enzyme-inducing or enzyme-inhibiting AEDs may alter the pharmacokinetics. Close monitoring of the pregnant patient by measuring the serum AED levels is needed. [1,6] Increased clearance may affect AED concentrations and require dose adjustments to avoid seizures throughout pregnancy. [1] EFFECTS OF EPILEPSY ON INFANT INFANT AED EXPOSURE AND NEUROCOGNITIVE DEVELOPMENT Reduced length and head circumference, low birth weights are observed in the newborns. Recent reports have shown that the babies born to WWE may have an increased risk of developmental delay or specific learning disabilities in children who are prenatally exposed Vol 7, Issue 3,

4 to sodium valproate. An increased risk of neurodevelopmental disorders and autism spectrum disorder was most frequently diagnosed in children exposed to VPA monotherapy. [1,4,6] FOETAL LOSS Approximately, two fold increased risk of spontaneous abortions, still births and perinatal loss among women with epilepsy have been consistently evidenced. [3] INTRAUTERINE GROWTH RETARDATION: Most of the studies have reported that lower birth weights are associated with AEDs. [3] RISK OF DEVELOPING EPILEPSY The risk of unprovoked epilepsy is higher in offsprings of WWE. offsprings of parents with absence seizures are also at higher risk. [3] FOETAL MALFORMATIONS One of the major concerns for WWE is the foetal malformations. Abnormal foetal development can be classified as major and minor malformations. the malformations observed commonly may affect CVS, gastrointestinal systems, CNS, skeletal and connective tissues. [4] Major abnormalities are the malformations which require surgical interventions eg: neural tube defects, congenital heart disease, orofacial clefts, urogenital defects (glandular hypospadias). [3] These abnormalities occur during organogenesis in the first trimester. 1 Reports show that malformations such as congenital heart defects and facial clefts are associated with phenytoin, phenobarbitol and primidone. Valproate is associated with skeletal defects such as radial aplasia and urogenital defects. Studies have shown an increase in major malformations, with increasing number of drugs used. [4,5] Minor abnormalities are the malformations that may not cause significant impairment or disability eg: hypertelorism, acral hypoplasia of nails. [3] Some of the malformations are: CVS - atrial septal defect Craniofacial - cleft lip, cleft palate Skeletal - club foot, hip dislocation CNS - neural tube defects Vol 7, Issue 3,

5 GIT - esophageal atresia, omphalocele, hernia, congenital hypertrophic pyloric stenosis GUT - hydronephrosis, glandular hypospadias, undescended testis. [4] FOLATE DEFECIENCY The supplementation of folic acid before pregnancy and during the first trimester is recommended for the management of epilepsy in pregnancy. In general population folate deficiencies have been associated with neural tube defects. [20,21] The risk of neural tube defects has been shown to reduce with supplementation of folic acid ( mg). But especially those on AEDs in WWE it is not clearly defined. In one study, no use of folic acid in preconception in WWE resulted in 23% foetal abnormalities, whereas use of folic acid (5mg per day) resulted in no maternity case management. In some studies there is enhanced vocabulary development, communicational skills and verbal comprehension at 18 months of age with high dose folic acid (>5 mg per day).there will be a risk of occurrence of MCM in WWE with low serum folate concentrations (<4.4mmol/l). [1,17,18] It is recommended that the use of folic acid in WWE prevents neural tube defects. The folic acid dosing is not clearly defined, but the ANN recommends folic acid dose of at least 0.4 mg per day prior to conception and during pregnancy. Due to AEDs alteration of folate metabolism occurs and this may contribute to their teratogenicity. In practical terms, all sexually active women of childbearing age on AEDs should receive folic acid. [19,20] ANTIEPILEPTIC DRUGS Commonly used antiepileptic drugs Carbamazepine Clonazepam Ethosuximide Phenobarbitone Phenytoin Primidone Sodium valproate Sulthiame Vol 7, Issue 3,

6 New antiepileptic drugs Gabapentin Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Tiagabine Topiramate Vigabatrin Zonisamide From the above drugs some of enzyme-inducing antiepileptic drugs are Carbamazepine Oxcarbazepine Phenobarbitone Phenytoin Primidone Topiramate In clinical relevants the most commonly used AEDs cross the placenta.the prescription of AEDs to women of childbearing age have changed over the last two decades: There is a decreased prescriptions of carbamazepine, phenytoin and valproate while there is increased prescriptions of lamotrigine, topiramate, and levetiracetam for pregnant women. MANAGEMENT OF EPILEPSY For the management of pregnant women with epilepsy the potential teratogenic risk of AEDs need not only take into considerations but also the seizure control and quality of life. Preconceptual counselling is the most important phase that should be discussedto all women of childbearing age and also discuss the risks of major malformations. All pregnant women with epilepsy should receive 5 mg/day of folic acid. If any change in medication it should be done pre-conceptually as formation of organs is almost complete in the first trimester. All pregnant women with epilepsy should be provided with information about the risks of commonly used AEDs 3. The choice of AED is determined by the epilepsy type. Nearly two-thirds of women Vol 7, Issue 3,

7 with epilepsy the frequency of seizures tend to improve or remain unchanged. In the first trimester of pregnancy and also around delivery time the risk of seizures is high. In cases of polytherapy with multiple drugs, after retaining the appropriate AEDs for seizure, it may be possible to eliminate the third, and occasionally the second AED. The higher doses of valproic acid have been implicated with an increased risk of neural tube defects so it is preferable to keep the total daily dose of valproic acid below 1000mg. The daily dose should split in to three or four doses in order to avoid high peak levels in the blood and make sure good compliance with AEDs throughout pregnancy in order to avoid relapse of seizures. In some patients the dosage have to be increased in the third trimester, especially if the blood levels (preferably free drug levels) are low. Around delivery time the risk of seizure relapse is three times more than during the rest of the pregnancy. At the time of delivery care should be taken to avoid the increased risk seizure relapse related to the lack of compliance, dehydration, prolonged fasting, or effect of concomitant medications. [3,4,21] Between weeks women with epilepsy should be referred for highquality ultrasound scanning to screen for structural abnormalities and at weeks screening using serum alpha-fetoprotein combined with structural ultrasound scan can identify 95% of foetuses with open neural tube defects. At the time of delivery for women with epilepsy the obstetric unit should be equipped with facilities for maternal and neonatal resuscitation and treatment of seizures during pregnancy andlabour should be managed in collaboration with an epilepsy team. Subbuccal midazolam, intravenous lorazepam or rectal diazepam are used to terminate recurrent or single prolonged tonic-clonic seizures. If increased in seizures frequency can be treated with clobazam 10mg twice daily. During pregnancy monitor AED serum concentrations as soon as pregnancy on a monthly basis. [3] Vol 7, Issue 3,

8 Fig.1 Algorithm for management of pregnant woman with epilepsy. PRECAUTIONS Some of the safety precautions should follow women with epilepsy while carrying baby. So that, they can build confidence and avoid anxiety. Baby should be carried by using a padded carry cot While dressing to baby it is better to done on the floor to prevent fall of baby if seizure happens. While feeding baby it is better to done on the floor. She should avoid tiredness. Safe and convenient place should found for baby, in case mother feel unwell. Bathing the baby should need some-ones support. [22] CONCLUSION Pregnant women with epilepsy should undergo ultrasound sonography in order to detect the foetal abnormalities. Drug monitoring should be required while taking AEDs. Pregnant woman with epilepsy should need careful attention from the attending neurologists and obstetricians.during delivery avoid them from all stress conditions by comforting to know them that they can have safe childbirth.preconception counselling management may reduce the risk and also counsel the women about teratogenic side effects, dose optimisation and effects of AEDs over infants. Vol 7, Issue 3,

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