1. WOMEN WITH EPILEPSY- AN UPDATE Dr. Sunil Kumar Sharma Senior Resident Moderator Dr. Bharat Bhushan(DM) (Asso. Prof.) Dept. of Neurology GMC Kota
2. INTRODUCTION Epilepsy is a highly prevalent neurological disorder 1% of the population. Men > women. About half of the women with epilepsy are in the reproductive age group of 1549 years. - Forsgren L, Beghi E, Oun A, et al. The epidemiology of epilepsy in Europea systematic review. Eur J Neurol 2005;12:24553. -OBrien MD, Gilmour-White SK. Management of epilepsy in women. Postgrad Med J 2005;81:27885.
3. The possibility of pregnancy should be considered in any woman of childbearing age with epilepsy. The National Institute for Health and Care Excellence (NICE) has also identified women in the reproductive age group to have specific and unique problems in managing their epilepsy
4. FACTORS AFFECTING CONTRACEPTION IN WOMEN WITH EPILEPSY Induction of hepatic cytochrome P450 enzyme activity Phenytoin ,Pheno.,CBZ etc. Increases the rate of metabolism of both oestrogen and progestogen. None of the newer AEDs share the broad spectrum enzyme-inducing activity of older generation agents.
5. The failure rate of contraceptive pill with AEDs is about twice that in the general population. Other modalities of contraception may need to be considered. Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy and fetal outcome. Epilepsia 1996;37(Suppl 6):S3444.
6. Enzyme-inducing AEDs can affect the metabolism of the progestogen only pill, progestogen implant and the morning after pill thus requiring higher doses or alternative forms of contraception. Medroxyprogesterone acetate depot injection is unaffected by enzyme-inducing AEDs.
7. Use of any oestrogen-based contraceptive can result in a significant reduction of lamotrigine levels (by 40- 60%) and lead to loss of seizure control. When a woman or girl starts or stops taking these contraceptives, the dose of lamotrigine may need to be adjusted. [NICE 2012] Sabers A, Buchholt JM, Uldall P, et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res 2001;47:1514.
8. CATAMENIAL EPILEPSY AND EFFECT OF SEX HORMONES ON EPILEPSY Catamenial epilepsy- Periodicity of the exacerbation of the seizure is in association with the menstrual cycle. Oestradiol decreases seizure threshold Progesterone has antiepileptic effects . Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38:10828.
9. There are three commonly recognised seizure Patterns: Perimenstrual Day 3 to +3), Periovulatory (day 10 to 3) Entire luteal phase in anovulatory cycles (day 10 to 3) Herzog AG. Catamenial epilepsy: update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial. Seizure 2015;28:1825.
10. Sometimes intermittent Rx in addition to regular drug Rx. Eg. Clobazam and progesterone
11. EPILEPSY AND PREGNANCY Managing epilepsy during pregnancy is often challenging. AEDs-higher doses risk of fetal malformation AEDs-lower doses - uncontrolled seizures
12. WOMEN WITH EPILEPSY Effect of epi. On pregnancy -15% fewer children -Blunt trauma -Does not affect the course of pregnancy - Risk of- severe pre-eclampsia, early pregnancy bleeding, pregnancy induction, cesarean section -Teratogenesis Effect of pregnancy on epi. - in one-fourth - in one-fourth -Half-no change -Consensus state.-insufficient evidence -CPS worsened -Hormonal changes -Vol. of distribution - level of unbound drug -Alt. metabolism
13. EFFECT OF EPILEPSY ON PREGNANCY In pregnant women, a diagnosis of epilepsy is associated with a small but significant increase in adverse pregnancy outcomes- - Spontaneous miscarriage - Antepartum haemorrhage - Postpartum haemorrhage - Hypertensive disorders - Induction of labour - Caesarean section - Any preterm birth before 37 weeks of gestation - Fetal growth restriction Viale L, Allotey J, Cheong-See F, et al. Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis. Lancet 2015;386:184552.
14. Women with epilepsy have approximately 15% fewer children than expected. Reasons -Social effects of epilepsy, -Menstrual irregularity- -1 of 3 women with epilepsy, -Oligo and polymenorrhea (1/3) -Anovulatory MC(1/3) . -Effect of some antiepileptic medications on the ovaries -Effect of seizures/AED on reproductive hormones. -Herzog AG. Menstrual disorders in women with epilepsy. Neurology. 2006 Mar 28. 66(6 Suppl 3):S238.[Medline]. - Murialdo G, Galimberti CA, Magri F, Sampaolo P, Copello F, Gianelli MV, et al. Menstrual cycleand ovary alterations in women with epilepsy on antiepileptic therapy. J Endocrinol Invest. 1997 Oct. 20(9):51926. [Medline].
15. In an Indian registry-based study, 38.4% of women with epilepsy were infertile. Age, lower education, and polytherapy with antiepileptic medications as risk factors (Sukumaran et al., 2010)
16. The relative impacts of different seizure types are difficult to determine. SPS have minimal effect on the fetus. CPS may leads to injuries due to L.O.C. GTCS are feared the most-injury, alterations in electrolytes, blood pressure and oxygenation.
17. INDICATIONS OF CAESAREAN SECTION If frequent seizures greatly impair cooperation in forthcoming labour and delivery Generalised seizure during labour Refractory status epilepticus in the third trimester -Sveberg L, Svalheim S, Taubll E. The impact of seizures on pregnancy and delivery. Seizure 2015;28:358. -Dubovick M. Neurobehavioral manifestations of developmental impairment of the brain. Interdiscip Toxicol 2010;3:5967.
18. EFFECT OF PREGNANCY ON EPILEPSY Many studies suggest- in one-fourth - in one-fourth A consensus statement and review of the evidence available concluded that there is insufficient evidence regarding change in the frequency of seizures or status epilepticus during pregnancy (Harden et al., 2009b)
19. TERATOGENIC EFFECTS OF AEDS AED teratogenicity should be considered during drug selection for all women of childbearing potential. Frequency of major malformations =1.8% in normal control population. With one AED (phenytoin, carbamazepine, or phenobarbital) this rate rose to 3.4% to 5.2%, With two or more to 8.6%. (Holmes et al., 2001)
20. Valproic acid causes a higher rate of teratogenicity than other commonly used AEDs. 9.1% for higher valproic acid doses in one study (Morrow et al., 2006). Higher-dose lamotrigine (>200 mg/day) also possibly increased teratogenicity up to 5.4% (Brodie, 2006).
21. Most serious teratogenic effects occur during the first 2.5 months of gestation. Changing medication before or during the first trimester is most useful. The neural tube closes between 3 and 4 weeks. Cleft lip and palate occur with exposure before 5 and 10 weeks, respectively Congenital heart disease occurs before 6 weeks.
22. Highest malformation rates were seen for valproate (4.7%10%) and the lowest for lamotrigine (2% 3.4%) . Valproate doses over 800 mg/day - highly teratogenic. Lamotrigine has been associated with low teratogenic risks. The major limitations of lamotrigine in pregnancy is the problem of induction by sex hormones -higher risks of seizures in up to 58% of pregnant women. -Tomson T, Battino D, Perucca E. Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol 2015;15:2108. -Vajda FJ. Effect of anti-epileptic drug therapy on the unborn child. J Clin Neurosci2014;21:71621. -Reimers A. New antiepileptic drugs and women. Seizure 2014;23:58591.
23. AED ASSOCIATED CONG MALFORMATIONS Cleft lip and cleft palate, Heart (ASD,VSD,TOF, COA, PDA and PS) Urogenital defects NTD
24. FETAL HYDANTOIN SYNDROME (FETAL ANTICONVULSANT SYNDROME) Midfacial hypoplasia, Long upper lip, Low birth weight, Cleft lip and palate, Digital hypoplasia and nail dysplasia Occurs with Phenytoin,Carbamazepine, Primidone, and Valproic acid. Some minor anomalies usually disappear during the first years of life.
25. Levetiracetam having low teratogenesis and good seizure control is a better choice . Rates of all seizures in pregnant women taking levetiracetam have been comparable to older AEDs. NICE recommends a high-resolution USG scan of pregnant women ,taking AEDs at 1820 weeks gestation. -Meador KJ. Epilepsy: Pregnancy in women with epilepsyrisks and management. Nat Rev Neurol 2014;10:61416. -Women and girls with epilepsy. Epilepsies: diagnosis and management. Published:11 January 2012. http://www.nice.org.uk/guidance/cg137/resources/ epilepsies-diagnosis-and-management (accessed 2.3.2016).
26. NON-TERATOGENIC EFFECTS OF AEDS ON CHILDREN EXPOSED , IN UTERO There is a longer term risk to the cognitive and behavioural development of the child exposed in utero to sodium valproate. Although less certain, there may also be risks associated with phenobarbital and phenytoin exposure. Bromley RL, Baker GA, Meador KJ. Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero. Curr Opin Neurol 2009;22:1626.
27. PREGNANCY AND AED LEVELS IN BLOOD CYP enzyme induction-eg Phenytoin ,Phenobarbitone Plasma concentration of AEDs metabolised through glucuronidation such as lamotrigine and oxcarbazepine can markedly decrease over the course of the pregnancy. Lamotrigine plasma concentrations can decline during gestation to as much as 30% or less of prepregnancy values. -Parry E, Shields R, Turnbull AC. The effect of pregnancy on the colonic absorption of sodium, potassium and water. J Obstet Gynaecol Br Commonw 1970;77:61619. - Messmer K, Ke