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Women with Epilepsy: Seizures in Pregnancy and Maternal/Fetal Outcomes

40th Annual Progress in OBGYN February 19, 2015 Jennifer L. DeWolfe, DO Associate Professor UAB Epilepsy Center Director, BVAMC Sleep Center

Disclosures Research Funding Marinus Pharmaceuticals, Inc. NINDS -- No bearing on this presentation

Objectives • Identify maternal outcomes in pregnant women with epilepsy • Identify fetal outcomes related to antiepileptic drug use in pregnant women with epilepsy • Describe neurodevelopmental effects of antiepileptic drug use during pregnancy and breastfeeding in women with epilepsy • Describe approach to managing seizures during pregnancy

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Goal in Epilepsy Management

• Seizure freedom on the lowest dose of the least number of antiepilpetic drugs (AEDs) with the least amount of side effects

Maternal Outcomes • Cesarean Delivery • Change in Seizure Frequency • Postpartum Depression

Cesarean Section Risk • Most women with epilepsy have vaginal delivery 1 • Pregnancy registries demonstrate no increased rates of cesarean section compared to general population 2 • Planned c-section solely based on history of epilepsy may result in increased number of unnecessary procedures • If signs of fetal distress – cesarean section

1. Nakken KO, et al. Tidsskr Nor Laegeforen. 2006;126(19):2507-10. 2. EURAP Study Group. Neurology. 2006;66(3):354-60.

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Seizure Control during Pregnancy Seizure Frequency • Unchanged for most women (1-4,6) • Some increased st • especially 1 trimester (1,6)

• 17% EURAP (2)

• Some decreased (1)

• 15% EURAP (2)

• 3.5% seizures during childbirth (7)

More likely to have seizures during pregnancy if higher # seizures prior to pregnancy (1, 5)

(1) http://www.mayoclinic.com/health/pregnancy/PR00123. (2) Pennell, P. Epilepsy Currents. Nov/Dec 2006;6(6):186-188. (3) Bardy AH. Acta Neurol Scand. 1987 May;75(5):356-60. (4) Tomson T et al. Epilepsia. 1994 Jan-Feb;35(1):122-30. (5) Gjerde IO, et al. Acta Neurol Scand. 1988 Sep;78(3):198- 205. (6) Epilepsia. 2013 Sep;54(9):1621-7. (7) (1) EURAP Study Group. Neurology. 2006;66(3):354-60

Seizure Control during Pregnancy Seizure Frequency • 84–92% seizure-free during pregnancy if seizure-free 9 months prior to pregnancy

Epilepsia. 2009;50(5):1229-36

Seizure Control during Pregnancy • Generalized epilepsy higher rate seizure freedom (73% vs 59%) • Lamotrigine • Less likely to be seizure-free, 58.2% • More convulsions, 21.1% • More seizures from 1st to 2nd or 3rd trimesters, 19.9% • More likely to require an increase in drug load, 47.7%

 Thus, more frequent Lamotrigine levels should be evaluated and proactive increases should be performed during pregnancy

Epilepsia. 2013 Sep;54(9):1621-7.

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Postpartum Depression

Postpartum Depression • General population: 11% • Women with Epilepsy: 25-29% • Risk factors include multiparity and AED polytherapy

1. Turner K, et al. Epilepsy Behav. 2006 Sep 9;9(2):293-7. 2. Epilepsy and Behav. 2009 Nov;16(3):426-430.

Fetal Outcomes

• Teratogenicity • Neurodevelopmental Effects

FDA Pregnancy Categories for Medications • Category A: Controlled studies in pregnant women demonstrate no evidence fetal risk. The possibility of harm appears remote.

• Category B: Presumed safety based on animal studies, with no controlled studies in pregnant women, or animal studies have shown an adverse effect that was not confirmed in controlled studies in women.

• Category C: Studies in women and animals are not available or studies in animals have revealed adverse effects on the fetus and no controlled studies in women. Give if potential benefits justify potential risks.

• Category D: Evidence of human fetal risk (unsafe), however in some cases such as a life- threatening illness the potential risk may be justified if there are no other alternatives

• Category X: Highly unsafe: risk of use outweighs any potential benefit. Contraindicated in women who are or may become pregnant.

US Code of Federal Regulations. 21CFR, 201.57.

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Generalized Seizure during Delivery

• Seizures increase risk of morbidity and mortality, thus need for AEDs during pregnancy for some WWE • Fetal heart rate tracing during a maternal generalized tonic clonic seizure demonstrated bradycardia, reduced short-term and long-term variability, and late decelerations suggesting asphyxia

Hiilesmaa VK, et al. Am J Obstet Gynecol. 1985;152(5):499-504.

Teratogenicity

Major malformations Minor malformations

• ~3% general population (1,3) • 5-10% general population (1) • Higher WWE on AED • 10-15% WWE on AED monotherapy (1) monotherapy (1) • Increased with 1st trimester AED exposure (2) • Higher AED doses and polytherapy associated with increased risk (2)

(1) www.epilepsyfoundation.org/answerplace/Life/adults/women/Professional/pregnancy.cfm. (2) Perucca E. Lancet Neurol. 2005 Nov;4(11):781-6. (3) CDC. MMWR. January 6, 2006 / 54(51&52);1301-1305

Folic Acid

• Folate may decrease birth defect risks by overcoming defect in homocysteine metabolism • Cooking and enzyme inducing AEDs reduce folic acid levels ~90% • folic acid supplementation in epilepsy • 1mg daily • 4mg daily (enzyme inducing AEDs and valproate)

(1) Morrell MJ. Epilepsy Currents, 2002, 2:31-34. (2) Wilson RD, et al. J Obstet Gynaecol Can. 2003 25:959-73. (3) Ono H, et. al. Metabolism. 1997;46:959- 962. (4) Schwaninger M, et. al. Epilepsia 1999;40:345-350. (7) Werler MM, et al. JAMA 1993;269:1257-1261. (8) Medical Research Council Vitamin Research Group. Lancet 1991;338:131-137.

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Major Malformation Rates

• Valproate 9-20% (Neural tube defects, hypospadias, cardiac defects, oral clefts) • Dose dependent effect > 800 – 1000 mg • Phenobarbital: 6% (cardiac defects, oral clefts) • Topiramate: 4.5% (oral clefts) • Carbamazepine: 3.1% • Phenytoin: 2.9% • Levetiracetam: 2.2% • Lamotrigine: 2.0% • Gabapentin: 1.2% • Zonisamide: none

1. Neurology. 2012 May 22;78(21):1692-9. 2. Arch Neurol. 2011 Oct;68(10):1275-81. 2. Birth Defects Res A Clin Mol Teratol. 2012 Aug;94(8):599-606. 3. Meador KJ. Neurology 2006 Aug ;67(3):407-12. 4. Neurology. 2013 Jan 22;80(4):400-5. NAED Pregnancy Registry Fall 2014.

Neurodevelopmental Effects of AEDs : VPA, CBZ, LTG, PHT 3 y/o • Verbal abilities were lower than non-verbal in children exposed in utero to each drug • Preconceptional folate use was associated with higher verbal outcomes • Valproate was associated with poorer cognitive outcomes, lower verbal and non-verbal scores • Carbamazepine: Lower verbal performance

Epilepsy Behav. 2011 Jun;21(2):147-52.

Meador KJ. Neurology 2006 Aug ;67(3):407-12.

Neurodevelopmental Effects of AEDs: 195 children – CBZ, PHT, LTG, VPA

6 y/o Adaptive & Emotional/Behavioral Cognitive Outcomes • Dose-related performance decline Valproate and Phenytoin • Valproate vs. Lamotrigine and Phenytoin: • Significantly lower scores on General Adaptive Composite • More atypical behaviors and inattention • Greater risk of ADHD

Epilepsy Behav. 2013 Nov;29(2):308-15.

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Neurodevelopmental Effects of AEDs: 6 y/o Cognitive Outcomes Breastfeeding Outcomes • Valproate worse by 7-13 IQ points (P < .001 vs. other drugs) • IQ higher if breastfed (106 vs. 94) • Drug dosage: higher dosage worse (P = 0.01) • Maternal IQ: higher child IQ with higher maternal IQ (P = .01) • Periconception folate use: IQ 6 points higher (P = .005) • Breastfeeding: IQ 4 points higher (P = .045)

JAMA Pediatr. 2014 Aug 1;168(8):729-36.

Seizures and Pregnancy

My Approach

1. Epileptologist visit in family planning stage  Review diagnosis  Optimize seizure control  Folic acid: 1mg daily, 4 mg if enzyme inducing antiepileptic drug 2. Patient education  Expectations during family pregnancy, postpartum  Educational handouts, websites 3. High Risk OB referral  2nd trimester targeted ultrasound  Genetics counselor

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My Approach

4. Frequent office visits  Every 2-3 months 5. AED levels  Monthly levels  Lamotrigine doses need to be increased throughout pregnancy  Neurologist/Epileptologist adjust meds 6. Breakthrough seizures  Call Epileptologist for any seizures, obtain AED levels  Check for infection, reduce stress, increase sleep  ER for any convulsions

My Approach 7. Pregnancy Registries  North American Antiepileptic Drug Pregnancy Registry  1-800-233-2334 8. Breastfeeding  Encouraged, discuss literature  Husband/family 3 AM feedings 9. Postpartum visit  2 months  Aim for pre-pregnancy AED dosages by 7-10 days postpartum  Ask about postpartum depression  Baby safety (changing, carrying child, bathing, night feeds)

Ongoing Research

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Maternal Outcomes and Neurodevelopment Effects of AEDs • Pregnant Women w/epilepsy vs. Pregnant Women w/out Epilepsy • Outcomes • Seizure frequency during pregnancy • C-section rate • Rate of depression • Small for gestational age • Child verbal ability • Childhood IQ • Breastfeeding effects

• Epilepsy Center Office: 934-1654, Cheryl Hall, LPN

Summary

• Most women with epilepsy have normal pregnancies delivered via vaginal delivery • Pregnancy Seizure frequency is unchanged for most WWE • High likelihood of remaining seizure free during pregnancy if seizure free 9 months prior to pregnancy • All AEDs are Pregnancy Category C or D, thus increased teratogenicity potential

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Summary

• Valproate monotherapy and polytherapy have highest rate of teratogencity followed by Phenobarbital and Topiramate • Dose dependent negative effects for teratogenic and cognitive outcomes • VPA and higher AED doses are associated with lower IQ, and attention/behavior problems • Breastfeeding, use of folic acid, higher maternal IQ associated with higher IQs and verbal cognitive abilities

Summary

• Preconception visit: Review diagnosis, Obtain seizure control, Optimize AEDs, Add folic acid (1 mg, 4 mg), High Risk OB referral • During Pregnancy: monthly levels, increase AED doses for levels trending down, High Risk OB, review postpartum depression, 2nd Trimester Structural US, breastfeeding data, postpartum care of infant • Encourage enrollment in Pregnancy Registry • Epilepsy Center Office: 934-1654, Cheryl Hall, LPN for MONEAD Study