Epilepsy in Pregnancy

1. Epilepsy in Pregnancy Sherifia Heron, M.D October 20, 2009 Ob Rotation Dept. of Family and Social Medicine

2. Case • 36yo G1P0000 at 35wks and 2 days with history of epilepsy sent from clinic for elevated BPs to rule out preeclampsia. She had no complaints. No LOF, No VB, and +FM. No HA, Visual Changes, or epigastric pain. • Initial BP 110/60, Range (100-125/60-80), Total of 9 visits. Initial weight 128160 = 32lbs gained. • PNI: Hx of Seizure disorder • PNL: O+, ab-, H/H 11.6/34.5, Syphilis NR, Rubella Immune, GC Neg/Chlamydia Neg, HBSag Neg, HIV neg, GBS neg, GTT Neg (109) • Ob Hx: None

3. Past Medical Hx: Seizure D/o • PSHx: None • SHx: Employed, married to FOB they live together. Denies Tob/etoh/Drugs/DV. Planned pregnancy – good support system • Medications: Lamotrigine (Lamictal) • Allergies: NKDA • PE: No epigastric pain, No edema, BP 136/67, Range (115-142/60-92) • FHT 140s, moderate variability, +accels, -Decels • SVE: Ft/L/High • EFW 3400 • Vertex by Sono

4. Assessment and Plan • 36yo G1P0 at 35 and 2 days with h/o seizure d/o admit to L&D to rule out PEC • Admit to L&D, PEC labs, • PEC: BP in normal to mild range 136/67, Range (115-142/60-92) No S/Sx of PEC,Will continue to monitor • FEN/GI: NPO, Except ice chips, IVF @125 cc/hr • Labor • Expectant management • Fetus: reassuring overall, Category 1 tracing

5. PEC Labs • UA: Neg for protein • AST/ALT: 16/11 • LDH: 170 • Creatinine: 0.5 • Platelets: 199

6. AED • Are antiepileptic drugs necessary • What effect do antiepileptic drugs have on the fetus? • What effect does maternal epilepsy have on the fetus? • What effect does pregnancy have on seizures? • How should the patient be managed during pregnancy and delivery? • How should the patient be managed during the postpartum period?

7. Case • At 2:10am, emergency alarm went off, two ob residents myself and nursing staff rushed to PACU • On arrival to the PACU, approximately 12hrs after Ms. X was admitted to monitor for PEC she was having a seizure • The seizure went on for approximately 30sec where Ms. X upper extremities was flexed and jerking. Head neck and shoulders was also jerking uncontrollably • Pts. Eyes were closed and rolled back in her heard. Pt. Grunted and responded to questions by blinking once for yes and twice for no. • Vitals were taken during the attack: BP 110/60, RR 26, HR 138 • After the seizure ended the pts. Reports feeling tired and drowsy and was allowed to rest until fully awake – at which time she was consented for a C-section • Vital Signs remained stable

8. Case continue • FHT: 140s  120s • During seizure episode • Returned to baseline 140s after seizure • Toco: Q15-20mins

9. Questions • What Happened? • Eclampsia vs. Epilepsy? • Could this have been prevented by appropriately managing her epilepsy • Labs was drawn again and decision made to perform a c-section

10. History of seizure since age 17 • Says EEG in D.R. was “abnormal” but subsequent EEGs in the US was negative • No family history of seizure • Last seizure was 2.5 years ago • No triggers but mostly occurs at night • No history postictal confusion, incontinence • Cryptogenic seizure

11. Epilepsy Pathophysiology • Seizures happen when there are sudden changes in the way normal brain cells interact electrically. • Consciousness, movement, sensation, speech, mood, memory, and emotions can all be affected during the one or two minutes that the seizure lasts.

12. Seizure Medications • *Glossary of generic to name brand drugs • Generic Name Brand • lamotrigine ....................Lamictal • carbemazepine ..............Tegretol, Carbatrol • gabapentin ....................Neurontin • levetiracetam..................Keppra • oxcarbazepine................Trileptal • phenytoin ......................Dilantin • tiagabine ........................Gabitril • topiramate......................Topamax • zonisamide ....................Zonegran

13. Drug Monitoring • Lamotrigine • Several studies suggest that lamotrigine clearance increase by about 65 to 94% and therefore should be monitored more frequently during the second and third trimesters, to reduce the possibility of increased seizures, as well as in the early postpartum period, to avert toxicity • Levetiracetam • Among 14 women monitored on levetiracetam therapy during pregnancy, plasma concentrations were observed to decline during pregnancy to 40% of baseline concentrations in the third trimester. Limited information on seizure control was provided, but the possibility of increased seizures during this time suggests the need for closer monitoring

14. Oxcarbazepine • In one large pregnancy registry oxcarbazepine monotherapy increased the risk of seizure, suggesting the possibility that it, too, is associated with pharmacokinetic changes in pregnancy, and requires more frequent monitoring. • Topiramate • A study describing 12 women on topiramate therapy during pregnancy reported that serum concentrations declined by about 30%. Increased seizure frequency in pregnancy was also observed in this series

15. Types of Seizures • Generalized Seizures • Absence seizures • Myoclonic seizures • Atonic seizures • Tonic seizures • Clonic seizures • Tonic-clonic seizures • Partial Seizures • Simple partial seizures (awareness retained) • Motor, autonomic, sensory or psychological • Complex partial seizures (awareness lost) • Secondary generalized seizures • Status Epilepticus Status epilepticus is prolonged, repetitive seizure activity that lasts more than 20 to 30 minutes, during time which the patient is unconscious. Status epilepticus is a medical emergency with a significantly poor outcome; it can result in death if not treated aggressively. Its causes include improper use of certain medications, stroke, infection, trauma, cardiac arrest, drug overdose, and brain tumor

16. Simple Partial Seizures • Awareness preserved • Memory preserved • Consciousness preserved • Complex Partial Seizures • Awareness preserved • Memory preserved • Consciousness preserved

17. Epilepsy Statistics • 90% of women with epilepsy have normal pregnancy • Nonetheless, there are a number of fetal and obstetrical complications associated with women with epilepsy.

18. Preconception Management • This should include information regarding risks associated with epilepsy and pregnancy, • potential interactions with oral contraceptive therapy, and • recommended folate supplementation

19. Contraception • inducers of the hepatic cytochrome P-450 system • hormonal contraceptive failure

20. Folic acid supplementation • Animal studies have shown that valproate and phenytoin decrease the concentration of certain forms of folate and are associated with neural tube defects

21. Folic acid supplementation • It has not yet been conclusively determined if folic acid supplementation prevents neural tube defects in women receiving AEDs.

22. Continued folic acid supplementation • Once a woman with epilepsy who is taking AEDs becomes pregnant, serum and red cell folate levels can be monitored (goal is concentration about 4 mg/ml).

23. Obstetrical Complications • Low birth weight • Lower apgar scores • Preeclampsia • Bleeding • Placental abruption • Prematurity • The rates of stillbirth, neonatal death, and perinatal death vary widely and have been reported to be as high as two to three times greater in infants born to women with epilepsy • The mechanism of risk is not well understood. In one study, the investigators found an increased risk of spontaneous abortion for both fathers and mothers with epilepsy

24. Necessity for antiepileptic drugs • Is the diagnosis of epilepsy well established? In some patients, routine EEG recordings or continuous video/EEG monitoring may be warranted to confirm the diagnosis • Does the patient require AEDs and if so, is she on the most appropriate medications and the minimum dose to maintain seizure control

25. Are Antiepileptic Drugs Necessary • Many physicians will consider withdrawal of AEDs after a period of two years without seizures. The frequency of seizure recurrence within six and twelve months of discontinuing therapy is 12 and 32 percent, respectively. • Thus, if a woman has been seizure-free for a satisfactory period, a taper and withdrawal of AEDs at least six months prior to becoming pregnant is suggested

26. Choice of antiepileptic drug • If it is felt that medications cannot be withdrawn, the patient should take the most suitable medication for the seizure type. • The optimal treatment of women with epilepsy who are of childbearing age is unclear because of a lack of conclusive data on the comparative teratogenicity of different AEDs.

27. Antiepilepsy Drugs • The most common major congenital malformations associated with AED are • neural tube, • congenital heart and urinary tract defects, • skeletal abnormalities, • and cleft palate. • Specific AEDs, combination drug therapy, a family history of birth defects, and other risk factors appear to be associated with increased risk of these, at least in some studies • Particularly valporate and carbemazepine monotherapy, • benzodiazepines in polytherapy, and caffeine in combination with phenobarbital • In addition to the specific AED used alone or in combination, the gestational timing of the exposure and the dose of AED used are also likely to be important. These have been best associated with valporate • Many of these drugs appear to be implicated in dysmorphisms such as hypoplasia of the nails and distal phalanges, hypertelorism, and the “anticonvulsant face” – Broad or depressed nasal bridge, short nose with anteverted nostrils, long upper lip, maxillary hypoplasia

28. Other newer AEDs • There is limited human information on the fetal risks of the newer antiepileptic drugs (eg, gabapentin, felbamate, topiramate, tiagabine, levetiracetam, pregabalin).

29. Management During Pregnancy • The AED should be administered at the lowest dose and lowest plasma level that protects against tonic-clonic and/or complex partial seizures • The plasma drug level should be monitored regularly during pregnancy including, if available, the physiologically important free or unbound drug concentration • The use of multiple agents should be avoided, if possible, especially combinations involving valproate, carbemazepine, and phenobarbital • If there is a family history of neural tube defects, both valproate and carbemazepine should be avoided, unless a patient’s seizures cannot otherwise be controlled • In established pregnancy, changes to alternate AED therapy should not be undertaken solely to reduce teratogenic risk for several reasons • Changing the AEDs may precipitate seizures • Overlapping AEDs during the change exposed the fetus to effects of an additional aED • There is limited advantage to changing AEDs if pregnancy has already been established for several weeks

30. Vitamin K Supplementation • Most physicians recommend administration of prophylactic vitamin K during the last month of pregnancy to women treated with AEDs to protect the child against severe postnasal bleeding due to a deficiency in vitamin K-dependent clotting factors • Enzyme-induced AEDs, such as phenobarbital, phenytoin, and carbemazepine, cross the placenta and may increase the rate of oxidative degradation of vitamin K in the fetus, an effect that can be overcome by large doses of vitamin K

31. Effects of Epilepsy on the Fetus • In addition to concerns about fetal exposure to antiepileptic drugs (AEDs), there are risks to the fetus from maternal seizures and maternal epilepsy. • Few studies have been performed on the direct effects of maternal seizures on the fetus. • Fetal hypoxia • One report of fetal heart rate monitoring during a maternal generalized tonic-clonic seizure lasting 2.5 mins revealed significant fetal heart rate deceleration lasting up to 30 mins after the seizure. While nonconvulsive seizures are believed to be less dangerous, another case report has documented significant fetal bradycardia during a one-minute, complex partial seizure.

32. Effects of pregnancy on seizures • The frequency of seizures does not increase during pregnancy in the majority of women with epilepsy.

33. At Delivery • Most women have a normal vaginal delivery. • Elective cesarean section • frequent seizures during the third trimester • history of status epilepticus during severe stress • A tonic-clonic seizure occurs during labor in 1 to 2% of women with epilepsy, and in another 1 to 2% 24hrs after delivery. • It is therefore essential to maintain a plasma AED level known to protect against seizures during the third trimester and during delivery. Doses must not be missed during the period of labor.

34. Speak • Most women have a normal vaginal delivery. However, elective cesarean section may be justified in women with frequent seizures during the third trimester or a history of status epilepticus during severe stress • A tonic-clonic seizure occurs during labor in 1 to 2% of women with epilepsy, and in another 1 to 2% 24hrs after delivery. It is therefore essential to maintain a plasma AED level known to protect against seizures during the third trimester and during delivery. • Doses must not be missed during the period of labor.

35. Reference • “Risk associated with epilepsy and pregnancy” and “Management of epilepsy and pregnancy” • www.uptodate.com • http://www.webmd.com/epilepsy/medications-treat-seizures • www.webMD.com • http://www.uptodate.com/patients/content/topic.do?topicKey=~84qqmS11.oaT1P