Nitin K. Sethi, MD; Amy Wasterlain, Pregnancy and —when MD candidate; Cynthia L. Harden, MD Department of , you’re managing both New York-Presbyterian Hospital, Weill Cornell Medical Center, When a patient with epilepsy is pregnant or planning New York, NY for pregnancy, you face the challenge of balancing sethinitinmd@hotmail. the benefi ts and teratogenic risks of her antiseizure com Dr. Sethi and Ms. Wasterlain medication. Here’s help. reported no potential confl ict of interest relevant to this article. Dr. Harden reported that she receives research support from Forest Pharmaceuticals; serves as a consultant to H. Lundbeck A/S, Novartis, Sepracor Inc., and UCB; and is on the speakers’ bout 500,000 women in the United States suff er from bureau of GlaxoSmithKline, PRACTICE epilepsy and are of childbearing age.1 For these pa- H. Lundbeck A/S, and UCB. RECOMMENDATIONS A tients and their physicians, family planning and › Use the dose of antiepilep- pregnancy are complex and fraught with risk. tic drug (AED) at which the Th e dilemma: Infants born to women with epilepsy have patient is -free prior to a 2- to 3-fold risk of congenital malformations compared with conception as a target level those whose mothers do not have epilepsy, mainly related to adjust dosing during to exposure to antiepileptic drugs (AEDs).2 Recent studies pregnancy. C also suggest that children exposed to AEDs such as valpro- › Avoid switching a pregnant ate, phenobarbital, and phenytoin in utero may have neuro- patient to an AED that she cognitive defi cits, even when there are no major congenital has not taken before. C malformations.1,3,4 › Start all women who have Yet discontinuing the drugs prior to conception or in ear- epilepsy and are of childbear- ly pregnancy is rarely a viable option. In 1 recent prospective ing age on ≥0.4 mg folic acid study, convulsive during the fi rst trimester (the type daily prior to conception. C and timing of seizure thought to have the most harmful eff ect

Strength of recommendation (SOR) on the developing fetus) were associated with malformations in 7.4% of pregnancies.2 Seizures also increase the risk of both A Good-quality patient-oriented evidence fetal and maternal death, although the extent of that risk is B Inconsistent or limited-quality not known.5 patient-oriented evidence C Consensus, usual practice, Ideally, pregnant women with epilepsy should be under opinion, disease-oriented the care of both an obstetrician experienced in high-risk preg- evidence, case series nancies and a neurologist or an epileptologist. In reality, those who live in areas with limited access to such specialized care or have limited health coverage may be cared for throughout their pregnancy by a family physician. Th is evidence-based review was developed with this family physician in mind.

Safeguarding mom and fetus starts before pregnancy Mechanisms by which AEDs cause fetal and embryonic harm remain unclear. Possible causes include drug toxicity, drug-

JFPONLINE.COM VOL 59, NO 12 | DECEMBER 2010 | THE JOURNAL OF FAMILY PRACTICE 675 drug interactions, folic acid defi ciency, the have been found to be especially notable for eff ect of suboptimally controlled convulsions, women taking .12 genetic predisposition, enhanced apoptotic Folic acid supplementation, of course, is , and alterations in thyroid important for all women of childbearing age. hormone status, among others.6-9 Major con- At a dose of 0.8 mg/d, folate has been shown to genital malformations may occur in a dose- reduce the risk of neural tube and ventricular dependent manner, and physicians should septal defects in the general population. Th e aim to use the most eff ective AED at the lowest American Academy of Neurology/American eff ective dose for women of childbearing age.2 Epilepsy Society (AAN/AES) Practice Param- In reviewing antiseizure therapy for such eters recommend that all women of child- patients, here are some considerations to bearing age taking AEDs also take folate sup- keep in mind: plements (0.4-4 mg/d).13 An optimal dose has ❚ Avoid polytherapy, if possible. Taking not been determined for this patient popula- multiple AEDs may increase the risk of major tion, but we routinely recommend 1 mg/d for congenital malformations, especially when women with epilepsy of childbearing age and valproate is one of the drugs.1 Hence, an at- increase the dose to 4 mg/d after conception. tempt should be made to switch women with epilepsy who are of childbearing age to mono- Switching (or stopping) AEDs therapy. Ideally, this should be done a year before conception Monotherapy before planned conception so that good sei- Changes in AEDs are rarely made after concep- with a newer zure control can be achieved and documented tion. Any switches that patients may desire— antiepileptic prior to pregnancy. from a potentially unsafe drug to a “safer” AED, drug appears ❚ Avoid high-risk AEDs. Overall, an in- for example—should be considered at least a to be the creased risk of major congenital malforma- year prior to planned pregnancy so good sei- safest and tions has been most convincingly found with zure control can be achieved before then. best-tolerated valproate and phenobarbital.1 Specifi c types In attempting a change in medication, option for of malformations have also been linked to start by checking the serum drug level of women of certain drugs (TABLE). Cardiac malforma- the patient’s eff ective, yet potentially unsafe, childbearing tions are associated with , antiseizure drug. Th at allows you to deter- age, provided phenobarbital, and valproate; spina bifi da, mine the baseline therapeutic drug level and adequate seizure hypospadias, porencephaly, and other brain dose at which the patient is seizure-free. Th en control can be anomalies, as well as limb reduction defects, add the second, safer AED and taper it up to obtained. are associated with valproate, particularly at its therapeutic dose, guided by serum drug doses >1100 mg/d.10 levels and the manufacturer’s recommended ❚ Choose newer agents, whenever pos- titration schedule. Once the new medication sible. Th e risk of malformations with newer has reached the therapeutic serum level, be- AEDs—including gabapentin, lamotrigine, le- gin titrating the older AED down. If the pa- vetiracetam, oxcarbazepine, and topiramate— tient suff ers a breakthrough seizure during remains unclear, but preliminary data for the cross-taper, we recommend aborting the monotherapy with these agents suggest a low- process and rapidly titrating the fi rst drug er teratogenic risk compared with traditional back to the predetermined therapeutic level. AEDs, such as phenobarbital and valproate.10 ❚ What about stopping AED therapy en- ❚ Initiate folic acid supplementation. tirely if your patient wants to get pregnant? Drug-induced folate defi ciency has been pro- Stopping AEDs is a clinical decision made by posed as a contributing factor in the terato- the treating physician in accordance with the genicity of AEDs, so diligence is essential in patient’s wishes on a case-by-case basis, and ensuring that patients who have epilepsy and should be considered only when it is highly are of childbearing age take folic acid.11 Stud- likely that seizures will not recur as a result. If ies have demonstrated a signifi cant reduction the patient has a history of poorly controlled in spontaneous abortion in women who are epilepsy despite adequate AED trials, a struc- receiving AED therapy and taking folic acid tural brain lesion, persistently abnormal elec- supplements, and the benefi ts of folic acid troencephalograms, or any other fi nding that

676 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2010 | VOL 59, NO 12 PREGNANCY AND EPILEPSY

TABLE Commonly used antiepileptic drugs: Major teratogenic risks1,10,19

FDA pregnancy AED category* Associated risks Recommendations for use during pregnancy

Carbamazepine C Cardiac malformations Lower teratogenic potential compared with phenobarbital and valproate

Gabapentin C No MCMs associated with Limited data suggest lower teratogenic risk monotherapy compared with traditional AEDs†

Lamotrigine C No distinctive pattern of MCMs Limited data suggest lower teratogenic risk compared with traditional AEDs†

Levetiracetam C Pyloric stenosis (in polytherapy Limited data suggest lower teratogenic risk with lamotrigine); spina bifi da (in compared with traditional AEDs† polytherapy with carbamazepine and valproate)

Oxcarbazepine C Urogenital malformations Limited data suggest lower teratogenic risk compared with traditional AEDs†

Phenobarbital D Cardiac malformations Best avoided in women of childbearing age

Increases risk of MCMs to at least double that of general population

Phenytoin D Bradycardia and hypotension; fetal Best avoided in women of childbearing age hydantoin syndrome

Topiramate C Hypospadias; oral clefts Limited data suggest lower teratogenic risk compared with traditional AEDs†

Valproate D Cardiac malformations; hypospadias; Best avoided in women of childbearing age limb reduction defects; neural tube defects; porencephaly; spina bifi da

Increases risk of MCMs to at least double that of general population

AED, antiepileptic drug; FDA, US Food and Drug Administration; MCMs, major congenital malformations. *Category C indicates that human data are lacking and animal studies were positive OR not done; Category D indicates that human data have shown a teratogenic risk but the benefi ts may outweigh the risk. †Traditional AEDs include carbamazepine, phenobarbital, phenytoin, and valproate. suggests she may have recurrent seizures, ex- mation regarding the risks associated with plain that the risk of discontinuing the medi- various antiseizure agents. Th e primary cation is greater than the risk of fetal exposure US-based registry is the AED Pregnancy to AEDs. It is also important to point out that Registry, available at http://aedpregnancy more than 90% of women with epilepsy have registry.org. We recommend that physicians normal, healthy children14—and that there are caring for pregnant women with epilepsy en- other steps to take to mitigate risk.13 courage them to enroll early on, before any prenatal tests are performed. Explain to your patient that by joining the registry, she will be What to consider helping others like her make informed deci- in the fi rst trimester sions about prenatal care. Registries that aim to gather data on the out- ❚ Prenatal testing. We also recommend comes of a large number of AED-exposed that pregnant women taking AEDs—par- pregnancies are a source of reliable infor- ticularly those on higher-risk drugs such as

JFPONLINE.COM VOL 59, NO 12 | DECEMBER 2010 | THE JOURNAL OF FAMILY PRACTICE 677 valproate—undergo a detailed fi rst trimester induction of UDP-glucuronosyltransferase ultrasound study between 16 and 20 weeks’ (UGT) enzymes,18 the drug’s main metabolic gestation. Amniocentesis should be avoid- enzymes. Increased clearance of lamotrigine ed, if possible; if needed, however, amniotic typically occurs within the fi rst several weeks alpha-fetoprotein levels may be determined of pregnancy and returns to baseline within for additional risk assessment.15 2 weeks after birth. ❚ Medication changes. Once a woman As a result, incremental dosing of la- is pregnant, stopping or switching AEDs re- motrigine is usually required early in the quires a higher level of caution and is usually pregnancy. In some cases, dramatic increas- ill advised. We generally avoid medication es—several multiples of the preconception switches after conception. But if a patient ex- dose—may be needed, followed by a rapid plicitly requests a change to a “safer” agent, decrease after delivery.18 we may attempt a cross-taper, as we would before pregnancy. Evidence suggests, how- Monitoring drug levels ever, that it may be too late to avoid the risk Our approach to monitoring AED levels in a for major congenital malformations, which pregnant woman with epilepsy includes the typically develop very early in pregnancy.1,3 following: ❚ Avoid untried AEDs. We advise against • Check levels at baseline—prior to concep- changing a pregnant woman’s seizure medi- tion, whenever possible—and monthly More than 90% cation to an agent she has not tried before, throughout the pregnancy, with more fre- of women with because of the risks of both common adverse quent checks for women with recurrent epilepsy have eff ects, such as allergies, and rare idiosyn- seizures and those taking lamotrigine. normal, healthy cratic reactions leading to aplastic anemia • Use the dose at which the patient was children. and Stevens-Johnson syndrome. seizure-free prior to conception as a target level during pregnancy. • Adjust the dose as needed to maintain the AED dosing throughout pregnancy preconception serum drug level. When seizures are well controlled prior to ❚ Drug-specifi c considerations. As phe- conception, they usually remain controlled nytoin and valproate are highly protein- during pregnancy, although both increases bound, we follow free levels during pregnancy and decreases in seizure frequency have been rather than total levels alone. (If your facility reported.16 Seizure exacerbations are usually is not equipped to track free drug levels, it is due to decreased AED levels; this may be the important to realize that total levels of these result of decreased plasma protein bind- AEDs may not accurately refl ect the drug ing, decreased albumin concentration, or level.) If your patient is taking phenytoin and increased drug clearance,16 although stress, you’re unable to obtain this information, you sleep deprivation, and noncompliance may can use the patient’s albumin level and the to- be contributing factors, as well. Th e changes tal phenytoin level to estimate the free level of in pharmacokinetics make it imperative that the drug with the following formula: seizure frequency as well as AED levels be Free phenytoin = measured level/ carefully monitored throughout pregnancy. [(0.2 × albumin level) + 0.1]. Although detailed information about ❚ Provide vitamin K augmentation late changes in serum levels of the newer AEDs in pregnancy. In addition to routinely prescrib- during pregnancy is not available, it can be ing 4 mg/d folic acid for pregnant women with assumed that they will decline somewhat epilepsy, we recommend oral augmentation of even if the dose remains the same. Carbam- vitamin K as another protective measure. azepine has the least alteration in metabolism AEDs that induce hepatic CYP enzymes during pregnancy,17 while a widely dispa- also induce vitamin K metabolism, thereby rate eff ect on lamotrigine metabolism during reducing the eff ectiveness of vitamin K- pregnancy has been noted. In some women, dependent clotting factors and predispos- serum levels of lamotrigine have been shown ing newborns to hemorrhagic disease.13 It to decrease by as much as 60% to 90% due to remains unclear whether only women who

678 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2010 | VOL 59, NO 12 PREGNANCY AND EPILEPSY

are taking CYP enzyme-inducing AEDs or all motrigine, levetiracetam, and topiramate are women taking AEDs should receive oral vita- excreted in breast milk in potentially clinical- min K supplementation in the last few weeks ly important amounts, no short-term adverse of pregnancy. We recommend oral vitamin eff ects have been observed in nursing infants K supplementation for all pregnant women of women being treated with AEDs.13 Little with epilepsy (phytonadione 10 mg/d) start- information is available regarding long-term ing at 36 weeks’ gestation and continuing un- eff ects, and the AAN and AES state that fur- til delivery despite the lack of a proven benefi t ther study is needed. Nonetheless, breast- because it is safe and carries little, if any, risk. feeding is generally believed to be a relatively An intramuscular injection of 1 mg safe option for patients with epilepsy who are vitamin K is generally given to all new- being treated with AEDs, and is not contra- borns—regardless of whether the mother indicated by the AAN/AES guidelines.13 has epilepsy and takes AEDs—to prevent Indeed, pregnancy itself is relatively safe hemorrhagic disease.13 for women with epilepsy. When you’re involved in their care, your awareness of the teratoge- nicity of various AEDs, the factors to consider Should women taking AEDs in managing epilepsy and pregnancy, and the breastfeed? steps to take to mitigate risk will help you maxi- Th e advantages of breastfeeding are largely mize the chance of a positive outcome. JFP undisputed, but women being treated with CORRESPONDENCE During AEDs are generally concerned about the pos- Nitin K. Sethi, MD, Comprehensive Epilepsy Center, New pregnancy, sibility of contaminated breast milk. While York-Presbyterian Hospital, Weill Cornell Medical Center, 525 East 68th Street, Room K-615, New York, NY 10021; changes in antiepileptic agents such as gabapentin, la- [email protected] pharmaco- kinetics may affect dosing requirements, References and serum levels 1. Harden CL, Meador KJ, Pennell PB, et al; American Academy 12. Pittschieler S, Brezinka C, Jahn B, et al. Spontaneous abortion of Neurology; American Epilepsy Society. Practice parameter and the prophylactic eff ect of folic acid supplementation in of antiepileptic update: management issues for women with epilepsy—focus epileptic women undergoing antiepileptic therapy. J Neurol. drugs should be on pregnancy (an evidence-based review): teratogenesis and 2008;255:1926-1931. perinatal outcomes: report of the Quality Standards Subcom- 13. Epilepsy Foundation. Pregnancy & parenting. Available at: monitored at mittee and Th erapeutics and Technology Assessment Sub- www.epilepsyfoundation.org/living/women/pregnancy/ least monthly. committee of the American Academy of Neurology and Ameri- weipregnancy.cfm. Accessed November 4, 2010. can Epilepsy Society. Neurology. 2009;73:133-141. 14. Harden CL, Pennell PB, Koppel BS, et al; American Academy 2. Sachdeo R. Th e evidence-based rationale for monotherapy of Neurology; American Epilepsy Society. Practice param- in appropriate patients with epilepsy. Neurology. 2007;69 eter update: management issues for women with epilepsy— (suppl 3):S1-S2. focus on pregnancy (an evidence-based review): vitamin K, 3. Holmes GL, Harden C, Liporace J, et al. Postnatal concerns folic acid, blood levels, and breastfeeding: report of the Qual- in children born to women with epilepsy. Epilepsy Behav. ity Standards Subcommittee and Th erapeutics and Tech- 2007;11:270-276. nology Assessment Subcommittee of the American Acad- 4. Bromley RL, Baker GA, Meador KJ. Cognitive abilities and emy of Neurology and American Epilepsy Society. Neurology. behaviour of children exposed to antiepileptic drugs in utero. 2009;73:142-149. Curr Opin Neurol. 2009;22:162-166. 15. Tettenborn B. Management of epilepsy in women of child- 5. Yerby MS, Kaplan P, Tran T. Risks and management of preg- bearing age: practice recommendations. CNS Drugs. 2006; nancy in women with epilepsy. Cleve Clin J Med. 2004;71 20:373-387. (suppl 2):S25-S37. 16. Harden CL, Hopp J, Ting TY, et al; American Academy of 6. Samren EB, van Duijn CM, Koch S, et al. Maternal use of anti- Neurology; American Epilepsy Society. Practice parameter epileptic drugs and the risk of major congenital malformations: update: management issues for women with epilepsy—focus a joint European prospective study of human teratogenesis as- on pregnancy (an evidence-based review): obstetrical compli- sociated with maternal epilepsy. Epilepsia. 1997;38:981-990. cations and change in seizure frequency: report of the Qual- ity Standards Subcommittee and Th erapeutics and Technol- 7. Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and ogy Assessment Subcommittee of the American Academy of apoptotic neurodegeneration in the developing brain. Proc Neurology and American Epilepsy Society. Neurology. 2009; Natl Acad Sci. 2002;99:15089-15094. 73:126-132. 8. Katz I, Kim J, Gale K, et al. Eff ects of lamotrigine alone and 17. Kennedy F, Morrow J, Hunt S, et al. PATH39 malformation risks in combination with MK-801, phenobarbital, or phenytoin of antiepileptic drugs in pregnancy: an update from the UK on cell death in the neonatal rat brain. J Pharmacol Exp Th er. Epilepsy and Pregnancy Registry. J Neurol Neurosurg Psychia- 2007;322:494-500. try. 2010;81:e18. 9. Meador KJ, Baker GA, Finnell RH, et al. In utero antiepileptic 18. Ohman I, Beck O, Vitols S, et al. Plasma concentrations drug exposure: fetal death and malformations. Neurology. of lamotrigine and its 2-N-glucuronide metabolite dur- 2006;67:407-412. ing pregnancy in women with epilepsy. Epilepsia. 2008;49: 10. Kaaja R, Hiilesmaa V. Major malformations in off spring of 1075-1080. women with epilepsy. Neurology. 2003;60:575-579. 19. Artama M, Auvinen A, Raudaskoski T, et al. Antiepileptic drug 11. Rasmussen MM, Clemmensen D. Folic acid supplementation use of women with epilepsy and congenital malformations in in pregnant women. Dan Med Bull. 2010;57:A4134. off spring. Neurology. 2005;64:1874-1878.

JFPONLINE.COM VOL 59, NO 12 | DECEMBER 2010 | THE JOURNAL OF FAMILY PRACTICE 679