Pregnancy and epilepsy—when you’re managing both

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Applied Evidence

Pregnancy and epilepsy—when you’re managing both

J Fam Pract. 2010 December;59(12):675-679

By

Nitin K. Sethi, MD

Amy Wasterlain, MD Candidate

Cynthia L. Harden, MD

When a patient with epilepsy is pregnant or planning for pregnancy, you face the challenge of balancing the benefits and teratogenic risks of her antiseizure medication. Here’s help.

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References

1. Harden CL, Meador KJ, Pennell PB, et al. American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73:133-141.

2. Sachdeo R. The evidence-based rationale for monotherapy in appropriate patients with epilepsy. Neurology. 2007;69 (suppl 3):S1-S2.

3. Holmes GL, Harden C, Liporace J, et al. Postnatal concerns in children born to women with epilepsy. Epilepsy Behav. 2007;11:270-276.

4. Bromley RL, Baker GA, Meador KJ. Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero. Curr Opin Neurol. 2009;22:162-166.

5. Yerby MS, Kaplan P, Tran T. Risks and management of pregnancy in women with epilepsy. Cleve Clin J Med. 2004;71 (suppl 2):S25-S37.

6. Samren EB, van Duijn CM, Koch S, et al. Maternal use of anti-epileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia. 1997;38:981-990.

7. Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci. 2002;99:15089-15094.

8. Katz I, Kim J, Gale K, et al. Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain. J Pharmacol Exp Ther. 2007;322:494-500.

9. Meador KJ, Baker GA, Finnell RH, et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology. 2006;67:407-412.

10. Kaaja R, Hiilesmaa V. Major malformations in off spring of women with epilepsy. Neurology. 2003;60:575-579.

11. Rasmussen MM, Clemmensen D. Folic acid supplementation in pregnant women. Dan Med Bull. 2010;57:A4134.-

12. Pittschieler S, Brezinka C, Jahn B, et al. Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy. J Neurol. 2008;255:1926-1931.

13. Epilepsy Foundation. Pregnancy & parenting. Available at: www.epilepsyfoundation.org/living/women/pregnancy/weipregnancy.cfm. Accessed November 4, 2010.

14. Harden CL, Pennell PB, Koppel BS, et al. American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73:142-149.

15. Tettenborn B. Management of epilepsy in women of child-bearing age: practice recommendations. CNS Drugs. 2006;20:373-387.

16. Harden CL, Hopp J, Ting TY, et al. American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73:126-132.

17. Kennedy F, Morrow J, Hunt S, et al. PATH39 malformation risks of antiepileptic drugs in pregnancy: an update from the UK Epilepsy and Pregnancy Registry. J Neurol Neurosurg Psychiatry. 2010;81:e18.-

18. Ohman I, Beck O, Vitols S, et al. Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia. 2008;49:1075-1080.

19. Artama M, Auvinen A, Raudaskoski T, et al. Antiepileptic drug use of women with epilepsy and congenital malformations in off spring. Neurology. 2005;64:1874-1878.

PRACTICE RECOMMENDATIONS

• Use the dose of antiepileptic drug (AED) at which the patient is seizure-free prior to conception as a target level to adjust dosing during pregnancy. C

• Avoid switching a pregnant patient to an AED that she has not taken before. C

• Start all women who have epilepsy and are of childbearing age on ≥0.4 mg folic acid daily prior to conception. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

About 500,000 women in the United States suffer from epilepsy and are of childbearing age.¹ For these patients and their physicians, family planning and pregnancy are complex and fraught with risk.

The dilemma: Infants born to women with epilepsy have a 2- to 3-fold risk of congenital malformations compared with those whose mothers do not have epilepsy, mainly related to exposure to antiepileptic drugs (AEDs).² Recent studies also suggest that children exposed to AEDs such as valproate, phenobarbital, and phenytoin in utero may have neuro-cognitive deficits, even when there are no major congenital malformations.^1,3,4

Yet discontinuing the drugs prior to conception or in early pregnancy is rarely a viable option. In 1 recent prospective study, convulsive seizures during the first trimester (the type and timing of seizure thought to have the most harmful effect on the developing fetus) were associated with malformations in 7.4% of pregnancies.² Seizures also increase the risk of both fetal and maternal death, although the extent of that risk is not known.⁵

Ideally, pregnant women with epilepsy should be under the care of both an obstetrician experienced in high-risk pregnancies 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. This 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-drug interactions, folic acid deficiency, the effect of suboptimally controlled convulsions, genetic predisposition, enhanced apoptotic neurodegeneration, and alterations in thyroid hormone status, among others.^6-9 Major congenital malformations may occur in a dose-dependent manner, and physicians should aim to use the most effective AED at the lowest effective dose for women of childbearing age.²

In reviewing antiseizure therapy for such patients, here are some considerations to keep in mind:

Avoid polytherapy, if possible. Taking multiple AEDs may increase the risk of major congenital malformations, especially when valproate is one of the drugs.1 Hence, an attempt should be made to switch women with epilepsy who are of childbearing age to monotherapy. Ideally, this should be done a year before planned conception so that good seizure control can be achieved and documented prior to pregnancy.

Avoid high-risk AEDs. Overall, an increased risk of major congenital malformations has been most convincingly found with valproate and phenobarbital.¹ Specific types of malformations have also been linked to certain drugs (TABLE). Cardiac malformations are associated with carbamazepine, phenobarbital, and valproate; spina bifida, hypospadias, porencephaly, and other brain anomalies, as well as limb reduction defects, are associated with valproate, particularly at doses >1100 mg/d.¹⁰

Choose newer agents, whenever possible. The risk of malformations with newer AEDs—including gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate—remains unclear, but preliminary data for monotherapy with these agents suggest a lower teratogenic risk compared with traditional AEDs, such as phenobarbital and valproate.¹⁰

Initiate folic acid supplementation. Drug-induced folate deficiency has been proposed as a contributing factor in the teratogenicity of AEDs, so diligence is essential in ensuring that patients who have epilepsy and are of childbearing age take folic acid.¹¹ Studies have demonstrated a significant reduction in spontaneous abortion in women who are receiving AED therapy and taking folic acid supplements, and the benefits of folic acid have been found to be especially notable for women taking valproate.¹²

Folic acid supplementation, of course, is important for all women of childbearing age. At a dose of 0.8 mg/d, folate has been shown to reduce the risk of neural tube and ventricular septal defects in the general population. The American Academy of Neurology/American Epilepsy Society (AAN/AES) Practice Parameters recommend that all women of child-bearing age taking AEDs also take folate supplements (0.4-4 mg/d).¹³ An optimal dose has not been determined for this patient population, but we routinely recommend 1 mg/d for women with epilepsy of childbearing age and increase the dose to 4 mg/d after conception.

TABLE
Commonly used antiepileptic drugs: Major teratogenic risks^1,10,19