Antiepileptics

From: Exposure to Psychotropic Medications and Other Substances during Pregnancy and Lactation: A Handbook for Health Care Providers

On this page:

Summary and recommendations
Fetal effects
Neonatal effects
Long-term effects on the child
Breastfeeding
Withdrawal effects on the mother
Effects of untreated illness

Examples

Older antiepileptics: carbamazepine (Tegretol), phenytoin (Dilantin), divalproex/valproate/valproic acid (Epival)

Newer antiepileptics: lamotrigine (Lamictal), gabapentin (Neurontin), oxcarbazepine (Trileptal), topiramate (Topamax)

Antiepileptics are frequently used to treat bipolar disorder, in addition to epilepsy.

Epilepsy is one the most commonly encountered neurological disorders in obstetrics. Incidence of seizure disorder during pregnancy is estimated at 0.3 to 0.5 per cent. ¹ Compared to the general obstetric population, having epilepsy while pregnant is considered high risk, mainly due to the teratogenic potential of antiepileptic drugs and increased risk of maternal, fetal and neonatal complications (e.g., hypertension, pre-eclampsia, antepartum hemorrhage, caesarean delivery, stillbirth, neonatal death, intrauterine growth retardation, preterm delivery).

Summary and Recommendations

Careful clinical management is extremely important because bipolar symptoms and/or seizure frequency can change during pregnancy, and both seizure activity and antiepileptic drug treatment can affect the developing fetus. Women should be treated with the drug that controls their disorder and, if at all possible, with monotherapy at the lowest effective dose.
Antiepileptics should never be abruptly discontinued because of the consequences to both the mother and the fetus.
Folic acid (four milligrams per day) should be taken for three months prior to conception and during the first trimester to help prevent folic acid deficiency–induced malformations (i.e., neural tube defects).
Women should be offered a detailed ultrasound examination and their levels of maternal serum alpha-fetoproteins should be monitored.
With proper prenatal and postpartum management, up to 95 per cent of pregnancies in which women took antiepileptics are reported to have had favourable outcomes. ²

Fetal effects

Major malformations

Older antiepileptics

Use of older antiepileptics during pregnancy increases the risk of major malformations:

Phenytoin increases the risk of neural tube defects by approximately 10 per cent (highest overall rate). ³
Valproic acid increases the risk of neural tube defects by approximately five to nine per cent. ³
Carbamazepine increases the risk of neural tube defects by approximately one per cent (lowest teratogenic effect). ³

Newer antiepileptics

Use of some newer antiepileptics during pregnancy minimally increases the rate of neural tube defects:

Lamotrigine: Preliminary data from pregnancy registries around the world suggest no increased risk for birth defects with the use of lamotrigine. ⁴ However, the North American Antiepileptic Drug Pregnancy Registry suggests a potential increased risk for non-syndromic cleft palate, which was observed among 564 exposed infants: three infants had isolated cleft palate, two had isolated cleft lip. This prevalence of oral clefts (0.89 per cent) is higher than the 0.037 per cent observed in the control group. ⁵
Gabapentin: The Gabapentin Pregnancy Registry assessed the safety of gabapentin exposure during pregnancy in 39 cases and found no increased risk for major malformations. ⁶
Topiramate: Only a few case reports exist of infants exposed to topiramate in utero, with no major malformations cited. ¹
Oxcarbazepine: A study of 309 pregnancies, 248 with maternal exposure to monotherapy and 61 with exposure to adjunctive therapy, cited six malformations among infants of mothers in the monotherapy group. This malformation rate of 2.4 per cent in the monotherapy group is within the baseline range for the general population. ⁷

Spontaneous abortion

A 1988 study found no increase in spontaneous abortion in pregnant women taking antiepileptic medications.⁸ There is no data available on the risk of spontaneous abortion with newer antiepileptics.

Neonatal effects

There are no reports of adverse neonatal effects resulting from a woman taking either older or newer antiepileptics.

Long-term effects on the child

One study ⁹ followed 36 pregnant women exposed to either carbamazepine or phenytoin monotherapy. Children exposed in utero to carbamazepine did not differ from children in the control groups in any of the administered neurobehavioural tests with respect to global IQ. However, on average, children in the phenytoin group scored 10 points lower on a measure of global IQ, and significantly more children in the phenytoin group had IQ scores of less than 84.8.

Another study ¹⁰ examined children exposed in utero to various antiepileptic drugs (monotherapy and polytherapy) into adolescence. This study found that maternal epilepsy and antiepileptic drug therapy during pregnancy appears to have long-term effects well into adolescence. These effects manifest in abnormal EEG patterns, minor neurologic dysfunction and poorer intellectual performance. The polytherapy group showed the most marked severity of effects. A recent review of studies examining possible neurobehavioural effects of valproic acid all reported that despite the different study designs and varied outcomes and cognitive tests, developmental delays and cognitive deficits were associated with valproic acid use in pregnancy—with the most prominent effect being on verbal IQ. ¹¹

Breastfeeding

Less than five per cent of the mother’s dose of any antiepileptic drug is excreted into breast milk. Antiepileptics can therefore be used safely during breastfeeding. ¹²

Withdrawal effects on the mother

One individual who took carbamazepine for trigeminal neuralgia became psychotic following abrupt discontinuation of the drug. ¹³ Three cases of acute withdrawal symptoms following gabapentin withdrawal have been documented. ¹⁴ In another report, 10 patients who abruptly stopped taking carbamazepine or phenytoin had changes in cardiac rhythm; three patients had a 10-fold increase in the rate of ventricular premature beats. ¹⁵

Effects of untreated illness

Pregnancy does not protect against mood fluctuations in women with untreated bipolar disorder. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course.

It is suspected, though not proven, that women with untreated epilepsy have a higher than baseline risk for giving birth to a child with malformations. Epilepsy per se has been thought to represent a teratogenic risk. A meta-analysis, however, found that the risk for congenital malformations in the children of mothers with untreated epilepsy was no higher than among the control group of women without epilepsy. ²

References

Yerby, M.S. (2003). Clinical care of pregnant women with epilepsy: Neural tube defects and folic acid supplementation. Epilepsia, 44 (Suppl. 3), 33–40.
Fried, S., Kozer, E., Nulman, I., Einarson, T.R. & Koren, G. (2004). Malformation rates in children of women with untreated epilepsy: A meta-analysis. Drug Safety: An International Journal of Medical Toxicology and Drug Experience, 27 (3), 197–202.
Wyszynski, D.F., Nambisan, M., Surve, T., Alsdorf, R.M., Smith, C.R. & Holmes, L.B. (2005). Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology, 64 (6), 961–965.
Cunnington, M. & Tennis, P. (2005). Lamotrigine and the risk of malformations in pregnancy. Neurology, 64 (6), 955–960.
Holmes, L.B. (2006). Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy [Abstract]. Teratology, 76 (5), 318.
Montouris, G. (2003). Gabapentin exposure in human pregnancy: Results from the Gabapentin Pregnancy Registry. Epilepsy & Behavior, 4 (3), 310–317.
Montouris, G. (2005). Safety of the newer antiepileptic drug oxcarbazepine during pregnancy. Current Medical Research and Opinion, 21 (5), 693–701.
Annegers, J.F., Baumgartner, K.B., Hauser, W.A. & Kurland, W.T. (1988). Epilepsy, antiepileptic drugs, and the risk of spontaneous abortion. Epilepsia, 29 (4), 451–458.
Scolnik, D., Nulman, I., Rovet, J., Gladstone, D., Czchta, D., Gardner, H.A. et al (1994). Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. Journal of the American Medical Association, 271 (10), 767–770.
Dean, J.C., Hailey, H., Moore, S.J., Lloyd, D.J., Turnpenny, P.D. & Little, J. (2002). Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. Journal of Medical Genetics, 39 (4), 251–259.
Koren, G., Nava-Ocampo, A.A., Moretti, M.E., Sussman, R. & Nulman, I. (2006). Major malformations with valproic acid [Review]. Canadian Family Physician, 52 (4), 441–447.
Crawford, P. (2005). Best practice guidelines for the management of women with epilepsy. Epilepsia, 46 (Suppl. 9), 117–124.
Heh, C.W., Sramek, J., Herrera, J. & Costa, J. (1988). Exacerbation of psychosis after discontinuation of carbamazepine treatment. American Journal of Psychiatry, 145 (7), 878–879.
Pittenger, C. & Desan, P.H. (2007). Gabapentin abuse, and delirium tremens upon gabapentin withdrawal. Journal of Clinical Psychiatry, 68 (3), 483–484.
Kenneback, G., Ericson, M., Tomson, T. & Bergfeldt, L. (1997). Changes in arrhythmia profile and heart rate variability during abrupt withdrawal of antiepileptic drugs: Implications for sudden death. Seizure: The Journal of the British Epilepsy Association, 6 (5), 369–375.