EPILEPSY and PREGNANCY

Epilepsy and Pregnancy Increased Risks

	General Population	Women with Epilepsy
Major Malformations	2 to 3 Percent	4 to 8 Percent
Minor Malformations	5 to 10 Percent	10 to 15 Percent
Fetal Death	2 to 7 Percent	2 to 14 Percent

More than 90 percent of women with epilepsy will have normal, healthy infants. However, they are at greater risk for complications of pregnancy, labor and adverse pregnancy outcomes than women without epilepsy. Preconceptional counseling and coordination of care among all members of the health care team is key to treating women with epilepsy of reproductive age.

Conception

Fertility

Women with epilepsy have fewer children than women in general, with a fertility rate 25 to 33 percent lower than average. While personal choice and/or societal pressure may play some role in this disparity, research has indicated that women with epilepsy have a higher incidence of menstrual irregularities, polycystic ovarian disease and reproductive endocrine disorders. Any of these may reduce fertility.

Unplanned Pregnancies

Women with epilepsy taking certain anti-epileptic drugs (AEDs) may experience failure of hormonal birth control methods. Some of the medications [carbamazepine, oxcarbazepine, phenytoin, barbiturates (phenobarbital, mephobarbital, and primidone) and topiramate] may lower concentrations of estrogen, thus reducing effectiveness of the hormonal contraceptive.

Congenital Malformations

Major Malformations

Major malformations are defined as defects of medical, surgical or cosmetic importance. This type of anomaly, which will seriously affect a child’s life, occurs in 2 to 3 percent of all liveborn children. For women with epilepsy on one seizure medication, the incidence is estimated to be 4 to 8 percent and possibly greater for women with epilepsy taking more than one drug. Types of major malformations occurring most often in children of women with epilepsy are orofacial clefts, cardiac abnormalities and neural tube defects.

Folic acid supplementation (at a minimum dose of 0.4 mg daily) is especially important prior to conception and during pregnancy in women with epilepsy to lower the risk of neural tube defects in the offspring.

In general, AED polypharmacy and higher blood levels of AEDs are associated with the increased incidence of birth defects in infants born to women with epilepsy. A single AED at the lowest possible dose for efficacy is recommended whenever possible.

Minor Anomalies

The incidence of minor physical defects in infants born to women with epilepsy is approximately 15 percent. Features such as hypertelorism, epicanthal folds, shallow philtrum, distal digital hypoplasia, and simian creases are often present as a familial trait. Although the incidence is reported as 2 to 3 times greater in women with epilepsy, these may be present in infants whose mothers use other types of medication or have excessive alcohol intake during pregnancy. Many of these minor physical defects appear to be idiopathic in nature. These anomalies do not cause any serious problems and are primarily of cosmetic concern.

Other CNS Effects

A greater incidence of mental retardation and/or microcephaly has been reported in children of women with epilepsy, but these studies have been inconsistent and have not always been controlled for other possible contributing factors (such as inherent genetics, and the effects of maternal seizures or AEDs in utero).

However, developmental delays may be significant in terms of risk to infants of women with epilepsy. Factors other than the maternal epilepsy that are thought to be important are IQ scores in the mother and AED polypharmacy (particularly exposure to phenobarbital in utero).

Spontaneous Abortion

There is no increased risk of early fetal death (the not uncommon, spontaneous abortion within the first 20 weeks post-conception) in women with epilepsy. Late fetal loss (a stillbirth or spontaneous abortion after 20 weeks of pregnancy) shows an increased incidence in women with epilepsy, as much as twofold over the general population (2 to 7 percent of all pregnancies and 2 to 14 percent in women with epilepsy, depending on the study).

Anti-epileptic Medications

Concerns

As stated earlier, the risk for adverse effects on the fetus increases when maternal AED polypharmacy is present. All commonly used AEDs have been associated with congenital malformations. Some of the newer AEDs have not been used in large enough numbers to have meaningful data.

Valproic acid (with a risk of 1 to 2 percent), and to a lesser degree, carbamazepine (with a risk of 0.5 percent) have been associated with neural tube defects, specifically spina bifida. Folate supplementation used prior to conception and throughout the childbearing years may minimize this risk.

Many experts believe that trimethadione is contraindicated in women with epilepsy who might become pregnant because it has been associated with a high incidence of fetal loss and congenital malformations.

You may wish to encourage all pregnant women taking AEDs to register with the North American AED Pregnancy Registry housed at Massachusetts General Hospital, Harvard Medical School. The toll free number is (888) 233-2334.

Management

Uncontrolled seizures, particularly generalized tonic-clonic episodes, are hazardous during pregnancy and discontinuing AEDs may pose a greater risk for both mother and fetus than the possible adverse effects of the medication. Miscarriage, trauma related to falls, fetal hypoxia and acidosis are all possible sequelae of maternal seizures.

Status epilepticus carries a high mortality rate for mother and fetus, and generalized seizures occurring during labor can result in fetal bradycardia.

During pregnancy, one quarter to one third of women with epilepsy have an increase in seizure frequency despite continued use of AEDs. Decreased protein binding of AEDs, increased drug clearance, and increased maternal plasma volume during pregnancy may lower serum concentrations of AEDs, requiring more frequent laboratory assessments, and dosage adjustments.

Plasma levels of unbound AEDs should be monitored closely throughout pregnancy and for at least 8 weeks following delivery, as it is common for levels to rise in the postpartum period.

Pregnancy Complications

Other potential obstetrical problems seen more frequently in women with epilepys are hyperemesis, gravidarum, vaginal bleeding, and anemia. Difficulties during labor and delivery include premature labor, failure to progress, and an increased rate of cesarean sections.

Hemorrhagic Disorder of the Newborn

This is a unique hemorrhagic disease of the neonate that occurs in the first 24 hours of life. Maternal AEDs competitively inhibit vitamin K transport across the placenta and the infant has prolonged prothrombin and partial thromboplastin times. The risk can be reduced by maternal supplementation with oral vitamin K (at a dose of 10 mg/ day) during the last month of pregnancy. This specific neonatal disorder seems to be associated with exposure to AEDs in utero (phenobarbital, primidone, phenytoin, and perhaps others).

Risk of Seizures in the Child

There is a higher risk for women with epilepsy to have children with the condition than for men with epilepsy. Seizure type and age of onset also affect incidence of epilepsy in the child. It is encouraging to recognize that even for patients in the highest risk groups, the risk that an offspring will develop epilepsy is less than 10 percent. Also see Genetics.

REFERENCES

1. Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. NEJM. 2001;344(15):1132-1138.
2. Yerby M. Treatment of epilepsy during pregnancy. In: Wyllie E, ed. The Treatment of Epilepsy, Second Edition. Baltimore: Williams & Wilkins; 1996:785-798.
3. Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-8.
4. Seizure disorders in pregnancy. In: ACOG Educational Bulletin. Washington, DC: American College of Obstetricians and Gynecologists; 1996:231.