1. How does epilepsy affect conception?

Epilepsy, in itself, has no impact on fertility. However, the treatment of epilepsy can impact conception. Phenobarbital, phenytoin, and carbemazepine are metaboized in the hepatic P450 system. Their metabolism increases the production of sex hormone-binding globulin, which can decrease the unbound, active fractions of hormonal contraceptive agents. Therefore, hormonal contraception with combination estrogen-progestin pills or progestin only is much less reliable in women taking these anticonvulsant medications. Unintended pregnancy may result. Non hormonal contraceptive choices should be emphasized to these women.

2. How does pregnancy affect the frequency of seizures?

Seizure disorders are the most common neurologic problem in pregnancy. Between 25% and 50% of women with idiopathic epilepsy have an increase in seizure fequency during pregnancy, usually during the first trimester. Of the remainder, most have no change in seizure pattern. Patients with frequent seizures before pregnancy are likely to experience worsening of seizure control during pregnancy. Likewise, good seizure control before pregnancy usually correlates with a lower risk of exacerbation during pregnancy.

3. What is the cause of increased seizure frequency during pregnancy?

The etiology is often unclear. Possible causes include not only poor seizure control before conception, but also little or no prepregnancy counseling, poor compliance, and lower serum levels of anticonvulsants during pregnancy. Note that increased seizure activity during one pregnancy does not predict a similar response in future pregnancies.

4. What is gestational epilepsy?

Occasionally, idiopathic epilepsy is diagnosed for the first time during pregnancy. Twenty-five percent of these newly diagnosed epileptics are known as gestational epileptics-individuals who only manifest symptoms during pregnancy. Gestational epilepsy in one pregnancy is not predictive of recurrence in future pregnancies.

5. How do seizures affect the course of pregnancy?

Several studies have suggested mildy increased risks for a multitude of obstetric complications. Included among these are preeclampsia, preterm labor, and stillbirth. However, other studies have failed to duplicate these associations. Vaginal bleeding is more common in epileptics, probably secondary to anticonvulsant therapy-induced vitamin K deficiency.

6. Which anticonvulsants are commonly used during pregnancy?

Phenytoin, phenobarbital, and carbamazepine are used more frequently than either primidone (a structural analogue of phenobarbital) or valproic acid. Each medication, however, is associated with specific fetal and neonatal risks. Therefore, monotherapy is preferred over polytherapy. (See Table Anticonvulsants commonly used during pregnancy)

Table Anticonvulsants commonly used during pregnancy

Medication Therapeutic Level (mg/L) Nonpregnant Dose Usual Half-Life Protein-Bound Fraction
Carbamazepine 4-10 600-1200 mg/day in 3-4 divided doses 16-36 hours 76%
Phenobarbital 15-40 90-180 mg/day in 2-3 divided doses 100 hours Variable
Phenytoin 10-20 total, 1-2 free 300-500 mg/day single or divided doses (for > 300) 24 hours 90%
Primidone 5-15 750-1500 mg/day in 3 divided doses 8 hours Metabolized to phenobarbital
Valproic acid 50-100 550-2000 mg/day in 3-4 divided doses 6-16 hours 90%

7. How does pregnancy affect blood levels of anticonvulsants?

Subtherapeutic levels of phenytoin, carbamazepine, and phenobarbital can occur as a result of the increased maternal plasma volume, delayed gastrointestinal absorption, and increased hepatic clearance associated with pregnancy. In addition, folic acid supplementation may lower plasma levels of phenytoin. Even though total levels of these medications may fall, the active (nonprotein-bound) levels often increase as serum albumin decreases during pregnancy. Therefore, anticonvulsant levels should be monitored periodically and adjusted as needed.

8. What metabolic abnormalities associated with anticonvulsant therapy should be corrected during pregnancy?

Folic acid is known to reduce the risk of neural tube defects (NTDs). Women at high risk of having a fetus affected by an NTD, including those on antiepileptic medications, should supplement their diet with 4 gm of folic acid per day. However, it has not been firmly established that folic acid reduces the rate of anticonvulsant-associated NTD.

Folic acid can decrease plasma levels of phenytoin. Therefore, serum anticonvulsant levels should be closely monitored throughout the pregnancy in women concurrently taking both folic acid and phenytoin.

9. Which anticonvulsants are safe during pregnancy?

Anticonvulsants in general should not be considered “safe” during pregnancy. Nevertheless, uncontrolled seizures are dangerous for both the woman and the fetus, supporting their judicious use when needed. Tailor the choice of medicine to the individual.

Key points: seizures in pregnancy

  • Anticonvulsant therapy should be optimized prior to conception, ideally using monotherapy at lowest doses.
  • Folic acid, 4 mg/day, has been shown to decrease the risk of NTDs in women with high risk and should be given to women on anticonvulsant medications.
  • The risk of congenital anomalies is 2-3 times baseline in women on anticonvulsants, but the risk is increased above baseline even in women with epilepsy who are not on medications.

10. Are any anticonvulsants absolutely contraindicated during pregnancy?

Yes. Most physicians avoid trimethadione. “Trimethadione syndrome” consists of developmental delay, low-set ears, palate anomalies, irregular teeth, speech disturbances, and V-shaped eyebrows. Intrauterine growth retardation, short stature, cardiac anomalies, ocular defects, simian creases, hypospadias, and microcephaly are also often present. Up to two-thirds of exposed fetuses will manifest congenital defects. Because trimethadione is associated with a greater risk of anomalies compared with other anticonvulsants, its use should be abandoned.

11. What neonatal complications have been associated with phenytoin, phenobarbital, carbamazepine, and valproic acid?

The fetal hydantoin (phenytoin) syndrome consists of various combinations of craniofacial and limb abnormalities. Because this pattern is also associated with other anticonvulsants, the combination of major anomalies, microcephaly, growth retardation, midface hypoplasia, and digital hypoplasia is also known as “anticonvulsant embryopathy.”

Although phenobarbital has been associated with some birth defects, its major risk is neonatal addiction and withdrawal syndrome.

Carbamazepine used to be considered among the safest anticonvulsants for use during pregnancy. However, more recent data suggest that carbamazepine may be associated with an increased incidence of craniofacial defects, developmental delay, and NTDs.

Valproic acid should be considered a human teratogen. It has been implicated in cardiac, orofacial, and limb abnormalities, but the major concern is with NTDs. When exposure occurs between 17 and 30 days after conception, the risk of an NTD is 1-2%. Women exposed during the critical period should be closely screened.

12. What are the recommendations regarding some of the newer anticonvulsants?

Felbamate, gabapentin, and lamotrigine are new anticonvulsant medications. There is little information regarding their use in pregnancy. Although their manufacturers have described these three medications as belonging to pregnancy category C, their routine use cannot be recommended without more supporting evidence.

13. With anticonvulsant therapy, what is the overall risk for congenital malformations?

In epileptic women on anticonvulsant medication, the risk of congenital anomalies is two to three times greater than that of the general population. However, it remains unclear whether this increased risk is due solely to the medications. It is possible that idiopathic epilepsy itself is associated with a risk of fetal anomalies. Accordingly, it also remains unclear whether epileptic women not on seizure medication are at increased risk of congenital malformations. It is known that seizure control with anticonvulsant monotherapy poses a lower risk than polypharmaceutical treatment.

14. Describe the role epoxide hydrolase plays in the development of congenital malformations.

Epoxide hydrolase is an enzyme within a metabolic pathway common to many anticonvulsant medications. Genetic heterogeneity within this enzyme can affect its overall efficacy. Homozygosity in the fetus for the genes producing lowered efficacy of this enzyme is associated with the highest development rate for features of congenital phenytoin syndrome.

15. What about hemorrhagic disease of the newborn?

Phenytoin, phenobarbital, and primidone may cause hemorrhagic disease of the newborn. The exact mechanism is unknown but is related to vitamin K deficiency, which results in suppression of factors II, VII, IX, and X. Therefore, it is recommended that exposed infants receive vitamin K in the delivery room and be closely observed for signs of a clotting abnormality.

Carbamazepine and valproic acid are not associated with this effect.

16. Should a woman with seizures stop her medications when she becomes pregnant?

Stopping anticonvulsant therapy during the first trimester can result in uncontrolled seizures that may be more harmful to the fetus than the therapy. Some suggest a trial off anticonvulsants prior to pregnancy if the woman has been seizure-free for at least 2 years. Once successfully withdrawn from her medication, a woman may be followed expectantly during a pregnancy.

17. What is the risk of epilepsy in the child if a parent has seizures?

In general, the child has a 3% risk of epilepsy. The risk may be higher if the parental seizure etiology is unknown, the mother is the affected parent, or the child has febrile seizures.

18. Is breastfeeding contraindicated for women taking anticonvulsants?

No. Anticonvulsants are excreted minimally in breast milk and generally do not harm the infant. However, accumulation of phenobarbital (and primidone, which is metabolized to phenobarbital) can cause lethargy, poor feeding, and inadequate weight gain. If this occurs, bottle feeding may need to be substituted. Breastfeeding does not increase the frequency of seizures.

Note that felbamate, gabapentin, and lamotrigine are not recommended during lactation because of the paucity of evidence supporting their safety.

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