Epilepsy in Pregnancy Case File

Epilepsy in Pregnancy Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 18

A 22-year-old woman presents to the emergency department after experiencing a tonic-clonic seizure witnessed by her husband at home. She is postictal and unable to give a history. Her husband states that she has a history of epilepsy, and has not had a seizure for over 3 years. She currently takes phenytoin (Dilantin) 300 mg daily and an oral contraceptive. He is not certain when her last menstrual period occurred.

An IV is started, and labs are drawn. As the patient becomes more responsive, she states that she has been taking her medications regularly, and her LMP was over 3 months ago. She states that this pattern is not unusual for her since starting low-dose oral contraceptive pills (OCPs) 6 months ago. Blood pressure is 90/60 mm Hg, pulse is 88, and respirations are 16 per minute. Labs show normal electrolytes, glucose, calcium, and magnesium, a borderline therapeutic level of phenytoin, and a positive urine pregnancy test. Urinalysis reveals trace protein and no WBCs or RBCs. Pelvic examination reveals a 14-week sized uterus with fetal heart tones present.

➤ What is the most likely diagnosis?

➤ What is your next step?

➤ What are potential complications of the patient’s disorder?

ANSWERS TO CASE 18:

Epilepsy in Pregnancy

Summary: This is a 22-year-old woman with an epileptic seizure who takes lowdose OCPs and phenytoin, which may reduce the effectiveness of OCPs by increasing liver metabolism. She is 14 weeks pregnant and has continued phenytoin during the first trimester, which increases the risk of adverse effects to the fetus.

➤ Most likely diagnosis: Epileptic seizure in pregnancy.

➤ Next step: Rule out eclampsia, space occupying brain lesions, trauma, infection, electrolyte or glucose abnormalities, intracranial bleeding, and toxins or drug exposure; evaluate the fetus for anomalies from phenytoin exposure; adjust and monitor her antiepileptic drugs (AED).

➤ Potential complications: Maternal risk with recurrent seizures with subtherapeutic medication levels; adverse effects on the fetus from AED exposure in first trimester.

ANALYSIS

Objectives

1. Recognize the differential diagnosis of convulsions in pregnancy.
2. Be familiar with the evaluation and management of pregnant patients with a history of epilepsy.
3. Learn about appropriate drug therapy for epilepsy and the potential adverse effects on the fetus.
4. Recognize pregnancy complications associated with epilepsy.

Considerations

Seizures in pregnancy may be the result of eclampsia after 20 weeks or in the presence of a molar pregnancy in any trimester. New-onset seizures may be the result of an intracranial hemorrhage, space occupying lesion, CNS infection, trauma, or toxin or drug exposure. Women with a history of idiopathic epilepsy who seize during pregnancy may have subtherapeutic drug levels and should be advised to increase their dose with careful serum monitoring of levels. Fetal effects of antiepileptic drugs may be significant, and should be sought by ultrasound and maternal serum screening.

APPROACH TO

Epilepsy in Pregnancy

A pregnant patient with new-onset seizures requires a much different evaluation than the one with a history of epilepsy. New-onset seizures after 20 weeks’ gestation should always considered to be the result of eclampsia and treated accordingly unless a thorough workup reveals another etiology. While a molar pregnancy prior to 20 weeks’ gestation has been associated with preeclampsia in early pregnancy, an intrauterine fetus makes eclampsia prior to 20 weeks’ gestation unlikely and another etiology should be sought. Acquired seizures may result from trauma, infection, metabolic disorders, drug or toxin exposure, intracranial hemorrhage, or space occupying lesion. The evaluation for new-onset seizures in pregnancy should include a history for evidence of trauma, drug usage (including cocaine) and toxin exposure, observation for signs of CNS infection or localizing neurologic signs, evaluation of the WBC count, measurement of electrolytes, calcium and magnesium, and glucose, lumbar puncture (LP) for evidence of infection or blood, EEG, and intracranial imaging for signs of bleeding or space-occupying lesion. If eclampsia is suspected, magnesium sulfate is administered and consideration for delivery is discussed with the patient. If no obvious etiology for the seizure is found or the patient has a history of epilepsy, consideration for therapy with AED should occur. Epilepsy in pregnancy with appropriate therapy usually results in a successful pregnancy and healthy neonate.

Effect of Pregnancy on Epilepsy

Nausea and vomiting, insufficient sleep, an expanding plasma volume, and a reduction in plasma proteins which attach and transport AEDs in the blood may all lead to a reduction in serum levels of AEDs and an increased incidence of seizures in pregnancy. Clearance of most of the AEDs increases during pregnancy, and returns to prepregnancy levels by 2 to 3 months postpartum. One notable exception is lamotrigine clearance, which increases dramatically up to 230% above baseline during pregnancy, and returns to prepregnancy levels within a few weeks of birth. Up to 33% of pregnant women will experience an increase in seizure frequency during pregnancy, while 7% to 25% report a decrease, and 50% to 83% report no change. Sleep deprivation or noncompliance may play a role in up to 70% of the increase of seizures in some patients during pregnancy, and the patient should be informed about the importance of compulsive drug maintenance.

Effect of Epilepsy on Pregnancy

Although it is difficult to separate the influence of AEDs from the background risk of maternal epilepsy to the fetus, children of women with epilepsy during pregnancy have an increased risk of mental deficiency that has been reported as high as 6% in some studies. However, while children of mothers with epilepsy have an increased risk of developmental delay, children of fathers with epilepsy do not show that same increased risk, and women with epilepsy who do not take AEDs during pregnancy have no increase in behavioral deficits compared to matched controls. It is clear that women with epilepsy who also take AEDs have an increased risk of fetal anomalies, including IUGR, major and minor malformations, cognitive disorders, microcephaly, and infant mortality, all encompassed in the term “fetal anticonvulsant syndrome” which has been associated with most of the currently prescribed AEDs. IUGR affects 7% to 10% of pregnancies of epileptic women on AEDs, and polytherapy seems to be an even more potent cause of reduced fetal growth. Minor anomalies including distal digital and nail hypoplasias and midline craniofacial anomalies occur in 6% to 20% of infants of epileptic mothers, a 2.5-fold increase compared to the general pregnant population.

Major malformations occur in 4% to 7% of infants of epileptic mothers and include congenital heart defects (ASD, VSD, PDA, pulmonary stenosis, coarctation of the aorta, and tetralogy of Fallot), cleft lip/palate, urogenital disorders (commonly glandular hypospadias), and neural tube defects (NTDs). In a cohort comparison investigating prescribing practices during two different time periods, the older cohort (1972-1979) had more women taking phenobarbital, primidone, and phenytoin while the newer cohort (1981-1985) saw women being prescribed more monotherapy with valproic acid or carbamazepine. The older series resulted in more infants with congenital heart defects, facial clefts, developmental retardation, and minor anomalies while the newer series saw an increased rate of neural tube defects and glandular hypospadias. While the risks of major anomalies vary by AED, multiple studies confirm the greatest risk occurs in the presence of polytherapy, with rates as high as 25% when four or more AEDs are taken during pregnancy. Other studies report malformation rates of 6.5% with monotherapy for epilepsy compared to 15.6% with polytherapy.

Generalized tonic-clonic seizures during pregnancy have been associated with maternal and fetal hypoxia and acidosis, and fetal intracranial hemorrhage has been reported after a single generalized tonic-clonic seizure.

The effect of nonconvulsive seizures increase the mother’s risk of trauma with resultant fetal injury or abruptio placenta. Although concerns have been raised about other obstetric complications resulting from maternal epilepsy, a recent large study from India evaluating a number of common pregnancy complications found only spontaneous abortion, anemia, ovarian cysts, fibroids, and peripartum seizures were more common in epileptic women when compared to a nonepileptic control group.

Effect of AEDs on the Fetus

Antiepileptic drug therapy may have a major impact on fetal development, and a thorough preconception discussion with patients who have epilepsy and who are contemplating pregnancy is critical. Taking a patient off all AEDs prior to conception is usually not feasible, and should be based on the same criteria as in nonpregnant situations. Supplemental folic acid 4 mg daily should be prescribed preconceptionally and during the antepartum period to minimize the risk of birth defects. Monotherapy at the lowest dose that prevents seizures should be the goal.

Antepartum Management

Preconception counseling, supplemental folic acid 4 mg daily, and monotherapy at the lowest dose that prevents seizures should be the practitioner’s goal. The frequency of monitoring serum levels of AEDs varies with the individual patient’s response, and with the level of protein binding of the AED. A recent review article by Patsalos et al in 2008 contains protein binding rates and other important information regarding therapeutic drug monitoring of AEDs.

In general, free serum levels of AED should be followed when the AED is highly or moderately protein bound, and total levels are adequate with minimal protein binding. A baseline level prior to pregnancy when the patient is seizure-free with repeat levels at least each trimester and within 4 weeks of the EDC may be adequate for most patients, although monthly levels should be considered for patients with widely fluctuating serum levels of AED. Maternal serum screening for NTDs at the appropriate time in gestation, and detailed anatomic ultrasound for anomalies associated with AEDs should be performed by 20 weeks of gestation.

While many experts recommend supplemental vitamin K administration 10 mg po daily to pregnant women taking AEDs from 36 weeks until delivery to minimize the chance of hemorrhagic complications in the newborn due to vitamin K deficiency, a recent literature review found inadequate evidence to recommend routine administration of vitamin K during that gestational period.

Intrapartum Management

Labor and delivery is usually uneventful and results in a successful vaginal delivery in the majority of women with epilepsy. Being npo and sleep deprived for extended periods of time predisposes women in labor to a lower seizure threshold, and when generalized tonic-clonic seizures occur during labor, they should be treated promptly and aggressively. The drug meperidine may reduce the seizure threshold and should be avoided when possible during labor. Convulsions in labor may be treated acutely with lorazepam or diazepam intravenously.

Postpartum Management

Most AED levels gradually increase after delivery and plateau around 10 weeks postpartum with the notable exception of lamotrigine which increases immediately and plateaus within 2 to 3 weeks of delivery. These changes necessitate close monitoring of drug levels to avoid toxicity from the increased doses commonly used during pregnancy. Although most AEDs are found in breast milk, breast-feeding is not contraindicated for any of the AEDs used in pregnancy. Sleep deprivation may increase the incidence of seizures in some postpartum individuals.

Comprehension Questions

18.1 A 22-year-old G1P0 woman has witnessed a tonic-clonic seizure. She is 19 weeks’ gestation. The obstetrician believes that eclampsia is a possible etiology of convulsions in this instance. Which of the following is most likely to be present?

A. Abnormal appearing fetus on ultrasound

B. Hypertension

C. Headaches

D. Proteinuria

E. Lower extremity edema

18.2 The antiepileptic drugs valproic acid and carbamazepine are associated with an increased risk of which of the following?

A. Hydrops fetalis

B. Multiple gestation

C. Neural tube defects

D. Preterm labor

E. Renal agenesis

18.3 A common minor anomaly in the fetus of a woman with epilepsy is which of the following?

A. Midline craniofacial defects

B. Polydactyly

C. Pyloric stenosis

D. Renal pyelectasis

E. Equinovarus

18.4 Intrapartum convulsions may be treated acutely with intravenously administered which of the following?

A. Diazepam

B. Phenobarbital

C. Valproic acid

D. Carbamazepine

E. Lamotrigine

ANSWERS

18.1 A. Unless a molar pregnancy is present, eclampsia occurs only after 20 weeks’ gestation so the presence of a normal appearing fetus allows the physician to exclude eclampsia as the etiology of seizures prior to 20 weeks’ gestation.

18.2 C. Valproic acid and carbamazepine are associated with an increased incidence of neural tube defects, and supplemental folic acid should be offered preconceptionally to women who must continue those drugs in early pregnancy.

18.3 A. Midline facial clefts are one of the most common minor anomalies associated with AEDs used in early pregnancy.

18.4 A. Acutely during labor, intravenous lorazepam or diazepam may be used to treat generalized convulsions.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ Most women with epilepsy have a normal and uncomplicated pregnancy (Level II-2).

➤ Because of increased liver metabolism generated by many of the AEDs, unanticipated pregnancy is more likely in women on those AEDs taking oral contraceptives (Level II-2).

➤ Epileptic patients require more intense monitoring of serum levels of AEDs and increasing doses of their medication up to delivery (Level II-1).

➤ Fetal effects of AEDs include IUGR, neural tube defects (primarily valproic acid and carbamazepine), and midline craniofacial defects and congenital heart defects (phenytoin and phenobarbital) (Level II-2).

➤ Monotherapy with AEDs has been associated with fewer fetal effects than polytherapy (Level II-2).

➤ Patients who take AEDs during the first trimester should be offered maternal serum screening and detailed fetal ultrasound prior to 20 weeks’gestation to observe for fetal anomalies that may result from the AEDs (Level III).

➤ Supplemental vitamin K during the last month of pregnancy may be associated with fewer episodes of neonatal hemorrhagic complications (Level III).

REFERENCES

1. Arpino C, Brescianini S, Robert E, et al. Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposure (MADRE). Epilepsia. 2000;41:1436-1443. 

2. Holmes LB, Rosenberger PB, Harvey EA, Khoshbin S, Ryan L. Intelligence and physical features of children of women with epilepsy. Teratology. 2000;61:196-202. 

3. Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in offspring of women with epilepsy. Neurology. 2003;60:575-579. 

4. Lindhout D, Meinardi H, Meijer J, Nau H. Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations. Neurology. 1992;42(Suppl 5):94-110. 

5. Meador KJ, Zupanc ML. Neurodevelopmental outcomes of children born to mothers with epilepsy. Cleve Clin J Med. 2004;71(Suppl 2):38S-40S. 

6. Minkoff H, Schaffer R, Delke I, Grunevaum A. Diagnosis of intracranial hemorrhage in utero after a maternal seizure. Obstet Gynecol. 1985;65(Suppl):22S-24S. 

7. Patsalos PN, Berry DJ, Bourgeois Blaise JD, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276. 

8. Pennell PB. Pregnancy in women who have epilepsy. Neurol Clin. 2004;22:799-820. 

9. Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology. 2004;62:292-295. 

10. Thomas SV, Sindhu K, Ajaykumar B, Sulekha Devi PB, Sujamol J. et al. Maternal and obstetric outcome of women with epilepsy. Seizure. 2009 Apr;18(3):163-166. 

11. Wide K, Winbladh B, Tomson T, Kallen B. Body dimensions of infants exposed to antiepileptic drugs in utero: observations spanning 25 years. Epilepsia. 2000;41:854-861. 

12. Yasasmit W, Chaithongwongwatthana S, Tolosa JE. Prenatal vitamin K1 administration in epileptic women to prevent neonatal hemorrhage: is it effective? J Reprod Med. 2006 June;51(6):463-466. 

13. Yerby MS. Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology. 2000;55:21-31.

HomeHigh-Risk Obstetrics Case FileEpilepsy in Pregnancy Case File