Helping your epileptic patient

December 1, 2015

An overview of anti-epileptic drugs and their use during pregnancy, as well as other perinatal considerations for women with seizure disorders.

 

Dr Aghajanian is Director of Labor and Delivery and Maternal Fetal Care Unit, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California.

 

 

 

 

Dr Gupta is a fellow in Maternal Fetal Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Neither author has a conflict of interest to report in respect to the content of this article.

 

 

Seizure disorders are common in women of childbearing age. Approximately 500,000 reproductive-aged women in the United States carry the diagnosis. It is estimated to affect 3–5 births per 1000 women but the exact incidence remains unknown.1

Seizure disorder overview

A diagnosis of seizure disorder or epilepsy is made when 2 or more spontaneous, unprovoked seizures occur more than 24 hours apart. Epilepsy may also be diagnosed after one unprovoked seizure in women who have risk factors and have a high recurrence risk. If a person has been free of seizures for at least 10 years, without the use of anti-seizure medications in the previous 5 years, epilepsy can be considered resolved.2 Seizures are classified as either generalized or focal per the International League Against Epilepsy Commission on Classification and Terminology.3 Generalized seizures are the result of neuron activation in both hemispheres. Most convulsive generalized seizures are of the tonic-clonic type although they may also include myoclonic, clonic, tonic, atonic and absence seizures. Loss of consciousness occurs during all generalized seizures.

Focal seizures involve activation of neurons in one hemisphere and may or may not result in loss of consciousness. Absence seizures are non-convulsive generalized seizures and are notable for their short duration with motor arrest and lack of postictal confusion. They are associated with brief lapses of consciousness and are more common in children than adults.

Initially, the diagnosis of epileptic seizure is suspected based on clinical history. A thorough history and physical examination including vitals is the first step in patient evaluation. Questioning eyewitnesses proves invaluable in ascertaining the presence of the following symptoms during and following a seizure episode: loss of consciousness, generalized or focal movements, loss of bladder or bowel function, presence of an aura, or characteristics of a postictal state (eg, confusion, focal weakness, headache).

Ancillary tests such as electroencephalography (EEG), brain imaging and laboratory studies can help confirm the diagnosis and rule out other etiologies for the seizure. In half of the cases, the electroencephalogram (EEG) will be normal. While a normal EEG does not exclude the diagnosis of seizure disorder, an abnormal EEG can aid in assessing the risk of seizure recurrence and help guide therapy. For all patients with new-onset seizures, brain imaging is recommended by the American Academy of Neurology and the American Society of Epilepsy.4 Although head magnetic resonance imaging (MRI) does not carry risk of radiation exposure and is more sensitive than computed tomography (CT) for detecting small lesions, CT scans are more easy to obtain and expose the developing fetus to very little radiation.

Initial laboratory studies should include a complete blood count, complete metabolic panel, urinalysis and toxicology screen. Consultation with a neurologist is recommended when a pregnant woman presents with seizures for the first time because the differential diagnosis is broad and includes brain tumors, intracranial bleeding, trauma, infection, and metabolic disturbances such as hypoglycemia and electrolyte abnormalities. Eclampsia should always be considered when seizures occur after 20 weeks’ gestation in women with or without a history of seizure disorder. Prior to 20 weeks, other etiologies for seizures include molar pregnancies and antiphospholipid syndrome. Cerebrovascular accidents, although rare, can have multiple etiologies and patients with them can also present with seizures. If a stroke is unrecognized and untreated, serious maternal and fetal morbidity may result.1 Pseudoseizures are nonepileptic seizures of psychogenic origin and can be distinguished from true epileptic seizures by several features including their long duration and lack of postictal confusion. Although pseudoseizures can co-exist with epileptic seizures, misdiagnosis may lead to inappropriate treatment with antiepileptic drugs (AED).5

 

 

Effects of pregnancy on seizure disorder

The most significant risk factor contributing to the increased frequency of seizures during pregnancy is uncontrolled maternal seizures prior to pregnancy.6 Other risk factors include maternal exhaustion and sleep deprivation. Noncompliance with AED use and inadequate dosing of the AED also contribute to worsening of seizure disorder during pregnancy.7

In 2013, the International Registry of Antiepileptic Drugs in Pregnancy (EURAP) conducted a prospective observational study by following 3451 women with epilepsy throughout their pregnancies to study seizure control. The study revealed that the majority (67%) of women with epilepsy had no seizures during pregnancy whereas 16% experienced worsening of seizure frequency. Only 0.6% of pregnancies were complicated by status epilepticus, resulting in one case of stillbirth and no cases of maternal death.8

Effects of seizure disorder on pregnancy

Women with seizure disorder are at an increased risk of maternal complications during pregnancy, including hypertensive disorders, intrauterine growth restriction (IUGR), and preterm delivery.9,10 Some studies also report increased risk for vaginal bleeding, anemia and hyperemesis gravidarum.11 While a history of seizure disorder in itself is not an indication for expedited delivery, obstetrical complications increase a patient’s risk of requiring induction of labor or cesarean delivery.10,12 Maternal mortality rates, although low, are estimated to be 10 times higher among women with a history of seizure disorder.13

Seizures can lead to interruption of the oxygen pathway to the fetus, resulting in fetal heart rate decelerations. Frequent seizures may lead to fetal harm as evidenced by one report of 14 fetal deaths occurring in 29 women with status epilepticus.11 In some studies but not in others, rates of perinatal death are reported to be higher in women who have epilepsy compared to controls. However, in a recent meta-analysis of women with epilepsy, no difference in fetal death was noted between women with and without epilepsy, women with epilepsy exposed to or not exposed to AEDs, or those using AED monotherapy versus polytherapy.10 In addition, the offspring of women with epilepsy have a higher likelihood of developing epilepsy in childhood compared with control children.14

Efficacy and safety of treatments during pregnancy

Currently, there are no guidelines regarding optimal management of epilepsy in pregnant women. A single seizure is not necessarily an indication for starting antiepileptic therapy, but many women with seizure disorder diagnosed in pregnancy require treatment with an AED to avoid recurrent seizures that could pose an increased risk to them and their fetuses.

When treatment is indicated, it is best to begin with a single medication at the lowest effective dose. The dose can be increased as needed to achieve seizure control. If single-agent therapy is unsuccessful in controlling the seizures, a change to a different medication is warranted. If the second medication fails, then use of a third drug or multiple agents can be considered. It is generally wise to avoid use of multiple drugs with similar mechanisms of action. The type of drug selected will depend on the type of seizure disorder and the patient’s past experience with a particular AED. All treatment regimens should be chosen in consultation with a neurologist.

Most women with seizure disorder have normal, healthy children. However, in utero AED therapy has been associated with an increased risk of fetal congenital malformations. Whereas the malformation rate in the general population ranges from 2% to 3%, infants of mothers who use AEDs during pregnancy have a 4% to 6% risk of birth defects.15 Pooled analysis of data has shown that AEDs are the main reason for the increased risk of birth defects. In one meta-analysis of 10 studies, prevalence of major congenital malformations was higher in the fetuses of women who received AEDs in pregnancy than in non-epileptic controls (OR 3.26; 95% CI 2.15–4.93) but the risk for congenital anomalies in women with untreated seizure disorder compared to controls was not statistically significantly different (OR 1.92; 95% CI 0.92–4.00).16

 

Table. Teratogenicity of common antiepileptic drugs

Drug

Risk of teratogenic effects with monotherapy1,27,28

Major congenital malformations

Valproate

4.7% to 13.8%

Neural tubal defects

Orofacial clefts

Limb anomalies

Cardiovascular anomalies

Abnormal facies

Impaired cognitive function

Phenobarbital

5.5 % to 7.4%

Cardiovascular anomalies

Orofacial clefts

Skeletal malformations

Impaired cognitive function

Phenytoin

2.4% to 6.7%

Fetal hydantoin syndrome

Orofacial clefts

Cardiovascular anomalies

Microcephaly

Dysmorphic facial features

Impaired cognitive function

Eye malformations

Carbamazepine

2.6% to 5.6%

Neural tubal defects

Orofacial clefts

Craniofacial anomalies

Lamotrigine

1.9% to 4.6%

Orofacial clefts

Levetiracetam

0.7% to 2.4%

Non-specific

Topiramate

2.4% to 7.7%

Orofacial clefts

Gabapentin

0-6%

Non-specific

Trimethadione

-- a

Orofacial clefts

Cardiovascular anomalies

Impaired cognitive function

aStudies on monotherapy with trimethadione are limited.

 

 

Although randomized trials are not available, observational studies and pregnancy registries have provided information on the risks of AEDs to the unborn child. The teratogenic risk depends on the class of AED used (Table). Orofacial clefts and cardiovascular anomalies occur most commonly. Valproate and carbamazepine have been shown to increase the risk of neural tube defects (NTDs). Maternal use of valproate has also been associated with fetal valproate syndrome, which includes features such as limb and heart defects, dysmorphic facies, and impaired cognitive function. If possible, use of valproate should be avoided in pregnancy, especially in the first trimester.17 Trimethadione carries an increased risk of fetal malformations and mental deficiency and should not be used in pregnancy. Phenytoin use during pregnancy has been associated with fetal hydantoin syndrome, which is characterized by growth restriction, microcephaly, dysmorphic facies, and mental deficiency. Newer drugs such as levetiracetam have not been linked to specific malformations but studies are limited.7 Clinicians can refer to the Reprotox or TERIS databases for the most up-to-date information on drug teratogenicity.

Management of patients prior to and during pregnancy

Women may be unaware of their pregnancy in the first 6 to 8 weeks after conception. Given that some AEDs are teratogenic during the time of organogenesis, it is crucial that physicians discuss contraceptive options with all patients with epilepsy who are of reproductive age and offer preconception counseling to those who are interested in pursuing a pregnancy.

Contraception

Many AEDs can alter the efficacy of certain hormonal contraceptives by inducing hepatic cytochrome P450. This can lead to rapid clearance of the contraceptive hormones and result in ovulation.18 AEDs that have the greatest effect on hormonal contraceptive levels include phenobarbital, phenytoin, carbamazepine, and topiramate.14,19 To avoid contraceptive failure, women using AEDs should be advised to use barrier contraception in conjunction with either oral contraceptives or medroxyprogesterone injections. Use of long-acting reversible contraception such as intrauterine devices should also be considered.19

Preconception considerations

To reduce the risk of neural tube defects, daily supplementation with 0.4 mg of folic acid or a prenatal vitamin containing folic acid is recommended for all women of childbearing age prior to conception and during pregnancy. 20 Additionally, the American College of Obstetricians and Gynecologists recommends 4 mg of folic acid daily for women at increased risk of having a child with NTDs, including women taking AEDs.20 Data are insufficient, however, to show that risk of NTDs is reduced in fetuses of women with epilepsy who take AEDs and receive folic acid supplementation.21 For women with epilepsy considering pregnancy, a seizure-free period of 1 year or longer is recommended prior to attempting discontinuation of AEDs for the purposes of conception. This decision should be made in consultation with a neurologist.

During pregnancy

Women with epilepsy should undergo screening for fetal malformations by a maternal-fetal medicine specialist. A targeted fetal anatomic ultrasound at 18 to 20 weeks’ gestation and maternal serum alpha-fetoprotein levels at 15 to 20 weeks should be offered to all patients. Abnormal screening results warrant further investigation with diagnostic procedures such as an amniocentesis. Consideration should be given to a prenatal ultrasound in the third trimester to assess fetal growth given the increased risk of IUGR in women with seizure disorder.10 Antenatal testing should be reserved for women with uncontrolled seizures or other comorbidities.

Pregnancy alters the absorption, distribution, metabolism and clearance of AEDs, thereby affecting the efficacy of the drugs in controlling seizures.22 Consequently, AED serum concentrations may be altered in pregnancy due to the increased clearance of the drug. Monitoring of free serum drug levels is recommended for certain AEDs including lamotrigine, carbamazepine, and phenytoin, and should be considered for others such as levetiracetam and oxcarbazepine, especially if seizures are uncontrolled.21 Throughout pregnancy as well as postpartum, patients on AEDs should be closely monitored for seizure activity and drug side effects in collaboration with a neurologist.

 

 

During delivery

Although seizures during delivery are uncommon, women taking AEDs should be advised to continue their medications throughout the intrapartum period.13 Anesthesiology consultation at the time of admission allows for assessment of the airway if the need for intubation arises. In the event of a seizure, the airway should be maintained and the patient repositioned on her left lateral side to prevent aspiration. Epileptic seizures should be treated with intravenous (IV) short-acting benzodiazepines such as lorazepam at a dose of 0.1 mg/kg IV with a maximum rate of 2 mg/min, or diazepam at a dose of 0.2 mg/kg IV up to 20 mg per dose.23 Intravenous phenytoin can also be used if the seizure persists at a dose of 18 mg/kg IV, running through a separate IV line, at a maximum rate of 50 mg/min. Blood pressure and cardiac monitoring during phenytoin infusion is recommended due to the risk of arrhythmias.24 Intrapartum maternal seizures may lead to fetal heart rate decelerations that generally resolve with maternal resuscitation. Placental abruption or traumatic injury to the fetus can occur if the mother incurs abdominal trauma during convulsive seizures.

Neonates of mothers treated with benzodiazepines may show signs of neonatal withdrawal syndrome although the effects are limited. The presence of the pediatric team at delivery is recommended. Evidence is insufficient upon which to determine if there is an increased risk of neonatal hemorrhage in the offspring of women taking AEDs. The routine practice for newborns exposed to AEDs in utero is to receive vitamin K 1 mg intramuscularly or IV at birth. The benefit of prenatal oral vitamin K supplementation for reducing the risk of hemorrhagic neonatal complications has not been established.21

Mode of delivery

Most women undergo successful vaginal deliveries. Cesarean delivery should be reserved for the usual obstetrical indications.

Postpartum issues

During the postpartum period, sleep deprivation and maternal exhaustion increase the risk of seizures; therefore, adequate rest is advised. In addition, strict compliance with AED dosing should be emphasized. AED dosing may require adjustments post-delivery, especially if the dose was increased during pregnancy. Patients should be monitored closely for signs of AED toxicity.

Lastly, precautions should be taken to ensure the safety of the mother and the infant in the event of maternal seizures. For example, to decrease the risk of falling, the mother should hold the infant while seated on a bed or couch. In addition, having the spouse, a family member, or friend in close proximity during the first few postpartum weeks is important, especially if medications are being adjusted to better control seizures.

 

 

Considerations for breastfeeding

All AEDs are measurable in breast milk. Therefore, most women with epilepsy using AEDs have concerns about drug exposure to the breastfed infant. Current recommendations are conflicting and based on limited data on the safety and potential harmful effects of breastfeeding while using AEDs.

While all AEDs are excreted into breast milk, medications that have the lowest degree of penetration into breast milk and are considered to be of minimal risk to the breastfeeding infant include phenytoin, valproate, and carbamazepine.25,26 Lamotrigine, on the other hand, is excreted extensively in breast milk. Some AEDs such as phenobarbital, primidone, zonisamide, and felbamate are considered potentially hazardous due to the neonatal adverse effects of drowsiness, irritability, feeding difficulties, and poor weight gain, or because of their serious side effects in adults. Regardless, most experts believe that taking AEDs is not a contraindication to breastfeeding and that the benefits of breastfeeding outweigh the risks of harm to the infant from AED exposure.1

 

References


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2. Fisher RS, Acevedo C, Arzimanoglou A, et al. A practical clinical definition of epilepsy. Epilepsia. 2014;55:475–482.

3. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676–685.

4. Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007;69:1996–2007.

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7. Kamyar M, Varner M. Epilepsy in pregnancy. Clin Obstet Gynecol. 2013;56:330–341.

8. Battino D, Tomson T, Bonizzoni E, et al. Seizure control and treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry. Epilepsia. 2013;54:1621–1627.

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

15. Yerby MS. Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation. Epilepsia. 2003;44:33–40.

16. Fried S, Kozer E, Nulman I, Einarson TR, Koren G. Malformation rate in children of women with untreated epilepsy: a meta-analysis. Drug Saf. 2004;27:197–202.

17. Harden CL, Meador KJ, Pennell PB, et al. 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.

18. Zupanc ML. Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy. Neurology. 2006;66:S37–45.

19. Use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin No. 73. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2006;107:1453–1472.

20. Neural tube defects. ACOG Practice Bulletin No. 44. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2003;102:203–213.

21. Harden CL, Pennell PB, Koppel BS, et al. 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.

22. Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54:405–414.

23. Walker SP, Permezel M, Berkovic SF. The management of epilepsy in pregnancy. BJOG. 2009;116:758–767.

24. Jones S, Pahl C, Trinka E, et al. A protocol for the inhospital emergency drug management of convulsive status epilepticus in adults. Pract Neurol. 2014;14:194–197.

25. Veiby G, Bjørk M, Engelsen BA, Gilhus NE. Epilepsy and recommendations for breastfeeding. Seizure. 2015;28:57–65.

26. Pennell PB, Gidal BE, Sabers A, et al. Pharmacology of antiepileptic drugs during pregnancy and lactation. Epilepsy Behav. 2007;11:263–269.

27. Tomson T, Xue H, Battino D. Major congenital malformations in children of women with epilepsy. Seizure. 2015;28:46–50.

28. Use of psychiatric medications during pregnancy and lactation. ACOG Practice Bulletin No. 92. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2008;111:1001–1020.