See also separate articles Epilepsy in Adults, Status Epilepticus Management and Managing Epilepsy in Primary Care.

Women of childbearing years account for 25% of all people with epilepsy and most of these women will require long-term treatment with anti-epileptic drugs (AEDs). Approximately 3-4 pregnancies in every 1,000 occur to women with epilepsy and 1,800-2,400 infants are born in the UK every year to women with epilepsy.¹

Appropriate advice should be made available to women with epilepsy; special advice on contraception and pre-conception and also greater levels of care are required in pregnancy, labour and postnatally.

Most pregnant women with epilepsy have a normal pregnancy and childbirth.² However, there is an increased risk of teratogenicity associated with the use of AEDs, especially if used during the first trimester and also if the patient takes two or more AEDs. Valproate is associated with the highest risk of major and minor congenital malformations, and with developmental delay. Valproate should not be prescribed unless there is no safer alternative (doses greater than 1 g daily are associated with an increased risk of teratogenicity).³

There is also an increased risk of teratogenicity with phenytoin, primidone, phenobarbital, lamotrigine, and carbamazepine. Topiramate causes an increased risk of cleft palate if taken in the first trimester of pregnancy. There is not enough evidence to establish the risk of teratogenicity with other AEDs.³

See also separate articles Anticonvulsants used for Generalised Seizures and Anticonvulsants used for Partial Seizures.

Contraception

Liver enzyme (cytochrome P-450) induction reduces the efficacy of the combined oral contraceptive pill, combined contraceptive patch, combined contraceptive vaginal ring and progestogen-only contraceptive pill and this may place women at greater risk of unplanned pregnancy.⁴ Women should be counselled about the increased risk of pregnancy (contraceptive failure) and any harmful effects of medication on the fetus.

• Women with a history of epilepsy, who are not taking anticonvulsants, may use any method. Women taking anticonvulsants that do not induce liver enzymes, e.g. gabapentin, levetiracetam, valproate, and vigabatrin, may use any method without restriction. Sterilisation should be undertaken with caution and seizures should be adequately controlled.
• Women taking anticonvulsants that induce liver enzymes, e.g. phenytoin, carbamazepine, barbiturates, primidone, topiramate and oxcarbazepine, may use depot medroxyprogesterone acetate, copper intrauterine contraceptive devices, the levonorgestrel-releasing intrauterine system, barrier methods and natural family planning methods.
• Subdermal implants may increase the risk of pregnancy in women with epilepsy on enzyme-inducing anti-epileptic drugs (AEDs).⁵ The progestogen-only contraceptive pill and the progestogen implant are not recommended as reliable contraception in patients taking enzyme-inducing AEDs.⁶
• Intramuscular medroxyprogesterone acetate (Depo-Provera®) can be used, but should be scheduled every 10 weeks rather than 12-weekly.
• The use of additional barrier methods should be discussed with women and girls taking enzyme-inducing AEDs and oral contraception or having depot injections of progestogen.⁶
• If women choose a combined contraceptive method, they should use a preparation containing at least 50 micrograms of oestrogen.⁴ Tricycling the packs, with no withdrawal bleed for 3-4 packs and then a reduced pill-free interval of only four days is also recommended.
• Any oestrogen-based contraceptive can result in a significant reduction of lamotrigine levels and lead to loss of seizure control.⁶
• Breakthrough bleeding does not necessarily indicate low serum hormone concentrations and risk of ovulation; nevertheless, women with breakthrough bleeding may increase their dose of ethinylestradiol above 50 micrograms daily.

Emergency contraception³

• The effectiveness of levonorgestrel, and possibly ulipristal, is reduced in women taking enzyme-inducing drugs (and possibly for four weeks after stopping).
• A copper intrauterine contraceptive device can be offered instead, or the dose of levonorgestrel should be increased to a total of 3 mg taken as a single dose (unlicensed dose).

Fertility

Women with epilepsy may have a lower fertility rate than average but the evidence is poor. While personal choice and/or societal pressure may play some role in this, women with epilepsy also appear to have a higher incidence of menstrual irregularities, polycystic ovarian disease and reproductive endocrine disorders. All of these may reduce fertility. These are thought to arise from both neuro-endocrine disturbances related to seizure activity, as well as the alteration of endogenous sex steroid metabolism in the presence of enzyme-inducing anti-epileptic drugs (AEDs).² There is an increase in polycystic ovaries and hyperandrogenism associated with valproate therapy.⁷

Pre-conception⁶

• Discuss the risk of anti-epileptic drugs (AEDs) causing malformations and possible neurodevelopmental impairments in an unborn child. Assess the risks and benefits of treatment with individual drugs.
• There are limited data on risks to the unborn child associated with newer drugs. Higher doses of sodium valproate (more than 800 mg/day) and polytherapy are associated with greater risk. The combination of valproate and lamotrigine has been shown to be particularly teratogenic.⁷
• Carbamazepine (risk of 0.5%) has a lesser risk of neural tube defects than valproic acid (risk of 1 to 2%), specifically spina bifida. Folate supplementation reduces the risk.
  There are relatively few data regarding the safety of the newer AEDs during pregnancy. However, a recent study in Denmark found that first-trimester exposure to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam compared with no exposure was not associated with an increased risk of major birth defects.⁸
• Many experts believe that trimethadione is contra-indicated in women with epilepsy who might become pregnant because it has been associated with a high incidence of fetal loss and congenital malformations.
• 5 mg per day of folic acid before any possibility of pregnancy should be advised in order to lower the risk of neural tube defects in the offspring.

Antenatal⁶

• There is an increased risk of complications during pregnancy and labour. Care of pregnant women and girls should be shared between the obstetrician and the epilepsy specialist. All pregnant women and girls with epilepsy should notify their pregnancy to the UK Epilepsy and Pregnancy Register - see website under 'Internet and further reading', below.
• An increase in seizure frequency is generally unlikely in pregnancy or in the first few months after birth. The risk of a tonic-clonic seizure during the labour and the 24 hours after birth is low (1-4%).
• The fetus may be at relatively higher risk of harm during a generalised tonic-clonic seizure, although the absolute risk remains low, and the level of risk may depend on seizure frequency. However, miscarriage, trauma related to falls, fetal hypoxia and acidosis are all possible sequelae of maternal seizures. There is no evidence that focal, absence or myoclonic seizures affect the pregnancy or developing fetus adversely unless they fall and sustain an injury.
• Status epilepticus carries a high mortality rate for mother and fetus, and generalised seizures occurring during labour can result in fetal bradycardia.
• Other potential antenatal problems seen more frequently in women with epilepsy are hyperemesis gravidarum, gestational hypertension, mild pre-eclampsia, vaginal bleeding and anaemia.⁹
• Difficulties during labour and delivery include premature labour, failure to progress and an increased rate of Caesarean sections.⁹

Congenital abnormalities

• The risk of congenital malformation is higher in women with epilepsy.
• A Finnish population-based study has compared the risk of major malformation in women, with and without treatment.¹⁰ This study confirmed that major congenital malformations were more common among women on anti-epileptic drugs (AEDs) (4.6%) than among untreated patients (2.8%). This compared to the background risk of 1-2% in the general population.¹ The risk is greater for women taking more than one drug.
• The most common malformations are orofacial clefts, cardiac abnormalities and neural tube defects.
• Minor physical defects are found in approximately 15% of children. These include hypertelorism, epicanthal folds, shallow philtrum, distal digital hypoplasia, simian creases (may be a familial trait). These features may also be found 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.
• Research has shown an increase in educational requirements, poorer neuropsychological performance and reduced verbal IQ among children exposed prenatally to sodium valproate.^11,12 This persists into adulthood.
• Children of mothers with and without epilepsy have been found to differ in IQ scores and height when assessed at 18-19 years of age.¹³ The significant adverse effect persisted when adjustment was made for confounders including maternal education, maternal age, birth order, marital status and birthweight.

Antenatal and intrapartum care

• Pregnant women taking AEDs should be offered a high-resolution ultrasound scan to screen for structural anomalies, performed at 18-20 weeks of gestation, but earlier scanning (11-13 weeks) may allow major malformations to be detected sooner.⁶
• Fetal growth should be monitored in women taking topiramate or levetiracetam.³
• All children born to mothers taking enzyme-inducing AEDs should be given 1 mg of vitamin K parenterally at delivery.⁶
• Genetic counselling should be considered if one partner has epilepsy, particularly if the partner has idiopathic epilepsy and a positive family history of epilepsy.⁶
• AED levels should not be monitored routinely during pregnancy but, if seizures increase or are likely to increase, monitoring AED levels (particularly levels of lamotrigine and phenytoin, which may be particularly affected in pregnancy) may be useful when making dose adjustments.⁶
• Intrapartum care should include the following:²
  • Women should deliver in a centre with adequate facilities for maternal and neonatal resuscitation.
  • Women should continue to take their anti-epileptic medication in labour.
  • Birthing pools are not recommended for women with epilepsy.
  • Intravenous access (in case of seizure).
  • Hyperventilation and maternal exhaustion should be avoided.
  • Generalised tonic-clonic seizures are associated with hypoxia, and continuous cardiotocography (CTG) tracing is recommended in the event of a seizure.
  • An intravenous benzodiazepine (e.g. lorazepam or diazepam) is recommended to terminate fitting.
  • In the event of benzodiazepine being used to terminate the seizure, loss of baseline variability of the fetal heart rate tracing can be expected for approximately one hour.

Postnatal

• Withdrawal effects in the newborn may occur with some antiepileptic drugs, especially benzodiazepines and phenobarbital.³
• If doses have been increased during pregnancy, toxicity may occur and medication requirement is likely to fall in the puerperium.
• Breast-feeding:
  • Breast-feeding for most women taking anti-epileptic drugs (AEDs) is generally safe and should be encouraged.⁶
  • The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant.⁷
  • Primidone, phenobarbital and the benzodiazepines may cause drowsiness in breast-fed babies.³
  • Withdrawal effects may occur in infants if a mother suddenly stops breast-feeding, especially if taking phenobarbital, primidone or lamotrigine.³
• Maternity services should be aware of the risk of postpartum seizures, particularly in the setting of sleep deprivation. Ensuring women get adequate sleep and take their medication is very important.
• Mothers may be anxious about the prospect of having a seizure whilst caring for a baby at home alone. Although the risk to the infant from maternal seizures is generally low, women with juvenile myoclonic epilepsy are a particular concern. The myoclonic jerks tend to be more frequent in the early morning, often around the time of infant waking.
• To reduce the risk of injury if the mother has a seizure, advice should include:
  • Change or feed the baby on the floor.
  • Avoid baby slings.
  • Where possible, minimise climbing of stairs.
  • Avoid bathing the baby when alone.

Document references

1. Primary care guidelines for the management of females with epilepsy, Royal Society of Medicine (2004)
2. Walker SP, Permezel M, Berkovic SF; The management of epilepsy in pregnancy. BJOG. 2009 May;116(6):758-67. [abstract]
3. British National Formulary; 62nd Edition (Sep 2011) British Medical Association and Royal Pharmaceutical Society of Great Britain, London (link to current BNF)
4. Drug Interactions with Hormonal Contraception, Faculty of Sexual and Reproductive Healthcare (2011)
5. Burakgazi E, Harden C, Kelly JJ; Contraception for women with epilepsy. Rev Neurol Dis. 2009 Spring;6(2):E62-7. [abstract]
6. Epilepsy, NICE Clinical Guideline (January 2012)
7. Crawford PM; Managing epilepsy in women of childbearing age. Drug Saf. 2009;32(4):293-307. doi: 10.2165/00002018-200932040-00004. [abstract]
8. Molgaard-Nielsen D, Hviid A; Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA. 2011 May 18;305(19):1996-2002. [abstract]
9. Borthen I, Eide MG, Veiby G, et al; Complications during pregnancy in women with epilepsy: population-based cohort study. BJOG. 2009 Sep 23. [abstract]
10. Artama M, Auvinen A, Raudaskoski T, et al; Antiepileptic drug use of women with epilepsy and congenital malformations in Neurology. 2005 Jun 14;64(11):1874-8. [abstract]
11. Kantola-Sorsa E, Gaily E, Isoaho M, et al; Neuropsychological outcomes in children of mothers with epilepsy. J Int Neuropsychol Soc. 2007 Jul;13(4):642-52. Epub 2007 May 18. [abstract]
12. Bromley RL, Baker GA, Meador KJ; Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero. Curr Opin Neurol. 2009 Apr;22(2):162-6. [abstract]
13. Oyen N et al. Maternal Epilepsy and Offsprings' Adult Intelligence: A Population-Based Study from Norway. Epilepsia. May 2007

Internet and further reading

• Epilepsy, Prodigy (June 2009)
• Epilepsy Action
• Epilepsy Society
• Epilepsy Scotland
• Epilepsy Wales
• UK Epilepsy and Pregnancy Register