Women with epilepsy, who are of childbearing age, need additional advice about issues such as contraception and pregnancy. The choice of epilepsy medication for women may be influenced by factors that include potential teratogenicity of the AED, interactions with the oral contraceptive and cosmetic side effects.

4.1 Contraception

Many pregnancies in women with epilepsy are unplanned.²⁰⁹

Advice on contraception should be given before young women are sexually active. Women with epilepsy should be advised to plan their pregnancies.

4.1.1 COMBINED ORAL CONTRACEPTIVE (COC)

Women taking AEDs which induce hepatic enzymes (see Table 6) are at increased risk of breakthrough bleeding and COC failure, estimated at up to 7 per 100 woman years, due to accelerated oestrogen metabolism.^{210, 211, 212} Current guidelines recommend a COC containing a minimum of 50micrograms oestrogen to reduce this risk, increasing to 80 or 100micrograms if breakthrough bleeding occurs.^{213, 214} Even with these measures the risk of pregnancy remains high and expert opinion advises “tricycling” ie taking three packs of the high dose COC consecutively and reducing pill-free days to four.²¹⁵ Enzyme induction persists up to four weeks after the AED is withdrawn.²¹⁶ AEDs which do not induce hepatic enzymes do not alter the efficacy of the COC. Evidence level 2-,4

If a patient is using oral contraception, an AED that does not induce hepatic enzymes is preferable.

When the combined oral contraceptive is given with an enzyme-inducing AED, one containing a minimum of 50micrograms of oestrogen should be used; women should be warned that its efficacy is reduced and barrier methods of contraception should also be used if maximal contraceptive effect is required.

If breakthrough bleeding occurs with 50micrograms of oestrogen the dose should be increased and “tricycling” of the combined oral contraceptive should be considered.

Table 6: Action of AEDs on hepatic enzymes

4.1.2 PROGESTERONE-ONLY CONTRACEPTION

Progesterone metabolism is increased by enzyme-inducing AEDs and the efficacy of the progesterone-only oral contraceptive cannot be guaranteed with these. Medroxyprogesterone (Depo-Provera) can be used with enzyme-inducing AEDs but the efficacy may be reduced after ten weeks. Implants of progesterone are not effective if given with enzyme-inducing AEDs.²²⁵ Evidence level 4

The progesterone-only oral contraceptive is not recommended for women taking enzyme- inducing AEDs.

Depot injections of progesterone may be used with enzyme-inducing AEDs but should be given every 10 weeks.

Progesterone implants are not suitable for women taking enzyme-inducing AEDs.

4.1.3 EMERGENCY CONTRACEPTION

Levonorgestrel 750micrograms two tablets taken not more than 12 hours apart is probably inadequate emergency contraception for women taking enzyme-inducing AEDs.^{226, 296} Evidence level 4

The dose of levonorgestrel for emergency contraception should be increased to 1.5mg and 750micrograms 12 hours apart in women taking enzyme-inducing AEDs.

4.2 Preconceptual counselling

Epilepsy is common in women of child-bearing age and exposure to AEDs occurs in approximately 1 in 250 pregnancies.²²⁷ Complications of pregnancy, mean birth weight and perinatal mortality are similar to those in the general population.^{209, 228}

Many women with epilepsy are not given preconceptual counselling and those that are, often forget it.²⁰⁹

Women with epilepsy should be reassured that most will have a normal pregnancy and delivery.

Information about the risk of epilepsy and AEDs in pregnancy and the need for folate and vitamin K should be given to all women of childbearing age and repeated at review appointments.

4.2.1 RISKS TO THE FETUS FROM MATERNAL EPILEPSY

Seizure frequency increases during pregnancy in between a quarter and a third of women²⁴⁷ due to a number of factors including changes in pharmacokinetics of AEDs and poor adherence to treatment because of concerns about adverse effects on the fetus.²⁰⁹ Evidence level 3

The long term effect of tonic-clonic seizures on the fetus is not well established although the associated hypoxia and acidosis may adversely affect the obstetric outcome, particularly if the seizures are prolonged. Risks to the woman of injury and, rarely, death in a seizure remain in pregnancy.²²⁹ Evidence level 3

Women should be made aware of the risks of uncontrolled seizures both to themselves and to the fetus.

4.2.2 RISKS TO THE FETUS FROM ANTIEPILEPTIC DRUGS

Major and minor fetal malformations occur more commonly in infants exposed to AEDs during pregnancy.^{209, 230, 231, 232} The overall risk of major fetal malformation in any pregnancy is approximately 2%. This increases two to three fold in women taking a single AED. Current data suggest that the risk with valproate may be higher than with carbamazepine or lamotrigine.²³³ Polytherapy, particularly with certain combinations of drugs, carries a much higher risk (up to 24% in women taking four AEDs). Evidence level 2+

The most common major malformations associated with established AEDs are: neural tube defects (valproate 3%, carbamazepine 1%), orofacial defects, congenital heart abnormalities and hypospadias.^{230, 234} The risk of minor malformations including hypertelorism, epicanthic folds and digital hypoplasia is increased with AED therapy in pregnancy.²³¹ Evidence level 2+,4

“Fetal anticonvulsant syndromes” comprising typical dysmorphic craniofacial appearances and a variety of musculoskeletal abnormalities have been described in association with AED treatment in pregnancy.^{235, 236} Although individual drugs have been associated with specific patterns, there is overlap between them and genetic factors may influence susceptibility.²³⁷ Evidence level 3,4

Whether AEDs taken during pregnancy can affect the child’s intellectual development is uncertain but concern about the effects of valproate on infant development has recently been raised.^{238, 239} Evidence level 3

At present there is insufficient evidence on which to base advice about the risks of most of the newer AEDs (gabapentin, levetiracetam, tiagabine, topiramate, vigabatrin) in pregnancy. Current data on lamotrigine show a malformation rate of 3% (95% confidence interval 1.5-5.7).²³³

Where possible women should have their epilepsy treatment reviewed before becoming pregnant. They should be advised about the risks of seizures and effects of AEDs on the fetus.

If the woman’s epilepsy is in remission, the risk of recurrent seizures is low and the woman is aware of the consequences of recurrent seizures, consideration may be given to withdrawal of AEDs prior to conception.

If AEDs are to be used in pregnancy the relative risks of seizures and fetal malformation should be discussed with the woman.

Whenever possible, a woman should conceive on the lowest effective dose of one AED appropriate for her epilepsy syndrome. If she has good seizure control and presents already pregnant, there is probably little to be gained by altering her AEDs.

Any woman who has given birth to a child with a malformation while taking AEDs should be offered review by an epilepsy specialist before becoming pregnant again.

All pregnant women with epilepsy, whether or not they are on medication, should be notified, with their consent, to the UK Pregnancy Register (Tel: 0800 389 1248).

4.2.3 FOLIC ACID

Many pregnancies in women with epilepsy are unplanned, very few women take folate in the correct dose at the appropriate time and advice given about malformation risk and folate is often forgotten.²⁰⁹ Evidence level 2+,4

Women taking AEDs, particularly valproate, are at greater risk of having a child with neural tube defects (NTD) and other malformations which may be related to altered folate metabolism.^{240, 241} It is recommended that all women should take daily folic acid from preconception and during the first trimester of pregnancy to reduce the incidence of NTD.^{242, 243, 244} While there is no evidence to show that folate can reduce the incidence of AED-associated malformations, current guidelines recommend that a high dose of folate, 5mg daily, be given from pre-conception to the end of the first trimester.²¹³ Evidence level 2+,4

All women with epilepsy should be prescribed a daily dose of 5mg folic acid from preconception until the end of the first trimester.

4.2.4 VITAMIN K1

Current guidelines recommend maternal Vitamin K1 supplementation with phytomenadione 10mg daily from 36 weeks of pregnancy for all mothers taking enzyme-inducing AEDs (see Table 6).²⁴⁵ However, the small risk of haemorrhagic disease of the newborn is not increased in infants of mothers taking enzyme-inducing AEDs provided the infant receives 1mg Vitamin K1 intramuscularly at birth.²⁴⁶ Evidence level 2+,3

All infants born to mothers taking AEDs should be given Vitamin K1 1mg intramuscularly at birth.

If there are additional risk factors for haemorrhagic disease of the newborn (eg maternal liver disease, anticipated premature delivery) oral vitamin K1 (phytomenadione 10mg daily) should also be given in the last month of pregnancy.

4.3 Pregnancy

In a maternity unit with 5,000 births per year, there will be around 20 pregnancies in women with epilepsy.²²⁷ Pregnancy may be associated with changes in seizure frequency requiring alteration in AEDs.²⁴⁷ Evidence level 3,4

Infants exposed to AEDs in utero are at higher risk of major and minor abnormalities. Ultrasound scanning can detect most major structural abnormalities if performed at 18 weeks gestation by skilled sonographers.²⁴⁸ Evidence level 3,4

Enzyme-inducing AEDs (see Table 6) accelerate metabolism of steroids, including betamethasone, given to mothers to reduce the risk of neonatal respiratory distress in preterm infants.²⁴⁹ Evidence level 3,4

Pregnancies in women with epilepsy should be supervised in an obstetric clinic with access to a physician specialising in epilepsy.

Seizure frequency should be monitored carefully during the pregnancy and adjustments made to AED doses to minimise the number of seizures, particularly generalised tonic-clonic seizures.

Detailed ultrasound scanning for detection of fetal abnormality should be done at 18 weeks.

If preterm labour is threatened in women taking enzyme-inducing AEDs, 48mg betamethasone (double the normal dose) should be given over 48 hours.

4.3.1 AED DOSES AND BLOOD LEVEL MONITORING DURING PREGNANCY

Pregnancy is associated with pharmacokinetic changes including: an increase in volume of distribution, an increase in drug metabolism through hepatic microsomal enzyme induction, a reduction in serum albumin concentration and an increase in renal clearance.²⁵⁰ There is a tendency for plasma levels of AEDs to fall during pregnancy²⁵¹ but there is no evidence to support routine increase of AED doses. The value of plasma AED monitoring in pregnancy is questionable; AED levels correlate poorly with seizure control except in the case of phenytoin. Total plasma levels may be misleading and the relationship between free levels and seizure control is complex.²⁵² Most published reviews and consensus guidelines recommend avoiding routine AED monitoring in pregnancy.^{245, 253, 254} Plasma level monitoring may occasionally be of use when there is concern about toxicity or adherence to therapy.²⁵⁵ Evidence level 3,4

Dose of AEDs should not be increased routinely in pregnancy but should only be adjusted on clinical grounds.

Other factors affecting AED levels in pregnancy, eg vomiting, should be considered if seizure control deteriorates.

Routine monitoring of AED concentrations is not indicated. Measurement can be useful in the following circumstances: adjustment of phenytoin dose, assessment of adherence and toxicity.

Interpretation of AED blood levels is best done by a doctor specialising in the management of epilepsy.

4.4 Labour

Most women with epilepsy will have a normal labour and vaginal delivery^{209, 228} but stress, pain, sleep deprivation, over-breathing and dehydration increase the risk of seizures during labour. Evidence level 3,4

Women with epilepsy should be delivered in a consultant led maternity unit and one to one midwifery care given during labour.

Factors predisposing to increased risk of seizures in labour should be reduced as much as possible and there should be a low threshold for epidural anaesthesia.

The usual oral AED medication should be continued during labour and postnatally. In women unable to tolerate oral medication, AEDs can be given by other routes.

An elective Caesarean section should be considered if there have been frequent tonic-clonic or prolonged complex partial seizures towards the end of pregnancy.

4.4.1 SEIZURES IN LABOUR

Up to five percent of women with epilepsy will have a tonic-clonic seizure during labour or the puerperium.²⁴⁷ In women with no prior history of epilepsy, eclampsia is the most common cause of seizures in labour. If tonic-clonic seizures occur during labour, maternal hypoxia, fetal hypoxia and acidosis will result. Status epilepticus (see section 3.11) in labour is associated with maternal as well as fetal mortality. Evidence level 3

There are no clinical trials to inform choice of emergency treatment of seizures in labour.

Seizures in labour should be terminated as soon as possible using intravenous lorazepam or diazepam. If seizures persist, manage as for status epilepticus.

Maternal airway and oxygenation should be maintained at all times.

If there is doubt whether a seizure in labour is due to eclampsia or epilepsy, then, in addition to intravenous lorazepam or diazepam, a slow intravenous bolus of 4grams magnesium sulphate over 5-10 minutes followed by 1gram/hour for 24 hours is recommended.

Delivery should be expedited following a seizure during labour, and neonatal expertise should be available.

4.5 Advice for mothers postpartum

Following labour, physiological changes associated with pregnancy gradually remit and blood levels of AEDs may rise; if an increase in AED dose was made in pregnancy this may lead to toxicity postpartum and AED doses need to be adjusted accordingly.

The postnatal check provides an opportunity to examine the infant for any abnormality and to discuss contraception and preconception advice for future pregnancies with the mother.

Caring for a young baby is often associated with fatigue and sleep deprivation, both of which can provoke seizures.

Although injuries to infants from maternal seizures are thought to be uncommon, babies of women with epilepsy, especially those with myoclonic epilepsies, are at risk. Bathing infants is potentially hazardous if the mother has seizures associated with loss of awareness.

The pregnant woman who has epilepsy should be encouraged to plan ahead before the birth of her child, particularly in relation to breastfeeding and safe practice in caring for the child. The safety of the infant should be paramount.

After the birth a review of the mother’s AED therapy should be undertaken.

Advice regarding contraception, the need for planning future pregnancies, folate requirements and risks associated with AEDs in pregnancy should be offered at the postnatal visit.

Extra support should be available to mothers who have a physical or learning disability.

4.6 Advice about breastfeeding

Blood levels of AEDs in infants who are breastfed are probably lower than in utero provided the infant is healthy and born close to term. Accumulation of AEDs may occur in the neonate as mechanisms for drug elimination are not fully developed at birth. AEDs will pass into the breast milk at varying levels but breastfeeding and subsequent weaning usually allow for a gradual withdrawal.^{256, 257, 258}

All mothers should be encouraged to breastfeed and receive support from their health visitor, midwife and GP.

The possibility of sedation should be considered in infants of mothers taking phenobarbital.

4.7 Risks of inheriting epilepsy

Chromosomal and single gene disorders causing epilepsy are rare, and the genetics of most epilepsies are complex with multiple genes involved and interaction with environmental factors. The risks of passing on epilepsy are higher for mothers with idiopathic than with symptomatic epilepsies.

4.7.1 IDIOPATHIC GENERALISED EPILEPSIES (IGE)

Based on retrospective studies the risk of any type of seizure in a child of a mother with IGE is 4-8%; in a child of a father with IGE, the risk is only slightly higher than that of the general population.²⁵⁹ When more than one first degree relative is affected the risk of a child being affected will be higher, and may sometimes approach 30% or more. Evidence level 2+,3,4

Multiple genes influence the phenotypes of idiopathic generalized epilepsy.²⁶⁰ The genetic susceptibility in IGE increases the risk of epilepsy associated with cerebral palsy as well as of IGE. The genetic contribution to epilepsy appears limited to epilepsy with onset aged under 35 years.^{261, 262} Photosensitive epilepsy is inherited in an autosomal dominant manner with age-dependent penetrance of the photoparoxysmal response. During maximum penetrance between the ages of 5 and 15, 50% of children of a photosensitive parent, will be photosensitive.²⁶³ Evidence level 2+,3,4

4.7.2 FOCAL EPILEPSIES

In relatives of patients with symptomatic focal epilepsy, there is no evidence for a significantly increased risk of epilepsy.^{261, 262} In idiopathic focal epilepsies the risks are higher. For example in autosomal dominant nocturnal frontal lobe epilepsy the risk of a child developing this disorder may be up to 50% depending on penetrance.²⁶⁴ Evidence level 2+,3,4

4.7.3 FEBRILE CONVULSIONS

Susceptibility to febrile convulsions also follows a multifactorial polygenic mode of inheritance with a maternal preponderance in transmission. There is a 27% risk in a child with an affected mother and 6% with an affected father.²⁶⁵ Population based studies indicate that 2-7% of children with febrile seizures will go on to develop epilepsy with afebrile seizures, the risk being higher with complicated febrile convulsions.²⁶⁶ Evidence level 3,4

In general the risk of epilepsy developing in the children of parents with epilepsy is low.

A comprehensive family history of epilepsy should be taken and expert advice on the genetics of epilepsy should be available as required.

4.8 Hormone replacement therapy (HRT)

Information about the effects of the menopause on epilepsy is limited but there is evidence to suggest that some women experience an increase in seizure frequency at this time.²⁶⁷ HRT may improve seizure control in those who previously experienced catamenial epilepsy (seizures with menstruation) but others may experience an increase in their seizure frequency on HRT.^{268, 269} Evidence level 2+,3,4

The benefit of HRT (oestrogen with or without progesterone) in reducing the risk of osteoporosis and hip fracture is well recognised.²⁷⁰ Women who have taken AEDs are known to be at increased risk of hip fractures.¹⁴² Evidence level 2+,3,4

Enzyme-inducing AEDs (see Table 6) reduce the efficacy of standard doses of HRT. Evidence level 2+,3,4

Women should be aware that their seizure pattern may change at the time of the menopause.

HRT should be prescribed for the same indications as in women who do not have epilepsy.