Antiepileptic Therapy During Pregnancy

Antiepileptic therapy in pregnancy aims for seizure freedom on the safest effective monotherapy at the lowest effective dose. More than 90% of women with epilepsy have a healthy child. Generalised tonic-clonic seizures endanger mother and foetus through hypoxia, trauma and foetal bradycardia, so stopping effective treatment is rarely safe.

Malformation risk by drug (added to a background of 2 to 4%). Valproate about 10% (dose related, highest over 1000 mg daily), phenobarbital 5 to 7%, topiramate about 4 to 5%, phenytoin 3 to 6%, carbamazepine 2 to 5% (dose related), lamotrigine about 2 to 3% (low at 325 mg daily or less), levetiracetam about 1 to 2%.

Neurodevelopment. Valproate in utero lowers IQ and raises autism and developmental delay (30 to 40% affected). Topiramate and phenobarbital also carry neurodevelopmental concern. Lamotrigine and levetiracetam show no clear excess.

Pharmacokinetics. Clearance of lamotrigine rises 2 to 3 fold, levetiracetam about 50%, oxcarbazepine metabolite about 40 to 50%; carbamazepine and valproate change less (free fraction of phenytoin and valproate rises as albumin falls).

Preconception. Specialist review before conception. Switch valproate, topiramate and phenobarbital where seizure control allows, ideally 3 to 6 months before conception so control is proven. Folic acid 5 mg orally once daily from before conception until 12 weeks.

First choice in generalised and unclassified epilepsy. Lamotrigine or levetiracetam.

• Lamotrigine: usual 100 to 400 mg daily in 1 or 2 doses (up to 700 mg daily with enzyme inducers). Pregnancy dose is directed by drug level.
• Levetiracetam: 500 to 1500 mg orally twice daily; maximum 3 g daily.

First choice in focal epilepsy. Lamotrigine, levetiracetam or carbamazepine (modified release 400 to 1200 mg daily in 2 divided doses; maximum 1.6 to 2.0 g daily; give with folic acid).

Valproate, only if no alternative. Lowest effective dose, modified release in 2 divided doses, ideally 600 mg daily or less (never over 1000 mg), with folic acid 5 mg and formal documented counselling. Never start in anyone who could become pregnant unless other drugs have failed and a pregnancy prevention programme is in place.

Dose adjustment by level. Measure a baseline level before or at the start of pregnancy, then every 4 weeks. Increase lamotrigine, levetiracetam or oxcarbazepine by 20 to 25% when the level falls 25 to 35% under the individual baseline, or when seizures recur.

Seizure emergency.

• Tonic-clonic seizure over 5 minutes: lorazepam 4 mg IV (0.1 mg/kg), repeat once after 10 minutes; or midazolam 10 mg IM (5 mg under 40 kg); or diazepam 10 mg IV or 20 mg rectally.
• Second line: levetiracetam 60 mg/kg IV (maximum 4.5 g) over 10 minutes, or phenytoin 20 mg/kg IV at no more than 50 mg/minute with ECG monitoring.
• After 20 weeks, assume eclampsia until excluded: magnesium sulphate 4 g IV over 5 to 15 minutes, then 1 g/hour for 24 hours.

Newborn. Vitamin K 1 mg IM to every newborn at birth. Extra antenatal vitamin K for mothers on enzyme-inducing drugs is not routine in most practice; regional practice varies.

Postpartum. Reduce doses raised in pregnancy within 1 to 2 weeks of birth: lamotrigine back to pre-pregnancy dose over 2 to 3 weeks (level falls fast, toxicity peaks at days 3 to 7), levetiracetam within days.

Avoid or restrict. Valproate, topiramate (clefts, small-for-gestational-age), phenobarbital and primidone (malformations, neonatal withdrawal, vitamin K deficiency bleeding), polytherapy, phenytoin (foetal hydantoin syndrome, hypoprothrombinaemia).

Interactions. Enzyme-inducing drugs (carbamazepine, phenytoin, phenobarbital, oxcarbazepine at 1200 mg or more, topiramate at 200 mg or more) cut hormonal contraceptive efficacy; use a levonorgestrel or copper intrauterine device or medroxyprogesterone acetate. Oestrogen-containing contraceptives lower lamotrigine levels by about 50%. Carbamazepine lowers methadone, nifedipine and antiretroviral levels.

Special groups.

• Kidney impairment: reduce levetiracetam by creatinine clearance.
• Liver impairment: avoid valproate; reduce lamotrigine by about 25% in moderate and 50% in severe impairment.
• Breastfeeding: lamotrigine (infant level up to 30 to 50% of maternal, watch rash and apnoea), levetiracetam, carbamazepine and valproate are usually acceptable with infant monitoring; phenobarbital and primidone cause infant sedation.
• Regional: phenobarbital and phenytoin are often the only agents available in East African facilities; if phenobarbital must continue, give vitamin K 10 mg orally daily for the last month and 1 mg IM to the newborn, and plan newborn withdrawal monitoring.

Monitoring. Seizure diary at each visit. Lamotrigine, levetiracetam and phenytoin (free) levels at booking and each trimester, or monthly; carbamazepine (total and free) each trimester. Detailed anomaly scan and neural tube assessment at 18 to 22 weeks; foetal growth scans from 28 weeks on enzyme-inducing drugs.

Safety counselling. Adherence, sleep, no driving after a seizure, supervised bathing, baby changing and feeding at floor level.

Stopping rules. Never stop abruptly in pregnancy. A planned withdrawal, only in someone seizure free for 2 years or more, is done before conception.

Referral and escalation. Refer to a joint epilepsy and obstetric clinic for any seizure, level fall, valproate exposure or polytherapy. Plan birth in a facility able to manage seizures and resuscitate the newborn.