Maternal epilepsy in pregnancy

In the UK, 1800-2400 infants are born every year to women with epilepsy (1).

Maternal epilepsy increases the risk to the fetus in pregnancy three fold, even in the absence of treatment. With treatment, there are recognised fetopathies with most drugs used.

Children with one epileptic parent or more have an increased risk of being epileptic. If one parent is epileptic, the risk of the child becoming epileptic is 2.5 to 6%; if both parents are epileptic, the risk increases to 15-20%. Other conditions associated with epilepsy are also more likely - for example, neurofibromatosis, tuberous sclerosis, and the genetically determined epilepsies such as juvenile myoclonic epilepsy.

Stillbirths and neonatal loss are up to twice as likely among pregnant women with epilepsy (whether or not they take antiepileptic drugs) compared with those without epilepsy (1)

It is important for women to take folic acid prophylaxis preconceptually and during the first trimester. The dose of folic 5mg PO/day is indicated for women receiving established antiepileptic medication (1,2,3,4).

Care of pregnant women and girls should be shared between the obstetrician and the specialist (4)

• it is important that there should be regular follow-up, planning of delivery, and liaison between the specialist or epilepsy team and the obstetrician or midwife
• aim for seizure freedom before conception and during pregnancy (particularly for women and girls with generalised tonic-clonic seizures) but consider the risk of adverse effects of AEDs and use the lowest effective dose of each AED, avoiding polytherapy if possible

NICE also state (4):

• discuss with women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), and their parents and/or carers if appropriate, the risk of 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
  • specifically discuss the risk of continued use of sodium valproate to the unborn child, being aware that higher doses of sodium valproate (more than 800 mg/day) and polytherapy, particularly with sodium valproate, are associated with greater risk. Follow the MHRA safety advice on sodium valproate
• be aware of the latest data on the risks to the unborn child associated with AED therapy when prescribing for women and girls of present and future childbearing potential
• all women and girls on AEDs should be offered 5 mg per day of folic acid before any possibility of pregnancy
• refer to the SPC and BNF for individual drug advice on the interactions between AEDs and hormonal replacement and contraception

Pregnancy:

• women and girls with epilepsy need accurate information during pregnancy, and the possibility of status epilepticus and "sudden unexpected death in epilepsy " should be discussed with all women and girls who plan to stop AED therapy
  
  
• women and girls with generalised tonic-clonic seizures should be informed that
  • fetus may be at relatively higher risk of harm during a seizure, although the absolute risk remains very low, and the level of risk may depend on seizure frequency
    
    
• women and girls should be reassured that there is no evidence that focal, absence and myoclonic seizures affect the pregnancy or developing fetus adversely unless they fall and sustain an injury
  
  
• women and girls should be reassured that an increase in seizure frequency is generally unlikely in pregnancy or in the first few months after birth
  
  
• generally, women and girls may be reassured that the risk of a tonic-clonic seizure during the labour and the 24 hours after birth is low (1-4%)
  
  
• women and girls with epilepsy should be informed that although they are likely to have healthy pregnancies, their risk of complications during pregnancy and labour is higher than for women and girls without epilepsy
  
  
• pregnant women and girls who are taking AEDs should be offered a highresolution ultrasound scan to screen for structural anomalies. This scan should be performed at 18-20 weeks' gestation by an appropriately trained ultrasonographer, but earlier scanning may allow major malformations to be detected sooner
  
  
• risk of seizures during labour is low, but it is sufficient to warrant the recommendation that delivery should take place in an obstetric unit with facilities for maternal and neonatal resuscitation and treating maternal seizures
  
  
• all children born to mothers taking enzyme-inducing AEDs should be given 1 mg of vitamin K parenterally at delivery
  
  
• genetic counselling should be considered if one partner has epilepsy, particularly if the partner has idiopathic epilepsy and a positive family history of epilepsy
  
  
• although there is an increased risk of seizures in children of parents with epilepsy, children, young people and adults with epilepsy should be given information that the probability that a child will be affected is generally low. However, this will depend on the family history
  
  
• do not routinely monitor AED levels during pregnancy. 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

For more detailed guidance then consult the full guideline (4)

A MHRA review states (5):

Summary of key conclusions of review

• Lamotrigine – Studies involving more than 12,000 pregnancies exposed to lamotrigine monotherapy consistently show that lamotrigine at maintenance doses is not associated with an increased risk of major congenital malformations

• Levetiracetam – Studies involving more than 1,800 pregnancies exposed to levetiracetam do not suggest an increased risk of major congenital malformations

• For both lamotrigine and levetiracetam, the data on neurodevelopmental outcomes are more limited than those for congenital malformations. The available studies do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to either lamotrigine or levetiracetam; however, the data is inadequate to rule out definitively the possibility of an increased risk

• For the other key antiepileptic drugs, data show:
  • an increased risk of major congenital malformations associated with carbamazepine, phenobarbital, phenytoin, and topiramate use during pregnancy
  • the possibility of adverse effects on neurodevelopment of children exposed in utero to phenobarbital and phenytoin
  • an increased risk of fetal growth restriction associated with phenobarbital, topiramate, and zonisamide use during pregnancy

Actions for prescribers

• At initiation and as part of the recommended annual review for patients with epilepsy, specialists should discuss with women the risks associated with antiepileptic drugs and with untreated epilepsy during pregnancy and review their treatment according to their clinical condition and circumstances – we have produced a safety information leaflet to assist with this discussion

• Urgently refer women who are planning to become pregnant for specialist advice on their antiepileptic treatment

• All women using antiepileptic drugs who are planning to become pregnant should be offered 5mg per day of folic acid before any possibility of pregnancy

• For lamotrigine, levetiracetam or any antiepileptic drugs that can be used during pregnancy, it is recommended to
  • use monotherapy whenever possible
  • use the lowest effective dose (see below for key dose monitoring advice, including for lamotrigine and levetiracetam)
  • report any suspected adverse effects experienced by the mother or baby to the Yellow Card scheme

Reminder of advice to give to women with epilepsy

• Do not stop taking antiepileptic drugs without discussing it with your doctor

• If you are taking an antiepileptic drug and think you may be pregnant, seek urgent medical advice, including urgent referral to your specialist

• Read the patient information leaflets that accompany your medicines and other information provided by your healthcare professional

A systematic review and meta-analysis found that women with epilepsy are at increased odds of maternal death and increased odds of having offspring with congenital conditions compared with women who do not have epilepsy (6)

• women with epilepsy had increased odds of
  • miscarriage ( OR (odds ratio), 1.62),
  • stillbirth (pregnancies; OR, 1.37),
  • preterm birth ( OR, 1.41) and
  • maternal death (OR, 5.00
  • neonates born to women with epilepsy had increased odds of congenital conditions (OR, 1.88), neonatal intensive care unit admission (OR, 1.99), and neonatal or infant death (OR, 1.87)
• increased odds of poor outcomes is associated with greater use of antiseizure medication

Reference:

1. Drug and Therapeutics Bulletin (2005); 43(2):13-16.
2. Prescriber (2001); 12 (18): 30-36.
3. BNF 4.8
4. NICE (April 2018). Epilepsies: diagnosis and management
5. MHRA(January 2021).Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review Drug Safety Update volume 14, issue 6: January 2021: 1.
6. Mazzone PP, Hogg KM, Weir CJ, Stephen J, Bhattacharya S, Chin RFM. Comparison of Perinatal Outcomes for Women With and Without Epilepsy: A Systematic Review and Meta-analysis. JAMA Neurol. Published online March 13, 2023. doi:10.1001/jamaneurol.2023.0148