Antiepileptic drugs in pregnancy

It is important to take specialist advice as to the management of epilepsy in women of childbearing potential.

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

A review of the risks of major congenital malformations and of adverse neurodevelopmental outcomes for antiepileptic drugs by the Commission on Human Medicines has confirmed that lamotrigine (Lamictal) and levetiracetam (Keppra) are the safer of the medicines reviewed during pregnancy (2):

• valproate (Epilim)
  • is highly teratogenic and evidence supports a rate of congenital malformations of 10% in infants whose mothers took valproate during pregnancy and neurodevelopmental disorders in approximately 30% to 40% of children (2)
    • for this reason, valproate should not be used in girls and women of childbearing potential unless other treatments are ineffective or not tolerated, as judged by an experienced specialist
  • valproate should not be used in pregnancy (3)
    • valproate must not be used in any woman or girl able to have children unless there is a Pregnancy Prevention Programme (PPP) in place
    • no one should stop taking valproate without advice from their specialist.

Major congenital malformations

• review of risk of major congenital malformations assessed data from meta-analyses of epidemiological studies and other large epidemiological studies. The studies reviewed include comparisons of pregnancy outcomes between women given antiepileptic drug monotherapy and women without epilepsy or women with epilepsy who were not treated with antiepileptic drugs.
• the results from these meta-analyses and other studies show that:
  • lamotrigine and levetiracetam
    • large amount of data exists for lamotrigine (more than 12,000 pregnancies exposed) and levetiracetam (more 1,800 pregnancies exposed) and these data do not suggest an increased risk of major congenital malformations when these antiepileptic drugs are used at the usual maintenance doses
    • for lamotrigine, studies investigating the effect of dose have shown conflicting results; one study using data from EURAP showed a statistically significant increase in the rate of major congenital malformations when doses of lamotrigine higher than 325mg per day were compared with doses of lamotrigine 325mg per day or lower. Other studies do not suggest dose-response effect on the risk of major congenital malformations.
  • carbamazepine, phenobarbital, phenytoin and topiramate
    • data for carbamazepine (around 9,000 pregnancies exposed), phenobarbital (around 1,800 pregnancies exposed), phenytoin (around 2,000 pregnancies exposed), and topiramate (around 1,000 pregnancies exposed) demonstrate that they are associated with an increased risk of major congenital malformations compared with that seen in the general population and women with epilepsy not on an antiepileptic drug
    • risk of major congenital malformations with carbamazepine, phenobarbital, and topiramate is dose-dependent
  • pregabalin
    • available data for pregabalin suggest it may be associated with a slightly increased risk of major congenital malformations, but these data include emerging findings that are currently under review and further evaluation is needed to reach definitive conclusions
  • due to limitations of the data for gabapentin, oxcarbazepine, and zonisamide, the risk remains uncertain; the possibility of an increased risk of major congenital malformations can neither be confirmed nor ruled out

Summary of key conclusions of review (2)

• 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 (2)

• 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

Reference:

• Drug and Therapeutics Bulletin 2005; 43(2):13-15.
• MHRA(January 2021).Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review Drug Safety Update volume 14, issue 6: January 2021: 1.
• MHRA (November 2023). Valproate use by women and girls - Information about the risks of taking valproate medicines during pregnancy