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Are antiepileptic drugs safe to use during pregnancy?

On January 7, the Medicines and Healthcare products Regulatory Agency published findings from a review of the safety of antiepileptic drug use during pregnancy

Unplanned learning

Approximately 2,500 women in the UK with epilepsy give birth to a baby each year. One of the concerns women with epilepsy have when they are planning a pregnancy is how the antiepileptic medication they are taking may affect their unborn baby. 

Valproate, or valproic acid, is known to have the potential to cause harm, developmental issues and physical birth abnormalities in a child when taken by a pregnant mother. The valproate pregnancy prevention programme was developed to restrict the use of valproate and ensure it is only used when there is no suitable alternative.

At the time of this review, similar reviews for other antiepileptic drugs had not been carried out. With more than 20 different antiepileptic drugs available in the UK, the Commission on Human Medicines recommended that the Medicines and Healthcare products Regulatory Agency (MHRA) review the safety of other antiepileptic drugs in pregnancy.(1)

Why was the review conducted?

The review was conducted in order to support informed decision making and to ensure those of childbearing potential with epilepsy, and their partners, were given accurate information about the risks and benefits of antiepileptic drugs in pregnancy, before determining the most appropriate treatment.(1)

What risks do antiepileptic drugs have in pregnancy?

Antiepileptic drugs carry a range of risks to an unborn baby. They may increase the risk of a baby being born with a congenital disorder, birth abnormality, birth defect or affect the baby’s growth or brain development (learning, thinking, social and behavioural skills). The risk of these occurring can range depending on the drug, the dose and whether multiple drugs are taken to control epilepsy.(1)

What drugs were included in the review?

Not all antiepileptic drugs were included in the review, instead they were prioritised based on:(1)

  • their use in national clinical guidelines
  • the availability of safety data, and
  • how often they are used in the UK.

Other drugs were included in the review for completeness.(1)

The drugs in the review included:(1)

  • brivaracetam
  • carbamazepine
  • clobazam
  • clonazepam
  • eslicarbazepine
  • ethosuximide
  • gabapentin
  • lacosamide
  • lamotrigine
  • oxcarbazepine
  • perampanel
  • phenobarbital
  • phenytoin
  • pregabalin
  • primidone
  • rufinamide
  • tiagabine
  • topiramate
  • vigabatrin
  • zonisamide.

Levetiracetam, not included, was recently part of a European review. This data was made available and used for inclusion in this review to inform a decision.(1)

What were the results of the review?

The review found that lamotrigine and levetiracetam were overall the safer of the reviewed antiepileptic drugs for use during pregnancy. When compared with the level of birth abnormalities in the general population these drugs, at their usual maintanence doses, do not appear to result in an increased risk. The findings showed there may not be an increased risk of learning and thinking difficulties with these drugs – however data was limited so firm conclusions cannot be made.(1)

The available information was used to determine the following findings:

Physical birth abnormality:(1)

  • Lamotrigine and levetiracetam are safer than other antiepileptic drugs.
  • Carbamazepine, phenobarbital, phenytoin and topiramate increase the risk.
  • Pregabalin, may slightly increase risk, however risks are not yet fully understood.
  • Gabapentin, risks are not yet fully understood.
  • Clobazam, may slightly increase risk, however risks are not yet fully understood and further data needed.
  • Zonisamide and oxcarbazepine, more data is needed.

Brain development:(1)

  • Phenobarbital and phenytoin increased risk of difficulties with thinking or learning.
  • Carbamazepine an increased risk of difficulties with thinking and learning is not likely.
  • Lamotrigine and levetiracetam an increased risk is not likely, however only limited data is available and further data is needed.
  • Gabapentin, oxcarbazepine, pregabalin, topiramate and zonisamide – further data is needed.

Growth in the womb:(1)

  • Phenobarbital, topiramate and zonisamide increase the risk of a smaller baby being born.
  • Lamotrigine and levetiracetam do not appear to increase the risk of a smaller baby being born.
  • Carbamazepine, gabapentin, oxcarbazepine, phenytoin and pregabalin, data is limited or conflicting, therefore unable to result in a conclusive decision.

There is insufficient data for the antiepileptic drugs listed below for a conclusion on safety during pregnancy to be made:(1)

  • brivaracetam
  • clonazepam
  • eslicarbazepine
  • ethosuximide
  • lacosamide
  • rufinamide
  • perampanel
  • primidone
  • tiagabine
  • vigabatrin.

Further information about the specific findings of the review can be found in the full review MHRA Public Assessment Report January 2021.

What advice can pharmacists give?

Women with epilepsy who are planning, or thinking about pregnancy will have many considerations they may want to discuss with a healthcare professional. While some of these may be more appropriate for the patient’s GP or neurologist, pharmacists are ideally placed to provide information and reassurance to these patients. It is important that any advice given to these patients is the most up to date and evidence-based advice available and that pharmacists are aware of the limitations of advice they can give. All women with epilepsy who are considering pregnancy should have a preconception discussion with their neurologist or GP.(1)

Pharmacists can discuss some of the following with patients:(1,2)

  • Benefit versus risk of epilepsy during pregnancy and antiepileptic drugs, such as risk to the unborn baby of uncontrolled seizures.
  • Level of evidence and safety in pregnancy for antiepileptic drugs.
  • Risk of major congenital malformations, this is increased in women taking antiepileptic drugs during pregnancy and is higher with increased doses or combination antiepileptics versus monotherapy.
  • Reassure women that the risk of malformations is low if there is no exposure to antiepileptic drugs during the periconception period and that most women will give birth to normal, healthy babies.
  • Advise women that 5mg daily of folic acid (a prescription only dosage) can decrease the risk of major congenital malformations if taken prior to conception and for the first trimester, as well as decreasing the risk of developing antiepileptic drug related cognitive deficits.
  • Reassure women that pregnancy will not result in seizure deterioration for approximately two-thirds of women.
  • Advise women of the risks of stopping antiepileptic drugs without medical advice, any women wanting to stop antiepileptic drugs should be referred to their GP, specialist nurse or neurologist.
  • Ensure women with epilepsy who are pregnant are given information about the UK Epilepsy and Pregnancy Register.
References
  1. Medicines and Healthcare products Regulatory Agency (2021) MHRA Public Assessment Report January 2021.
  2. Royal College of Obstetricians & Gynaecologists (2016) Epilepsy in Pregnancy, Green-top Guideline No. 68.
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