Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review
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. This review was initiated in the context of the known harms of valproate in pregnancy, which should only be prescribed to women of childbearing potential if there is a pregnancy prevention programme in place. Clinicians should use this information when discussing treatment options with women with epilepsy at initiation and at routine recommended annual reviews and with women who are planning to become pregnant.
Post-publication note: June 2024
Following the conclusion of the Major Safety Review, MHRA has now introduced new safety measures for Topiramate, including a Pregnancy Prevention Programme. Please see MHRA’s June 2024 Drug Safety Update and Public Assessment Report.
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
Background
Antiepileptic drugs are crucial to control seizures and other epilepsy symptoms and untreated epilepsy can cause harm to both the mother and the unborn baby. However, use of these antiepileptic drugs during pregnancy has been associated with a range of harmful effects to the baby.
Valproate: reminder of the known risks and requirements
In particular, 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. 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 is contraindicated in women of childbearing potential unless a pregnancy prevention programme is in place. All healthcare professionals must continue to identify and review all female patients on valproate, including when it is used outside the licensed indications, and provide them with the patient information materials every time they attend their appointments or receive their medicines (including the patient information leaflet at dispensing).
Updated educational materials to support healthcare professionals and female patients on valproate were re-circulated to UK healthcare professionals by Sanofi in December 2020. We remind healthcare professionals that these materials must be used to ensure that the conditions of the valproate pregnancy prevention programme are met, as described in the documents.
National review of safety data
In the context of the known harms with valproate, the Commission on Human Medicines (CHM) has reviewed available safety data relating to the use of other key antiepileptic drugs in pregnancy for the risk of major congenital malformations, neurodevelopmental disorders and delay, and other effects on the baby. The key antiepileptic drugs were selected for the review on the basis of their place in UK clinical practice.
On this basis, data on the use of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, and zonisamide in pregnancy were reviewed. The data and conclusions from a European review in 2018 of levetiracetam in which the UK participated were also taken into account.
Full information on the antiepileptic drugs included in the review, in addition to studies considered and findings from these studies, can be found in the public assessment report. This report also includes a plain language summary of the review and findings.
Post-publication note: August 2022
In July 2022, the MHRA initiated a new safety review into topiramate as a result of an observational study reporting an increased risk of neurodevelopmental disabilities in children whose mothers took topiramate during pregnancy. Please see Drug Safety Update July 2022 for more information.
Post-publication note: May 2022
In April 2022, the MHRA reviewed the findings of a new safety study that suggested pregabalin may slightly increase the risk of major congenital malformations if used in pregnancy. Please see Drug Safety Update April 2022 for more information. Patient Safety Leaflets are available on epilepsy medicines and pregnancy and pregabalin and the risks in pregnancy
How to use the review findings
We are communicating the conclusions of this review to help support decisions by prescribers and women who are starting or currently being treated with antiepileptic medicines. This information should also be considered when selecting a medicine for girls with epilepsy who may need treatment into adulthood and in particular for women planning a pregnancy.
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. This advice for patients and their families and carers was developed following consultation with relevant stakeholder organisations, charities, and patient groups.
Where new information has been identified or where it is considered that the product information (Summary of Product Characteristics, SmPC, and patient information leaflet) could be more informative, these will also be updated to reflect the latest information. For patient information leaflets for each medicine, we will be working with relevant patient groups to ensure that the information to patients is as clear as possible.
Some medicines included in the review are also authorised for medical conditions other than epilepsy (for example, pain and anxiety). Much of the evidence base relates to epilepsy and, as such, our review focused on the risks and decisions for epilepsy treatment. However, the advice in the product information should be considered to be relevant to any indication for these medicines where necessary.
Individual clinical decisions on the benefits and risks of using medicines during pregnancy may differ for other indications. As such, advice in this article and other materials (including the safety information leaflet) focuses on patients with epilepsy.
Key review findings
Major congenital malformations
Our 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:
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a 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
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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:
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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
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the risk of major congenital malformations with carbamazepine, phenobarbital, and topiramate is dose-dependent
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the 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
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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
Neurodevelopmental disorders and delay
The review also considered meta-analyses and epidemiological studies that investigated the risk of adverse effects on neurodevelopmental outcomes including measures of intelligence, developmental outcomes, and symptoms or diagnoses of autism spectrum disorders in children exposed in-utero to antiepileptic drugs.
These data support the following conclusions:
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for carbamazepine, lamotrigine, and levetiracetam, data do not suggest an increased risk of neurodevelopmental disorders or delay, however, due to the limitations of these data the possibility of an increased risk cannot be definitively ruled out
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for phenobarbital and phenytoin, although the clinical studies report inconsistent findings, the totality of the data show the possibility of adverse effects on neurodevelopment
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some recent data raise concerns that topiramate use during pregnancy may be associated with poorer developmental outcomes, however, the numbers in the available studies remain limited and further data are needed to reach firm conclusions
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for gabapentin, oxcarbazepine, pregabalin, and zonisamide the data are either lacking, extremely limited, or have limitations, and the risks remain uncertain
Other effects during pregnancy
The available meta-analyses and epidemiological studies also provide data on the risk of fetal loss, prenatal growth restriction, and preterm birth associated with antiepileptic drug use during pregnancy. These studies support that:
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use of lamotrigine or levetiracetam during pregnancy is not associated with an increased risk of fetal loss, prenatal growth restriction, or preterm birth
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use of phenobarbital, topiramate, and zonisamide during pregnancy is associated with an increased risk of intrauterine growth retardation (small for gestational age)
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for carbamazepine, gabapentin, oxcarbazepine, and pregabalin, the risks associated with use during pregnancy remain uncertain
We will continue to review information for these risks as it becomes available. We encourage all healthcare professionals, patients, and caregivers to report any suspected effects associated with drugs taken during pregnancy, including on the neurodevelopment of a child, to the MHRA.
Monitoring and dosing advice in pregnancy
For any antiepileptic drug that is used during pregnancy, it is recommended to use monotherapy treatment and the lowest effective dose, where possible. Physiological changes during pregnancy (and post-partum) can affect concentrations of antiepileptic medicines, particularly for lamotrigine and phenytoin.
Key issues are described below. However, prescribers should consult advice from the SmPC and relevant clinical guidance for dosing and monitoring recommendations of any antiepileptic drugs in pregnancy.
Lamotrigine
There have been reports of decreased lamotrigine plasma levels during pregnancy with a potential risk of loss of seizure control. After birth, lamotrigine levels may increase rapidly with a risk of dose-related adverse events.
Therefore, lamotrigine serum concentrations in the woman should be monitored before, during, and after pregnancy, including shortly after birth. If necessary, the dose should be adapted to maintain the lamotrigine serum concentration at the same level as before pregnancy or adapted according to clinical response. In addition, dose-related undesirable effects should be monitored after birth.
Levetiracetam
Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (by up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured.
Oxcarbazepine
Data from a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving oxcarbazepine during pregnancy to ensure that adequate seizure control is maintained. Measurement of MHD plasma concentrations should be considered. If dosages have been increased during pregnancy, postpartum MHD plasma levels may also be considered for monitoring.
Phenytoin
An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage.
Report adverse drug reactions in pregnancy
Report any suspected adverse drug reactions in the mother or child following use of a medicine in pregnancy, including adverse pregnancy outcomes such as congenital malformations or adverse neurodevelopment outcomes, on a Yellow Card.
When reporting ADRs related to medicines used in pregnancy, the following information is particularly valuable for our assessment of the report:
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Timings of when the medicine was taken during the pregnancy
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The outcome of the pregnancy (when known)
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Details of any relevant family history, including any obstetric history
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For reports concerning congenital malformations, a detailed clinical description of any congenital anomaly and the results of any imaging (for example, scans), or laboratory tests
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For reports concerning adverse developmental outcomes, whether the child has met their key developmental milestones and whether they have had any further health issues
Please include any other relevant information; including other medications or substances taken during the pregnancy, as well as folic acid intake.
Report Yellow Cards electronically using:
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the Yellow Card app; download from the Apple App Store or Google Play Store
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some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.
Article citation: Drug Safety Update volume 14, issue 6: January 2021: 1.