Pregabalin (Lyrica): findings of safety study on risks during pregnancy

A new study has suggested pregabalin may slightly increase the risk of major congenital malformations if used in pregnancy. Patients should continue to use effective contraception during treatment and avoid use in pregnancy unless clearly necessary.

From:
Medicines and Healthcare products Regulatory Agency
Published
19 April 2022
Therapeutic area:
Dispensing GP practices, Neurology, Pain management and palliation and Psychiatry

Advice for healthcare professionals:

  • an observational study of more than 2,700 pregnancies exposed to pregabalin has shown use in the first trimester to be associated with a slightly increased risk of major congenital malformations compared with exposure to no antiepileptic drugs or to lamotrigine or to duloxetine – see details of the study data below
  • continue to provide counselling to patients using pregabalin on:
  • continue to avoid use of pregabalin during pregnancy unless clearly necessary and only if the benefit to the patient clearly outweighs the potential risk to the fetus – ensure the patient has a full understanding of the benefits, risks, and alternatives, and is part of the decision-making process
  • advise patients planning a pregnancy or who become pregnant during treatment to make an appointment to discuss their health condition and any medicines they are taking
  • in cases where the benefit outweighs the risk, and it is clearly necessary that pregabalin should be used during pregnancy, it is recommended to:
    • use the lowest effective dose
    • report any suspected adverse drug reactions, including for the baby, via the Yellow Card scheme

Reminder for prescribers of ANY antiepileptic drug:

  • at initiation and as part of the recommended annual review for patients with epilepsy, discuss the risks associated with antiepileptic drugs and with untreated epilepsy during pregnancy and review their treatment according to clinical condition and circumstances – see advice for antiepileptic drugs in pregnancy
  • urgently refer anyone planning a pregnancy or who is suspected to be pregnant for specialist advice on their antiepileptic treatment
  • if a patient is planning to have a baby, offer 5mg per day of folic acid before any possibility of pregnancy

Pregabalin indications and scope of this advice

Pregabalin (brand names Alzain, Axalid, Lecaent, Lyrica, plus generic versions) is indicated for the treatment of peripheral and central neuropathic pain in adults, as adjunctive therapy in adults with partial seizures with or without secondary generalisation, and for generalised anxiety disorder in adults (see NHS Guidance.

The advice in this article is relevant for patients taking pregabalin who are pregnant or may become pregnant.

Previous reviews of pregabalin in pregnancy

Following a national review into the safety of antiepileptic drugs in pregnancy, including pregabalin, in January 2021 we published new safety advice in Drug Safety Update with patient advice, and a Public Assessment Report.

At the time of publication, we noted that due to conflicting data, no firm conclusions could be drawn on the potential teratogenic effect of pregabalin. This review included one US cohort study of 477 infants exposed to pregabalin in the first trimester, which did not show an increased risk after adjustment, but was unable to rule out a small effect on the rate of congenital malformations.[footnote 1] The review considered preliminary data from a study, from which further information and analyses have become available and evaluated (as below).

At the time, the product information noted that the potential risk for humans in pregnancy was unknown. As such, patients were advised to use effective contraception and avoid pregabalin in pregnancy unless necessary.

New review of study of pregabalin in pregnancy

Fuller data is now available from a Nordic observational study of more than 2,700 pregnancies exposed to pregabalin in the first trimester (see detailed description below).

We have carefully reviewed the results of the study alongside a recent European review of the same findings. The review concluded that pregabalin use during the first trimester of pregnancy may cause a slightly increased risk of major congenital malformations in the unborn child.

The MHRA has considered the recommendations of the European review, together with the other limited safety data available regarding pregabalin safety in pregnancy, and agreed that the product information should be updated to include information from this study. The Summary of Product Characteristics and Patient Information Leaflet has now been updated.

The product information continues to advise that effective contraception should be used during treatment and that use in pregnancy avoided unless clearly necessary.

Healthcare professionals are advised to consider our guidance on contraceptive methods, and take into account the patient’s personal circumstances when advising on contraception.

Detailed information on study and outcomes data

Study design and population

The Pregabalin pregnancy outcomes study was a population-based cohort study.[footnote 2] The study used data from national administrative registries from 4 Nordic countries (Denmark, Finland, Norway, and Sweden) to characterise pregnancy outcomes.

The study examined use of pregabalin in all authorised indications. The prevalence of usage for each indication of pregabalin differed between the countries, but (where recorded) it was most commonly prescribed for anxiety and neuropathic pain. This is thought to be similar to the clinical situation in the UK.

The exposure data from the study indicated that the proportion of women using pregabalin in pregnancy had increased over the 10-year period (up to 2015/2016) and that exposure to pregabalin in pregnancy was most frequent in the first trimester.

Study methods and comparator groups

The study aimed to estimate the risk of major congenital malformations, other birth outcomes, and selected neurodevelopmental postnatal outcomes for babies who were exposed to pregabalin in-utero (in the womb).

The study also aimed to collect this information for babies exposed to an alternative medicine for epilepsy (lamotrigine) and an alternative medicine for neuropathic pain and generalised anxiety disorder (duloxetine). Outcomes were also compared to babies not exposed to pregabalin or another antiepileptic drug (the comparison population).

For the outcome of major congenital malformations, exposure to any of the 3 specified medicines in the first trimester only (or no antiepileptic drug during this period for the comparison population) was examined. For all remaining birth and postnatal outcomes, exposure (or no exposure) in any trimester was examined. Comparisons were drawn for all use (including in combination regimens) and for monotherapy only.

Study findings for major congenital malformations

Full study findings are published online.

The study showed a higher prevalence of major congenital malformations in the babies (live or stillborn) exposed to pregabalin in the first trimester of pregnancy (crude percentage 5.9%) compared with those not exposed to pregabalin or any other antiepileptic drug (crude percentage 4.1%). After adjustment, the risk of major congenital malformations was slightly higher but not statistically significant with pregabalin monotherapy use in the first trimester versus the comparison group (adjusted prevalence ratio 1.14 (95% confidence interval (95% CI) 0.96 to 1.35)).

The data suggested modest but statistically significantly increased risks (less than 2-times) of major congenital malformations in pregnancies exposed to pregabalin compared with pregnancies exposed to lamotrigine or duloxetine. The adjusted prevalence ratios for congenital malformations with first-trimester pregabalin monotherapy were 1.29 (95% CI 1.01 to 1.65) versus lamotrigine and 1.39 (1.07 to 1.82) versus duloxetine.

Slightly higher risks of specific malformations of the nervous system, eye, face (orofacial clefts), urinary system, and genitals were observed in babies exposed to pregabalin compared with those exposed to the other medicines or in the comparison population. However, estimates may be imprecise due to the low number of cases. Effects on the central nervous system and eye defects have also been observed in animals in preclinical studies.

Limitations in the study findings for major congenital malformations

This study was observational and based on registries. Comparisons of outcomes between the patients taking pregabalin and patients taking other medicines, or no antiepileptic drugs, may have been affected by other factors that affect the risk of congenital malformations (confounding).

Other factors include that the study did not take into account the purpose for which lamotrigine or duloxetine were being used, and so there might have been differences due to the underlying medical conditions.

That being said, although the risk estimates in the study are modest and some are not statistically significant, this is the largest population-based study currently available and there is an indication of a slight increased risk of major congenital malformations with use of pregabalin in the first trimester. It is important for patients to receive this information and consider it carefully with their prescriber.

It is noted that the prevalence of major congenital malformations in the comparison group (not exposed to any antiepileptic drug during the first trimester) was higher than the estimated prevalence in the UK general population (2–3%). This may be due to differences between the Nordic registries and UK studies in how they measure and categorise congenital malformations. It may also possibly reflect improved diagnoses of these conditions over the study period.

Study findings for other birth outcomes and postnatal neurodevelopmental outcomes

The study also examined the risk of other birth outcomes (stillbirth, small for gestational age, low birth weight, preterm birth, low Apgar score at 5 minutes, and microcephaly) and neurodevelopmental outcomes (attention deficit hyperactivity disorder, autism spectrum disorders and learning disabilities).

The small numbers of cases and limited follow-up time of exposed live-birth infants meant that firm conclusions on these other birth and neurodevelopmental outcomes cannot be drawn. These risks remain uncertain and we will continue to keep under close review.

Antiepileptic medicines in pregnancy: new registry

We remind all healthcare professionals of the actions required of them following the 2021 antiepileptic medicines in pregnancy review.

The MHRA and NHS Digital are working together on the Medicines in Pregnancy Registry, which is built around a core register of routinely collected prescribing data for all women in England who are taking NHS-prescribed valproate and other antiepileptic medications. Healthcare professionals can use the data provided to review comparative use of antiepileptic medicines in pregnancy.

The report from the registry was updated on 31 March 2022 to include data up to September 2021. An interactive dashboard is available to review the data and how prescribing of antiepileptic medicines in pregnancy has changed over time.

Further resources for prescribers

Clinicians should continue to use resources for prescribers about medicines of potential teratogenic effects. The UK Teratology Information Service provides independent advice about the risks and benefits of medicines use in pregnancy.

Report suspected reactions on a Yellow Card

Please continue to report any suspected adverse drug reactions (ADRs) associated with pregabalin or any other medicines via the Yellow Card scheme.

Please report any suspected ADRs associated with medicines taken during pregnancy or breastfeeding, including any suspected effects on the baby or child.

All patients, caregivers, and healthcare professionals can report a Yellow Card when they suspect a medication used during pregnancy has caused an adverse reaction or adverse pregnancy outcome.

When reporting ADRs related to medicines used in pregnancy, the following information is particularly valuable for our assessment of the report:

  • Timings of when the medicine was taken during the pregnancy
  • The outcome of the pregnancy (when known)
  • Details of any relevant family history, including any obstetric history
  • 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

Please include any other relevant information, including other medications or substances taken during the pregnancy, as well as folic acid intake.

Report Yellow Cards using:

Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment 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 15, issue 9: April 2022: 1.

  1. Patorno E and others. Pregabalin use early in pregnancy and the risk of major congenital malformations. Neurology 2017: volume 88, pages 2020 to 2025. ↩

  2. Toft G, and others. Pregabalin A0081359 Non-Interventional Final Study Report Abstract. Last accessed March 2022. ↩

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Published 19 April 2022
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