Pregabalin in pregnancy and congenital malformation risks

As we (hopefully) start to see reductions in the deluge of winter illness, I’m sure Practices will be desperately trying to get back to some of the crucial work we do for managing long term conditions, which for many of us has been effectively put on hold over the last 6-8 weeks given the pressures of acute demand. Medication reviews will continue to be an important part of managing people with long term conditions, and minimising the risks associated with prescribing. For those in PCNs we are being encouraged to do structured medication reviews, as part of the Impact and Investment Fund, with one of the focusses being around people using potentially addictive medications, including gabapentinoids. 

It’s been two years since I wrote a blog on gabapentinoids and the increasing recognition of the risks associated with this class of drug. Since then we have had new NICE guidance on chronic pain (NG 193, April 2021) and medicines associated with addiction and withdrawal (NG 215, April 2022), both of which address the potential harms of gabapentinoids. A further concern with pregabalin, which surfaced later in 2022 and could easily have gone under our radars, is the risk of congenital malformations if pregabalin is used in pregnancy. This was highlighted with updated MHRA advice April 2022 and a subsequent review in the Drug and Therapeutics Bulletin 2022;60:117. 

It is almost 20 years since pregabalin was given marketing authorisation in Europe for some relatively specific indications, namely peripheral neuropathic pain (e.g. diabetic neuropathy and post-herpetic neuralgia), generalised anxiety disorder and as an anti-epileptic medication. As we all know gabapentinoid use expanded rapidly, and at one point it felt like they was being used for every, and any, pain condition we knew. Then evidence started accumulating that they were ineffective for many of the conditions for which they were being used (e.g. low bak pain, sciatica, spinal stenosis), and that these drugs had the potential for addiction and abuse, culminating in them being changed to a class C controlled drug in 2019. Then NICE guidance was published specifically stating we should not use gabapentinoids for chronic primary pain, and that if considering gabapentinoids we counsel patients on the risks of addiction and withdrawal. 

Whilst the addiction and withdrawal risks of gabapentinoids are now well established, we still have a large cohort of women of child bearing age on gabapentoinoids so this new data and advice on the teratogenic risks of pregabalin is important. The MHRA published a comprehensive review of anti epileptic drug safety in 2021, and at that stage the data on pregabalin was limited, but there were signals pregabalin may be associated with an increased risk of congenital malformations. Subsequently a large Nordic study has been published reviewing 2700 pregnancies exposed to pregabalin in the first trimester of pregnancy. The study showed statistically significant increased risks of congenital malformations in pregnancies exposed to monotherapy of pregabalin compared to lamotrigine (adjusted prevalence ratio = 1.29, 95% CI = 1.01-1.65) or duloxetine (adjusted prevalence ratio = 1.39, 95% CI = 1.07-1.82). Given it was a cohort study there will always be risks of confounding, but this is the largest study we have on the teratogenic risks of pregabalin and the evidence has been strong enough for the MHRA to strengthen its warnings about pregabalin in pregnancy:

• We should counsel patients using pregabalin on the potential risks of exposure during pregnancy - see patient information here.
• We should advise on the importance of using effective contraception.
• We should ‘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’.

There are two important caveats to remember here if considering withdrawing pregabalin - withdrawal should be done gradually and for that relatively small number of people on pregabalin for more specific indications (e.g. as an anti epileptic, significant generalised anxiety disorder, significant peripheral neuropathy) any changes in medication should be done under specialist supervision. So whether you are reviewing someone ‘ad hoc’ on pregabalin, or as part of a structured medication review, it would be a good quality improvement project to make sure all those involved in medication reviews (particularly your clinical pharmacists) are aware of this information. For women of child bearing potential we should warn them of the teratogenic risks of pregabalin, direct them to the patient information above, check they are on effective contraception, and consider withdrawing the medication if potential risks outweigh the benefits, and then obviously document those discussions clearly.