United Kingdom National Register Study of Anti-Epileptic Medications: Suspected Foetal Congenital And Pregnancy-Associated Side Effects
Authors: Phillips Benjamin , Evans Ismay , Skerrett Victoria , Jones Alan M. 
Published: March 2024

Objective

There continue to be concerns regarding exposure during pregnancy to anti-epilepsy drugs (AEDs). The study aims were to determine the suspected adverse drug reactions (ADRs) associated with AEDs and potential mechanistic hypotheses.

Methods

Suspected ADR profiles for 8 AEDs were data-mined from the MHRA Yellow Card scheme (January 2018-August 2022) together with prescribing data from OpenPrescribing (August 2017-July 2022). The physicochemical, pharmacokinetic, and pharmacology of the AEDs were data-mined from public databases.

Results

The suspected ADRs per 1,000,000Rxidentified across all AEDs are statistically significant (χ2test,P< .05). Pregnancy, puerperium & perinatal conditions associated with lamotrigine (1.51 per 1,000,000Rx,χ2test,P< .05,d= 2.720, 95% CI [1.656, 4.469]) had a larger size effect than valproic acid (2.28 per 1,000,000Rx,χ2test,P< .05,d= 1.846, 95% CI [1.150, 2.964]). The large size effect associated with valproic acid for congenital and hereditary disorders (d= 9.069, 95% CI [5.807, 14.163]) and foetal exposure during pregnancy (d= 6.632, 95% CI [4.894, 8.988]) were notable amongst the AEDs. Valproic acid, a known teratogen, had the unique and clinically achievable targeting of histone deacetylase (HDAC 1 IC50= 54.4, HDAC2 IC50= 82.4 micromolar, HDAC3 IC50= 148 micromolar, HDAC8 IC50= 144 micromolar, Cmax= 184.3 micromolar) associated with teratogenicity.

Significance

There is renewed discussion about the management of epilepsy in pregnancy, and the risks of different AEDs. Whilst 1 in 250 women have epilepsy, they account for 1 in 10 of women who die in childbirth or postpartum. Fears about ADRs impact on adherence to medication, whilst pregnancy itself reduces the serum level of AEDs. As a result of this women are at increased risk of seizures during pregnancy and childbirth. There has been a doubling of Sudden and Unexpected Death in Epilepsy (SUDEP) in mothers between 2013-2015 and 2019-2021 in the UK and Ireland. The AEDs studied have diverse modes of action, and the unique polypharmacology of AEDs influences their ADR profiles. Lamotrigine had a larger size effect than valproic acid (d=2.720 vs 1.846) for suspected pregnancy, puerperium and perinatal ADRs. As noted in other studies, there is a suspected association between valproic acid exposure and 1) congenital and hereditary disorders (d= 9.069), and 2) foetal exposure during pregnancy (d= 6.632) compared to other studied AEDs. Pregnancy-related ADRs with levetiracetam and topiramate did not reach statistical significance, however neurological ADRs in children who were exposed to lamotrigine and levetiracetam continue to be the subject of scrutiny.

Key Points

There are ongoing concerns regarding exposure to all anti-epilepsy drugs (AEDs) during pregnancy. Poor seizure control in pregnancy is a cause of maternal death, valproic acid continues to be used by women despite it being a known teratogen, and other AEDs also carry risks of significant ADRs.

AEDs have diverse modes of action, and the unique polypharmacology of AEDs influences their ADR profiles.

Lamotrigine had a larger size effect than valproic acid (d=2.720 vs 1.846) for suspected pregnancy, puerperium and perinatal ADRs.

There is a strong association between valproic acid exposure and congenital and hereditary disorders including foetal valproate spectrum disorder (FVSD), autism spectrum disorder (ASD), spina bifida, polydactyly and cleft palate (d= 9.069).

There is an association between valproic acid and foetal exposure during pregnancy (d= 6.632).