United Kingdom National Register Study of Anti-Epileptic Medications: Suspected Foetal Congenital And Pregnancy-Associated Side Effects

OObjective 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 datamined from public databases. Results The suspected ADRs per 1,000,000 Rx identified across all AEDs are statistically significant (χ2 test, P < .05). Pregnancy, puerperium & perinatal conditions associated with lamotrigine (1.51 per 1,000,000 Rx, χ2 test, P < .05, d = 2.720, 95% CI [1.656, 4.469]) had a larger size effect than valproic acid (2.28 per 1,000,000 Rx, χ2 test, 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used only openly available human data that were originally located at https://yellowcard.mhra.gov.uk/idaps and https://openprescribing.net/ I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript and supporting information.