5D-02 - Assessing a Signal of Congenital Anomalies Following Dydrogesterone Exposure in Pregnancy: Results From a Disproportionality Analysis (DPA) and Systematic Review

Background: Dydrogesterone (DYD) has been indicated for luteal support to reduce the risk of pregnancy loss for over 60 years. Since 2017, DYD has been used in Assistive Reproductive Technologies (ART). Although considered to have a favourable benefit-risk profile, a signal of Congenital Anomalies (CA) was detected following use in pregnancy and ART in June 2023 (1). As part of signal validation, further evaluation of this signal was required.

Objectives: To evaluate the signal of CA following DYD use in pregnancy and ART by (i) a disproportionality analysis (DPA) using global spontaneous reports from the World Health Organisation’s VigiBase database, and (ii) a systematic review of current scientific literature to contextualise the signal.

Methods: DPA was conducted using Individual Case Safety Reports (ICSRs) reported to VigiBase from 1968-31st December 2021. The Standardised MedDRA Query (SMQ) of ‘Pregnancy and Neonatal topics’ was used to identify a pregnancy cohort to which a ‘case-non-case' methodology was applied. ‘Cases’ were ICSRs with >1 CA according to MedDRA Preferred Term reported under the System Organ Class ‘Congenital, Familial and Genetic Disorders’. ‘Non-cases’ were ICSRs with any other event.

Reporting Odds Ratios (RORs) were calculated for three drug-pair combinations, comparing the number of ICSRs with DYD to the number of ICSRs with (1) all other drugs, (2) drugs used for ART; and (3) progesterone only. A Signal of Disproportionate Reporting (SDR) was identified if the ROR 95% CI lower boundary was >1 and ICSRs for DYD were ≥5 (2).

A systematic review (SR) was also conducted using PubMed/Medline and Embase from March 2021-October 2023 to expand on two previous reviews (3-4).

Results: A total of 339,715 ICSRs were identified in the pregnancy cohort. 145 ICSRs had DYD as the suspect/interacting drug, of which 65 ICSRs were identified as cases. All three drug-pair comparisons resulted in a ROR (95% CI) consistent with an SDR: (1) ROR 3.95 (2.80-5.50); (2) ROR 3.41 (2.39-4.84); and (3) ROR 5.05 (3.43-7.38).

Of the 19 studies included in the SR, none indicated a statistically significant increase in CA. However, most studies did not include neonatal safety outcomes as a primary outcome and therefore may be underpowered.

Conclusions: A signal for CA following DYD exposure during pregnancy was detected in VigiBase based on reports received between 1968-2021. However, this study highlighted challenges in evaluating events of CA in pregnancy cohorts in pharmacovigilance datasets, including defining the pregnancy population, misclassification and missing data. Whilst the SR provided an understanding of the signal, it did not provide conclusive results due to limitations in the studies. Further signal assessment activities are necessary to confirm or refute the signal.