O-150 Birth defects reporting and the use of oral dydrogesterone in assisted reproductive technology : a global pharmacovigilance study

Abstract Study question Is dydrogesterone exposure during early pregnancy associated with the reporting of birth defects ? Summary answer We observed an increased reporting of birth defects, such as congenital heart defects and hypospadias, with dydrogesterone, especially compared to progesterone use. What is known already In assisted reproductive technology (ART), intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation. In the recent years, the Lotus I and Lotus II randomized controlled clinical trials, demonstrated that oral dydrogesterone, a synthetic progesterone derivative, was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone (MVP). Safety profiles in both mother and child were similar. However, concerns have been raised recently regarding an association between dydrogesterone usage during early pregnancy and congenital heart disease in the offspring. Study design, size, duration We performed a case-non case study, similar in the concept to case-control study, using the international pharmacoviligance database, VigiBase. Study cohort consisted in spontaneous reports regarding pregnant women identified using the ad-hoc standardized query (SMQ “Pregnancy and neonatal topics”). Birth defect cases were reports containing a term related to “congenital, familial and genetic disorders” System Organ Classes (SOCs) (excluding genetic, infectious and metabolic abnormalities). Non-cases were reports of any other adverse drug reaction. Participants/materials, setting, methods Through a case–non case study conducted since database inception to 12/31/2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% confidence interval (95%CI). For each comparison, two sensitivity analyses were performed. Main results and the role of chance Among 29,120,563 individual case safety reports, 50,653 were related to the use of drugs for ART. Of these, 375 were cases of birth defects, including 60 (16%) with dydrogesterone. Dydrogesterone cases were mostly reported from Europe (73%) by physicians (82%). No other teratogenic drug was suspected in the onset of birth defect for dydrogesterone. 44 cases out of 60 (73.3%) were compatible with major birth defect (MBD) cases according to EUROCAT classification. These cases contained a total of 55 MBD, consisting mainly in genital defects such as hypospadias (n = 18, 32.7%), congenital heart defects (n = 15, 27.3%) limb defects (n = 10, 18.2%) and digestive system defects (n = 6, 10.9%). In the primary analysis, a significant disproportionate reporting of birth defects was found with dydrogesterone when compared to any other drug (ROR 5.4, 95%CI [3.9-7.6]) and to any other ART agent (ROR 5.9, 95%CI [4.2-8.4]). In the head-to-head comparison to progesterone, we found an increased reporting of birth defect with dydrogesterone (ROR 5.4, 95%CI [3.7-7.9]).These results were confirmed in both sensitivity analyses. Limitations, reasons for caution First, under-reporting, being inherent to pharmacovigilance systems, impedes the measurement of the incidence of adverse drug reaction and can limit the sensitivity of signal detection. Second, drug causality, not being the same for all cases, is challenging for such events and requires further assessment. However, sensitivity analyses showed consistent results. Wider implications of the findings Physicians should be aware of this potential risk and caution should be used when prescribing dydrogesterone for luteal phase support. Further data are needed to confirm that safety signal. Trial registration number Not applicable