Safety Concerns: Dydrogesterone in Pregnancy Linked to Higher Birth Defect Risk Than Progesterone, Study Finds
France: Researchers in a real-world observational analysis of global safety data revealed a significant and consistent increase in reported birth defects, primarily congenital heart defects (CHD) and isolated hypospadias, in pregnancies exposed to dydrogesterone, particularly when compared to progesterone. These findings, supported by other studies, highlight a potential safety signal and the need for further investigation into the fetal safety of dydrogesterone.
The study, published in Human Reproduction Open, was led by Alexandra Henry from the INSERM research unit at Université Paris Cité, France. It utilized data from the World Health Organization's global pharmacovigilance database (VigiBase) to examine the potential association between early pregnancy exposure to dydrogesterone and the occurrence of congenital anomalies.
Dydrogesterone, an oral progestin, has in recent years been considered a viable alternative to intravaginal progesterone in assisted reproductive technologies (ART), with clinical trials suggesting comparable efficacy in achieving pregnancy and similar safety profiles. However, concerns have emerged over a potential link between dydrogesterone use during early gestation and an elevated risk of birth defects, especially CHD.
To explore this issue, researchers conducted a disproportionality analysis—a type of case–non-case study used in pharmacovigilance—to evaluate pregnancy-related safety reports recorded in VigiBase up to December 2021. The analysis focused on identifying cases of birth defects versus other types of adverse events in reports involving dydrogesterone, progesterone, or other ART drugs.
The key findings include the following:
• Among over 362,000 pregnancy-related safety reports, 50,653 involved medications used in assisted reproductive technology (ART).
• Of these, 145 reports were linked to dydrogesterone and 1,222 to progesterone.
• A total of 374 reports documented birth defects—60 associated with dydrogesterone and 141 with progesterone.
• According to the EUROCAT classification, 48 dydrogesterone-related cases and 92 progesterone-related cases were classified as major congenital anomalies.
• The most frequently reported anomalies in the dydrogesterone group were genital malformations such as hypospadias and congenital heart defects.
• The analysis showed a significantly higher likelihood of reported birth defects with dydrogesterone compared to:
• All other medications (ROR 5.4)
• Other ART drugs (ROR 6.0)
• Progesterone (ROR 5.4)
• These associations remained consistent across multiple sensitivity analyses.
While the authors caution that under-reporting and difficulties in establishing causality limit definitive conclusions, the consistency of the findings across various comparisons points to a potential safety signal. The study emphasizes that more targeted research is needed to evaluate the fetal safety of dydrogesterone in early pregnancy.
The authors call for a reassessment of dydrogesterone's use in pregnancy, particularly in ART, and advocate for further investigations to ensure the safety of both expectant mothers and their unborn children.
Reference:
Henry, A., Santulli, P., Bourdon, M., Maignien, C., Chapron, C., Treluyer, J., Guibourdenche, J., & Chouchana, L. (2025). Birth defects reporting and the use of dydrogesterone: A disproportionality analysis from the World Health Organization pharmacovigilance database (VigiBase). Human Reproduction Open, 2025(1). https://doi.org/10.1093/hropen/hoae072
