Recent studies have raised concerns about the safety of dydrogesterone use during early pregnancy, suggesting a potential association with an increased risk of birth defects compared to progesterone. [1]
A global pharmacovigilance analysis using the World Health Organization's VigiBase database examined over 362,000 safety reports involving pregnant women. Among these, 145 reports were associated with dydrogesterone use, and 1,222 with progesterone. The study identified 60 birth defect cases linked to dydrogesterone and 141 to progesterone. Notably, the reporting odds ratio (ROR) for birth defects was significantly higher for dydrogesterone compared to progesterone, with an ROR of 5.4 (95% CI: 3.7–7.9) .
The most frequently reported anomalies associated with dydrogesterone were genital defects, such as hypospadias, and congenital heart defects. These findings suggest a disproportionate reporting of certain birth defects with dydrogesterone use during early pregnancy.
The Maternal Drug Exposure Birth Cohort (DEBC) study conducted in China further supports these observations. Analyzing data from 112,986 pregnant women, the study found that first-trimester exposure to dydrogesterone was associated with increased rates of stillbirth, preterm birth, low birth weight, and birth defects. In contrast, progesterone use did not show a similar association. While dydrogesterone was linked to a reduced incidence of miscarriage or abortion, the study emphasized that due to its observational nature, definitive causal conclusions cannot be established.
A systematic review and meta-analysis published in PubMed analyzed nine studies, including six randomized controlled trials and three observational studies, encompassing a total of 5,070 participants and 2,680 live births. The review concluded that dydrogesterone use in the first trimester for recurrent or threatened pregnancy loss or as luteal support in assisted reproductive technology was not associated with a significant increase in congenital anomalies. The overall risk ratio (RR) was 0.92 (95% CI: 0.55–1.55) in randomized controlled trials and 1.11 (95% CI: 0.73–1.68) when observational studies were included.
However, the review acknowledged limitations, including the fact that congenital anomalies were not the primary outcome in the included studies and that reporting was often not standardized.[2]
The divergent findings from these studies highlight the need for cautious consideration when prescribing dydrogesterone during early pregnancy. While some data suggest an increased risk of specific birth defects, other analyses do not find a significant association. Healthcare providers should weigh the potential benefits and risks when considering dydrogesterone for luteal support or treatment of threatened pregnancy loss.
References:
1. Henry A, Santulli P, Bourdon M, Maignien C, Chapron C, Treluyer JM, Guibourdenche J, Chouchana L. Birth defects reporting and the use of dydrogesterone: a disproportionality analysis from the World Health Organization pharmacovigilance database (VigiBase). Hum Reprod Open. 2025 Jan 2;2025(1): hoae072. doi: 10.1093/hropen/hoae072. PMID: 39807112; PMCID: PMC11726828.
2. Katalinic A, Noftz MR, Garcia-Velasco JA, Shulman LP, van den Anker JN, Strauss Iii JF. No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis. Hum Reprod Open. 2024 Jan 23;2024(1): hoae004. doi: 10.1093/hropen/hoae004. PMID: 38344249; PMCID: PMC10859181.
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