Congenital anomalies after first-trimester dydrogesterone therapy during in vitro fertilization

TL;DR

This study found no increased risk of birth defects in newborns exposed to dydrogesterone during early pregnancy, with some specific anomalies showing lower rates.

Contribution

The study provides new evidence on the safety of dydrogesterone use during in vitro fertilization in relation to congenital anomalies.

Findings

DYG-exposed newborns had a significantly lower overall congenital anomaly rate compared to unexposed groups.

Musculoskeletal malformations were notably lower in DYG-exposed newborns, especially in frozen embryo cycles.

No increased risk of congenital anomalies was found in multivariate analysis adjusted for confounders.

Abstract

Congenital anomalies are a critical public health concern and warrant prioritization in research. However, the teratogenic potential of dydrogesterone (DYG) remains uncertain and a subject of ongoing debate.

This retrospective cohort study included patients undergoing embryo transfer between January 2010 and December 2018. It analyzed 124,815 embryo transfer cycles (80,103 [64.2%] fresh; 44,712 [35.8%] frozen), resulting in 52,175 live births. Newborns were stratified by maternal luteal phase support (DYG-exposed vs. unexposed). Patients with known congenital malformation risk factors were excluded. Congenital anomaly incidence was compared between groups. Stratified analysis and multivariate logistic regression models adjusting for confounders were employed.

The total congenital anomaly rate was significantly lower in DYG-exposed newborns compared to unexposed groups (6.05‰ vs. 7.90‰, P = 0.020), with particularly notable differences in musculoskeletal malformations (0.63‰ vs. 1.33‰, P = 0.025). No significant differences were observed in other congenital anomaly categories. After stratifying by fresh or frozen cycles, DYG-exposed and unexposed groups showed no significant differences in birth defects during fresh cycles. In frozen cycles, musculoskeletal anomalies were significantly lower in the DYG group both before (0.60‰ vs. 2.37‰, P = 0.020) and after adjustment (P = 0.009, OR: 0.19, 95% CI: 0.05–0.66). Other anomaly categories remained unaffected. However, this specific association did not remain significant after rigorous correction for multiple testing with the application of both the Bonferroni and False Discovery Rate (FDR) methods. Multivariate analysis adjusted for confounders revealed no increased risk of congenital anomalies associated with DYG exposure.

First-trimester dydrogesterone therapy was not associated with an increased risk of congenital anomalies. Due to the limitations of this cohort study, further follow-up and in-depth data analysis are planned for future studies.

The online version contains supplementary material available at 10.1186/s12958-025-01507-8.

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