Introduction

Despite large clinical trials and meta-analyses that show no association between dydrogesterone and congenital anomalies, some recently retracted publications have postulated an association with teratogenicity. Dydrogesterone is also often rated as less safe than bioidentical progestins. This review looks at all the available scientific evidence on taking dydrogesterone in the first trimester of pregnancy and the risk of birth deformities.

Aim

To provide a complete and systematic review of the available literature to determine whether exposure to dydrogesterone in the first trimester is a risk factor for congenital anomalies

Methods

• Nine studies were included: six randomized controlled trials (RCTs) and three observational studies (OSs)
• Systematic literature review and meta-analysis of eligible studies
• Meta-analysis was performed on the prevalence of congenital anomalies for dydrogesterone-exposed live births stratified by the different types of studies

  Patient Profile

• N=5070 participants and 2680 live births from 16 countries
• Women >17 years old treated for threatened miscarriage, recurrent pregnancy loss, and/or ART
• Possible interventions: Use of dydrogesterone in the first trimester; and comparators were placebo, no treatment, or interventions other than dydrogesterone.

Study endpoints

Primary outcome: Presence of congenital malformation in exposed and non-exposed live births

Results

• In the meta-analysis of RCTs, overall Risk Ratio (RR) was 0.92 [95% CI 0.55; 1.55] with a low certainty

  Table 1: Overall findings for RCTs only

  	Absolute risk without Dydrogesterone exposure	Absolute risk with Dydrogesterone exposure	Relative effect (95% CI)	No. of participants (studies)		Certainty of the evidence (GRADE)
  Congenital anomalies (RCTs only)	38 per 1000	35 per 1000	RR 0.92 (0.55; 1.55)		1512 (6 studies)	Lowa,b

  Absolute risk without

  a Downgraded −1 due to serious limitations in study design (randomization process).

  b Downgraded −1 due to serious imprecision (wide 95% CIs, low number of events).

• When the two OSs were included, the overall RR was 1.11 [95% CI 0.73; 1.68] with low certainty

  Table 2: Results of meta-analysis stratified by study design

  Study or Subgroup	Risk Ratio MH, Random, 95% CI
  Design = RCT
  El-Zibdeh, 2005 Quality = low	1.06 [0.15; 7.30]
  El-Zibdeh & Yoursef, 2009 Quality = low	0.63 [0.09; 4.34]
  Pandian, 2009 Quality = low	NA
  Tournaye et al., 2017 Quality=high	0.62 [0.19; 1.99]
  Griesingler et al., 2018 Quality=high	1.28 [0.58; 2.82]
  Chan et al., 2021 Quality=high	0.73 [0.24; 2.26]
  Total (95% CI)	0.92 [0.55; 1.55]
  Design = cohort study
  Vuong et al., 2021	0.77 [0.11; 5.43]
  Xu et al., 2021	1.71 [0.81; 3.63]
  Total (95% CI)	1.55 [0.77; 3.11]
  Total (95% CI)	1.11 [0.73; 1.68]

• Total (95% CI) RR based on study quality
  • RR of 0.94 [0.53; 1.65] for high-quality-rated studies
  • RR of 0.82 [0.21; 3.20] for low-quality-rated studies

Conclusion

This meta-analysis provided clear reassurance to both clinicians and patients that dydrogesterone, when given in the first trimester for recurrent / threatened pregnancy loss or as luteal support in ART, is not associated with congenital anomalies above the rate that might be expected due to environmental and genetic factors.

Reference

Hum Reprod Open. 2024; 2024(1): hoae004