Dydrogesterone — Latest Clinical Evidence (2024–2026)

1. Threatened & Recurrent Miscarriage

Network Meta-Analysis (2025) — Best evidence for threatened miscarriage

• Oral dydrogesterone reduced miscarriage risk vs. placebo (OR 0.50, 95% CI 0.32–0.76) in women with first threatened miscarriage.
• Oral dydrogesterone was superior to vaginal progesterone for miscarriage prevention (OR 0.57, 95% CI 0.36–0.89).
• No significant difference was found between progestogens for preterm birth, congenital abnormalities, or live birth rate.
• Conclusion: Oral dydrogesterone is the preferred progestogen for first threatened miscarriage based on current comparative evidence.

Meta-Analysis (2024) — Broad progestogen evidence

• Progestogens probably increase live births in threatened miscarriage (RR 1.04, 95% CI 0.99–1.10; moderate certainty).
• Benefit appears restricted to women with prior miscarriage history — absolute live birth increase ~5% in this subgroup.
• No increase in congenital anomalies or serious adverse events (moderate certainty).

Cochrane Review (2025) — Recurrent miscarriage of unclear etiology

• Little to no difference in miscarriage rate for progestogens vs. placebo in women with recurrent miscarriage of unclear etiology (RR 0.91, 95% CI 0.76–1.07; moderate certainty).
• Notable caveat: Two previously included trials have been retracted since 2019 — this update removed them, substantially changing conclusions.
• Key message: The previous evidence base supporting dydrogesterone for recurrent miscarriage was partially built on retracted data. Current moderate-certainty evidence does not support routine use for recurrent miscarriage.

2. Luteal Phase Support (LPS) in Fresh IVF Cycles

Network Meta-Analysis (2026) — Strongest recent IVF evidence

• Oral administration (predominantly dydrogesterone) was the only route reaching statistical significance for increased clinical pregnancy rate vs. placebo.
• For live birth rate, only oral and intramuscular routes showed statistically significant improvement vs. placebo; vaginal and subcutaneous routes did not.
• ESHRE already recommends dydrogesterone as one of four standard LPS options alongside vaginal, IM, and SC progesterone.
• Conclusion: Oral dydrogesterone may be superior for fresh IVF cycles based on emerging NMA data — but overlapping confidence intervals indicate remaining uncertainty.

Pharmacokinetics & Endometrial Study (2024) — Mechanistic insight

• After oral dydrogesterone, the primary active metabolite 20α-dihydrodydrogesterone (DHD) dominates (Cmax ~88 ng/mL vs. dydrogesterone Cmax ~3.6 ng/mL).
• Despite very low systemic progesterone concentrations after oral DYD, endometrial histology and transcriptomics were equivalent to vaginal micronized progesterone.
• Confirms that dydrogesterone achieves adequate endometrial transformation through local receptor activity rather than high circulating progesterone levels.

RCT (2024) — Combination oral DYD + vaginal progesterone

• Adding oral dydrogesterone 20 mg to vaginal micronized progesterone 90 mg gel did not improve IVF outcomes vs. vaginal progesterone 800 mg alone.
• Pregnancy rate, live birth rate, implantation rate, miscarriage rate: no significant differences.
• Conclusion: Combination LPS confers no added benefit over high-dose vaginal progesterone in fresh IVF.

3. Frozen Embryo Transfer (FET) with HRT

Network Meta-Analysis (2025) — FET outcomes

• Oral dydrogesterone + GnRH agonist ranked highest for combined ongoing pregnancy/live birth rate (SUCRA 97.3%) — significantly superior to all other protocols (very low to low certainty).
• For live birth alone, vaginal suppository progesterone ranked highest (SUCRA 89.7%).
• Individualized DYD supplementation for low serum progesterone: A 2025 meta-analysis (Cucchietti O et al., [PMID: 41115974]) found that adding oral DYD when serum P4 < 11 ng/mL achieves comparable live birth rates to adequate-P4 cycles (aOR 1.14, 95% CI 0.91–1.42), supporting individualized luteal rescue strategies.

4. Preterm Birth Prevention

Systematic Review & Meta-Analysis (2026)

• Dydrogesterone showed non-significant trends toward increased gestational age at delivery (MD +0.42 weeks, 95% CI −0.70 to +1.55) and reduced NICU admission (RR 0.74, 95% CI 0.47–1.18).
• GRADE certainty: low to very low for all outcomes.
• Trial Sequential Analysis confirms evidence is underpowered and insufficient for clinical recommendations.
• Conclusion: No current evidence to support oral dydrogesterone for routine preterm birth prevention.

Summary Table

Key Takeaways

1. Strongest indication remains threatened miscarriage (first episode) — dydrogesterone outperforms vaginal progesterone in the latest Bayesian NMA.
2. Recurrent miscarriage evidence has weakened — the 2025 Cochrane update removed retracted trials and now shows little to no benefit.
3. IVF luteal support: Oral dydrogesterone has now demonstrated superiority over vaginal and subcutaneous routes for CPR in fresh cycles (2026 NMA), aligning with ESHRE guideline recommendations.
4. Pharmacologically validated: The 2024 PK/endometrial study confirms dydrogesterone achieves equivalent endometrial effect to vaginal progesterone despite low systemic levels — via its active metabolite DHD.
5. Preterm birth: Insufficient evidence; not recommended outside trials.