4 Supplementary Dydrogestrone

Overview

• Topic: Comparison of five luteal phase support (LPS) regimens in artificial frozen-thawed embryo transfer (FET) cycles using hormone replacement therapy (HRT-FET).
• Regimens studied:
  • (1) Oral dydrogesterone (DYD) 30 mg/day, $DYD = 30\ \mathrm{mg/day}$
  • (2) Vaginal micronized progesterone gel (MPG) 90 mg/day, $MPG = 90\ \mathrm{mg/day}$
  • (3) DYD 20 mg/day + MPG 90 mg/day (DYD+MPG), $DYD = 20\ \mathrm{mg/day},\; MPG = 90\ \mathrm{mg/day}$
  • (4) Micronized progesterone capsules (MPC) 600 mg/day, $MPC = 600\ \mathrm{mg/day}$
  • (5) Subcutaneous progesterone 25 mg/day (subcutan-P4), $\text{Subcutan-P4} = 25\ \mathrm{mg/day}$
• Reference group: MPG alone.
• Design: Single-center retrospective cohort of all women undergoing FET cycles from 2013–2019; endometrial thickness threshold for luteal support was reached after estradiol priming.
• Primary outcome: Clinical pregnancy rate (CPR).
• Secondary outcomes: Live birth rate (LBR), ongoing pregnancy, miscarriage, biochemical pregnancy; maternal/fetal complications noted.
• Key conclusion: Adding dydrogesterone (DYD) to MPG showed higher CPR and LBR than MPG alone; DYD alone also improved CPR and LBR relative to MPG; DYD+MPG had the strongest signal for CPR in adjusted analyses.

Study design and methods

• Design: Retrospective observational cohort study, real-world population.
• Setting: Division of Reproductive Medicine and Gynecological Endocrinology, Lucerne Cantonal Hospital, Switzerland.
• Period: 2013–2019.
• Population: 391 FET cycles in women aged 18–46 years with endometrial thickness ≥7 mm on secretory transformation day.
• Exclusion criteria: ICSI; fertilization with testicular sperm extraction; treated congenital uterine malformations; uterine fibroids.
• Data source: Medical database; informed consent obtained.
• Endometrial preparation (HRT-FET protocol):
  • Start 2 mg oral estradiol valerate on cycle day 1, titrating up to a max of 8 mg/day.
  • After 12–16 days of estrogen, transvaginal ultrasound to assess endometrial thickness.
  • Cycle canceled if endometrium < 7 mm after day 16 of estrogen.
  • Luteal phase support started if endometrium ≥ 7 mm, continued until 12 weeks gestation if pregnancy achieved.
  • Estradiol continued for at least 14 days post-LPS initiation for β-hCG assessment.
• Group assignment and regimens: Based on progesterone application chosen by patient preference; five groups as above.
• Embryo transfer details:
  • Embryo quality assessed on day 3 and day 5.
  • Transfers: maximum of two embryos.
  • Cleavage-stage embryos transferred on day 4 after initiation of LPS; blastocysts transferred on day 6.
• Outcomes definitions:
  • CPR: clinical pregnancy with fetal heartbeat on ultrasound.
  • LBR: live birth per embryo transfer.
  • Biochemical pregnancy: positive hCG without ultrasound-confirmed pregnancy.
  • Miscarriage: pregnancy loss before 12 weeks.
  • Secondary obstetric outcomes recorded (preeclampsia, vaginal bleeding, gestational diabetes).
• Statistical analyses:
  • MPG chosen as reference group due to higher cycle count.
  • Descriptive statistics: categorical data as frequencies (%); continuous data as median (Q1–Q3) and range.
  • Multivariable logistic regression adjusting for predefined covariates: age group, type of infertility, embryo transfer stage (cleavage vs blastocyst) combined with number of transferred embryos.
  • Outcomes reported as odds ratios (ORs) with 95% confidence intervals (CIs).
  • Also reported unadjusted ORs for comparison.
  • Significance level: 5% (two-sided).
  • No multiplicity adjustment due to exploratory nature.
  • Software: STATA (v16.1 or higher).
• Ethics: Approved by local ethics committee; BASEC 2020-01527; conducted per the Declaration of Helsinki.

Study population and baseline characteristics

• Total cycles included: 391 out of 402 HRT-FET cycles.
• Group sizes: MPG (n = 281), DYD (n = 52), DYD+MPG (n = 17), MPC (n = 37), Subcutan-P4 (n = 4).
• Age: overall median 35 years (IQR 32–38); Subcutan-P4 group significantly older than others.
• Infertility characteristics: Most common etiology was anovulation/dysovulation/PCOS (overall ~70–71%), with distribution differing by group (e.g., MPG 71% vs other groups 56–60% in some instances).
• Fertilization method distribution: IVF vs ICSI balanced across groups (no significant differences; p-values not indicating major disparities).
• Number of previous transfers: Similar across groups with some variation; no significant difference overall (p ≈ 0.095–0.095).
• Embryo transfer stage distribution:
  • Blastocyst transfers differed markedly by group (p < 0.001):
  • MPG: 56/281 (19.9%) blastocysts.
  • DYD: 41/52 (78.8%).
  • DYD+MPG: 14/17 (82.4%).
  • MPC: 32/37 (86.5%).
  • Subcutan-P4: 4/4 (100%).
  • Single-embryo transfers were more common in DYD, DYD+MPG, MPC, and Subcutan-P4 groups than MPG (p < 0.001).
• Embryo transfer counts:
  • 1 embryo transferred: MPG 98/281 (34.9%); DYD 44/52 (84.6%); DYD+MPG 12/17 (70.6%); MPC 33/37 (89.2%); Subcutan-P4 3/4 (75%).
  • 2 embryos transferred: MPG 183/281 (65.1%); DYD 8/52 (15.4%); DYD+MPG 5/17 (29.4%); MPC 4/37 (10.8%); Subcutan-P4 1/4 (25%).

Embryo quality and timing details

• Embryo quality assessed on day 3 and day 5 using standard criteria.
• Transfer timing:
  • Cleavage-stage embryos transferred on day 4 after LPS initiation.
  • Blastocysts transferred on day 6 after LPS initiation.
• Endometrial and implantation context:
  • Endometrial thickness threshold for proceeding with LPS: ≥7 mm.
  • Adequate endometrial maturation and secretory transformation essential for implantation and pregnancy maintenance.

Primary and secondary outcomes

• Primary outcome: Clinical pregnancy rate (CPR).
• Secondary outcomes:
  • Live birth rate (LBR) per embryo transfer.
  • Ongoing pregnancy rate.
  • Biochemical pregnancy rate.
  • Miscarriage rate.
  • Other pregnancy outcomes: preeclampsia, vaginal bleeding, gestational diabetes.
• Key results (unadjusted and adjusted odds ratios vs MPG reference):
  • CPR:
  • Unadjusted:
    • DYD: $OR = 3.39$ (95% CI $1.81-6.36$), p < 0.001.
    • DYD+MPG: $OR = 6.60$ (95% CI $2.40-18.18$), p < 0.001.
    • MPC: $OR = 0.41$ (95% CI $0.12-1.38$).
    • Subcutan-P4: $OR = 1.54$ (95% CI $0.16-15.11$).
  • Adjusted (covariates described above):
    • DYD: $OR = 2.87$ (95% CI $1.38-6.00$), p = $0.005$.
    • DYD+MPG: $OR = 5.19$ (95% CI $1.76-15.36$), p = $0.003$.
    • MPC: $OR = 0.36$ (95% CI $0.10-1.34$), p = 0.13 (not significant).
    • Subcutan-P4: not statistically significant in adjusted model.
  • LBR:
  • Unadjusted:
    • DYD: $OR = 2.77$ (95% CI $1.36-5.64$), p = 0.005.
    • DYD+MPG: $OR = 3.13$ (95% CI $1.04-9.45$), p = 0.043.
    • MPC: $OR = 0.43$ (95% CI $0.10-1.87$), p = 0.26.
    • Subcutan-P4: $OR = 2.51$ (95% CI $0.25-24.79$), p = 0.43.
  • Adjusted:
    • DYD: $OR = 2.58$ (95% CI $1.11-6.00$), p = $0.028$.
    • DYD+MPG: $OR = 2.49$ (95% CI $0.74-8.38$), p = 0.14.
    • MPC: $OR = 0.45$ (95% CI $0.09-2.15$), p = 0.32.
    • Subcutan-P4: not significant.
• Miscarriage rates (group comparisons):
  • DYD+MPG group: 29% miscarriage rate (highest among groups).
  • DYD group: 15% miscarriage rate.
  • MPG group: 7% miscarriage rate.
  • Overall group comparison: p = $0.005$ for miscarriages across groups (as per Figure 2).
• Adjusted miscarriage analysis (logistic regression):
  • DYD vs MPG: OR = $2.94$ (95% CI $0.76-11.0$), p = $0.12$ (not statistically significant).
  • DYD+MPG vs MPG: OR = $6.02$ (95% CI $1.45-124.91$), p = $0.013$ (statistically significant increased miscarriage risk in adjusted model).
• Pregnancy timing and year effects: No difference observed for endometrial transfer stage (blastocyst vs cleavage) or year of ET after adjustments.
• Sensitivity analyses: Robust treatment effects across multiple covariates (grade of infertility, reason for infertility, fertilization method, prior transfers, calendar year, embryo development) with model selection sometimes favoring luteal treatment alone as predictor; however, no model achieved high predictive power (Pseudo R-squared < 0.11).

Key findings and interpretation

• DYD alone (30 mg/day) as LPS improves CPR and LBR compared with MPG alone, even after adjustment for covariates.
• DYD+MPG combination leads to the strongest signal for CPR improvement vs MPG, with adjusted ORs indicating higher odds of clinical pregnancy and live birth.
• Among secondary outcomes, DYD alone also showed higher LBR; the DYD+MPG combination showed high CPR but an elevated miscarriage rate in this study, necessitating cautious interpretation.
• The results align with prior LOTUS trials in fresh IVF where DYD demonstrated comparable or superior efficacy to MPG, and support the tolerability and patient-friendly administration of oral DYD in FET cycles.
• The study adds real-world evidence that DYD can be a promising LPS option in FET cycles, potentially improving implantation and pregnancy outcomes when used alone or in combination with MPG.

Context and implications

• Endometrial receptivity and synchronization: Successful FET depends on synchronized endometrial maturation and embryo development; exogenous P4 is used in HRT-FET to compensate for lack of corpus luteum.
• Routes of progestin administration vary; oral DYD offers a patient-friendly alternative with favorable tolerability and high receptor specificity.
• Prior large RCTs (LOTUS I and II) showed no difference in early pregnancy outcomes between DYD and MPG in fresh cycles, but subsequent analyses in FET cycles and real-world data suggest DYD may offer benefits in LPS for FET.
• Safety considerations: No increased maternal or fetal complications observed in this study; available evidence suggests acceptable safety for DYD in early pregnancy, though ongoing monitoring and prospective studies remain important due to its synthetic nature.
• Practical implications: Oral DYD may improve patient satisfaction and adherence due to ease of use; clinicians may consider DYD as an LPS option in HRT-FET, either alone or in combination with MPG, depending on patient profile and preferences.

Strengths and limitations

• Strengths:
  • Real-world, single-center experience reflecting everyday clinical practice.
  • Large overall sample for an observational study (N = 391 cycles).
  • Comprehensive comparison across five regimens, including a standard reference (MPG).
  • Robustness of findings across multiple sensitivity analyses and adjustment for key covariates.
  • Consistency of CPR as a clinically relevant primary endpoint.
• Limitations:
  • Retrospective and nonrandomized design; potential for selection bias and confounding.
  • Imbalance in group sizes (e.g., Subcutan-P4 n = 4; DYD+MPG n = 17) which may affect precision.
  • Temporal changes in practice and regulatory environment during 2013–2019 (e.g., Swiss law changes affecting embryo transfer practices) potentially influencing results; adjustments attempted but residual confounding possible.
  • Higher blastocyst transfer proportion in MPG group vs others, which could influence CPR/LBR; adjusted analyses attempted to mitigate this.

Methods in brief (for quick reference)

• Population: 391 FET cycles, HRT-FET; endometrial thickness ≥7 mm; 2013–2019; age 18–46.
• Interventions: Five LPS regimens as above; MPG as reference.
• Outcomes: CPR, LBR, ongoing pregnancy, miscarriage, biochemical pregnancy; additional obstetric outcomes.
• Analysis: Multivariable logistic regression adjusting for age group, infertility type, and embryo transfer stage with number of embryos transferred; both crude and adjusted ORs reported; p = 0.05 threshold; no multiplicity adjustment.
• Ethical: BASEC 2020-01527; consent obtained; Helsinki declaration adherence.

Key numerical references (selected)

• Total cycles: $N = 391$.
• Group sizes: $n<em>{ ext{MPG}}=281,\, n</em>{ ext{DYD}}=52,\, n<em>{ ext{DYD+MPG}}=17,\, n</em>{ ext{MPC}}=37,\, n_{ ext{Subcutan-P4}}=4$.
• Endometrial thickness threshold: $≥7\ \mathrm{mm}$.
• DYD dose: $30\ \mathrm{mg/day}$.
• MPG dose: $90\ \mathrm{mg/day}$.
• DYD+MPG: $20\ \mathrm{mg/day}$ + $90\ \mathrm{mg/day}$.
• MPC dose: $600\ \mathrm{mg/day}$.
• Subcutan-P4 dose: $25\ \mathrm{mg/day}$.
• Primary outcome CPR (group comparisons):
  • MPG: CPR = $18\%$ (95% CI $14\% - 23\%$).
  • DYD: CPR = $59\%$ (95% CI $39\% - 82\%$).
  • DYD+MPG: CPR = $42\%$ (95% CI $29\% - 57\%$).
  • MPC: CPR = $8\%$ (95% CI $2\% - 22\%$).
  • Subcutan-P4: CPR = $25\%$ (95% CI not stated).
• Adjusted CPR ORs vs MPG (selected):
  • DYD: $OR = 2.87$ (95% CI $1.38-6.00$), p = $0.005$.
  • DYD+MPG: $OR = 5.19$ (95% CI $1.76-15.36$), p = $0.003$.
• Secondary outcome LBR (group comparisons):
  • MPG: LBR = $12\%$; DYD: $27\%$; DYD+MPG: $29\%$; MPC: $5\%$; Subcutan-P4: $25\%$.
• Unadjusted LBR ORs vs MPG: DYD $OR = 2.77$; DYD+MPG $OR = 3.13$; MPC $OR = 0.43$; Subcutan-P4 $OR = 2.51$.
• Adjusted LBR ORs vs MPG: DYD $OR = 2.58$; DYD+MPG $OR = 2.49$ (p = 0.14 for DYD+MPG).
• Miscarriages: highest in DYD+MPG group (29%), followed by DYD (15%) and MPG (7%); p = $0.005$ for group differences; adjusted miscarriage OR for DYD+MPG vs MPG: $OR = 6.02$ (95% CI $1.45-124.91$), p = $0.013$.

Summary takeaways

• In HRT-FET cycles, supplementary DYD (30 mg/day) improves CPR and LBR compared with MPG alone.
• The combination of DYD (20 mg/day) + MPG (90 mg/day) may yield even higher CPR, with substantial but not uniformly significant gains in LBR; there may be an increased miscarriage rate that warrants caution and further study.
• Oral DYD is a practical, well-tolerated alternative to vaginal MPG for LPS in FET, aligning with broader evidence from fresh IVF cycles and emerging FET data.
• Clinicians should consider patient preference, tolerability, and risk–benefit trade-offs when selecting between DYD alone vs. DYD+MPG for LPS in FET.
• Further randomized trials and comprehensive safety data are needed to confirm these findings and to define optimal dosing and combinations in diverse populations.