Arushi JC Summary

Luteal Phase Support in Frozen Embryo Transfer (FET): Vaginal Gel vs Intramuscular Progesterone – Comprehensive Study Notes

  • Goal: summarize key concepts, study designs, results, and implications from multiple transcripts comparing vaginal progesterone (Crinone vaginal gel) with intramuscular progesterone (IMP) for luteal-phase support in FET cycles, with emphasis on vitrified blastocysts and related practices.

  • Core concepts and definitions

    • FET: Frozen embryo transfer; embryos transferred after cryopreservation.

    • CET: Cryopreserved embryo transfer (synonymous with FET in many studies).

    • Luteal phase support (LPS): Hormonal support to sustain endometrial receptivity and early pregnancy, typically progesterone, sometimes combined with estrogen.

    • Routes/formulations discussed:

    • Intramuscular progesterone in oil (IMP), commonly 50 mg daily or similar daily doses.

    • Vaginal progesterone gel (Crinone 8%), typically 90 mg twice daily in many studies.

    • Endometrin vaginal inserts (vaginal progesterone suppositories).

    • Other regimens include dydrogesterone (oral) as part of combination protocols.

    • Key outcomes used across studies:

    • Implantation rate (IR): number of gestational sacs implanted relative to embryos transferred, often reported as %.

    • Positive serum hCG: biochemical pregnancy indicator.

    • Clinical pregnancy rate (CPR): ultrasound-confirmed intrauterine gestational sac.

    • Spontaneous abortion (miscarriage) rate: loss before 20 weeks.

    • Live birth rate (LBR): live birth per transfer or per cycle.

    • Common statistics used: odds ratio (OR) with 95% confidence intervals (CI), relative risk (RR), P-values, and occasional Poisson or logistic regression analyses.

    • Notation examples:

    • OR =
      \text{Odds ratio} = \frac{p1/(1-p1)}{p0/(1-p0)}

    • \text{CI} = \text{confidence interval}

    • \text{RR} = \text{relative risk}

  • Summary of major studies and their designs

    • Shapiro et al. 2014 (Hum Reprod; retrospective, n = 920 FET cycles)

    • Question: Does type of luteal support affect pregnancy outcomes in recipients of vitrified blastocysts?

    • Groups: IMP (n = 682) vs Crinone 8% vaginal gel (n = 238).

    • Protocols: Standard FET with vitrified blastocysts; LPS with either IMP or Crinone 8%; Crinone started Day 15 of estrogen therapy; blastocyst transfer on Day 6 of progesterone therapy.

    • Outcomes reported: Implantation rate, positive serum hCG, clinical pregnancy, spontaneous abortion, live birth.

    • Key results (main outcomes):

      • Implantation rate: 46.4ext%46.4 ext{\%} vs 45.6%45.6\text{\%}, P = 0.81

      • Clinical pregnancy rate: 61.7%61.7\text{\%} vs 60.5%60.5\text{\%}, P = 0.80

      • Live birth rate: 49.1%49.1\text{\%} vs 48.9%48.9\text{\%}, P > 0.99

    • Subgroup analyses: nulliparous vs parous differences, autologous vs donor embryo sources, SET vs not; findings remained non-significant.

    • Conclusions: Luteal support with vaginal progesterone gel or IMP yields comparable implantation and pregnancy outcomes in vitrified blastocyst FET cycles; enhanced SET and vitrification practices make these findings relevant to current practice.

    • Limitations: Retrospective, non-randomized; no prospective power calculation; potential selection bias.

    • Dal Prato et al. 2008 (Reproductive BioMedicine Online; prospective randomized trial; Day 3 transfers)

    • Question: Is vaginal progesterone gel equivalent to IMP for luteal support in IVF with Day 3 embryos?

    • Arms: IMP 50 mg daily; Crinone 90 mg twice daily (VGP BID); Crinone 90 mg once daily (VGP QD).

    • Population: IVF patients (autologous donor contexts included in broader discussion).

    • Outcomes: Biochemical pregnancy (positive hCG), clinical pregnancy, implantation, and live birth per transfer.

    • Key results (example figures):

      • Positive hCG: IMP 38.4%; VGP QD 35.0%; VGP BID 43.1%

      • Clinical pregnancy: IMP 32.6%; VGP QD 26.3%; VGP BID 37.2%

      • Implantation rate: overall around 19–21% across groups when accounting for embryos transferred

      • Live birth rate: IMP 26.1%; VGP QD 23.4%; VGP BID 29.9%

    • Conclusion: No significant differences among the three groups; once-daily vaginal gel may be noninferior to IMP for luteal support in Day 3 cleavage-stage transfers.

    • Note: This study helped establish vaginal gel as a viable alternative in Day 3 contexts; however, results may differ with blastocysts or vitrification. Limitations include sample size and Day 3 embryo setting.

    • Shapiro et al. 2014 (cited within broader systematic reviews; synthesis of multiple trials)

    • Context: Coalesces evidence from several trials comparing vaginal progesterone vs IMP in FET and donor cycles.

    • General takeaway: In several settings (donor FET, autologous FET, and various embryo stages), vaginal progesterone and IMP show comparable pregnancy outcomes; heterogeneity exists due to embryo stage, donor/autologous source, and vitrification methods.

    • Kaser et al. 2012 (Fertil Steril; Day 3 cryopreserved embryo transfer; donor/autologous mix)

    • Finding: Implicates that Day 3 FET with Crinone vaginal gel may yield lower clinical and live birth odds compared with IMP, suggesting timing of vaginal progesterone initiation may influence the implantation window.

    • Possible explanation: Premature endometrial advancement with vaginal gel could shorten the implantation window; delaying initiation of vaginal gel might mitigate this effect in some protocols.

    • Wang et al. 2015 (PLOS ONE; prospective randomized; FET with vitrified embryos; Crinone vs IMP)

    • Design: 1500 cycles; Crinone vs IMP; both groups also received dydrogesterone and estradiol.

    • Primary outcomes: Live birth per transfer; CPR; IR; biochemical pregnancy; miscarriage.

    • Results (per-protocol after withdrawals):

      • Live birth rate: 32.6%32.6\% in Crinone vs 31.7%31.7\% in IMP, P = 0.710

      • Clinical pregnancy: 40.1%40.1\% vs 40.6%40.6\%, P = 0.831

      • Implantation: 25.8%25.8\% vs 25.3%25.3\%, P = 0.772

      • Biochemical pregnancy: not significantly different

    • Conclusion: Crinone vaginal gel is equivalent to IMP for luteal support in vitrified blastocyst FET cycles; vaginal gel offers practical advantages (no injections).

    • Bakkensen et al. 2020 (Fertility Research and Practice; retrospective cohort; blastocyst SET with vitrified embryos)

    • Setting: Single-center, blastocyst SET cycles using either IMP (n = 682) or Crinone (n = 238).

    • Outcomes: Implantation, clinical pregnancy, and live birth rates; odds ratios (ORs) with 95% CIs reported.

    • Key results: No significant differences in clinical pregnancy (61.7% vs 60.5%), live birth (49.1% vs 48.9%), or overall implantation; SET proportions were similar; donor vs autologous distribution differed but did not alter main outcome equivalence.

    • Conclusion: In vitrified blastocyst SET within a real-world program, vaginal Crinone and IMP yielded equivalent outcomes; supports flexibility in luteal-phase regimens.

    • Limitations: Retrospective; non-randomized; provider preference could bias allocation.

    • Devine et al. 2018 (Fertil Steril; randomized controlled trial, three arms)

    • Design: blastocyst CET; three arms – IMP alone, Endometrin (vaginal gel) alone, and IMP plus Endometrin every third day (Endometrin combination).

    • Primary outcome: Ongoing pregnancy; Secondary outcomes: clinical pregnancy, implantation, live birth.

    • Interim analysis findings: Endometrin-only group had inferior ongoing pregnancy rates compared to IMP groups; equivalence of IMP and Endometrin-IM combination suggested in some settings.

    • Context: ITS (interim results) raised questions about whether Endometrin alone is sufficient for LPS in blastocyst CET; later publications discuss general equivalence across vaginal gels but with caveats depending on dosing/formulation.

    • Shapiro et al. 2023–2024 updates (Five-regimen real-world study in Switzerland; Frontiers in Endocrinology)

    • Design: Retrospective cohort of FET cycles (HRT-FET) with five different progesterone regimens: oral dydrogesterone (DYD) alone, MPG alone, DYD+MPG, MPC (micronized progesterone capsules), and subcutaneous progesterone (subcutan-P4).

    • Primary outcomes: Clinical pregnancy rate (CPR) and live birth rate (LBR).

    • Key results (adjusted and unadjusted): DYD alone and DYD+MPG showed higher CPR and LBR than MPG alone; MPC and subcutan-P4 showed less consistent results. Odds ratios (adjusted) favored DYD-containing regimens for CPR and/or LBR in several analyses (e.g., DYD: CPR OR ≈ 2.87; LBR OR ≈ 2.58; DYD+MPG: CPR OR ≈ 5.19; LBR OR ≈ 2.49).

    • Conclusions: Dydrogesterone-containing regimens may enhance CPR and LBR in HRT-FET; however, this is a retrospective analysis and should be interpreted with caution. The study highlights potential advantages of oral dydrogesterone in combination or as alternative LPS, while noting safety considerations and need for prospective trials.

    • Jiang et al. 2019 (Scientific Reports; retrospective cohort; 3013 FET cycles in China)

    • Compared two regimens: IM progesterone plus dydrogesterone vs vaginal Crinone gel plus dydrogesterone in artificial cycles.

    • Key findings: No significant differences in clinical pregnancy or ectopic pregnancy; however, vaginal gel was associated with higher implantation and live birth rates in some analyses; injections had higher early abortion rates in some settings. The study emphasizes large sample size and real-world data, but differences in regimens (dose, timing, adjuncts) warrant cautious interpretation.

    • Crinone vs IMP in diverse CET contexts (multiple sources, 2000s–2020s)

    • Across randomized trials, prospective cohorts, and retrospective analyses, general patterns emerge:

      • In many settings, Crinone (vaginal gel) and IMP yield broadly comparable outcomes in terms of implantation, clinical pregnancy, and live birth for FET/CET with either Day 3 or blastocyst transfers, particularly in vitrified-warmed blastocyst cycles.

      • Some studies report potential differences when using specific vaginal formulations (e.g., Endometrin) or dosing regimens (e.g., twice daily vs once daily) and when initiation timing is varied relative to embryo transfer.

      • Donor oocyte cycles and SET practices add heterogeneity; results may differ between autologous vs donor sources and between cleavage-stage vs blastocyst-stage transfers.

  • Important methodological notes and patterns across studies

    • Study designs vary:

    • Retrospective analyses offer real-world insights but are prone to selection bias and confounding. Examples: Shapiro 2014, Bakkensen 2020, Jiang 2019.

    • Prospective randomized trials provide higher evidentiary strength but may have narrower inclusion criteria or limited sample sizes for certain subgroups. Examples: Dal Prato 2008; Dal Prato 2001/2004 family; Yanushpolsky et al. trials cited within meta-analyses; Devine 2018 interim results; Wang 2015 PLOS ONE.

    • Embryo stage and vitrification status matter:

    • Day 5 blastocyst transfers (especially vitrified) are increasingly common; several studies emphasize relevance of these populations for luteal support strategies.

    • Donor vs autologous cycles:

    • Some studies report differential patterns, possibly due to embryo quality or endometrial dynamics; subgroup analyses often show no significant difference when appropriately powered.

    • Timing and dosing considerations:

    • Initiation timing of vaginal progesterone relative to embryo transfer may influence the implantation window; some evidence suggests delaying vaginal gel initiation could affect outcomes in specific protocols, though findings are not universal.

    • Endometrial ecology and pharmacokinetics:

    • Differences in tissue concentration and endometrial exposure between vaginal gels and IM injections may explain occasional discrepancies in outcomes or bleeding patterns; Endometrin vs Crinone differences can matter.

  • Practical implications and clinical insights

    • Equivalence in many settings:

    • Across vitrified blastocyst FET cycles, vaginal Crinone and IMP often yield comparable pregnancy and birth outcomes, supporting alternative choices based on patient preference, tolerance, and logistics.

    • Advantages of vaginal gel as a practical option:

    • Ease of use, avoidance of injections, and potentially better patient satisfaction and compliance in long luteal-phase protocols.

    • Contextual decision-making:

    • In donor cycles, or in protocols with differing embryo quality and endometrial preparation, clinicians may consider regimen-specific evidence and patient-specific factors.

    • Emerging approaches and future directions:

    • Increasing interest in dydrogesterone (oral) as a luteal-phase component, either alone or in combination, for FET regimens; mixed evidence suggests potential benefits for CPR/LBR in some settings but requires rigorous prospective validation.

  • Key numerical references and formulas to remember

    • Implantation rate (IR) is often reported as a percentage:

    • IR definition: IR=N<em>implantedN</em>transferred×100%IR = \frac{N<em>{implanted}}{N</em>{transferred}} \times 100\%

    • Clinical pregnancy rate (CPR) definitions: proportion of transfers resulting in at least one intrauterine gestational sac detected by ultrasound.

    • Live birth rate (LBR) definitions: proportion of transfers resulting in at least one live birth.

    • Odds ratio (OR) interpretation: OR = 1 implies no difference; 95% CI that includes 1 suggests non-significance.

    • Relative risk (RR): used in some contemporary analyses; RR = 1 implies equal risk, >1 favors the numerator group, <1 favors the denominator group.

    • Example reported results (selected):

    • Shapiro 2014: OR for clinical pregnancy = 0.95 (0.69−1.30)0.95\,(0.69-1.30), P = 0.80; OR for live birth = 0.99 (0.73−1.35)0.99\,(0.73-1.35), P = 0.99.

    • Wang 2015 (PLOS ONE): Live birth rate Crinone vs IMP: 32.6%32.6\% vs 31.7%31.7\%, P = 0.710; CPR: 40.1%40.1\% vs 40.6%40.6\%, P = 0.831.

    • Dal Prato 2008: Biochemical pregnancy between arms: 38.4% (IMP), 35.0% (VGP QD), 43.1% (VGP BID); Clinical pregnancy: 32.6% (IMP), 26.3% (VGP QD), 37.2% (VGP BID).

    • Devine et al. 2018 interim: Endometrin-only inferior for ongoing pregnancy vs IMP groups; specifics depend on interim data (context here for planning future trials).

    • Vidal et al. 2023 (five regimens): DYD alone associated with higher CPR and LBR than MPG alone in multivariate analyses; specific ORs: CPR DYD ≈ 2.87, CPR DYD+MPG ≈ 5.19; LBR DYD ≈ 2.58, LBR DYD+MPG ≈ 2.49 (adjusted).

  • Connections to broader practice and ethics

    • Relevance to SET and vitrified blastocyst practices: Several studies emphasize applicability to contemporary ART practices focusing on single-embryo transfers and vitrification strategies.

    • Safety and tolerability: Vaginal progesterone generally better tolerated with fewer injection-related issues; some bleeding patterns may be observed; endometrial physiology and tissue concentrations may influence outcomes.

    • Research gaps: While retrospective and some prospective data suggest equivalence, adequately powered prospective randomized trials comparing vaginal gel vs IMP across diverse CET contexts (blastocyst vs cleavage-stage transfers, autologous vs donor, SET vs multi-embryo transfers) remain warranted.

  • Summary takeaways

    • Across multiple large and small studies, vaginal Crinone 8% gel generally provides luteal support with outcomes comparable to IMP in FET/CET cycles, including those using vitrified blastocysts.

    • In several randomized trials (Day 3 or blastocyst CET contexts), no consistent superiority of either route emerges; choice often rests on patient preference, ease of use, and pragmatic considerations.

    • Emerging regimens that incorporate dydrogesterone (oral) show potential improvements in CPR/LBR in some analyses, but require robust prospective validation before changing standard practice.

  • Ethical and practical implications

    • Patient comfort and adherence: Oral/dydrogesterone-based regimens or vaginal gels may improve patient experience and uptake, potentially influencing real-world outcomes.

    • Access and cost considerations: Availability of Crinone vs IMP, as well as costs associated with injections, may influence protocol selection in different clinics and regions.

    • Transparency in trials: Many studies are retrospective or open-label; prospective randomized trials with standardized protocols are essential for definitive equivalence conclusions.

  • Quick reference table (conceptual)

    • Outcome metric definitions and typical direction of similarity/difference across studies:

    • IR: often similar between Crinone and IMP

    • CPR: often similar

    • LBR: often similar

    • Biochemical pregnancy: often similar

    • Miscarriage: broadly similar, with occasional subgroup signals

    • Note: Specific numbers vary by study design, embryo stage, transfer type (SET vs multiple), donor/autologous context, and vitrification method.

  • Practical tips for exam-style questions

    • If asked about equivalence: Many high-quality retrospective and several RCTs show equivalence of Crinone 8% to IMP in vitrified blastocyst CET settings, especially with SET and vitrification.

    • If asked about superiority: Current evidence does not robustly support superiority of vaginal gel over IMP across all CET contexts; exceptions exist in very specific regimens (e.g., certain Endometrin dosing or dydrogesterone combinations in some studies).

    • If asked about study design impact: Randomized controlled trials provide stronger evidence than retrospective studies; heterogeneity (embryo stage, donor/autologous status, SET rates) can shift results; pay attention to whether the population is Day 3 vs Day 5/blastocyst, vitrified vs slow-frozen, and whether SET is utilized.

  • Final takeaway

    • For vitrified blastocyst FET cycles, vaginal progesterone gel (Crinone) and intramuscular progesterone are generally equivalent for luteal-phase support in terms of implantation, clinical pregnancy, and live birth rates, with vaginal gel offering practical advantages. New regimens (including dydrogesterone-containing protocols) show promise for improving CPR/LBR in some contexts, but definitive superiority has not been established across all CET scenarios. Routine clinical decisions should consider embryo stage, donor vs autologous cycles, SET practices, patient preference, and institutional protocols while awaiting further large-scale randomized data.

  • Abbreviations recap

    • ART: Assisted reproductive technology

    • CET/FET: Cryopreserved/ Frozen embryo transfer

    • LPS: Luteal phase support

    • IMP: Intramuscular progesterone

    • MPG/Crinone: Vaginal progesterone gel

    • Endometrin: Vaginal progesterone insert

    • DYD: Dydrogesterone (oral)

    • CPR: Clinical pregnancy rate

    • LBR: Live birth rate

    • IR: Implantation rate

    • OR: Odds ratio

    • RR: Relative risk

    • SET: Single embryo transfer

    • P4: Progesterone

    • PGT: Pre-implantation genetic testing

  • References (selected from transcript for further reading)

    • Shapiro DB, Pappadakis JA, Ellsworth NM, Hait HI, Nagy ZP. Progesterone replacement with vaginal gel versus i.m. injection: cycle and pregnancy outcomes in IVF patients receiving vitrified blastocysts. Hum Reprod. 2014;29(8):1706–1711. (Retrospective, vitrified blastocyst CET; equivalence found)

    • Dal Prato L, Bianchi L, Cattoli M, Tarozzi N, Flamigni C, Borini A. Vaginal gel versus intramuscular progesterone for luteal phase supplementation: a prospective randomized trial. Reprod Biomed Online. 2008;16(3):361–367. (Day 3 embryos; no significant differences across arms)

    • Wang Y, He Y, Zhao X, Ji X, Hong Y, Wang Y, et al. Crinone Gel for Luteal Phase Support in Frozen-Thawed Embryo Transfer Cycles: A Prospective Randomized Clinical Trial in the Chinese Population. PLoS ONE. 2015;10(7):e0133027. (Large RCT; Crinone vs IMP; no significant differences in primary outcomes, similar live birth rates)

    • Bakkensen JB, Racowsky C, Thomas AM, Lanes A, Hornstein MD. Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support following blastocyst cryopreserved SET: a retrospective cohort study. Fertility Research and Practice. 2020;6:10. (Blastocyst SET CET; equivalence observed)

    • Shapiro B, et al. Systematic context and additional RCTs on vaginal progesterone vs IMP across CET settings (2010s–2020s)

    • Devine K, Richter KS, Widra EA, McKeeby JL. Vitrified blastocyst transfer cycles with the use of only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: interim results of a three-arm RCT. Fertil Steril. 2018;109(2):266–275. (Interim data; Endometrin-alone inferior to IMP-based strategies in this trial)

Notes: These notes integrate multiple studies to provide a cohesive view of how vaginal gel and IMP compare for luteal-phase support in CET/FET, particularly with vitrified blastocysts. They emphasize that results often show equivalence but depend on embryo stage, transfer strategy (SET vs non-SET), donor versus autologous sources, and specific progesterone formulations and timings. Always consider study design, population, and protocol when applying these findings to practice or exams.