Fresh donor egg recipient (DE) and frozen embryo transfer (FET) pregnancy rates using oral micronized estradiol (E2) in a simplified fixed-dose endometrial preparation protocol

Abstract Study question Does the use of pessaries of 400 mg of micronized progesterone provide comparable results as pessaries of 200 mg x2, in terms of progesterone levels? Summary answer The administration of pessaries of Cyclogest® 400 mg reduces the probability of presenting suboptimal level of progesterone on the day of the embryo transfer. What is known already The endometrial preparation for frozen embryo transfer (FET) in Artificial Cycle (AC) with vaginally-administered progesterone, is one of the most common IVF procedures nowadays. Now, it has been shown that suboptimal progesterone levels on the day of the embryo transfer compromise the results of FET treatments. Recently, a new preparation of 400 mg vaginal pessaries has been introduced in the market of European countries. Efficacy of this new preparation has been studied in “fresh” IVF cycles but we lack the comparative studies in AC making it necessary to further investigate this area. Study design, size, duration Non-inferiority retrospective case-control trial based on 347 embryo transfer treatments with endometrial preparation in AC carried out at Instituto Bernabeu between January 2019 and July 2020. 153 patients received 1 pessary of 400 mg every 12 hours (group A) and 194 received 2 pessaries of 200 mg every 12 hours (group B). Sampled size calculation resulted in 182 patients required to detect a minimum difference of 2 ng/ml so sample was powered for the purpose. Participants/materials, setting, methods Patients receiving embryos in AC preparation were included. All embryo transfers were performed at blastocyst stage after 5 days of progesterone administration. Progesterone levels were assessed the day of the embryo transfer by an electrochemiluminescence immunoassay.Primary outcome was the incidence of suboptimal progesterone levels according with the cutoff value stablished in the literature at 8.8 ng/mL. Secondary outcomes were pregnancy rates (PR), clinical pregnancy rates (CPR), ongoing pregnancy rates (OPR) and miscarriage rates (MR). Main results and the role of chance Incidence of suboptimal levels of progesterone was significantly lower in the group of 400 mg (9,8% in Group A vs 19,7% in the Group B, p = 0.011). Given that there was an imbalance between groups in the body weight (66.9 +/- 14 vs. 61.9 +/- 13.165 kg, p < 0.001) and BMI (24.63 +/- 4.861 vs. 22.54 +/- 3.092, p < 0.001), we decided to perform a binary logistic regression setting patient’s weight and BMI as confounding variables. The result confirms a higher risk of suboptimal progesterone levels (<8.8) with the 2x200 mg regimen (OR: 2.52 95%CI: 1.28–4.96; p = 0.007). Mean progesterone levels were similar in both groups (13,8035 ng/mL +/- 4.62159 vs. 13.9799 ng/mL +/- 7.73243 respectively, p = 0.146). No differences were observed in clinical outcomes: PR (52.3% vs. 53.1%, p = 0.881), BM (14.7% vs. 17.6%, p = 0.597), CM (20% vs. 18.6%, p = 0.819) and OPR (33.1% vs. 33.7%, p = 0.912). The subjective medical decision to administer additional progesterone from the day of the embryo transfer onwards (taking values other than 8.8 ng / mL as a reference), was significantly lower in the group of 400 mg (24,3% vs 37,3%, p = 0.009 ). Limitations, reasons for caution The inherent limitations of a retrospective analysis. The study was not powered to detect differences in clinical outcomes. Therefore, results other than progesterone levels should be interpreted with caution. Wider implications of the findings: A single pessary of 400 mg minimizes the necessity of additional medication (usually subcutaneous progesterone). Presentation of 400 mg is superior to 2x200 providing adequate progesterone levels and patient comfort. Dose finding and pharmacokinetics studies of the vaginal administration will be necessary for the future to optimize FET under AC. Trial registration number NCT04722471

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P–605 Low serum progesterone on the day of frozen embryo transfer after artificial endometrial preparation: exploring the clinical impact of “rescue” strategies

Human Reproduction ◽

10.1093/humrep/deab130.604 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

A Herencia ◽

J Llácer ◽

J A Ortiz ◽

J C Castillo ◽

C Gavilán ◽

...

Keyword(s):

Clinical Outcomes ◽

Embryo Transfer ◽

Pregnancy Rates ◽

Frozen Embryo Transfer ◽

Control Group ◽

Ongoing Pregnancy ◽

Serum Progesterone ◽

Endometrial Preparation ◽

Vaginal Progesterone ◽

Low Serum

Abstract Study question Can we rescue treatments with low progesterone (PG) levels the day of frozen embryo transfer (FET) by adding subcutaneous progesterone? Summary answer After receiving additional supplementation with subcutaneous progesterone, women with low serum progesterone on cryotransfer day, have similar ongoing pregnancy rates as women with normal levels. What is known already Micronized vaginal progesterone fails to achieve optimal serum levels in up to 30% of patients receiving frozen embryos under artificial cycles (AC) despite the administration of 400 mg twice daily. Cancelling the thawing process and restarting a new treatment is a very disappointing option for patients and doctors. An alternative strategy is to administrate additional progesterone subcutaneously. The efficacy of the additional administration of subcutaneous progesterone as a “rescue” strategy in terms of clinical outcomes remains to be validated. Study design, size, duration We included 356 FET performed at Instituto Bernabeu between January 2019 - August 2020 in a retrospective case-control study. Groups were established according to PG levels on the day of the embryo transfer. The Control Group included: patients with optimal progesterone levels (≥8.8 ng ml); while the Rescue Group included those with suboptimal progesterone levels (<8.8 ng ml). Participants/materials, setting, methods All patients performed frozen embryo transfer after artificial endometrial preparation. All embryo transfers were performed at blastocyst stage after 5 days of progesterone administration. Progesterone levels were assessed the day of the embryo transfer by an electrochemiluminescence immunoassay. Samples were obtained 2–5 hours after the last vaginal progesterone administration. Primary outcome was Ongoing Pregnancy Rates (OPR). Secondary outcomes were pregnancy rates (PR), miscarriage rates (MR) and biochemical miscarriage (BM). Main results and the role of chance 301 patients were included in the Control Group and 55 in the Rescue Group. No significant differences were found between both groups. OPR rate was 34.7% for patients in the control group versus 26.4% in the rescue group (p = 0.240) PR was 52.5% for patients with optimal PG levels vs 54.5% when PG levels were below 8.8 ng/mL. Both BM and MR tend to be higher in women who had low serum PG: BM (21.4% vs 15.5%) and MR (28.6% vs 18.1%), without reaching significant statistical difference. In addition, we analyzed data from a sub-group of patients who received extra subcutaneous progesterone (based on cliniciańs decision), despite having normal serum PG levels. No differences in clinical outcomes between these groups were observed either. OPR was 29%, vs 35.4% (p = 0.241), PR was 51.8% vs 53.7%; BM was 16.7% vs 16.3% and MR was 26.9% vs 17.1% between women who received an extra subcutaneous PG dose versus women who did not, respectively. Weight and BMI distribution were homogeneous across groups. A discreet difference was observed in age distribution (control group mean age 41.6 years vs. 39.7 years in the rescue group). Limitations, reasons for caution The retrospective collection of data and a limited sample size constitutes the main limitations of the study. Significant statistical differences were not found between groups but still differences might be clinically relevant. Larger studies are needed to reach robust conclusions on the strategy. Wider implications of the findings: In AC cycles, when supplemented with additional subcutaneous progesterone, women showing low serum progesterone on cryotransfer day may expect similar clinical outcomes as women with normal levels. Pending on confirmatory studies, this strategy could consider as an alternative to cycle cancellation. Trial registration number Not applicable

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Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study

Human Reproduction ◽

10.1093/humrep/deab031 ◽

2021 ◽

Author(s):

Manuel Álvarez ◽

Sofía Gaggiotti-Marre ◽

Francisca Martínez ◽

Lluc Coll ◽

Sandra García ◽

...

Keyword(s):

Pregnancy Rate ◽

Embryo Transfer ◽

Pregnancy Outcomes ◽

Luteal Phase ◽

Frozen Embryo Transfer ◽

Ongoing Pregnancy ◽

Serum Progesterone ◽

Endometrial Preparation ◽

Group 2 ◽

Group 1

Abstract STUDY QUESTION Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer? SUMMARY ANSWER Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels. WHAT IS KNOWN ALREADY The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET. STUDY DESIGN, SIZE, DURATION A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day. PARTICIPANTS/MATERIALS, SETTING, METHODS Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 > 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 < 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 > 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2). MAIN RESULTS AND THE ROLE OF CHANCE Patient’s demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) −2.7%, 95% CI [−11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD −4.2%, 95% CI [−13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD −3.2%, 95% CI [−12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [−4.3; 10.7]). LIMITATIONS, REASONS FOR CAUTION Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved. WIDER IMPLICATIONS OF THE FINDINGS Our study provides information regarding an ‘opportunity window’ for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 < 10.6 ng/ml) and restored values the day of FET (P4 > 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER NCT03740568.

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