Impact of serum progesterone levels on the day of embryo transfer in artificial endometrial preparation cycles on the ongoing pregnancy rate. An interim analysis

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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Endometrial compaction and serum progesterone measurements at the day of embryo transfer cannot predict pregnancy outcomes in frozen-thaw embryo transfer cycles

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v12i1.4050 ◽

2021 ◽

Vol 12 (1) ◽

pp. 407-415

Author(s):

Dalal M. Al Jarrah ◽

Manal Taha Al Obaidi ◽

Itlal J. AL Asadi

Keyword(s):

Pregnancy Rate ◽

Embryo Transfer ◽

Pregnancy Outcomes ◽

Endometrial Thickness ◽

Transvaginal Ultrasound ◽

P Value ◽

Ongoing Pregnancy ◽

Ongoing Pregnancy Rate ◽

Serum Progesterone ◽

The Impact

Endometrial receptivity plays a basic role in successful embryo implantation and pregnancy outcomes and can be assessed by many of non-invasive markers. Our study evaluated the impact of two of these markers specifically serum progesterone and endometrial thickness at embryo transfer day in prediction pregnancy outcomes on (60) patients attempting medicated frozen embryo transfer (FET) cycles. All patients were received sequential estrogen & progesterone medications for endometrial preparation then submitted to measurements of endometrial thickness (EMT) by transvaginal-ultrasound (TV-US) & serums progesterone (P) analysis at the embryo transfer day, thereafter day 3 verified-thawed embryos grades (A±B) were transferred. Compacted (decreased) EMT was seen in 48.3% of patients with higher pregnancy rate (PR) of 58.6%t than non-compacted EMT (no change or increased) which was seen in 51.7% of patients with (PR) of 29.0%, (P value=0.021). However ongoing pregnancy rate (Ong PR) not differed significantly between both groups (44.8% in compacted vs 25.8% in non-compacted, P value=0.053), also the means of serum P not differed between pregnant and non-pregnant patients (P value=0.374). ROC curves for Ong PR prediction in relations to endometrial compaction & serum progesterone at embryo transfer day were poor (AUC= 0.630, & AUC=0.576, respectively). This study suggested that endometrial compaction or serum P levels measurements at embryo transfer day were poor predictors for ongoing pregnancy where any kind of EMT changes (decreased or not) seen after P administration not significantly affect pregnancy outcomes in frozen-thaw cycles of cleavage stage embryos transfer.

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P–404 Low serum progesterone on the day of frozen blastocyst transfer is associated with a diminished ongoing pregnancy rate in hormonal replacement therapy cycles

Human Reproduction ◽

10.1093/humrep/deab130.403 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

C Maignien ◽

B Mathilde ◽

B Valérie ◽

C Ahmed ◽

C Charles ◽

...

Keyword(s):

Replacement Therapy ◽

Pregnancy Rate ◽

Embryo Transfer ◽

Frozen Embryo Transfer ◽

Blastocyst Transfer ◽

Progesterone Level ◽

Ongoing Pregnancy ◽

Ongoing Pregnancy Rate ◽

Serum Progesterone ◽

Hormonal Replacement

Abstract Study question Is there a relationship between progesterone levels on the day of frozen blastocyst transfer and ongoing pregnancy rate (OPR), in hormonal replacement therapy (HRT) cycles? Summary answer Women undergoing HRT-frozen embryo transfer with progesterone levels≤9.76ng/ml on the day of blastocyst transfer had a significantly lower OPR than those with progesterone levels>9.76 ng/ml. What is known already The importance of serum progesterone levels around the time of frozen embryo transfer (FET) is a burning issue, in view of the growing number of FET worldwide. However, the optimal range of serum progesterone levels is not clearly determined and discrepancies arise from the current literature. Study design, size, duration: Observational cohort study with 915 patients undergoing HRT-FET at a tertiary care university hospital, between January 2019 and March 2020. Participants/materials, setting, methods Patients undergoing single autologous blastocyst FET under HRT using exogenous estradiol and vaginal micronized progesterone for endometrial preparation. Women were only included once during the study period. The serum progesterone level was measured in the morning of the FET, in a single laboratory. The primary endpoint was OPR beyond pregnancy week 12. Statistical analysis was conducted using univariate and multivariate logistic regression models. Main results and the role of chance Mean serum progesterone level on the day of FET was 12.90 ± 4.89 ng/ml). The OPR was 35.5% (325/915) in the overall population. Patients with a progesterone level ≤ 25th percentile (≤9.76ng/ml) had a significantly lower OPR and a higher miscarriage rate (MR) compared with women with progesterone level over Centile 25 (29.6% versus 37.4%; p = 0.033 and 34.8% versus 21.3%; p = 0.008, respectively). After adjustment for the potential confounders in a multivariate analysis, a serum progesterone level ≤ 9.76 ng/ml on the day of FETand FET of a Day 6-blastocyst (versus Day 5-blastocyst) were found as independent risks factor of lower OPR. Limitations, reasons for caution The main limitation of our study is linked to its observational design. Extrapolation of our results to other laboratories, or other routes and/or doses of administering progesterone also needs to be validated. Wider implications of the findings: This study suggests that a minimum serum progesterone level is needed to optimize reproductive outcomes in autologous blastocyst FET, in HRT-cycles. Further studies are needed to evaluate if modifications of progesterone routes and/or doses may improve pregnancy chances, in an approach to individualize the management of ART patients. Trial registration number NA

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Impact of low serum progesterone levels on the day of embryo transfer on pregnancy outcome: a prospective cohort study in artificial cycles with vaginal progesterone

Human Reproduction ◽

10.1093/humrep/deaa322 ◽

2020 ◽

Author(s):

Elena Labarta ◽

Giulia Mariani ◽

Stefania Paolelli ◽

Cristina Rodriguez-Varela ◽

Carmina Vidal ◽

...

Keyword(s):

Logistic Regression ◽

Cohort Study ◽

Embryo Transfer ◽

Prospective Cohort ◽

Independent Factor ◽

Ongoing Pregnancy ◽

Multivariate Logistic Regression ◽

Serum Progesterone ◽

Endometrial Preparation ◽

Day Of Embryo Transfer

Abstract STUDY QUESTION Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER Serum P levels <8.8 ng/ml on the day of ET lower ongoing pregnancy rate (OPR) in both own or donated oocyte cycles. WHAT IS KNOWN ALREADY We previously found that serum P levels <9.2 ng/ml on the day of ET significantly decrease OPR in a sample of 211 oocyte donation recipients. Here, we assessed whether these results are applicable to all infertile patients under an artificial endometrial preparation cycle, regardless of the oocyte origin. STUDY DESIGN, SIZE, DURATION This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE Women with serum P levels <8.8 ng/ml (30th percentile) had a significantly lower OPR (36.6% vs 54.4%) and live birth rate (35.5% vs 52.0%) than the rest of the patients. Multivariate logistic regression showed that serum P < 8.8 ng/ml was an independent factor influencing OPR in the overall population and in the three treatment groups. A significant negative correlation was observed between serum P levels and BMI, weight and time between the last P dose and blood tests and a positive correlation was found with age, height and number of days on HRT. Multivariate logistic regression showed that only body weight was an independent factor for presenting serum P levels <8.8 ng/ml. Obstetrical and perinatal outcomes did not differ in patients with ongoing pregnancy regardless of serum P levels being above/below 8.8 ng/ml. LIMITATIONS, REASONS FOR CAUTION Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER NCT03272412.

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O-200 Frozen embryo transfer: Miscarriage rates depending on the starting day of intramuscular progesterone

Human Reproduction ◽

10.1093/humrep/deab128.011 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

N Kalhorpour ◽

B Martin ◽

O Kulski ◽

J M Mayenga ◽

I Grefenstette ◽

...

Keyword(s):

Pregnancy Rate ◽

Embryo Transfer ◽

Live Birth ◽

Frozen Embryo Transfer ◽

Ongoing Pregnancy ◽

Miscarriage Rate ◽

Ongoing Pregnancy Rate ◽

Group A ◽

Group B ◽

Day Of Embryo Transfer

Abstract Study question Objective was to assess whether adjusting starting day of intramuscular progesterone the day of vaginal supplementation versus day of embryo transfer or later, might affect the outcome of the cycle. Summary answer additional injection of intramuscular progesterone the day of progesterone initiation or later, is not likely to be more effective on live birth and miscarriage rates. What is known already There is no consensus on the most effective method of endometrium preparation prior to FET. However, many studies report that high serum progesterone concentration during the implantation period is associated with optimal live birth rates. Adjusting progesterone treatment the day of embryo transfer seems to be too late and ineffective for rescuing low progesterone levels and should be done before. Study design, size, duration In this single center prospective study from October 2019 to november 2020, 239 patients undergoing hormonal replacement therapy protocol for frozen embryo transfer were randomly divided into two groups: additional injection of intramuscular progesterone the day of progesterone initiation or intramuscular progesterone the day of embryo transfer. We compare these results to our previous protocol beginning intramuscular progesterone day 22 of the treatment. Participants/materials, setting, methods Our frozen embryo transfer protocol consists to initiate GnRH agonist the day 1 of the cycle. After 14 days of estrogens, we introduce vaginal progesterone, prior to embryo transfer. Patients in group A received an additional injection of intramuscular progesterone the day of progesterone initiation. The group B received intramuscular progesterone the day of embryo transfer. For both, intramuscular injection of progesterone was followed every 3 days. Main results and the role of chance 239 patients were enrolled in this study, 125 in the group A and 114 in the group B. The ongoing pregnancy rate in the group A was 26.4 % and miscarriage rate 7.2%, not statistically different from ongoing pregnancy rate and miscarriage rate of women in the group B (22.81 %, p = 0.66/ 6.14%, p = 0.8). The ongoing pregnancy rate in the group D22 was 24.89 % et miscarriage rate 7.2%, not statistically different from ongoing pregnancy rate of women in the group A and B (p = 0.78 and p = 0.31). Limitations, reasons for caution The main limitation of our study is the lack of randomization for the group with additional progesterone IM on day 22. The study is actually followed to enroll more patients in 3 different groups. Wider implications of the findings This study tries to determine optimal adaptive management of hormonal replacement treatment for embryo transfer in patients with potential low progesterone values. Trial registration number no applicable

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PP-011 - A comparison of ongoing pregnancy rate between frozen embryo transfer following freeze-all cycle and fresh embryo transfer

Reproductive BioMedicine Online ◽

10.1016/s1472-6483(16)30146-8 ◽

2016 ◽

Vol 32 ◽

pp. S6

Author(s):

Huynh Gia Bao ◽

Tran Tu Cam ◽

Ha Thanh Que ◽

Pham Duong Toan ◽

Ho Manh Tuong

Keyword(s):

Pregnancy Rate ◽

Embryo Transfer ◽

Frozen Embryo Transfer ◽

Ongoing Pregnancy ◽

Fresh Embryo Transfer ◽

Ongoing Pregnancy Rate

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P–411 Does subcutaneous progesterone (SC-P) administration eliminate the necessity of serum progesterone level monitoring in frozen embryo transfer (FET) cycles?

Human Reproduction ◽

10.1093/humrep/deab130.410 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

F K Boynukalin ◽

R Abalı ◽

M Gultomruk ◽

B Demir ◽

Z Yarkiner ◽

...

Keyword(s):

Logistic Regression ◽

Clinical Outcomes ◽

Embryo Transfer ◽

Endometrial Thickness ◽

Hormone Replacement ◽

Pregnancy Rates ◽

Ongoing Pregnancy ◽

Ongoing Pregnancy Rate ◽

Serum Progesterone ◽

Female Age

Abstract Study question Does SC-P provide similar ongoing pregnancy rates (OPRs) as intramuscular progesterone(IM-P) in hormone replacement therapy (HRT)-FET cycles and do serum progesterone (P) levels on FET day effect on pregnancy outcome? Summary answer: SC-P administration had similar OPR compared to IM-P in HRT-FET cycles. In SC-P group embryo transfer(ET) day P found to be insignificant factor for outcome. What is known already Different P routes can be used in HRT-FET cycles such as vaginal P, IM-P and recently SC-P. Only retrospective studies evaluated the comparison of SC-P with other routes in HRT-FET cycles. Here, we assessed prospectively whether SC-P is effective for HRT-FET cycles. Previous studies reported that serum P levels on ET day after vaginal P administration clinical outcomes were closely correlated. The correlation between serum P after IM-P administration and clinical outcomes were conflicting. In addition, there is lack of data on the serum P levels after SC-P administration. Serum P levels on ET day were evaluated in this study. Study design, size, duration This prospective cohort study was performed between July 1-October 31 2020, enrolled 224 patients scheduled for HRT-FET cycles with SC-P(25 mg twice daily) or IM-P(50 mg once daily). The route of P was decided according to the patient’s eligibility to hospital. First FET cycle was included after freeze-all cycles for each patients. Female age>35, PGT-A cycles, cleavage ET, >1 ET, patients with uterine pathology and hydrosalpinx, FET with surplus embryos, endometrial thickness<7mm were excluded. Participants/materials, setting, methods Female age ≤ 35 years old with a triple-layer endometrium >7 mm underwent transfer of single blastocysts after the first ET after freeze-all cycles. The indications for freeze-all were ovarian hyperstimuation syndrome and trigger day P level>1.5 ng/ml. 224 patients were eligible for study; 133 in SC-P group and 91 in IM-P group.The primary endpoint was the ongoing pregnancy rate (OPR) beyond pregnancy week 12. Main results and the role of chance The demographic, cycle, embryologic characteristics were similar between groups. The median circulating P levels on the day of ET were 19.92(15.195–27.255)ng/ ml and 21(16.48–28)ng/ml in the SC-P and IM-P groups,(p = 0.786). The clinical pregnancy rates [86/133(64.7%) vs 57/91(62.6%);p=0.757], miscarriage rates [21/86(24.4%) vs 10/57(17.5%) ;p=0.329], and OPR [65/133 (48.9%) vs 47/91(51.6%); p = 0.683] were comparable between the SC-P and IM-P. Binary logistic regression was performed for ongoing pregnancy as the dependent factor blastocyst morphology was found to be the only significant independent prognostic factor (p = 0.006), whereas the route of P was insignificant. In the SC-P and IM-P  groups, the effect of ET day P levels were divided into quartiles(Q) to evaluate the effect on ongoing pregnancy. In SC-P group OPR were similar in four Q [Q1:33.3%(11/33),Q2:50%(17/34),Q3:60.6%(20/33),Q4:51.5%(17/33) (p = 0.1)].For IM-P group; Q1 had a significantly reduced OPR than Q2, Q3, Q4. [26.1%(6/23),65.2%(15/23),54.5%(12/22) and 60.9%(14/23), p = 0.031]. Logistic regression analysis for OP was performed separately in SC-P group and IM-P group. Although in SC-P group, ET day P levels was not found to be a significant factor, in IM-P ET day P level was found to be an independent factor for OP in IM-P group (Q1vs Q2+Q3+Q4; OR: 8,178 95% CI: [1.387–48.223] p:0.02). . Limitations, reasons for caution Although this study has the advantage of being prospective and in a homogenous study population, randomized controlled trials are warranted to evaluate the effectiveness of SC-P to other routes of P. Extrapolation to unselected populations of this study is needed. Wider implications of the findings: Assignment of threshold of serum P on the day of ET for HRT-FET cycles to optimize outcomes is critical for every route of P. Regarding these results, individual luteal phase for HRT-FET cycles can improve IVF outcome. Trial registration number None

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