Day Of Progesterone Administration Research Articles

The natural cycle protocol of endometrial preparation for frozen embryo transfer decreases the miscarriage rate in women with recurrent pregnancy loss

Objective To investigate whether different endometrial preparation methods lead to different results. Design Retrospective cohort study. Patients Women with recurrent pregnancy loss undergoing frozen embryo transfer (FET). Interventions Natural cycle (NC) protocol (n = 111) with no drug or human chorionic gonadotropin (HCG) used for endometrial preparation, vs. the hormone replacement therapy (HRT) protocol (n = 797) with estrogen or gonadotropin releasing hormone agonist (GnRH-a) plus estrogen used for endometrial preparation. Main outcome measures Miscarriage rate and live birth rate (LBR). Results Compared to women in the HRT protocol, women undergoing NCs had fewer previous FET cycles, lower antral follicle counts (AFCs), fewer oocytes retrieved and a thicker endometrium on the day of progesterone administration. Women in the HRT group had a higher miscarriage rate (29.4% vs. 17.2%) and a lower LBR (37% vs. 46.9%) than the rates of women in the NC group. Univariate analysis showed that female age also had a negative association with the miscarriage rate. Logistic regression indicated that endometrial preparation using the NC protocol was linked to a decreased likelihood of miscarriage. Conclusions The NC protocol decreased the miscarriage rate and increased the LBR for patients with recurrent pregnancy loss compared with the HRT protocol.

Rectal progesterone administration secures a high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol: a prospective interventional study.

Can supplementation with rectal administration of progesterone secure high ongoing pregnancy rates (OPRs) in patients with low serum progesterone (P4) on the day of blastocyst transfer (ET)? Rectally administered progesterone commencing on the ET day secures high OPRs in patients with serum P4 levels below 35 nmol/l (11 ng/ml). Low serum P4 levels at peri-implantation in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles impact reproductive outcomes negatively. However, studies have shown that patients with low P4 after a standard vaginal progesterone treatment can obtain live birth rates (LBRs) comparable to patients with optimal P4 levels if they receive additionalsubcutaneous progesterone, starting around the day of blastocyst transfer. In contrast, increasing vaginal progesterone supplementation in low serum P4 patients does not increase LBR. Another route of administration rarely used in ART is the rectal route, despite the fact that progesterone is well absorbed and serum P4 levels reach a maximum level after ∼2 h. This prospective interventional study included a cohort of 488 HRT-FET cycles, in which a total of 374 patients had serum P4 levels ≥35 nmol/l (11 ng/ml) at ET, and 114 patients had serum P4 levels <35 nmol/l (11 ng/ml). The study was conducted from January 2020 to November 2022. Patients underwent HRT-FET in a public Fertility Clinic, and endometrial preparation included oral oestradiol (6 mg/24 h), followed by vaginal micronized progesterone, 400 mg/12 h. Blastocyst transfer and P4 measurements were performed on the sixth day of progesterone administration. In patients with serum P4 <35 nmol/l (11 ng/ml), 'rescue' was performed by rectal administration of progesterone (400 mg/12 h) starting that same day. In pregnant patients, rectal administration continued until Week 8 of gestation, and oestradiol and vaginal progesterone treatment continued until Week 10 of gestation. Among 488 HRT-FET single blastocyst transfers, the mean age of the patients at oocyte retrieval (OR) was 30.9 ± 4.6 years and the mean BMI at ET 25.1 ± 3.5 kg/m2. The mean serum P4 level after vaginal progesterone administration on the day of ET was 48.9 ± 21.0 nmol/l (15.4 ± 6.6 ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35 nmol/l (11 ng/ml). The overall, positive hCG rate, clinical pregnancy rate, OPR week 12, and total pregnancy loss rate were 66% (320/488), 54% (265/488), 45% (221/488), and 31% (99/320), respectively. There was no significant difference in either OPR week 12 or total pregnancy loss rate between patients with P4 ≥35 nmol/l (11 ng/ml) and patients with P4 <35 nmol/l, who received rescue in terms of rectally administered progesterone, 45% versus 46%, P = 0.77 and 30% versus 34%, P = 0.53, respectively. OPR did not differ whether patients had initially low P4 and rectal rescue or were above the P4 cut-off. Logistic regression analysis showed that only age at OR and blastocyst scoring correlated with OPR week 12, independently of other factors like BMI and vitrification day of blastocysts (Day 5 or 6). In this study, vaginal micronized progesterone pessaries, a solid pessary with progesterone suspended in vegetable hard fat, were used vaginally as well as rectally. It is unknown whether other vaginal progesterone products, such as capsules, gel, or tablet, could be used rectally with the same rescue effect. A substantial part of HRT-FET patients receiving vaginal progesterone treatment has lowserum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient, and progesterone pessaries are easy to administer rectally and of low cost. Gedeon Richter Nordic supported the study with an unrestricted grant as well as study medication. B.A. has received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA and Marckyrl Pharma. P.H. has received honoraria for lectures from Gedeon Richter, Merck, IBSA and U.S.K. has received grant from Gedeon Richter Nordic, IBSA and Merck for studies outside this work and honoraria for teaching from Merck and Thillotts Pharma AB and conference expenses covered by Merck. The other co-authors have no conflict of interest to declare. EudraCT no.: 2019-001539-29.

Pretreatment with a long-acting GnRH agonist for frozen-thawed embryo transfer cycles: how to improve live birth?

BackgroundWhether pretreatment with gonadotropin-releasing hormone agonist (GnRHa) can improve the pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles is controversial. The inconsistencies in the results of different studies would be related to the characteristics of the included patients and the protocol of GnRHa use. In this study, we investigated the efficacy of pretreatment with a long-acting GnRH agonist in the early follicular phase of FET cycles and determined which population was suitable for the protocol.ResultsWe retrospectively included 630 and 1141 patients in the GnRHa FET and hormone replacement treatment (HRT) FET without GnRHa groups respectively, between October 2017 and March 2019 at a university-affiliated in vitro fertilization center. On the second or third day of menstruation, 3.75 mg of leuprorelin was administered. After 14 days, HRT was initiated for endometrial preparation. No significant differences were observed between the two groups in terms of patient characteristics. However, the GnRHa FET group showed a higher percentage of endometrium with a triple line pattern (94.8% vs 89.6%, p < 0.001) on the day of progesterone administration, with increased implantation (35.6% vs 29.8%, p = 0.005), clinical pregnancy (49.8% vs 43.3%, p = 0.008), and live birth rate (39.4% vs 33.7%, p = 0.016), than the HRT FET cycles with similar endometrial thickness, ectopic pregnancy and early miscarriage rates. Binary logistic regression analysis showed the GnRHa FET group to be associated with an increased chance of clinical pregnancy (P=0.028, odds ratio [OR] 1.32, 95% confidence interval [CI] 1.03–1.70) and live birth (P=0.013, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.06–1.70) compared to the HRT FET without GnRHa group. After subgroup analysis, we found that the GnRHa FET group showed a significantly higher live birth rate in the subgroups of age < 40 years, primary infertility, with polycystic ovary syndrome (PCOS), and irregular menstruation.ConclusionsPretreatment with a long-acting GnRHa during the early follicular phase improved the live birth rate in FET cycles. Age < 40 years, primary infertility, PCOS, and irregular menstruation are effective indications for endometrial preparation with GnRHa pretreatment in FET cycles. However, further randomized controlled trials are required to verify these results.

Metabolomics analysis of serum metabolites during endometrial transformation: association with recurrent implantation failure in hormonal replacement therapy-frozen embryo transfers cycles.

The purpose of this study was to investigate alterations in serum metabolites during endometrial transformation and possibleassociations with recurrent implantation failure (RIF) in hormonal replacement therapy (HRT)-frozen embryo transfer (FET) cycles. We performed a prospective study involving 100 patients scheduled for HRT-FET cycles during January 2022 to April 2022. Blood serum samples were collected on the day of progesterone administration (dPA) and on the third day of progesterone administration (d3PA). Gas chromatography-mass spectrometry (GC-MS) analysis was performed to identify and quantify serum metabolites. A nested case-control study including 19 RIF patients and 19 matching controls was conducted to explore the predictive value of serum metabolites for RIF. Partial least squares discriminant analysis (PLS-DA) and receiver operating characteristic (ROC) curve analysis were performed to establish prediction models. We identified 105 serum metabolites, with 76 of them exhibiting significant alterations during the initial 3 days of endometrial transformation. Metabolites involved in amino acid metabolism and tricarboxylic acid (TCA) cycle showed lower levels during endometrial transformation. In the nested case-control study, the prediction model based on the ratio of serum metabolites between d3PA and dPA showed the highest area under the ROC curve (AUC), accuracy, and R2 and Q2 values. Eight metabolites, including indol-3-propionic acid, beta-alanine, myristoleic acid, malic acid, indole, DL-isocitric acid, proline, and itaconic acid, exhibited high predictive values for RIF. This study demonstrates alterations in serum metabolites during endometrial transformation, particularly in amino acid metabolism and TCA cycle. The identified metabolites, especially indol-3-propionic acid and malic acid, show potential as predictive markers for RIF. These findings contribute to a better understanding of the metabolic changes associated with endometrial receptivity and provide insights for the development of personalized approaches to improve implantation outcomes in FET cycles.

O-024 Exploring the optimal transfer day of day 6 (D6) vitrified blastocysts in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles - a cohort study

Abstract Study question Should blastocysts cryopreserved D6 be transferred on the 5th or 6th day of progesterone administration in HRT-FET cycles? Summary answer No significant differences in outcome parameters were found when D6 vitrified blastocysts were transferred on either day 5 or day 6 of progesterone in HRT-FET. What is known already Several studies have shown that D6 blastocyst transfer should be avoided in fresh transfer IVF cycles; consequently, these more slowly developing embryos are transferred in a HRT-FET cycle on the 6th day of progesterone administration in line with day 5 (D5) blastocysts. For successful implantation, a receptive endometrium and optimal synchronization between the endometrium and embryo are important. However, no definitive evidence exists regarding the optimal timing of transferring D6 blastocysts. Interestingly, a few studies have reported better reproductive outcomes if D6 blastocysts are transferred on the 5th day of progesterone administration instead of the 6th day of progesterone administration. Study design, size, duration This cohort study included a total of 718 vitrified D6 single blastocyst HRT-FET cycles performed between 2013 and 2022. 576 blastocysts were transferred on the 6th day of progesterone administration (2013-2021), and 142 blastocysts transferred on the 5th day of progesterone administration (2021-2022). Main outcomes were biochemical pregnancy rate (PR), implantation rate (IR), clinical pregnancy rate (CPR), and early pregnancy loss rate (EPLR). Participants/materials, setting, methods Patients undergoing HRT-FET in a public Fertility Clinic. Endometrial preparation included oral oestradiol (6mg/24hours), followed by vaginal micronized progesterone. As mentioned above, single blastocyst transfer was performed on either the 5th or 6th day of progesterone administration. Serum β-hCG level was measured 9-11 days after embryo transfer and biochemical pregnancy was defined as an hCG level &amp;gt;10 IU/L. Clinical pregnancy was defined as visualization of a gestational sac and fetal heartbeat in gestational week 7. Main results and the role of chance In this cohort of a total of 718 HRT-FET cycles transferred on either the 5th or 6th day of progesterone administration the mean age of the patients at embryo transfer was 34.5±4.5 years vs. 33.0±4.9 years, respectively, p = 0.30. There was no significant difference between numbers of top-quality blastocyst transfers within the two groups 63% (89/142) vs. 64% (369/576), p = 0.76. The overall, biochemical pregnancy rate (PR), implantation rate (IR), clinical pregnancy rate (CPR) and early pregnancy loss (EPLR) in the group of patients transferred on the 5th day of progesterone administration were 38% (54/142), 29% (41/142), 25% (36/142) and 33% (18/54). In the group of patients transferred on the 6th day of progesterone administration 41% (235/576), 33% (191/576), 30% (170/576) and 28% (65/235). There were no significant differences between PR, IR, CPR and EPLR when transferring D6 vitrified blastocysts on either the 5th or the 6th day of progesterone administration (38% vs. 41%, p = 0.53, 29% vs. 33%, p = 0.33, 25% vs. 30%, p = 0.33 and 33% vs. 28%, p = 0.41). Limitations, reasons for caution Limitations of the study are the retrospective design and the limited number of D6 vitrified blastocysts transferred on the 5th day of progesterone administration. Furthermore, the two groups represented two different time periods. Wider implications of the findings Growing evidence shows that D5 vitrified blastocysts have better reproductive outcomes than slower developing embryos which are vitrified on day 6. Whether this is caused by intrinsic embryonic factors or poor timing of transfer in a subsequent FET cycle still needs to be unraveled. Trial registration number not applicable

P-511 Prolonging the time of vaginal progesterone supplementation does not improve pregnancy outcomes after day 6 blastocyst transfer

Abstract Study question Does the administration of vaginal progesterone for 6 days improve pregnancy outcomes when transferring day 6 blastocysts, as opposed to 5 days of progesterone treatment? Summary answer We observed similar pregnancy outcomes after 5 and 6 days of vaginal progesterone supplementation following day 6 blastocyst transfer in oocyte recipient cycles. What is known already Progesterone administration promotes the final phase of endometrial preparation for embryo transfer. However, the optimal duration of progesterone transformation still remains unknown. The implantation potential of blastocysts formed at different timepoints is also contentious, as blastocysts on day 6 have been linked to poorer clinical outcomes compared to their day 5 counterparts. It is unclear whether this effect stems from an intrinsic impaired implantation capacity of slow-developing blastocysts, or a displaced window of implantation (WOI). It has been hypothesized that 6 days of progesterone administration may improve clinical outcomes after frozen day 6 blastocyst transfer. Study design, size, duration Retrospective cohort study of oocyte recipients undergoing single day 6 blastocyst transfer, between January 2020 and December 2022. This study compared two groups: day 6 blastocysts transferred after 5 days of progesterone administration (n = 284) and day 6 embryo transfers performed after 6 days of progesterone administration (n = 69). Participants/materials, setting, methods Our study included oocyte recipients who underwent a single embryo transfer of a day 6 blastocyst and hormonal replacement treatment for endometrial preparation with vaginal external progesterone administration (800mg/24h) for either 5 or 6 days prior to embryo transfer. Outcomes were analyzed using unpaired t-test or Fisher’s test and logistic regression. Multivariate models were adjusted for oral or transdermal estrogen administration and endometrial thickness on the day of embryo transfer. P-values &amp;lt;0.05 were considered significant. Main results and the role of chance Mean maternal age was 43.5 years, while patients had a mean BMI of 25.1. Mean days of estrogen therapy prior to embryo transfer were 22.4, with 75.3% of patients using transdermal estrogen administration, and achieving a mean endometrial thickness of 9.6 mm on the day of transfer. Mean progesterone levels on the day of transfer were 11.9 ng/ml. Thirty-seven percent of the day 6 blastocysts were of high quality. None of the demographic or cycle characteristics were significantly different between the study groups. When considering outcomes of day 6 blastocyst transfers, we found no significant differences in biochemical (26.33% vs 20.13%, p = 0.343), clinical (22.06% vs 17.46%, p = 0.49) and ongoing (14.64% vs 9.52%, p = 0.41) pregnancy rates between 5 and 6 days of progesterone administration. Our adjusted analysis further corroborated these results. Limitations, reasons for caution The retrospective nature of the study and low number of transfers performed after 6 days of progesterone treatment warrant careful interpretation. This study only evaluated endometrial preparation by vaginal progesterone administration in oocyte recipients and cannot be extrapolated to other routes of progesterone administration or other patient populations. Wider implications of the findings Poorer reproductive outcomes associated with the transfer of day 6 blastocysts appear to be related to a reduced implantation capacity of slow-developing embryos rather than a displaced WOI due to rising progesterone. WOI appears wider than assumed, as prolonged progesterone transformation times had no effect on pregnancy outcomes. Trial registration number Not applicable

P-475 Effect of transdermal estradiol on endometrial preparation in frozen-thawed embryo transfer: A randomized control study.

Abstract Study question Is patient usage of transdermal estradiol more effective than oral estradiol on endometrial preparation in frozen-thawed embryo transfer cycles? Summary answer This study showed no significant differences in clinical pregnancy rates between the 2 groups. Transdermal gel have advantage of better patient comfort, lesser side effects. What is known already Estrogen and progesterone are crucial factors for endometrial preparation in frozen embryo transfer (FET) cycles. Studies assessing different forms of estradiol in FET have already been published. However, literature and studies in Vietnam are still limited to evaluating, research evaluating transdermal estrogen in ART. This study aimed to evaluate the use of transdermal estradiol gel and compare it with oral estradiol for the endometrium preparation in frozen-thawed embryo transfer (FET) cycles. Study design, size, duration This randomized clinical trial (RCT) included 380 frozen embryo transfer (FET) cycles from February 2020 to August 2021 at the IVF Department, Hung Vuong Hospital. Participants/materials, setting, methods They were randomized into one of the two groups. Group A (n = 190) received oral estradiol and group B (n = 190) received estradiol gel. In both groups, medication was started on day 2 of the menstrual, and endometrial thickness was monitored by ultrasound. Main outcomes were the following: serum estradiol level , endometrial thickness,.... Secondary outcomes were CPR, MR, and side effects in the 2 groups. Statistical testing was performed with Stata 14. Main results and the role of chance There was a significant difference in estradiol level on the day of progesterone administration and embryo transfer between the two groups (270.5 pg/ml versus 186.5 pg/ml, p, p. &amp;lt;0.001). According to the comparison, the two groups were not significantly different in the endometrial thickness on the day of progesterone administration (p = 0.85). as the data suggest, the total dose of estradiol used and the total number of days of dosing were similar in the two groups. The biochemical and clinical pregnancy rates were similar between the two groups and did not a significantly differ (56.2% vs. 52.2%, p = 0.474). The rate of miscarriage was higher than in the study group, but it was not statistically significant. Almost 20.3% of patients (n = 37) in group A had mild adverse effects when compared with only 10.1% (n = 18) in group B, and this was clinically significant (P = 0.007). Limitations, reasons for caution The limitation of our study was not asses ongoing pregnancy rate and live-birth rate. Wider implications of the findings Patients who estradiol valerate is contraindicated such as, high risk for deep vein thrombosis, hyperlipidemia, and clotting disturbance we can use oestrogel to be safe. It is suggested that estradiol transdermal patches be used instead of oral estradiol in FET cycles Trial registration number ISRCTN15301227

P-355 Thin endometrium is associated to higher risk of having a displaced window of implantation (WOI)

Abstract Study question Is thin endometrium (&amp;lt;6 mm) associated to an abnormal receptivity status? Summary answer Thin endometrium (&amp;lt;6 mm) is significantly associated with a displaced WOI. What is known already The measurement of endometrial thickness by 2D vaginal ultrasound (US) is a routine practice in Assisted Reproduction Techniques (ART). Thin endometrium (&amp;lt;6 mm) is associated with poor reproductive outcome; however, the potential reason is unknown. Study design, size, duration Retrospective cohorts study including 25,888 patients in which endometrial lining was measured by 2D US the day before progesterone supplementation in HRT cycles for frozen embryo transfers and Endometrial Receptivity Analysis (ERA) was performed after 5 days of progesterone administration. Endometrial thickness was classified as &amp;lt; 6 mm, 6-12 mm, or &amp;gt; 12 mm; ERA results were considered as receptive or displaced WOI (Pre-receptive, post-receptive, proliferative, and late-receptive) that needs a personalized embryo transfer (pET). Participants/materials, setting, methods Endometrial thickness was measured from one endometrial layer to the other on a longitudinal transvaginal scan at the site of maximum thickness evidenced by 2D US. For ERA analysis, RNA was extracted and sequenced by NGS. Then, the ERA computational predictor obtained the diagnosis as standard or displaced WOI. Main results and the role of chance RA results reveal that women with thin endometrium (&amp;lt;6mm) present significantly higher incidence of displaced WOI (47.49%) than 6-12mm (38.20%) (p = 0.0038), and &amp;gt;12mm (39.75%) (p = 0.026). No other differences were found. *Significant different against other two groups. Global Chi-square test for association P = 0.002. Limitations, reasons for caution This is a retrospective study, having innate limitations of its nature. Wider implications of the findings Thin endometrium (&amp;lt;6mm) is associated to a higher displaced WOI compared to normal lining or hypertrophic endometrium. Normal endometrial thickness (6-12 mm) considered as “receptive” does not preclude a transcriptomic receptivity status in 38.20% of the cases. This finding should be considered when embryo transfer is planned. Trial registration number Not applicable

P-596 Rectal progesterone administration secures high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol - a prospective interventional study

Abstract Study question Can supplementation with additional rectal administration of progesterone secure high ongoing pregnancy rates (OPR) in patients with low serum progesterone (P4) at blastocyst transfer (ET)? Summary answer Rectally administered progesterone starting on the blastocyst transfer day secures high OPR in patients with serum P4 levels lower than 35 nmol/l (11ng/ml). What is known already Low serum P4 levels at peri-implantation in HRT-FET cycles impact reproductive outcomes negatively. However, studies have shown that patients with low P4 after a standard vaginal progesterone treatment can obtain live birth rates (LBR) comparable to patients with optimal P4 levels if they receive additional subcutaneous progesterone, starting close to the day of blastocyst transfer. In contrast, increasing vaginal progesterone supplementation in low serum P4 patients does not increase LBR. Another route of administration rarely used in ART is the rectal route, although progesterone is well absorbed and serum P4 levels reach a maximum level after approximately two hours. Study design, size, duration This prospective interventional study included a cohort of 488 patients treated with single blastocyst HRT-FET, in which a total of 374 patients had a serum P4 level ≥35nmol/l (11ng/ml) at ET, and 114 patients had a serum P4 level &amp;lt;35nmol/l (11ng/ml). The study was conducted from January 2020 to November 2022. Participants/materials, setting, methods Patients undergoing HRT-FET in a public Fertility Clinic. Endometrial preparation included oral oestradiol (6mg/24hours), followed by vaginal micronized progesterone, 400mg/12hours. Single blastocyst transfer and P4 measurements were performed on the 6th day of progesterone administration and patients with serum P4 &amp;lt;35nmol/l (11ng/ml) additional rectal administration of progesterone (400mg/12hour) was started the same day. In pregnant patients, vaginal and rectal administration continued until week 8, and oestradiol and vaginal progesterone treatment continued until week 10. Main results and the role of chance Among 488 HRT-FET single blastocyst transfers, the mean age of the patients at oocyte retrieval (OR) was 30.9 ±4.6 years and the mean BMI at ET 25.1 ±3.5 kg/m2. The mean serum P4 level after vaginal progesterone administration on the day of blastocyst transfer was 48.9 ±21.0 nmol/l (15.4 ±6.6ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35nmol/l (11ng/ml). The overall, positive hCG rate, clinical pregnancy rate, OPR week 12, and total pregnancy loss rate were 66% (320/488), 54% (265/488), 45% (221/488), and 31% (99/320), respectively. There was no significant difference in neither OPR week 12 nor total pregnancy loss rate between patients with P4 ≥35nmol/l (11ng/ml) and patients with P4 &amp;lt;35nmol/l, who received rescue in terms of rectally administered progesterone, 45% vs. 46%, p = 0.77 and 30% vs. 34%, p = 0.53, respectively. OPR did not depend on whether patients had initially low P4 and rectal rescue or were above the P4 cut-off. Logistic regression analysis showed that only age at OR and blastocyst scoring correlated with OPR week 12, independently of other factors like BMI, and vitrification day of blastocysts (day 5 or 6). Limitations, reasons for caution In this study vaginal progesterone (Cyclogest®), a solid pessary with progesterone suspended in vegetable hard fat, was used vaginally as well as rectally. It is unknown whether other vaginal progesterone products could be used rectally as easily with the same rescue effect. Wider implications of the findings A substantial part of HRT-FET patients receiving vaginal progesterone treatment has low serum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient by the majority of patients; moreover, progesterone pessaries are easy to administer rectally and of low cost. Trial registration number EudraCT no.: 2019-001539-29

Using 2D/3D ultrasound observation of endometrial thickness, endometrial volume, and blood flow changes to predict the outcome of frozen embryo transfer cycles: a prospective study.

Endometrial thickness (EMT) and blood flow are commonly used indicators of endometrial receptivity. However, the results of single ultrasound examination studies differ. Therefore, we used 3-dimensional (3D) ultrasound to study the influence of changes in EMT, endometrial volume, and endometrial blood flow on frozen embryo transfer cycles. This was a prospective cross-sectional study. Women who underwent in vitro fertilization (IVF) at Dalian Women and Children's Medical Group and met the inclusion criteria were enrolled between September 2020 and July 2021. Ultrasound examinations were performed in patients who underwent frozen embryo transfer cycles on the day of progesterone administration, the third day after progesterone administration, and the day of embryo transplantation. Two-dimensional ultrasound was used to record EMT, 3D ultrasound was used to record endometrial volume, and 3D power Doppler ultrasound imaging was used to record the following endometrial blood flow parameters: vascular index, flow index, and vascular flow index. Changes in the 3 inspections of the EMT, volume, vascular index, flow index, and vascular flow index and 2 inspections of estrogen levels were categorized as "declining" or "nondeclining". The relationship between changes in a certain indicator and the IVF outcome was analyzed by univariate analysis and multifactorial stepwise logistic regression. In total, 133 patients were enrolled in this study, 48 were excluded, and 85 were included in the statistical analysis. Among these 85 patients, 61 were pregnant (71%), 47 had a clinical pregnancy (55%), and 39 had an ongoing pregnancy (45%). The results showed that if the first change in endometrial volume was nondeclining, the outcomes of clinical and ongoing pregnancies were more likely to be unfavorable (P=0.03, P=0.01). Additionally, if the second change in endometrial volume on the day of embryo transplantation was nondeclining, the outcome of an ongoing pregnancy was more likely to be favorable (P=0.03). The changes in endometrial volume was a factor helpful in predicting the IVF outcome, whereas the changes in EMT and endometrial blood flow analyses were not helpful in predicting IVF outcome.

Does Endometrial Compaction Predict Clinical Pregnancy Rate after Cleavage Stage Frozen Embryo Transfer?

Objectives: This study aimed to determine the relationships between endometrial compaction and pregnancy outcome in patients receiving artificial endometrial preparation for frozen embryo transfer (FET) cycles. Materials and Methods: This prospective cohort study was performed in a university-affiliated fertility clinic from March 2020 to March 2021. The eligible women undergoing their first or second FET cycle and having the top grading cleavage stage embryos were enrolled. All patients received the same endometrial preparation regime. The alteration in endometrial thickness (EMT) between the day of progesterone initiation and the day of embryo transfer (ET) was measured using consecutive transvaginal sonography. The patients were divided into three groups based on the percentage of endometrial compaction (i.e., the difference of EMT at end of the estrogen-only phase and after three days of progesterone administration (ET day) divided by the EMT on the terminal day of the estrogen-only exposure). Results: Overall, 300 eligible women were evaluated and only 27.3% (82/300) of the studied cycles showed ≥5% compaction, whereas 72.6% (218/300) either expanded or showed minimal compaction. The clinical and ongoing pregnancy rates in group 2 (any expansion) were significantly higher than those in groups 1 and 3 (P=0.002 and P=0.01, respectively). Multivariable logistic regression test indicated that the cycles with any expansion in ET were independently associated with 3.1 times improvement in clinical pregnancy rate in comparison to those with any compaction (P=0.002). Conclusion: Gross endometrial compaction occurred in one-third of FET cycles with no significant positive effect on pregnancy outcomes after cleavage-stage ET.

Analysis of the effect of phloroglucinol on pregnancy outcomes involving frozen embryo transfers in patients with endometriosis: A retrospective case-control study.

Abnormal contraction of uterus and vascular smooth muscle lead to the formation of hypoxia environment in uterus. Abnormal contraction may be the basis of dysmenorrhea, endometriosis, infertility and other diseases. Phloroglucinol is a non-atropine and non-papaverine smooth muscle spasmolytic agent, which can reduce the abnormal contraction of uterine smooth muscle. This study investigated the effect of phloroglucinol on frozen embryo transfer in patients with endometriosis. The data of patients with endometriosis who underwent a frozen embryo transfer in Shanghai Changzheng Hospital from August 2018 to August 2021, comprising a total of 453 cycles, were retrospectively analyzed. The patients for whom phloroglucinol was included over 217 cycles were administered intramuscully 40 mg phloroglucinol starting on the day of progesterone administration, then once daily up to day 7 after the embryo transfer. Those for whom phloroglucinol was not administered over 236 cycles were used as the control group. The age of 35 years was used as a boundary in this study to observe the pregnancy outcomes of patients in the two different age groups. The biochemical pregnancy rate (63.13% vs. 51.27%), embryo implantation rate (44.64% vs. 33.60%), clinical pregnancy rate (59.64% vs. 48.30%), and live birth rate (52.99% vs. 36.86%) after the administration of phloroglucinol were higher than for patients in the control group, and the early abortion rate (7.75% vs. 20.18%) was also lower. The differences were statistically significant (P < 0.05). In particular, in the age group <35 years old, the embryo implantation rate (51.81% vs. 39.38%), clinical pregnancy rate (69.34% vs. 57.55%), and the live birth rate (63.50% vs. 44.60%) after phloroglucinol intervention rose significantly, and the abortion rate dropped (6.32% vs. 17.5%), indicating a statistically significant difference (P < 0.05). However, pregnancy outcomes showed no difference in the age group ≥35 years old (P > 0.05). Continuous low-dose phloroglucinol pretreatment before and after frozen embryo transfer can improve both the clinical pregnancy and live birth rates and reduce the risk of abortion in younger infertile patients with endometriosis.

Evaluation of the IVF success in frozen-thaw in vitro fertilization cycles in terms of endometrial thickness

The aim of this research was to analyze the link between endometrial thickness (EMT), as measured during progesterone administration, and the results observed in individuals who underwent frozenthawed embryo transfer. A retrospective analysis was performed on 233 hormone replacement therapy (HRT) methods of endometrial preparation in frozen-thawed embryo transfer (FET) cycles (HRT-FET). HRT-FET cycles that were conducted between January 2021 and December 2022 at the In vitro fertilization (IVF) Clinic of 19 May University Medical Faculty Training and Research Hospital. The patients' age, infertility duration, basal follicle-stimulating hormone (FSH) level, body mass index (BMI), number and day of embryos transferred, and pregnancy rates were evaluated. Endometrial thickness was measured using transvaginal ultrasound (TV USG) on the day of progesterone administration. The endometrial thickness of patients who achieved clinical pregnancy and those who did not were analyzed. No significant differences in demographic factors were found between the groups in terms of age, infertility duration, basal FSH level, and BMI (p=0.209, p=0.959, p=0.866 and p=0.685, respectively) . The success rates of clinical pregnancy did not strongly correlate with endometrial thickness. The study found that EMT is not a valid indicator for clinical pregnancy in frozen-thawed embryo transfer cycles.

Uterine cytokine profiles after low-molecular-weight heparin administration are associated with pregnancy outcomes of patients with repeated implantation failure.

Low molecular-weight heparin (LMWH) plays a role in repeated implantation failure (RIF), but outcomes are controversial. LMWH can potentially modulate local immune responses associated with the establishment and maintenance of pregnancy. The study aimed to explore the effects of LWMH in uterine inflammatory cytokine profiles and pregnancy outcomes of patients with repeated implantation failure (RIF) but without thrombophilia. We compared clinical characteristics and reproductive outcomes among 326 patients with RIF, but not thrombophilia, undergoing frozen embryo transfer (FET) cycle with or without LMWH treatment. Endometrium secretions were aspirated from both groups after 3 days of progesterone administration before and after LMWH treatment. Cytokine mRNA expression was analyzed in primary endometrial cells in vitro. The clinical and ongoing pregnancy rates did not significantly differ between the groups (31.5% vs. 24.4%, p = 0.15; 29.6% vs. 20.7%, p = 0.06). Concentrations of IL-6 and granulocyte-colony stimulating factor (G-CSF) in uterine secretions were significantly increased in the LWMH group, regardless of pregnancy outcomes (P < 0.05). And, in all patients treated with LWMH, those of secreted IL-6, IL-15 and G-CSF were significantly increased in pregnant group (P < 0.05). The expression of mRNA for G-CSF and IL-6 was significantly increased in human endometrial stromal cells in vitro (P < 0.05) after stimulation with LWMH (10 IU/mL). Uterine cytokine profiles after LMWH administration are associated with pregnancy outcomes and LMWH may be beneficial for patients with three implantation failures who do not have coagulation disorders.

Impact of endometrial thickness change in response to progesterone on live birth rates embryo transfers with fresh oocyte donation cycles

Endometrial thickness (ENT) measurements are important to evaluate endometrial receptivity. The effect of endometrial thickness on pregnancy outcomes has been discussed for many years with conflicting results. The aim of our study was to find out the effect of endometrial thickness (ENT) change in response to progesterone on pregnancy outcomes in embryo transfer (ET) of fresh oocyte donation (OD) recipients. The study was designed retrospectively including 134 embryo transfers with fresh OD recipients. ENT was measured by ultrasonography (USG) on the day of initial progesterone administration (ENT1) and on ET day (ENT2). The primary outcome was to determine any correlation between the ENT change and pregnancy outcomes. ENT increased in 56.7% of cases and decreased in 43.4%. Clinical pregnancy rate (CPR) in recipients with increased ENT was 76.3%, and live birth rate (LBR) was 72.4%. CPR in recipients with decreased ENT was 69.0% and LBR was 65.5%. There was no significant difference between recipients with either increased or decreased ENT regarding CPR and LBR (p = .225 and p = .253, respectively). Our study revealed that ENT change after 6 days of progesterone administration, whether increased or decreased, does not have any significant effect on LBR and CPR in fresh OD recipients. IMPACT STATEMENT What is already known on this subject? Measurement of endometrial thickness is beneficial to determine the endometrial receptivity. However, there is controversy in the literature regarding the usefulness of measuring endometrial thickness. What do the results of this study add? To the best of our knowledge, this is the first study performed with fresh oocyte donation cycles with large number of recipients for live birth rate outcomes in the literature so far. In this study, we sought to assess the impact of endometrial thickness change, in response to 6 days of progesterone administration, on live birth rate and clinical pregnancy rate in embryo transfer of fresh oocyte donation recipients. We did not find no significant effect of endometrial thickness change on live birth rate when fresh young donor oocytes are fertilised with sperms having normal parameters, and implanted in oestrogen and progesterone primed endometrium. What are the implications of these findings for clinical practice and/or further research? Measurement of endometrial thickness in patients under infertility treatment provides little benefit to clinical outcomes.

The Effects of City Lockdown Policy on Frozen Embryo Transfer Outcome during COVID-19 Epidemic in Hubei Province, China.

Objective To evaluate whether there is a difference in clinical pregnancy rate and live birth rate between the corresponding period in 2019 and COVID-19 city lockdown period in 2020 in frozen embryo transfer (FET). Methods In one single in vitro fertilization (IVF) center (Shiyan, Hubei province, China), a retrospective cohort analysis was conducted, with a sample size of 59 patients in the lockdown period (2020.1.23-2020.2.23, 2020 group) and 34 patients in the corresponding 2019 period (2019.1.23-2019.2.23, 2019 group). Implantation, biochemical and clinical pregnancy, miscarriage, and live birth rates were all measured. Results Age, basal serum follicle-stimulating hormone (FSH), basal serum luteinizing hormone (LH), basal serum E2, and serum total T were all comparable between the two groups. On the day of progesterone administration, endometrial thickness was similar (8.5 ± 1.3 vs. 8.2 ± 1.4, P = 0.356). The number of transferred blastocysts was not significantly different. The two groups had similar clinical pregnancy rate (61.8% vs. 61.0%, P > 0.05) and live birth rate (47.1% vs. 49.2%, P > 0.05), which did not significantly differ. Nonetheless, there was a significant difference in the cancelled cycle rate between the two groups (0% vs. 28.0%, P = 0.043). Conclusions Lockdown period FET versus corresponding period FET outcome did not show any significant difference in terms of pregnancy rate and live birth rate between two groups of patients. Although there was no significant difference, in the 2020 group, the live birth rate was higher compared with that in the 2019 group. There was a significant difference in the rate of cancelled cycles due to the seal off control. In summary, artificial endometrial preparation is an appropriate protocol for special periods.

Live Birth Rate of Frozen-Thawed Single Blastocyst Transfer After 6 or 7 Days of Progesterone Administration in Hormone Replacement Therapy Cycles: A Propensity Score-Matched Cohort Study.

BackgroundProgesterone administration before transfer in hormone replacement treatment (HRT) is crucial to pregnancy outcomes in frozen-thawed blastocyst transfer (FET), but the optimal progesterone duration is inconsistent. The objective of this study was to investigate live birth rate (LBR) of different progesterone duration before blastocyst transfer in HRT–FET cycles.MethodIn this retrospective cohort study, patients underwent first HRT–FET (including suppression HRT) from January 2016 to December 2019 were included. Logit-transformed propensity score matching (PSM) was performed to assess covariates. The primary outcome was live birth rate after 28 weeks’ gestation. Basing on different duration of progesterone before transfer, patients were classified into P6-protocol (blastocyst transfer performed on the sixth day), or P7-protocol (blastocyst transfer performed on the seventh day). Subgroup analyses were conducted as follows: age stratification (–35, 35–38, 38–), development days of blastocyst (D5 or D6), blastocyst quality (high-quality or poor-quality), and endometrial preparation protocols (HRT or suppression HRT).ResultAfter case matching with propensity score methods, a total of 1,400 patients were included finally: 700 with P6-protocol and 700 with P7-protocol. Significantly higher live birth rate (38.43% versus 31.57%, respectively, P = 0.01) and clinical pregnant rate (50.43% versus 44.14%, respectively, P = 0.02) were observed in P6-protocol than those of P7-protocol. First-trimester abortion rates (18.13% versus 20.71%, P = 0.40) and ectopic pregnancy rates (2.27% versus 1.94%, P = 0.77) were similar between P6- and P7-groups. Preterm birth rate, low birth weight rate, newborn sex proportion, neonatal malformation rate were comparable between groups. Significantly higher LBRs were observed in patients with: age under 35, D5 blastocyst transfer, high-quality blastocyst transfer, and undergoing HRT cycles combined P6-protocol.ConclusionFrozen-thawed blastocyst transfer on the sixth day of progesterone administration in first HRT cycle is related to higher live birth rate compared with transfer on the seventh day, especially among patients aged under 35, D5 blastocyst and/or high-quality blastocyst transfer.

P–627 Optimal timing of day 6 blastocyst transfer in artificially prepared frozen-thawed embryo transfer cycles

Abstract Study question When is the optimal timing of day 6 (D6) blastocyst transfer between the 6thday (P6)and the 7th(P7) day of progesterone administration in artificially prepared frozen-thawed embryo transfer(FET) cycle Summary answer When transferring D6 blastocysts in artificially prepared FET cycles, live birth rate tended to be higher in P6 group than in P7 group. What is known already Blastocyst transfer in FET cycles has increased due to several reasons including convenience for optimization of endometrial synchronization, improvement of laboratory techniques and preimplantation genetic testing. Meanwhile, D6 blastocyst which cryopreserved on day 6 after being developed to the full blastocyst stage, presented lower pregnancy outcomes in FET cycle than D5 blastocysts. However, there have been few studies on the optimal duration of progesterone administration when transferring D6 blastocysts. Study design, size, duration This was a retrospective cohort study including patients who underwent frozen-thawed blastocyst transfer in artificially prepared cycles from January 2000 to May 2020. Patients with D6 blastocyst transfer on the 6th day of progesterone administration were included in D6-P6 group, and patients with D6 blastocyst transfer on the 7th day of progesterone administration were included in D6-P7 group. Participants/materials, setting, methods Increasing dose of estradiol valerate was administered from the 3rd day of menstruation: 4 mg/day for the first four days, 6 mg/day for next four days, and then 8 mg/day until the confirmation of pregnancy. Progesterone was administered from the 14th day of menstruation if the endometrial thickness reached ≥7 mm. The independent t-test or Mann-Whitney test, chi-square test, and logistic regression analysis were performed. Main results and the role of chance A total of 50 patients were included, and 13 patients underwent FET on P6 and 37 patients underwent FET on P7. Live birth rate was comparable between the P6 group and the P7 group (18.9% vs. 15.4%, p = 0.775). Live birth rate was higher in the D6-P6 group than in the D6-P7 group after adjusting for age, AMH, endometrial thickness on the starting day of progesterone administration and good embryo rate transferred with statistical significance (OR: 6.716, p = 0.005). Limitations, reasons for caution Limitations of the present study is the retrospective design and the small sample size. Caution is needed in extrapolating results of this study because only intramural and vaginal progesterone supplementations were included in this study. Wider implications of the findings: Even if the duration of blastocyst formation was delayed, frozen-thawed D6 blastocyst may need to be considered for on P6 rather than P7. The difference of live birth rate is not statistically significant. This study should be acknowledged for the underestimation of the difference because of the small sample size. Trial registration number Not applicable

P–630 Progesterone levels using pessaries of 400 mg of vaginal progesterone (Cyclogest®) in artificial cycles for frozen embryo transfer

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 &amp;lt; 0.001) and BMI (24.63 +/- 4.861 vs. 22.54 +/- 3.092, p &amp;lt; 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 (&amp;lt;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

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

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 (&amp;lt;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