Comparison of clinical outcomes and perinatal outcomes between natural cycle and hormone replacement therapy of frozen-thawed embryo transfer in patients with regular menstruation: a propensity score-matched analysis.

Purpose: To investigate potential differences in pregnancy outcomes among patients with regular menstruation who underwent frozen-thawed embryo transfer using natural cycle (NC) or hormone replacement therapy (HRT). Methods: This study retrospectively analyzed 2672 patients with regular menstruation who underwent FET from November 2015 to June 2021 at the single reproductive medical center. A one-to-one match was performed applying a 0.02 caliper with propensity score matching. Independent factors influencing the live birth and clinical pregnancy rates were screened and developed in the nomogram by logistic regression analysis. The efficacy of live birth rate and clinical pregnancy rate prediction models was assessed with the area under the ROC curve, and the live birth rate prediction model was internally validated within the bootstrap method. Results: The NC protocol outperformed the HRT protocol in terms of clinical pregnancy and live birth rates. The stratified analysis revealed consistently higher live birth and clinical pregnancy rates with the NC protocol across different variable strata compared to the HRT protocol. However, compared to the HRT treatment, perinatal outcomes indicated that the NC protocol was related to a higher probability of gestational diabetes. Multifactorial logistic regression analysis demonstrated independent risk factors for live birth rate and clinical pregnancy rate. To predict the two rates, nomogram prediction models were constructed based on these influencing factors. The receiver operating characteristic curve demonstrated moderate predictive ability with an area under curve (AUC) of 0.646 and 0.656 respectively. The internal validation of the model for live birth rate yielded an average AUC of 0.646 implying the stability of the nomogram model. Conclusion: This study highlighted that NC yielded higher live birth and clinical pregnancy rates in comparison to HRT in women with regular menstruation who achieved successful pregnancies through frozen-thawed embryo transfer. However, it might incur a higher risk of developing gestational diabetes.

Preovulatory progesterone levels are the top indicator for ovulation prediction based on machine learning model evaluation: a retrospective study.

BACKGROUND: Accurately predicting ovulation timing is critical for women undergoing natural cycle-frozen embryo transfer. However, the precise predicting of the ovulation timing remains challenging due to the lack of consensus among different clinics regarding the definition of this significant event. OBJECTIVE: To compare the effectiveness of preovulatory serum progesterone levels (P4) versus luteinizing hormone levels (LH) in predicting ovulation time using two machine learning models. METHODS: 771 patients who underwent autologous natural cycle-frozen embryo transfer between January 2015 and February 2022 were recruited. Utilizing variables including follicle diameters, preovulatory serum levels of LH, E2, and P4, two machine learning models were constructed to predict the ovulation time, the importance of the variables in predicting ovulation timing was further ranked. RESULTS: Two machine learning models have the capability to accurately predict the timing of ovulation, specifically within 72, 48, or 24 h. The overall accuracy rates of the validation dataset, as determined by the classification trees and random forest models, were found to be 78.83% and 85.28% respectively. Notably, when predicting ovulation within 24 h, the accuracy rate of P4 ≥ 0.65ng/ml exceeded 92%. Furthermore, it was important to consider LH or E2 levels in conjunction with P4 when assessing ovulation timing in cases where P4<0.65ng/ml. CONCLUSIONS: Preovulatory serum P4 levels are better predictors of ovulation timing than LH levels and could be used as an alternative in clinical settings, and the model we developed can be used to pinpoint the day of ovulation. Ongoing research and advancements in technology are anticipated to enhance and refine the ovulation method.

Use of hCG for luteal support in natural frozen-thawed blastocyst transfer cycles: a cohort study.

Introduction: In the realm of natural frozen-thawed embryo transfer (FET) cycles, the application of luteal phase support (LPS) is a prevalent practice, primarily due to its beneficial impact on reproductive outcomes. Among the various LPS medications, human chorionic gonadotropin (hCG) is one that exerts its function on both the corpus luteum and the endometrium. Objective: To evaluate the effect of hCG administration as LPS on reproductive outcomes in natural FET cycles. Methods: This study was a retrospective cohort analysis conducted at a tertiary care hospital. It included women who underwent natural FET treatment from January 2018 to December 2022. Participants were divided into the hCG LPS group and the non-hCG LPS group on the basis of whether they used hCG as LPS after blastocyst transfer. The primary outcome was the clinical pregnancy and live birth rates. The secondary outcomes included the early miscarriage rate (before 12th gestational week) and total miscarriage rate. Results: A total of 4762 women were included in the analysis, and 1910 received hCG LPS and 2852 received no hCG LPS (control group). In the general cohort, the clinical pregnancy and live birth rates in the hCG LPS group were significantly lower than those in the control group (63.82% vs 66.41%, aOR 0.872, 95% CI 0.765-0.996, P=0.046; 53.98% vs 57.15%, aOR 0.873, 95% CI 0.766-0.991, P=0.035, respectively). The early miscarriage and total miscarriage rates were similar between the two groups. In a subgroup analysis, in women who received an hCG trigger, there was no significant difference in the clinical pregnancy rate or live birth rate between the two groups. However, in women who ovulated spontaneously, the clinical pregnancy and live birth rates in the hCG LPS group were significantly lower than those in the control group (60.99% vs 67.21%, aOR 0.786, 95% CI 0.652-0.946, P=0.011; 50.56% vs 57.63%, aOR 0.743, 95% CI 0.619-0.878, P=0.001, respectively). Conclusion: Among women undergoing natural cycle frozen-thawed blastocyst transfer, hCG LPS is associated with lower clinical pregnancy and live birth rates. Additionally, the adverse effect of hCG LPS is more pronounced in women who ovulate spontaneously.

The natural menstrual cycle revisited - can natural cycle be trusted.

BACKGROUND: The serum progesterone (P4) level during the luteal phase (LP) plays a crucial role in the initiation and maintenance of pregnancy. However, it is unclear whether the natural cycle consistently provides the best endocrine profile and whether mid-luteal serum P4 levels are always sufficient to support implantation and early pregnancy. The question has become more relevant in relation to fertility treatment, as more frozen embryo transfer cycles are performed in the natural cycle. Moreover, can serum hormone levels and covariates measured during the follicular phase (FP), such as Follicle Stimulation Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2), Anti-Mullerian Hormone (AMH) and Antral Follicle Count (AFC), be used to predict P4 levels during the luteal phase (LP)? RESULTS: This observational prospective cohort study analysed 26 healthy women with a cycle length between 21-35 days and a body mass index (BMI) < 30 kg/m2. Blood sampling started on the fifth day of the menstrual cycle and continued every fifth day until the next cycle. The procedure was repeated for a total of three cycles. The study found that only ten women had a P4 level greater than 30 nmol/L on cycle day 20 or 25 in all three cycles. In total, only 45 cycles out of 77 cycles had serum P4 levels ≥ 30 nmol/L. The E2 level ≥ 345 pmol/L on cycle day 10 proved to be predictive of a P4 level of ≥ 30 nmol/L on either day 20 or day 25 with a sensitivity of 57% and a specificity of 89%. No other covariates, including the FSH level cycle day 5, LH levels during the follicular phase, age, weight, AFC and AMH cycle day 5 correlated with LP P4 levels. CONCLUSIONS: A significant correlation between FP E2 levels cycle day 5 (> 131pmol/L) and cycle day 10 (> 345pmol/L) and a LP P4 level ≥ 30 nmol/l was found; thus, the FP E2 level is a predictor of corpus luteum competence. Our findings highlight the existence of suboptimal P4 levels during the LP and a significant inter-individual and intra-cycle variation in P4 levels during the LP in regular menstruating women.

Ibuprofen delays ovulation by several hours: prospective controlled study in natural cycles with HCG-triggered ovulation.

RESEARCH QUESTION: Does ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), delay ovulation? DESIGN: Two-stage, proof-of-concept, controlled study, assessing the percentage of non-ovulated follicles 42 h after HCG injection in patients taking ibuprofen. The intervention group consisted of women undergoing natural cycle IVF treatment taking ibuprofen 3 × 400 mg per day. The control group consisted of women undergoing timed sexual intercourse or intrauterine insemination. The proportion of patients with non-ovulated follicles in the ibuprofen group was first compared against a reference of 50% using a one-sample binomial test, and second against the proportion observed in the control group using an adjusted logistic regression. RESULTS: A total of 26 women were recruited in the ibuprofen intervention group. Twenty-five patients were recruited in the control group. The proportion of patients with delayed ovulation observed (22/26 [84.6%]; 95% CI 65.1% to 95.6%) was significantly higher than the reference of 50% (P < 0.001). In the control group, the proportion of patients with delayed ovulation was 20.0% ([5/25], 95% CI 6.8% to 40.7%). Compared with the ibuprofen group, a significantly increased probability of a delayed ovulation was found in the ibuprofen intervention group (adjusted OR 22.72, 95% CI 5.77 to 115; P < 0.001). Of the 22 women with delayed ovulation, oocytes were retrieved in 20 women (90.9%) and all oocytes were mature (metaphase II). CONCLUSIONS: Women trying to conceive should avoid non-selective NSAIDs around the time of ovulation. Ibuprofen or other NSAID can be used to delay ovulation for several hours in assisted reproductive technology and other infertility treatments if required.

Ongoing pregnancy rates in single euploid frozen embryo transfers remain unaffected by female age: a retrospective study.

RESEARCH QUESTION: Is female age a significant factor in the likelihood of an ongoing pregnancy in single euploid frozen embryo transfers (FET)? DESIGN: Retrospective study of 1923 single euploid FET cycles in 1464 women, either in a natural cycle or a hormone replacement therapy cycle. The primary outcome was the ongoing pregnancy rate (OPR). RESULTS: There were 990 (51.48%) ongoing pregnancies among 1923 included transfers. The OPR were 51.4%, 49.1%, 53.3% and 52.3% for women aged ≤35, >35-≤37, >37-≤40 and >40 years at oocyte retrieval (OCR), without a significant trend for decreasing OPR (P = 0.679). No significant differences in female age at embryo transfer (P = 0.609) and female age at OCR (P = 0.816) were found between the groups (ongoing pregnancy versus no pregnancy or miscarriage). Women who received good-quality embryos (P < 0.001), had a lower body mass index (BMI) (P < 0.001), had achieved at least one pregnancy previously (P < 0.001), and underwent natural cycle endometrial preparation (P < 0.001) were more likely to achieve an ongoing pregnancy. Multivariable regression analysis (adjusted for BMI, embryo quality and endometrial preparation) did not show a significant effect of female age at OCR on achieving an ongoing pregnancy. Compared with women aged ≤35 years, none of the age groups had significantly higher or lower OPR. A multinomial regression analysis showed that BMI, embryo quality and endometrial preparation were associated with miscarriage/no pregnancy versus ongoing pregnancy (P = 0.001, 0.001 and 0.001, respectively). Female age had no significant association with either outcome. CONCLUSIONS: Female age in itself does not have a substantial impact on the OPR in single euploid FET cycles, but the OPR is impacted significantly by embryo quality, BMI, previous parity, and a natural cycle endometrial preparation protocol.

Circadian serum progesterone variations on the day of frozen embryo transfer in a modified natural cycle protocol.

STUDY QUESTION: Is there a circadian variation of serum progesterone (P) on the day of frozen embryo transfer (FET) in a modified natural cycle (mNC)? SUMMARY ANSWER: There is a statistically significant diurnal variation of serum P on the day of a FET in an mNC protocol. WHAT IS KNOWN ALREADY: In recent years, the proportion of FET cycles has increased dramatically. To further optimize pregnancy outcomes after FET, recent studies have focused on serum luteal P levels in both natural and artificially prepared FET cycles. Despite the different cut-off values proposed to define low serum P in the NC, it is generally accepted that lower serum P values (<10 ng/ml) around the day of FET are associated with negative reproductive outcomes. However, a single serum P measurement is not reliable given that P levels are prone to diurnal fluctuations and are impacted by patients' characteristics. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was conducted in a single university-affiliated fertility center, including 22 patients performing a single blastocyst mNC-FET from August 2022 to August 2023. Serum P levels were measured on the day of transfer at 08:00h, 12:00h, 16:00h, and 20:00h. Differences between P levels were compared using the Wilcoxon signed-rank test. The sample size was calculated to detect a difference of 15% between the first and last P measurements with a 5% false-positive rate and a 95% CI. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a normal BMI, between 18 and 40 years old, without uterine diseases were eligible. Patients utilizing donated oocytes were excluded. The mNC-FET protocol involved monitoring the normal ovarian cycle and triggering ovulation with an injection of 250 µg of choriogonadotropin alfa when a pre-ovulatory follicle (16-20 mm diameter) was visualized. The blastocyst was transferred seven days later. The patients were not supplemented with exogenous P at any time before the day of the FET. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age and BMI of the study population were 33.6 ± 3.8 years and 22.7 ± 1.8 kg/m2, respectively. Mean P values at 08:00h, 12:00h, 16:00h, and 20:00h were 14.6 ± 4.5, 14.7 ± 4.1, 12.9 ± 3.5, and 14.6 ± 4.3 ng/ml, respectively. The mean P levels at 16:00h were significantly lower compared to all other time points (P < 0.05: P = 0.007 between P at 8:00h and 16:00h; P = 0.003 between P at 12:00h and 16:00h; P = 0.007 between P at 16:00h and 20:00h). No statistically significant difference was observed between P values at the other time points (P > 0.05: P = 0.88 between P at 8:00h and 12:00h; P = 0.96 between P at 8:00h and 20:00h; P = 0.83 between P at 12:00h and 20:00h). LIMITATIONS, REASONS FOR CAUTION: The study's limitations include the small sample size that may cause a bias when the results are extrapolated to a larger subfertile population undergoing mNC-FET. Ideally, larger prospective trials including a more heterogeneous patient population would be necessary to validate our findings. WIDER IMPLICATIONS OF THE FINDINGS: The current study demonstrates the existence of a diurnal fluctuation of serum P on the day of mNC-FET highlighting the importance of a standardized time point for its measurement. This is especially important for considering clinical actions, such as additional exogenous P supplementation, when encountering P values lower than 10 ng/ml on the day of FET. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained for the study. The authors have no conflicts of interest to declare regarding the content of the study. TRIAL REGISTRATION NUMBER: NCT05511272.

Association between endometrial thickness and birthweight of singletons from vitrified-warmed cycles: a retrospective cohort study.

RESEARCH QUESTION: What is the association between endometrial thickness (EMT) and the birthweight of singleton infants born from frozen-thawed embryo transfer cycles? DESIGN: This retrospective cohort study was conducted from January 2016 to December 2019. Participants were categorized into a natural cycle (NC, n = 8132) group and hormone replacement therapy (HRT, n = 4975) group. Only singleton deliveries were included. The primary outcomes were measures of birthweight and relevant indexes. Multivariable logistic regression and multivariable-adjusted linear regression models that incorporated restricted cubic splines were used. RESULTS: In the HRT group, the risk of delivering a small for gestational age (SGA) infant was increased in women with an EMT <8.0 mm (adjusted odds ratio [aOR] 1.85, 95% confidence interval [CI] 1.17-2.91) compared with women with an EMT of 8.0 to <12.0 mm, and increased with an EMT ≥12.0 mm (aOR 1.85, 95% CI 1.03-3.33). An inverted U-shaped relationship was found between EMT and birthweight in women with HRT. No significant differences were shown in birthweight z-score, or being SGA or large for gestational age, in singletons among the three EMT groups in the natural cycles. CONCLUSIONS: A thinner endometrium seen in women undergoing HRT cycles was associated with a lower birthweight z-score, as well as a higher risk of SGA. However, no significant association was observed between EMT and birthweight z-score or SGA in the NC group. It is noteworthy that a thicker endometrium was not associated with a higher birthweight in frozen-thawed embryo transfer (FET) cycles. Women with a thin endometrium who achieve pregnancy require specialized attention, particularly if they are undergoing FET with HRT cycles.

Progesterone concentrations on blastocyst transfer day in modified natural cycle frozen embryo transfer cycles.

RESEARCH QUESTION: Are serum progesterone concentrations on the day of modified natural cycle (mNC) frozen blastocyst transfer (FET) without luteal phase support (LPS) associated with clinical pregnancy rate (CPR)? DESIGN: Data were collected between January 2019 and October 2022 as a sub-study of an ongoing randomized controlled trial assessing pregnancy outcomes in mNC-FET. The sub-study included all women (n = 209) randomized to mNC-FET without LPS at the time of data extraction. Participants were aged 18-41 years, had regular menstrual cycles and underwent mNC-FET treatment with single-blastocyst transfer. Associations between the serum progesterone concentration on the day of blastocyst transfer and CPR, pregnancy rate and pregnancy loss rate (PLR) were examined between groups with low and higher progesterone concentrations using the 25th and 10th percentiles as cut-offs. Multivariate logistic regression analyses were performed to adjust for potential confounding factors. RESULTS: Progesterone concentrations on the day of blastocyst transfer in mNC-FET without LPS ranged from 4.9 to 91.8 nmol/l, with the 25th and 10th percentiles at 29.0 nmol/l and 22.5 nmol/l, respectively. Serum progesterone concentrations did not differ between women with or without a clinical pregnancy (mean [SD] 38.5 [14.0] versus 36.8 [12.4] nmol/l; P = 0.350). Furthermore, the CPR, pregancy rate and PLR were similar in women with low or high progesterone concentrations when using the 25th or the 10th progesterone percentile as cut-off. Multivariate regression analyses showed no association between progesterone concentrations and CPR. CONCLUSIONS: No association was found between progesterone concentration on the day of blastocyst transfer and pregnancy outcome in women undergoing mNC-FET without progesterone LPS.

Modified natural cycle allows a window of 7 days for frozen embryo transfer planning.

RESEARCH QUESTION: Should ovulation be triggered in a modified natural cycle (mNC) with recombinant human chorionic gonadotrophin (rHCG) as soon as a mean follicle diameter of 17 mm is visible, or is more flexible planning possible? DESIGN: This multicentre, retrospective, observational study of 3087 single frozen blastocyst transfers in mNC was carried out between January 2020 and September 2022. The inclusion criteria included endometrial thickness ≥7 mm and serum progesterone <1.5 ng/ml. The main outcome was ongoing pregnancy rate. Secondary end-points were pregnancy rate, implantation rate, clinical pregnancy rate and miscarriage rate. The mean follicle size at triggering was stratified into three groups (13.0-15.9, 16.0-18.9 and 19.0-22 mm). RESULTS: The baseline characteristics between the groups did not vary significantly for age, body mass index and the donor's age for egg donation. No differences were found in pregnancy rate (64.5%, 60.2% and 57.4%; P = 0.19), clinical pregnancy rate (60.5%, 52.8% and 50.6%; P = 0.10), implantation rate (62.10%, 52.9% and 51.0%; P = 0.05) or miscarriage rate (15.0%, 22.2%; and 25.0%; P = 0.11). Although ongoing pregnancy rate (54.9%, 46.8% and 43.1%; P = 0.02) varied significantly in the univariable analysis, it was no longer significant after adjustment for the use of preimplantation genetic testing for aneuploidies and egg donation. CONCLUSIONS: The findings showed rHCG could be flexibly administered with a mean follicle size between 13 and 22 mm as long as adequate endometrial characteristics are met, and serum progesterone is <1.5 ng/ml. Considering the follicular growth rate of 1-1.5 mm/day, this approach could allow a flexibility for FET scheduling of 6-7 days, simplifying mNC FET planning in clinical practice.

Natural proliferative phase frozen embryo transfer-a new approach which may facilitate scheduling without hindering pregnancy outcomes.

STUDY QUESTION: How does a natural proliferative phase (NPP) strategy for frozen embryo transfer (FET) compare with the conventional artificial (AC) and natural (NC) endometrial preparation protocols in terms of live birth rates (LBR)? SUMMARY ANSWER: This study supports the hypothesis that, just as for NC, NPP-FET may be a superior alternative to AC in terms of LBR. WHAT IS KNOWN ALREADY: Although FETs are increasing worldwide, the optimal FET protocol is still largely controversial. Despite recent evidence supporting a possibly higher efficacy and safety of NC FETs, their widespread use is limited by the difficulties encountered during cycle monitoring and scheduling. STUDY DESIGN, SIZE, DURATION: In this single center retrospective cohort study, we describe the NPP-FET protocol, in which vaginal progesterone is initiated during the proliferative phase as soon as an endometrium with a thickness of at least 7 mm is identified and ovulation is ruled out, regardless of mean diameter of the dominant follicle. PARTICIPANTS/MATERIALS, SETTING, METHODS: For comparison, we considered all blastocyst stage FET cycles preformed at a private infertility center between January 2010 and June 2022, subdivided according to the following subgroups of endometrial preparation: AC, NPP, and NC. We performed multivariable generalized estimating equations regression analysis to account for the following potential confounding variables: oocyte age at retrieval, oocyte source (autologous without preimplantation genetic testing for aneuploidies (PGT-A) versus autologous with PGT-A versus donated), number of oocytes retrieved/donated, embryo developmental stage (Day 5 versus Day 6), number of embryos transferred, quality of the best embryo transferred, and year of treatment. The main outcome measure was LBR. The secondary outcomes included hCG positive, clinical pregnancy and miscarriage rates, and the following perinatal outcomes: first trimester bleeding, second/third trimester bleeding, preterm rupture of membranes, gestational diabetes, gestational hypertensive disorders (GHD), and gestational age at delivery. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 5791 FET cycles were included in this analysis (2226 AC, 349 NPP, and 3216 NC). The LBR for FET was lower in the AC subgroup when compared to the NPP and NC (38.4%, 49.1%, and 45.2%, respectively; P < 0.01 AC versus NPP and AC versus NC). The rates of miscarriage were also lower in the NPP and NC subgroups when compared to AC (19.7%, 25.0%, and 34.9%, respectively; P < 0.01 NPP versus AC and NC versus AC). Considering perinatal outcomes, NPP-FET and NC were associated with a significantly lower first trimester bleeding compared to AC (17.3%, 14.7%, and 37.6%, respectively; P < 0.01 NPP versus AC and NC versus AC). Additionally, NC was associated with a lower rate of GHD when compared with AC (8.6% versus 14.5%, P < 0.01), while the rate following NPP-FET was 9.4%. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design. Moreover, there was also a low number of patients in the NPP subgroup, which may have led the study to be underpowered to detect clinically relevant differences between the subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Our study posits that the NPP-FET protocol may be an effective and safe alternative to both NC and AC, while still allowing for enhanced practicality in patient follow-up and FET scheduling. Further investigation on NPP-FET is warranted, with prospective studies including a larger and more homogeneous subsets of patients. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the IVI-RMA-Lisbon (2008-LIS-053-CG). The authors did not receive any funding for this study. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Clinical Outcomes in Hormone Replacement Therapy (HRT)-Frozen Embryo Transfer (FET) Protocol Increased by Administering Gonadotropin-Releasing Hormone Agonist (GnRH) in the Initial Stage of the Luteal Phase: A Retrospective Analysis.

OBJECTIVE: The objective of this study was to determine if gonadotropin-releasing hormone agonist (GnRH) administration supporting the luteal phase in frozen embryo transfer (FET) improves clinical outcomes Methods and materials This is a retrospective cohort study and we analyzed 3515 cycles of FET at the Department of Reproductive Medicine in our hospital from February 2018 through December 2021. Patients were divided into the GnRH (triptorelin+progesterone and human chorionic gonadotropin (hCG)) group and the non-GnRHa (existing treatment without triptorelin) group. There were 1033 and 2485 cases in the above groups, respectively. Live birth rates (LBR) and clinical pregnancy rates (CPR) were contrasted in the two groups. RESULTS: We found greater CPR (58.00% versus 48.40%, P-value = 0.003) and LBR (52.70% versus 45.60%, P-value = 0.001) for HRT-FET cycles, and found no clinical significance for natural cycle FET (NC-FET) (58.20% versus 52.90%, P-value = 0.364 and 54.40% versus 47.00%, P-value=0.211), GnRH+HRT-FET (53.00% versus 53.00%, P-value=0.176 and 46.20% versus 47.30%, P-value=0.794), and stimulation-FET (59.30% versus 52.90%, P-value=.00.566 and 59.30% versus 47.10%, P-value=.00.247) in terms of CPR and LBR in the two groups. There was a 47% increase in CPR in the GnRH group, and there was a 33% increase in LBR in the same group. CONCLUSION: During HRT-FET cycles, administering triptorelin three to four times in the existing luteal support can improve CPR and LBR, and administering triptorelin during the initial stage of the luteal phase can prove a new option for luteal support.

Avoiding weekend frozen embryo transfer in modified natural cycles: is it possible?

In this era of the freeze-all strategy, the prevalence of frozen embryo transfer (FET) cycles is increasing rapidly. Although still quite often used, the hormone replacement therapy cycle to prepare a FET should now belong to the past, unless strictly necessary. This raises questions about possible flexible protocols for the preparation of an FET cycle in a (modified) natural cycle. In this viewpoint, an overview of the different options is discussed, stressing the importance of the corpus luteum.

Assessing obstetric outcomes: A systematic review and meta-analysis comparing fresh, artificial, and natural thaw embryo transfer cycles.

BACKGROUND: The increasing utilisation of in vitro fertilisation (IVF) has prompted significant interest in determining the optimal endometrial environment to increase pregnancy rates and minimise the obstetric complications associated with various embryo transfer strategies. AIMS: To determine which cycle is associated with increased obstetric complications: fresh embryo transfer (FreshET), natural thaw (NatThawET) or artificial thaw (ArtThawET). Outcomes of interest included: hypertensive disorders of pregnancy (HDP), gestational diabetes (GD), pre-term birth (PTB), post-partum haemorrhage (PPH) and large for gestational age (LGA). MATERIALS AND METHODS: A comprehensive search of MEDLINE, EMBASE, CENTRAL, and PUBMED was conducted from 1947 to May 17, 2022. Two independent reviewers carried out the screening, and data extraction for the following comparisons: ArtThawET vs NatThawET, ArtThawET vs FreshET, and NatThawET vs FreshET. Meta-analysis was conducted using a fixed-effect Mantel-Haenszel model. The quality of the studies was assessed using GRADEpro. RESULTS: A total of 23 studies were included in this review. ArtThawET was associated with a significantly increased odds of HDP (odds ratio (OR) 1.76, confidence interval (CI) 1.66-1.86), PTB (OR 1.18, CI 1.13-1.23), PPH (OR 2.61, CI 2.3-2.97) and LGA (OR 1.11, CI 1.07-1.15), compared to NatThawET. ArtThawET was also associated with increased odds of HDP (OR 2.13, CI 1.89-2.4), PPH (OR 3.52, CI 3.06-4.04) and LGA (OR 2.12, CI 1.77-2.56), compared to FreshET. Furthermore, NatThawET demonstrated increased odds of HDP (OR 1.20, CI 1.11-1.29), PPH (OR 1.25, CI 1.14-1.38) and LGA (OR 1.85, CI 1.66-2.07) compared to FreshET. CONCLUSION: When clinically feasible, ArtThawET should be avoided as a first-line option for IVF to reduce the risk of obstetric complications. An adequately powered, multicentre randomised controlled trial is necessary to confirm these findings and investigate the underlying pathophysiology.

Initiating luteal phase support with sc progesterone based on low serum progesterone on the transfer day in true natural cycle frozen embryo transfers.

Introduction: Concerning contemporary in-vitro fertilisation (IVF) practice, the use of frozen embryo transfer (FET) cycles has become more common than fresh transfers. Natural cycle (NC), programmed artificial cycle and mild stimulation cycle are primary endometrium preparation cycles. Monitoring serum progesterone levels in FET cycles are in the scope of current research focus. Low progesterone levels on the day of embryo transfer is presumed to negatively affect pregnancy outcomes, while progesterone supplementation may improve pregnancy rates. The purpose of our trial is to evaluate whether initiating subcutaneous (SC) progesterone supplementation on the day of embryo transfer when serum progesterone levels are below 10 ng/mL in tNC-FET will result in pregnancy rates comparable to those of patients with sufficient serum progesterone. Methods: Retrospective single centre study was conducted between August 2022 and April 2023 with 181 tNC-FETs. Patients were separated into groups according to serum progesterone concentrations (≥10 ng/mL and <10 ng/mL) on embryo transfer (ET) day. S.c progesterone (25 mg) was given on the day of ET when serum progesterone was <10 ng/mL, continuing until the 10th gestational week. Blood samples for pregnancy tests were collected 12 days after ET. Outcome parameters were pregnancy rate, clinical pregnancy rate (CPR), miscarriage rate, multiple pregnancy rate, biochemical pregnancy, and ongoing pregnancy rate (OPR). Results: About half (49.7%) had adequate progesterone concentrations (≥10ng/mL) on ET day. There was no significant difference between the groups regarding positive pregnancy test, OPR, multiple pregnancies, and miscarriage rates (57.8% versus 52.7%; 34.4% versus 29.7%, 1.1% versus 2.2%; 7.8% versus 5.5%; respectively, for progesterone concentrations on ET day ≥10 ng/mL and <10 ng/mL). With 55.2% of transfers leading to clinical pregnancy, significant differences emerged in biochemical pregnancy and CPR (3.3% vs 12.1%, P=0.02; 54.4% vs 40.7%, P=0.03, for ≥10 ng/mL and <10 ng/mL progesterone concentrations on ET day). Discussion: This study indicates that nearly half of the tNC-FETs may need luteal phase support due to low progesterone. However, 25 mc sc progesterone rescued the luteal support and yielded similar OPR as compared to normal progesterone group. Further studies are needed for understanding optimal progesterone levels, supplementation effectiveness, and potential benefits of earlier supplementation in FETs.

Impact of Endometrial Preparation on the Maternal and Fetal Cardiovascular Variables of the First Trimester Combined Screening Test.

The modality of endometrial preparation for the transfer of frozen-thawed embryos may influence maternal and fetal adaptation to pregnancy and could thus impact the results of the first trimester combined screening test. We conducted a retrospective cross-sectional study on singleton pregnancies achieved by embryo transfer of a single frozen-thawed blastocyst, comparing two different endometrial preparation protocols: natural cycle (n = 174) and hormone replacement therapy (HRT) (n = 122). The primary outcome was the risk of preeclampsia at the first trimester combined screening test. Secondary endpoints included variable reflecting fetal cardiac function (nuchal translucency and fetal heart rate), maternal adaptation (median arterial blood pressure-MAP and uterine arteries pulsatility index-UtA-PI), and placentation (pregnancy associated plasma protein A and placental growth factor). The risk of early preeclampsia was comparable in the two groups (38% vs. a 28%, p = 0.12). However, women in the natural cycle group showed lower fetal heart rate (159 [155-164] vs. 164 [158-168], p = 0.002) and higher UtA-PI (0.96 [0.74-1.18] vs. 0.72 [0.58-0.90], p < 0.001). The frequency of a screening test at high risk for aneuploidies was similar. The modality of transfer of frozen-thawed embryos is associated with changes in the variables reflecting maternal and fetal cardiovascular function.

Nature (almost) always prevails - challenging the status quo of artificial cycle frozen embryo transfers.

Frozen embryo transfers (FET) have become increasingly popular in assisted reproductive technology (ART) due to advancements in cryopreservation techniques and the implementation of the 'freeze-all' strategy. The choice between artificial or natural cycles for FET preparation has been a subject of debate, considering factors such as endometrial receptivity, flexibility of scheduling and pregnancy outcomes. While artificial cycle protocols offer convenience and flexibility, studies have suggested potential drawbacks, including higher miscarriage rates and a greater risk of hypertensive disorders during pregnancy. In contrast, natural cycle protocols involve a frequently demanding monitoring of both endometrial proliferation and follicular growth, which may lead to increased clinic visits and scheduling issues. Multiple strategies have been proposed to enhance the usage of natural cycle FET, including addressing anovulation through minimal stimulation, reducing cycle monitoring and exploring novel FET approaches. These novel approaches, such as widening the window for human chorionic gonadotrophin administration and the natural proliferative phase protocol, offer promising outcomes and increased convenience for patients. However, further research is needed to establish the optimal timing and effectiveness of these strategies. Overall, enhancing the practicality of natural cycle FETs is crucial for expanding their utilization during ART.

Endometrial receptivity change: ultrasound evaluation on ovulation day and transplantation day during the natural frozen embryo transfer cycle.

Objective: To obtain quantitative and comprehensive results of the changes in comprehensive ER indicators from ovulation day to transplantation day by ultrasonography during the natural frozen-thawed embryo transfer cycle (FET). Methods: This is a prospective analysis of 230 infertile women undergoing their first FET cycles from April 2019 to July 2021. To evaluate ER, ultrasound scans were performed on the days of ovulation and embryo transfer for all included patients. All included patients were divided into a pregnancy group and a nonpregnancy group according to whether clinical pregnancy was achieved. The ER changes from ovulation day to transplantation day in the overall study population (n=230), pregnancy group (n=158) and nonpregnancy group (n=72) were analyzed. Results: In the overall population, type C was predominant on ovulation day, but type B was the most common on transplantation day (P<0.001). From ovulation day to transplantation day, endometrial thickness was significantly increased (11.26 ± 2.14 vs. 11.89 ± 2.08 mm, P<0.001), but endometrial volume (4.26 ± 1.75 vs. 4.03 ± 1.62 ml, P<0.001), endometrial VI (1.34 ± 1.64 vs. 0.95 ± 1.99, P<0.001), VFI (0.47 ± 0.72 vs. 0.40 ± 1.03, P<0.001), subendometrial VI (5.04 ± 3.89 vs. 3.29 ± 2.92, P<0.001), FI (34.07 ± 4.61 vs. 33.41 ± 5.30, p=0.004), VFI (2.07 ± 2.65 vs. 1.19 ± 1.19, P<0.001) and frequency of endometrial peristalsis (2.90 ± 1.44 vs. 1.40 ± 1.41, P<0.001) were significantly decreased. In the pregnancy group, the changes in all ultrasound parameters were in the same direction as those in the overall population. In the nonpregnancy group, except for endometrial volume and VI, which showed no difference, other ultrasound parameters showed the same direction of change as those in the overall population. No significant difference was found in the pregnancy probability among the different absolute change groups. Conclusion: During a natural cycle, the morphology of the endometrium changes mostly from type C to type B, the endometrial thickness increases, and the volume decreases. The blood supply of the endometrium, the subendometrial 5 mm and the frequency of peristalsis decrease from ovulation day to transplantation day. Compared with the nonpregnancy group, the pregnancy group tended to have more obvious decreases in endometrial volume and blood flow perfusion. However, these endometrial changes do not mean that pregnancy is bound to occur. endometrial receptivity, in vitro fertilization, frozen-thawed embryo transfer, natural cycle, ultrasound evaluation, ovulation day, transplantation day.

The effects of different endometrial preparation regimens on pregnancy outcomes in frozen-thawed embryo transfer cycles: a prospective randomized controlled study.

OBJECTIVE: An increasing number of research have emerged to compare the pregnancy outcomes between the natural cycle and the hormone replacement therapy (HRT) cycle in preparing the endometrium for frozen-thawed embryo transfer (FET), but the results are controversial. This prospective randomized controlled study was hence designed to obtain more solid evidence. MATERIALS AND METHODS: In this study, patients with regular menstrual cycle length (21-35 days) who underwent FET between January 2010 to December 2017 were recruited for this study. Upon further filtering with the selection criteria of patients being, a total of 405 patients were recruited and randomized. Finally, analysis was performed on 384 patients: 178 belonged to the natural cycle group whereas the remaining 206 were in the HRT group. The primary outcome was live birth rate, while the secondary outcomes were implantation rate, clinical pregnancy rate, early miscarriage rate, late miscarriage rate, multiple birth rate and low birth weight rate. RESULTS: The live birth rate (37.6% vs 30.1%, p = 0.119) of natural cycle group were higher than those of the hormone replacement therapy group, although the difference was not significant. The secondary outcomes were not found to differ significantly between the two groups. Nonetheless, the endometrium was found to be thicker in the natural cycle group (10.75 mm) than the HRT group (9.00 mm) (p < 0.001). CONCLUSION: No significant differences were observed between the pregnancy outcomes of the natural cycle group and the HRT group which comprised of patients with regular menstrual cycle length.