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.

Circadian serum progesterone variations on the day of frozen embryo transfer in artificially prepared cycles.

RESEARCH QUESTION: What is the intra-day variation of serum progesterone related to vaginal progesterone administration on the day of frozen embryo transfer (FET) in an artificial cycle? DESIGN: A prospective cohort study was conducted including 22 patients undergoing a single blastocyst artificial cycle (AC)-FET from August to December 2022. Endometrial preparation was achieved by administering oestradiol valerate (2 mg three times daily) and consecutively micronized vaginal progesterone (MVP; 400 mg twice daily). A blastocyst FET was performed on the 6th day of MVP administration. Serum progesterone concentrations were measured on the day of transfer at 08:00, 12:00, 16:00 and 20:00 hours. The first and last blood samples were collected just before MVP was administered. RESULTS: The mean age and body mass index of the study population were 33.95 ± 3.98 years and 23.10 ± 1.95 kg/m2. The mean P-values at 08:00, 12:00, 16:00 and 20:00 hours were 11.72 ± 4.99, 13.59 ± 6.33, 10.23 ± 3.81 and 9.28 ± 3.09 ng/ml, respectively. A significant decline, of 2.41 ng/ml (95% confidence interval 0.81-4.00), was found between the first and last progesterone measurements. CONCLUSION: A statistically significant intra-day variation of serum progesterone concentrations on the day of FET in artificially prepared cycles was observed. This highlights the importance of a standardized procedure for the timing of progesterone measurement on the day of AC-FET. Of note, the study results are applicable only to women using MVP for luteal phase support; therefore it is necessary to confirm its validity in comparison with the different existing administration routes of progesterone.

Impact of dydrogesterone use in cycles with low progesterone levels on the day of frozen embryo transfer.

PURPOSE: This study aims to evaluate whether the clinical outcomes of cycles with frozen embryo transfer (FET) in hormonal replacement treatment supplemented with dydrogesterone (DYD) following detection of low circulating levels of progesterone (P4) were comparable to the results of cycles with otherwise normal serum P4 values. METHODS: Extended analyses of a retrospective cohort that included FET cycles performed between July 2019 and March 2022 after a cycle of artificial endometrial preparation using valerate-estradiol and micronized vaginal P4 (400 mg twice daily). Whenever the serum P4 value was considered low on the morning of the planned transfer, 10 mg of DYD three times a day was added as a supplement. Only single-embryo transfers of a blastocyst were considered. The primary endpoint was live birth rate. RESULTS: Five-hundred thirty-five FET cycles were analyzed, of which 136 (25.4%) underwent treatment with DYD. There were 337 pregnancies (63%), 207 live births (38.6%), and 130 miscarriages (38.5%). The P4 values could be modeled by a gamma distribution, with a mean of 14.5 ng/ml and a standard deviation of 1.95 ng/ml. The variables female age on the day of FET, ethnicity, and weight were associated with a variation in the serum P4 values. There were no differences in the results between cycles with or without the indication for DYD supplementation. CONCLUSIONS: Live birth rate did not vary significantly in females with low and normal serum P4 levels on the day of FET when DYD was used as rescue therapy.

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.

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.

Association between serum progesterone levels on the day of frozen-thawed embryo transfer and pregnancy outcomes after artificial endometrial preparation.

BACKGROUND: Previous studies have examined that a range of optimal serum P level during the implantation period was associated with optimal live birth rates. However, those results obtained with vaginal or intramuscular route of progesterone administration for luteal phase support (LPS) alone. Is there a relationship between the serum progesterone (P) on the day of frozen-thawed embryo transfer (FET) with the likelihood of a live birth (LB) in artificial cycles (AC) when using a combination of oral dydrogesterone and vaginal progesterone for LPS? METHODS: This was a retrospective study of 3659 FET cycles with artificial endometrial preparation in a Chinese tertiary-care academic medical centre from January 2015 to February 2017. Endometrial preparation was performed using estradiol (E2) valerate (Fematon-red tablets) 8 mg/d beginning on day 3 of the cycle, followed by administration of P both orally (8 mg/d Fematon-yellow tablets) and vaginally (400 mg/d; Utrogestan). The primary endpoint was live birth rate (LBR). The association between the serum P level on the embryo transfer day and pregnancy outcomes was evaluated by univariable and multivariable logistic regression analysis. RESULTS: The LBRs according to the serum P quartiles were as follows: Q1: 35.7%; Q2: 37.4%; Q3: 39.1% and Q4: 38.9%. Logistic regression analysis showed that the odds of a LB were not significantly different between the low (P < 7.9 ng/mL) and high (P ≥ 7.9 ng/mL) progesterone groups before or after adjustment (crude OR = 0.89, 95% CI: 0.76-1.04; adjusted OR = 0.89, 95% CI: 0.75-1.04). CONCLUSION: The present study suggests that the serum P levels on the day of embryo transfer (ET) do not correlate with the likelihood of a LB in artificial cycles when using a combination of oral dydrogesterone and vaginal progesterone for luteal phase support.

Personalized embryo transfer based on RNA sequencing endometrial receptivity test in repeated implantation failure patients: artificial cycle versus natural cycle.

INTRODUCTION: Embryo implantation provides an efficient way for patients with repeated implantation failure (RIF) to achieve pregnancy. The aim of this study is to compare the implantation outcomes of RIF patients in artificial cycle to those in natural cycle, both were treated with RNA sequencing endometrial receptivity test (rsERT) based personalized embryo implantation. METHODS: The endometrial receptivity (ER) analysis was performed using rsERT followed by personalized embryo transfer at optimal window of implantation (WOI). The implantation rate (IR), clinical pregnancy rate (CPR) and live birth rate (LBR) were calculated. The expression levels of biomarkers involved in pregnancy process in the patients detected as in receptivity status were also analyzed. RESULTS: The rsERT shown that 44.8% (natural cycle) and 47.8% (artificial cycle) patients were in non-receptive status, which indicated a WOI displacement. After personalized embryo transfer, the IR of patients in artificial cycle was higher than those in natural cycle (52.2% vs 27.6%). The expressions of FKBP52, MUC1 and LPAR3 were significantly lower in artificial cycle than in natural cycle. CONCLUSION: Using artificial cycle for personalized embryo transfer based on rsERT may yield better pregnancy outcomes for RIF patients. A gene expression analysis of FKBP52, MUC1 and LPAR3 provided a potential way to increase implantation outcomes for RIF patients.

Comparison of serum progesterone levels on the day of frozen embryo transfers according to type of endometrial preparation: a single centre, retrospective study.

The live birth rate following embryo transfer is comparable between spontaneous, stimulated and artificial cycles. However, the pregnancy loss rate appears elevated with hormonal therapy, possibly due to luteal insufficiency. This study aimed to determine whether the serum progesterone level on transfer day differed according to the endometrial preparation method for frozen embryo transfer (FET). Twenty spontaneous cycles (SC), 27 ovarian stimulation cycles (OS) and 65 artificial cycles (AC) were retrospectively studied from May to December 2019 in a single French hospital. The primary endpoint was the level of serum progesterone on the day of FET between the three endometrial preparation methods. The mean serum progesterone level on transfer day was 29.47 ng/ml in the OS group versus 20.03 ng/ml in the SC group and 14.32 ng/ml AC group (P < 0.0001). Progesterone levels remained significantly different after logistic regression on age and anti-Müllerian hormone (AMH) level. There was no significant difference in demographic and hormone characteristics (age, body mass index, embryo stage of embryo, type of infertility, basal follicle stimulating hormone, luteinizing hormone, estradiol and AMH levels), endometrial thickness, number and type of embryos transferred, duration of infertility, pregnancy rate, live birth rate and pregnancy loss rate. No difference was found in serum progesterone levels between clinical pregnancy with fetal heartbeat and no clinical pregnancy (no pregnancy or pregnancy loss, 17.49 ng/ml vs 20.83 ng/ml, respectively, P = 0.07). The lower serum progesterone level found on FET day in the AC group should be further investigated to see whether this difference has a clinical effect on the live birth rate.

Effects of gonadotropin-releasing hormone agonist pretreatment on frozen embryo transfer outcomes in artificial cycles: a meta-analysis.

PURPOSE: Gonadotropin-releasing hormone agonist (GnRHa) before artificial cycle (AC) is expected to improve pregnancy outcomes in frozen-thawed embryo transfer (FET). Many studies have explored the impact of GnRHa pretreatment of AC in FET, but the results were inconsistent. This meta-analysis was performed to systematically evaluate the effect of GnRHa pretreatment on AC in FET. METHODS: The last search was January 31, 2022. Randomized controlled trials and cohort studies aiming to assess the effect of GnRHa as the pretreatment of AC for endometrial preparation in FET were included. GnRHa was used before AC in the treatment group. In the control group, no pretreatment was used before AC. The eligible studies included at least one of the following outcomes: implantation, clinical pregnancy, and live birth. We calculated the odds ratio (OR) or mean difference (MD) and 95% confidence interval (CI) for each study and used a random-effects or fixed model to estimate the results. RESULTS: 27 articles (10 RCTs and 17 non-RCTs) and 14152 patients were included. AC + GnRHa improved the implantation rate (OR = 1.31, 95% CI 1.03-1.66, I2 = 79%), clinical pregnancy rate (OR = 1.27, 95% CI 1.10-1.45, I2 = 53%), and live birth rate (OR = 1.16, 95% CI 1.05-1.29, I2 = 39%). We also found that AC + GnRHa increased the implantation rate (OR = 1.35, 95% CI 1.07-1.69, I2 = 53%) and clinical pregnancy rate (OR = 1.50, 95% CI 1.12-2.01, I2 = 50%) in repeated implantation failure. In addition, AC + GnRHa was positively associated with preterm birth (OR = 1.5, 95% CI 1.15-1.94, I2 = 0%). CONCLUSIONS: GnRHa pretreatment in FET can improve implantation, clinical pregnancy, and live birth rates, especially in patients with repeated implantation failure. GnRHa pretreatment seems to improve FET outcomes, though with a higher preterm birth rate.

Effect of artificial cycle with or without GnRH-a pretreatment on pregnancy and neonatal outcomes in women with PCOS after frozen embryo transfer: a propensity score matching study.

BACKGROUND: In frozen embryo transfer (FET), there is limited consensus on the best means of endometrial preparation in terms of the reproductive outcomes in women with polycystic ovary syndrome (PCOS). The present study aimed to compare the pregnancy and neonatal outcomes following artificial cycle FET (AC-FET) with or without gonadotropin-releasing hormone agonist (GnRH-a) pretreatment among women with PCOS. METHODS: A total of 4503 FET cycles that satisfied the inclusion criteria were enrolled in this retrospective cohort study between 2015 and 2020. The GnRH-a group received GnRH-a pretreatment while the AC-FET group did not. Propensity score matching (PSM) method and multivariate logistic regression analysis were performed to adjust for potential confounding factors. RESULTS: After PSM, women in the GnRH-a group suffered a significantly lower miscarriage rate (11.2% vs. 17.1%, P = 0.033) and a higher live birth rate (LBR) compared with those in the AC-FET group (63.1% vs. 56.8%, P = 0.043). No differences were observed in the rates of biochemical pregnancy, clinical pregnancy and ectopic pregnancy between the two groups. A higher mean gestational age at birth was observed in the GnRH-a group than in the AC-FET group (39.80 ± 2.01 vs. 38.17 ± 2.13, P = 0.009). The incidence of neonatal preterm birth (PTB) in the GnRH-a group was lower than that in the AC-FET group (7.4% vs. 14.9%, P = 0.009). Singleton newborns conceived after GnRH-a group were more likely to be small for gestational age (SGA) than those born after AC-FET group (16.4% vs. 6.8%, P = 0.009). However, no significant differences were found between the two groups in terms of mean birthweight, apgar score, the rates of macrosomia, large for gestational age and low birth weight. CONCLUSION(S): In women with PCOS who underwent AC-FET, GnRH-a pretreatment was significantly associated with a higher live birth rate and a reduced risk of neonatal PTB. However, there was a concomitant increase in the risk of developing SGA babies.

Serum progesterone concentrations are reduced in obese women on the day of embryo transfer.

RESEARCH QUESTION: Does serum progesterone concentration vary on the day of embryo transfer according to female body mass index (BMI)? DESIGN: Retrospective analysis including 3210 infertile patients undergoing an embryo transfer in the context of an artificial endometrial preparation cycle with sequential administration of oestrogens and micronized vaginal progesterone (MVP) (400 mg/12 h). Serum progesterone was measured on the day of embryo transfer, 6 ± 2 h after last MVP administration. Serum progesterone concentrations were subdivided into optimal (≥9.2 ng/ml) or suboptimal (<9.2 ng/ml) concentrations, and the cut-off point was defined according to our previous results. The primary objective was the correlation between progesterone concentrations on the day of embryo transfer and patient BMI, as a continuous variable and according to four ranges (underweight: <18.5 kg/m2; normal weight: 18.5-24.9 kg/m2; overweight: 25-29.9 kg/m2; and obesity: ≥30 kg/m2), according to the World Health Organization classification. Secondary objectives included the evaluation of reproductive outcome according to patient BMI and progesterone concentrations on the day of embryo transfer. RESULTS: Mean serum progesterone concentrations and the ratio of patients with progesterone concentrations above the cut-off point of 9.2 ng/ml fell progressively as BMI increased. Overweight and obese patients had lower mean serum progesterone concentrations than underweight and normal weight women (P < 0.001). A trend was observed towards impaired reproductive results in obese patients with suboptimal progesterone concentrations, absent when concentrations were optimal. CONCLUSIONS: Serum progesterone concentrations on the day of embryo transfer in artificial cycles with MPV decrease as BMI increases. It is highly recommended that serum progesterone concentrations are moitored to ensure optimal concentrations and reproductive outcomes.

Vitrification does not affect birth weight: lessons from the oocyte donation model.

RESEARCH QUESTION: Is embryo cryopreservation a cause of high birth weight and large for gestational age (LGA) in singletons resulting from vitrified-warmed embryo transfer? DESIGN: Retrospective cohort study evaluating 670 oocyte recipients who underwent fresh (367 cycles) or vitrified-warmed embryo transfer (303 cycles) at Instituto Bernabeu between July 2017 and March 2019. All single blastocyst transfers carried out in an artificial cycle that resulted in a singleton live birth were included. RESULTS: Maternal age (42.21 ± 4.45; 42.79 ± 3.83; P = 0.519), body mass index (23.34 ± 3.69; 23.80 ± 3.78; P = 0.075), gestational age (38.96 ± 1.97; 38.77 ± 2.15; P = 0.207), maternal smoking (10.8%; 13.0%; P = 0.475), gestational diabetes (4.9%; 4.3% P = 0.854), preeclampsia (2.7%; 5.6%; P = 0.074), hypertensive disorders (3.3%; 2.3%; P = 0.494), maternal parity (multiparous 18.5%; 14.5%; P = 0.177) and liveborn gender (female 44.5%; 48.8%; P = 0.276) were not significantly different between fresh or vitrified-warmed groups. Endometrial thickness was significantly higher in the fresh versus vitrified-warmed group (8.83 ± 1.73 versus 8.57 ± 1.59; P = 0.035, respectively). Oocyte donor height was similar between the fresh versus vitrified-warmed group (163.22 ± 5.88 versus 164.27 ± 6.66 cm; P = 0.057, respectively). Mean birth weight was not significantly different (3239.21 ± 550.43; 3224.56 ± 570.83; adjusted P = 0.058). No differences were observed in macrosomia (7.1%; 6.3%; adjusted OR 0.857, 95% CI 0.314 to 2.340, P = 0.764), LGA (6.0%; 6.7%; adjusted OR 0.450, 95% CI 0.176 to 1.149, P = 0.095), pre-term birth (10.9%; 9.0% adjusted P = 0.997), very pre-term birth (0.8%; 1.3%; adjusted P = 1.000), extremely pre-term birth (0%; 1.0%; adjusted P = 0.998); underweight (10.0%; 7.0%; adjusted P = 0.050); very low weight (0.6; 1.1%; adjusted P = 1.000) and small for gestational age (1.9%; 0.7%; adjusted P = 0.974) between fresh or vitrified-warmed groups. CONCLUSION: This study eliminates potential confounders that might influence fetal growth and demonstrates that embryo vitrification and warming procedures do not affect birth weight.

The effect of mildly stimulated cycle versus artificial cycle on pregnancy outcomes in overweight/obese women with PCOS prior to frozen embryo transfer: a retrospective cohort study.

BACKGROUND: Previous studies have shown that frozen embryo transfer (FET) resulted in increased live birth rates (LBR) and reduced the risk of ovarian hyperstimulation syndrome (OHSS) than did fresh embryo transfer in women with polycystic ovary syndrome (PCOS). In addition, overweight/obese women with PCOS are at increased risk of subfertility and complications of pregnancy, compared with normal-weight women. The ovarian stimulation and artificial hormone regimes are the two more commonly used endometrial preparation protocols in PCOS patients.This retrospective study aims to compare the pregnancy outcomes of mildly stimulated cycles (mSTC) and artificial cycles (AC) prior to FET in overweight/obese women with PCOS. METHODS: A retrospective analysis was conducted in overweight/obese women with PCOS who underwent their first FET cycles from January 2018 to December 2020. Two endometrial preparation protocols were used: the mildly stimulated cycles (N = 173) and the artificial cycles (N = 507). All pregnancy outcomes were analyzed by Student's t-test, Chi-square (χ2) statistics and multivariable logistic regression analyses. RESULTS: This study enrolled 680 cases of FET cycles. The mSTC group exhibited significantly higher LBR compared with the AC group (49.7% vs. 41.0%; P = 0.046), while the rate of miscarriage was significantly lower (6.4% vs. 23.0%; P < 0.001). No statistically significant differences were observed in positive pregnancy rate (57.8% vs. 60.0%, P = 0.618), clinical pregnancy rate (54.3% vs. 55.6%, P = 0.769), and ectopic pregnancy rate (2.1% vs. 3.2%, P = 0.860) between two groups. After adjusting for possible confounding factors, multivariate logistic regression analysis also yielded similar results. CONCLUSIONS: For overweight/obese women with PCOS, mSTC-FET demonstrated a higher LBR and a lower pregnancy loss rate than that in the AC-FET. When considering the most cost-effective treatment with the least adverse effects on patients, the mSTC for FET endometrial preparation may be considered. To corroborate our findings, additional prospective randomized clinical trials with larger sample sizes are required.

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

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

Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?

RESEARCH QUESTION: What are the obstetric and neonatal risks for women conceiving via frozen-thawed embryo transfer (FET) during a modified natural cycle compared with an artificial cycle method. DESIGN: A follow-up study to the ANTARCTICA randomized controlled trial (RCT) (NTR 1586) conducted in the Netherlands, which showed that modified natural cycle FET (NC-FET) was non-inferior to artificial cycle FET (AC-FET) in terms of live birth rates. The current study collected data on obstetric and neonatal outcomes of 98 women who had a singleton live birth. The main outcome was birthweight; additional outcomes included hypertensive disorder of pregnancy, premature birth, gestational diabetes, obstetric haemorrhage and neonatal outcomes including Apgar scores and admission to the neonatal ward or the neonatal intensive care unit and congenital anomalies. RESULTS: Data from 82 out of 98 women were analysed according to the per protocol principle. There was no significant difference in the birthweights of children born between groups (mean difference -124 g [-363 g to 114 g]; P = 0.30). Women who conceived by modified NC-FET have a decreased risk of hypertensive disorders of pregnancy compared with AC-FET (relative risk 0.27; 95% CI 0.08-0.94; P = 0.031). Other outcomes, such as rates of premature birth, gestational diabetes or obstetric haemorrhage and neonatal outcomes, were not significantly different. CONCLUSIONS: The interpretation is that modified NC-FET is the preferred treatment in women with ovulatory cycles undergoing FET when the increased risk of obstetrical complications and potential neonatal complications in AC-FET are considered.

Pregnancy outcome and cost-effectiveness comparisons of artificial cycle-prepared frozen embryo transfer with or without GnRH agonist pretreatment for polycystic ovary syndrome: a randomised controlled trial.

OBJECTIVE: To compare the live birth rate and cost effectiveness of artificial cycle-prepared frozen embryo transfer (AC-FET) with or without GnRH agonist (GnRH-a) pretreatment for women with polycystic ovary syndrome (PCOS). DESIGN: Open-label, randomised, controlled trial. SETTING: Reproductive centre of a university-affiliated hospital. SAMPLE: A total of 343 women with PCOS, aged 24-40 years, scheduled for AC-FET and receiving no more than two blastocysts. METHODS: The pretreatment group (n = 172) received GnRH-a pretreatment and the control group (n = 171) did not. Analysis followed the intention-to-treat (ITT) principle. MAIN OUTCOME MEASURES: The primary outcome measure was live birth rate. Secondary outcome measures included clinical pregnancy rate, implantation rate, early pregnancy loss rate and direct treatment costs per FET cycle. RESULTS: Among the 343 women randomised, 330 (96.2%) underwent embryo transfer and 328 (95.6%) completed the protocols. Live birth rate according to ITT did not differ between the pretreatment and control groups [85/172 (49.4%) versus 92/171 (53.8%), absolute rate difference -4.4%, 95% CI -10.8% to 2.0% (P = 0.45). Implantation rate, clinical pregnancy rate and early pregnancy loss rate also did not differ between groups, but median direct cost per FET cycle was significantly higher in the pretreatment group (7799.2 versus 4438.9 RMB, OR = 1.9, 95%CI 1.2-3.4, P < 0.001). Median direct cost per live birth was also significantly higher in the pretreatment group (15663.1 versus 8189.9 RMB, odds ratio [OR] = 1.9, 95% CI 1.2-3.8, P < 0.001). CONCLUSIONS: Pretreatment with GnRH-a does not improve pregnancy outcomes for women with PCOS receiving AC-FET, but significantly increases patient cost. TWEETABLE ABSTRACT: For women with PCOS, artificial cycle-prepared FET with GnRH agonist pretreatment provides no pregnancy outcome benefit but incurs higher cost.

Abdominal ectopic pregnancy following a frozen embryo transfer cycle: a case report.

BACKGROUND: Abdominal ectopic pregnancy (AEP) is a rare form of ectopic pregnancy. As the number of in-vitro fertilization (IVF) procedures continues to increase, the incidence of AEP will also rise. However, the rarity and atypical presentation of AEP make early diagnosis challenging. CASE PRESENTATION: Herein, we report an AEP following frozen-thawed embryo transfer (FET) in an artificial cycle. The patient was misdiagnosed with implantation failure when the serum human chorionic gonadotropin (hCG) level was detected as 2.59mIU/ml at fourteenth day after embryo transfer. Therefore, she was suggested to stop luteal phase support. However, a ruptured AEP was developed 33 days following embryo transfer, which was diagnosed by laparoscopic surgery. CONCLUSIONS: The case highlighted the delayed serum ß-hCG and massive intraperitoneal hemorrhage may be clues to make early diagnosis of AEP. Clinicians must attach great importance to close monitoring and bear in mind the possibility of abdominal pregnancy.

The timing for initiating estrogen stimulation in artificial cycle for frozen-thawed embryo transfer can be flexible.

BACKGROUND: There remains a lack of evidence to demonstrate whether the initiation time of estrogen stimulation is flexible in the proliferative endometrial phase during the artificial cycle for frozen-thawed embryo transfer (AC-FET). METHODS: FET records were retrospectively reviewed from a large university-affiliated reproductive medicine center. Only the patients who were undergoing their first embryo transfer with a single blastocyst in the AC-FET cycles were included: thereby 660 cycles were recruited, and the patients were grouped according to their day of estrogen usage initiation as early initiation group (estrogen stimulation initiated during days 2-5 of menses, n = 128) and the late initiation group (estrogen stimulation initiated on or after the 6th day of menses, n = 532). The primary outcome was the ongoing pregnancy rates (OPR). RESULTS: The rates of biochemical and clinical pregnancies were significantly higher in the late initiation group relative to those in the early initiation group, however, no significant differences were noted between the two groups for OPR. Furthermore, after adjusting for the results of the potential confounders, no impact was observed in the initiation time of estrogen stimulation on the OPR. CONCLUSIONS: This study provides evidence that initiating the estrogen stimulation on after days 2-5 of menses do not exert adverse effects on the OPR in AC-FETs. Thus, AC-FET can be scheduled in a flexible manner without compromising on the pregnancy outcomes.

Despite the continuous efforts invested in exploring and optimizing therapeutic regimens to improve the success rate of frozen-thawed embryo transfer (FET), we found that there are little evidence to demonstrate whether the initiation time of estrogen stimulation is flexible in the proliferative endometrial phase during the artificial cycle for FET (AC-FET). Thus, we retrospectively reviewed the FET records from a large university-affiliated reproductive medicine center to explore whether the relatively late start of endometrial stimulation for FET influences the pregnancy outcome. Results provided evidences that initiating the estrogen stimulation on after days 2­5 of menses do not exert adverse effects on the ongoing pregnancy rates in AC-FETs. Therefore, FET can be scheduled in a flexible manner, according to the ovulatory and endometrial statuses and patient and/or clinic preference, without compromised clinical outcomes.

Progesterone and estrogen levels are associated with live birth rates following artificial cycle frozen embryo transfers.

PURPOSE: Does an association exist between serum progesterone and estradiol levels and live birth rates in artificial cycle frozen embryo transfer (AC-FET)? METHODS: Retrospective cohort study was based on prospectively collected data at a university-affiliated fertility center. Included were all cycles using an artificial endometrial preparation with estradiol hemihydrate (Estrofem, 2 mg/8 h) and vaginal progesterone (Endometrin 100 mg/8 h), autologous oocytes, and cleavage stage embryo transfers. Serum progesterone and estradiol levels were measured 14 days after FET. A total of 921 cycles in 568 patients from to December 2010 to June 2019 were investigated. Live birth was the primary outcome measure. RESULTS: Significant association was found between live birth and progesterone as well as estradiol levels (progesterone 14.65 vs 11.62 ng/ml, p = 0.001; estradiol 355.12 vs 287.67 pg/ml, p = 0.001). A significant difference in live birth rate was found below and above the median progesterone level (10.9 ng/ml, p = 0.007). Lower estradiol level was significantly associated with lower live birth rate (< 188.2 pg/ml 8.3%, > 263.1 pg/ml 16%, p = 0.02). CONCLUSIONS: Serum progesterone and estradiol levels impact live birth rate in AC-FET.

Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.

STUDY QUESTION: Does the endometrial preparation protocol for frozen embryo transfer (FET) have an impact on perinatal outcomes? SUMMARY ANSWER: Singleton newborns from conceptions after an artificial FET cycle had a higher risk of being large for gestational age (LGA). WHAT IS KNOWN ALREADY: Most previous studies have concentrated on the clinical pregnancy, miscarriage and live birth rates of different endometrial preparation protocols for FET. However, the impacts of these cycle regimens on perinatal outcomes including birthweight, gestational age (GA) and related outcomes require more investigation. STUDY DESIGN, SIZE, DURATION: We retrospectively analysed all singletons conceived by women who underwent non-donor FET cycles between July 2014 and July 2017. The propensity score matching (PSM) method using nearest neighbour matching at a proportion of 1:1 was established to adjust for factors that influence the probability of receiving different FET cycle regimens. The main outcomes of the study included birthweight and its related outcomes, Z-score, low birthweight (LBW, <2500 g), small for gestational age (SGA, ≤10th percentile of referential birthweight), LGA (≥90th percentile of referential birthweight) and macrosomia (birthweight >4000 g). The study outcomes also included GA at birth, preterm delivery (<37 weeks), very preterm delivery (<32 weeks), very low birthweight (VLBW, <1500 g), term LBW (at 37 weeks of gestation or greater) and preterm LBW (at <37 weeks of gestation). PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 9267 cycles with live-born singletons were included in the analysis in our centre between July 2014 and July 2017. Of these, 2224, 4299 and 2744 live-born singletons were conceived by natural cycle FET, stimulated cycle FET and artificial cycle FET, respectively. After PSM, 1947 cycles of natural cycle FET versus stimulated cycle FET, 1682 cycles of stimulated cycle FET versus artificial cycle FET and 2333 cycles of natural cycle FET versus artificial cycle FET were included in the analysis. MAIN RESULTS AND THE ROLE OF CHANCE: A higher mean birthweight and Z-score were observed in the artificial cycle FET group than in the stimulated cycle FET group (P = 0.005; P = 0.004, respectively). Singleton newborns conceived after artificial cycle FET were more likely to be LGA than those born after natural cycle FET or stimulated cycle FET (19.92% versus 16.94% and 19.29% versus 16.12%, respectively). The adjusted ORs (95% CIs) were 1.25 (1.05, 1.49) for artificial cycle FET compared with natural cycle FET (P = 0.014) and 1.26 (1.08, 1.46) for artificial cycle FET compared with stimulated cycle FET (P = 0.003). Newborns conceived after stimulated cycle FET had a lower mean GA at birth and a lower mean birthweight than those born after natural cycle FET or artificial cycle FET. The stimulated cycle FET group had lower adjusted odds of being macrosomia than the natural cycle FET group. No significant differences between natural cycle FET and stimulated cycle FET were found for any of the other outcomes. LIMITATIONS, REASONS FOR CAUTION: This study had the disadvantage of being retrospective, and some cases were excluded due to missing data. The original allocation process was not randomized, which may have introduced bias. We have chosen not to account for multiple comparisons in our statistical analysis. WIDER IMPLICATIONS OF THE FINDINGS: LGA can have long-term consequences in terms of risk for disease, which means that the influences of artificial cycle FET are of clinical significance and deserve more attention. Furthermore, these findings are critical for clinicians to be able to make an informed decision when choosing an endometrial preparation method. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Natural Science Foundation of China (NSFC) (31770989 to Y.W.) and the Shanghai Ninth People's Hospital Foundation of China (JYLJ030 to Y.W.). None of the authors have any conflicts of interest to declare.