Endometrial Preparation Protocols Research Articles

Comparing the effects of two different progesterone vaginal gels, Progeson™ and Crinone™, from pharmacokinetics study to clinical applications in patients undergone fresh embryo transfer and frozen-thawed embryo transfer via natural cycle endometrial preparation protocol.

The pharmacokinetics performance and clinical pregnancy rate of two vaginal progesterone gel, Progeson™ and Crinone™, were compared in this study. In the pharmacokinetics performance, Progeson showed similar long-term dissolution rate as Crinone. In the clinical study, 141 subjects undergone invitro fertilization (IVF) treatments were included to compare serum progesterone level and clinical pregnancy rates. Among the subjects, 78 subjects received fresh embryo transfer and 63 subjects received frozen embryo transfer via natural cycle endometrial preparation protocol. In each group, subjects were given either Crinone™ or Progeson™ for luteal phase support without combination with other progesterone products. The study showed that Crinone™ group led to higher estrogen level at mid-luteal phase in the fresh embryo transfer group, and Progeson™ group led to higher progesterone level at mid-luteal phase and pregnancy test day in the frozen-thawed embryo transfer group. Subjects received Crinone™ or Progeson™ had similar rate of pregnancy, live birth, and stillbirth in both fresh embryo transfer and frozen-thawed embryo transfer group. Thus, Progeson™ might be a suitable substitute for Crinone™ in assisted reproductive therapy.

No advantage of single day 6 good-quality blastocyst transfer versus single day 5 poor-quality blastocyst transfer in frozen-thawed cycles stratified by age: a retrospective study

BackgroundBlastocyst developmental speed, morphological grading and patient age are associated with pregnancy outcomes of frozen-thawed cycles. This study aimed to compare the clinical and neonatal outcomes between poor-quality D5 blastocysts and good-quality D6 blastocysts stratified by patient age.MethodsA total of 1,623 cycles were divided into two groups: group A (n = 723) received one D5 poor-quality blastocyst; group B (n = 900) received one D6 good-quality blastocyst. Pregnancy and neonatal outcomes were compared among the four groups stratified by 35 years of age.ResultsWhen patients were in the same age group, there was no significant difference in terms of age, body mass index, infertility duration, infertility type, fertilization method, proportion of endometrial preparation protocols, and endometrial thickness between D5 poor-quality and D6 high-quality blastocysts groups. Live birth rate of D5 poor-quality blastocysts was higher than that of D6 high-quality blastocysts for patients aged < 35 years (35.48% vs. 31.13%, p > 0.05), but there was no statistical difference. The same trend was showed for patients aged ≥ 35 years (29.09% vs. 21.28%, p > 0.05). Moreover, when patients were in the same age category, there was no significant difference in terms of gestational age, birth weight, birth height, and rates of preterm birth, low birth weight, and very low birth weight between groups A and B.ConclusionsThe preferential selection of poor-quality D5 blastocysts for transfer compared to high-quality D6 blastocysts is recommended, especially for advanced age patients. Single good-quality D6 blastocyst transfer can be considered for the acceptable live birth rate.

Comparison of different endometrial preparation protocols in frozen-thawed embryo transfer cycles in women with polycystic ovary syndrome

Aim: This study aimed to evaluate the most suitable endometrial preparation protocols such as hormone replacement therapy (HRT) with gonadotropin releasing hormone analogue (GnRH-a) suppression, HRT without GnRH-a suppression and mild ovarian stimulation (OS) for women with polycystic ovary syndrome (PCOS) undergoing frozen-thawed embryo transfer (FET).Material and Method: We conducted a historical cohort analysis of 161 women with PCOS who underwent the “freeze-all” strategy between December 2018 and August 2020 because of their high risk for ovarian hyperstimulation syndrome. Three endometrial preparation protocols were used: HRT with GnRH-a suppression (n=43); HRT without GnRH-a suppression (n=86); mild-OS (n=32).Results: The biochemical pregnancy results (55.8 % vs 54.65 % vs 53, p=0.900), ongoing pregnancy rates (44.2 % vs 43 % vs 40.62, p=0.572), and abort rates (20.8 % vs 21.3 % vs 23.52, p=0.900) were similar between the HRT with GnRH-a suppression, without GnRH-a suppression and mild-OS, respectively. This study showed no statistically significant difference between the three protocols in laboratory parameters (p&amp;gt;0.05). Conclusion: There was no statistically difference between three groups in terms of pregnancy outcomes. Dependent on clinical experience and facility, one of these protocols could be deployed for FET in women with PCOS.

Which endometrial preparation protocol provides better pregnancy and perinatal outcomes for endometriosis patients in frozen-thawed embryo transfer cycles? A retrospective study on 1413 patients

ObjectiveTo determine the optimal endometrial preparation protocol for a frozen embryo transfer in patients with endometriosis.DesignRetrospective cohort study.SettingTertiary care academic medical center.Patient(s)One thousand four hundred thirteen patients with endometriosis who underwent oocyte aspiration from 2015 to 2020 and frozen embryo transfer from 2016 to 2020 and received natural cycle, hormone replacement treatment with or without GnRHa pretreatment endometrial preparation.Intervention(s)None.Main outcome measure(s)Clinical pregnancy rate, live birth rate, miscarriage rate, multiple pregnancy rate, biochemical pregnancy rate and ectopic pregnancy rate. Singleton live births were assessed for perinatal outcomes and obstetric complications.Result(s)There were no differences in clinical pregnancy outcomes or prenatal outcomes among the three commonly used endometrial preparation protocols for frozen embryo transfer cycles in patients with endometriosis. Results remained after screening variables using univariate logistic regression into multivariate logistic regression. No advantages or disadvantages were found among the three endometrial preparation protocols in patients with endometriosis.Conclusion(s)Natural cycle, hormone replacement cycle, or hormone replacement treatment with GnRHa pretreatment showed no superiority or inferiority in pregnancy and perinatal outcomes in patients with endometriosis.

Outcome of Different Endometrial Preparation Protocols Prior to Frozen-Thawed Embryo Transfer on Pregnancy Outcomes in Women with Repeated Implantation Failure.

To compare the pregnancy outcomes of frozen-thawed embryo transfer (FET) cycles among women with repeated implantation failure (RIF) treated with various endometrial preparation protocols. A total of 605 women with RIF were retrospectively recruited between January 2017 and December 2020 from Northern Theater General Hospital. Patients were divided into natural cycles, hormone replacement therapy (HRT) cycles, depot gonadotropin-releasing hormone (GnRH) agonist-HRT, and endometrial scratching (ES) plus depot GnRH agonist-HRT. The primary endpoint was clinical pregnancy rate, while secondary endpoints included live birth rate and pain assessment. Of the 605 recruited patients, 63 were undergoing natural cycles, 281 were treated with HRT cycles, 141 treated with depot GnRH agonist-HRT, and 120 treated with ES combined with depot GnRH agonist-HRT. There were significant differences among protocols on clinical pregnancy rate (P=0.029), while no significant difference was observed among protocols on live birth rates (P=0.108). Multivariate analyses suggested that HRT (odds ratio [OR]: 0.50; 95% confidence interval [CI]: 0.28-0.89; P=0.019) and depot GnRH agonist-HRT (OR: 0.49; 95% CI: 0.27-0.91; P=0.021) cycles were associated with a lower clinical pregnancy rate as compared with natural cycles, while no significant difference between ES combined with depot GnRH agonist-HRT and natural cycles for clinical pregnancy rates (OR: 0.72; 95% CI: 0.38-1.36; P=0.313). Moreover, the HRT (OR: 0.70; 95% CI: 0.39-1.28; P=0.239), depot GnRH agonist-HRT (OR: 0.67; 95% CI: 0.35-1.29; P=0.229), and ES combined with depot GnRH agonist-HRT (OR: 1.11; 95% CI: 0.58-2.14; P=0.754) cycles had no significant effects on live birth rate as compared with natural cycles. A total of 87.50% patients treated with ES combined with depot GnRH agonist-HRT reported pain during the procedure. ES and depot GnRH agonists could be considered for RIF women with high-quality blastocysts, 14 days after verified transplantation failure.

Agonist long protocol improves outcomes of vitrified-warmed embryo transfer in repeatedly thin endometrium

Research questionDoes follicular stimulation using human menopausal gonadotrophin (HMG) after pituitary down-regulation by a GnRH agonist improve endometrial thickness (EMT) and clinical outcomes of frozen-thawed embryo transfer (FET; using vitrified-warmed embryos) in women with thin endometrium after intensified oestrogen administration (IOA)? DesignThis was a retrospective study. A total of 627 patients attempted 683 FET cycles with at least one previous history of thin endometrium. None of the cycles reached over 7 mm EMT after using oral and vaginal oestradiol for more than 21 days (IOA protocol). A total of 129 cycles proceeded with FET, 305 cycles were cancelled, and 249 cycles involved administration of HMG following GnRH agonist pituitary down-regulation (GnRH agonist + HMG protocol) for further endometrial preparation. ResultsEMT became significantly greater (7.18 ± 1.14 mm versus 6.13 ± 0.63 mm, P < 0.001) using GnRH agonist + HMG compared with previous IOA cycles, but this was not related to serum oestrogen concentrations. A total of 213 cycles after the GnRH agonist + HMG protocol proceeded with FET, showing a significantly increased clinical pregnancy rate, implantation rate and live birth rate compared with those after IOA. ConclusionsThe GnRH agonist + HMG protocol for endometrial preparation in FET cycles improves EMT in women with a thin endometrium after IOA and showed significantly better clinical outcomes than IOA. The authors suggest that the GnRH agonist + HMG protocol should be used for EMT that is less than 7 mm after there has been no optimal response to IOA.

Clinical outcomes and placental pathological characteristics after fresh embryo transfer and frozen-thawed embryo transfer with different endometrial preparation protocols

Clinical outcomes and placental pathological characteristics after fresh embryo transfer and frozen-thawed embryo transfer with different endometrial preparation protocols

Prediction of risk factors for first trimester pregnancy loss in frozen-thawed good-quality embryo transfer cycles using machine learning algorithms.

Can the risk factors that cause first trimester pregnancy loss in good-quality frozen-thawed embryo transfer (FET) cycles be predicted using machine learning algorithms? This is a retrospective cohort study conducted at Sisli Memorial Hospital, ART and Reproductive Genetics Center, between January 2011 and May 2021. A total of 3805 good-quality FET cycles were included in the study. First trimester pregnancy loss rates were evaluated according to female age, paternal age, body mass index (BMI), diagnosis of infertility, endometrial preparation protocols (natural/artificial), embryo quality (top/good), presence of polycystic ovarian syndrome (PCOS), history of recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), severe male infertility, adenomyosis and endometriosis. The first trimester pregnancy loss rate was 18.2% (693/ 3805). The presence of RPL increased first trimester pregnancy loss (OR = 7.729, 95%CI = 5.908-10.142, P = 0.000). BMI, which is > 30, increased first trimester pregnancy loss compared to < 25 (OR = 1.418, 95%CI = 1.025-1.950, P = 0.033). Endometrial preparation with artificial cycle increased first trimester pregnancy loss compared to natural cycle (OR = 2.101, 95%CI = 1.630-2.723, P = 0.000). Female age, which is 35-37, increased first trimester pregnancy loss compared to < 30 (OR = 1.617, 95%CI = 1.120-2.316, P = 0.018), and female age, which is > 37, increased first trimester pregnancy loss compared to < 30 (OR = 2.286, 95%CI = 1.146-4,38, P = 0.016). The presence of PCOS increased first trimester pregnancy loss (OR = 1.693, 95%CI = 1.198-2.390, P = 0.002). The number of previous IVF cycles, which is > 3, increased first trimester pregnancy loss compared to < 3 (OR = 2.182, 95%CI = 1.708-2.790, P = 0.000). History of RPL, RIF, advanced female age, presence of PCOS, and high BMI (> 30kg/m2) were the factors that increased first trimester pregnancy loss.

EFFECT OF BMI ON SERUM ESTRADIOL LEVELS AND CORRELATION WITH PREGNANCY OUTCOMES IN PROGRAMMED FROZEN EMBRYO TRANSFER CYCLES

Among reproductive aged women in 2017-2018, the prevalence of obesity was 39.7% in those aged 20-39, and 43.3% in those aged 40-59 (1). Obese patients are known to require larger doses of gonadotropins in comparison with their normal-weight counterparts during IVF stimulation (2). A recent study also showed that both increasing BMI and increasing weight negatively affected the serum progesterone levels on the day of the pregnancy test after FET (2). Other studies have shown that increasing BMI was associated with a decreased peak estradiol level in FET cycles that utilized programmed hormone replacement endometrial preparation protocols (3).

Is there an optimal window of time for transferring single frozen-thawed euploid blastocysts? A cohort study of 1170 embryo transfers.

Is there an optimal window of time when the transfer of single frozen-thawed euploid blastocysts is associated with a maximal live birth rate (LBR)? Performing a single frozen-thawed euploid blastocyst transfer at 160 ± 4 h post-hCG trigger in modified-natural frozen-thawed embryo transfer (FET) cycles was independently associated with a higher LBR as compared to transfers outside this window; however, in natural FET cycles, LBRs were comparable across a wider range of time intervals. There is compelling evidence for maintaining embryo-endometrial synchrony to optimize clinical outcomes following FETs, which could potentially be achieved by matching the transfer time of an embryo post-ovulation to its developmental age post-oocyte retrieval. For modified-natural cycles, ovulation is widely accepted to occur ∼40 h following the hCG trigger, whilst ovulation following spontaneous LH surge onset is thought to vary from 24 to 56 h. This is a multicentered retrospective cohort study analyzing 1170 single frozen-thawed euploid blastocyst transfers following trophectoderm biopsy and preimplantation genetic testing (PGT) between May 2015 and February 2019. Limiting the analysis to single euploid embryo transfers allowed for a more accurate estimation of the endometrial synchrony factor by controlling for the developmental stage of the embryo (full blastocyst or more advanced) and its genetic composition. LBR per FET was the primary outcome measure. Patients underwent natural or gonadotrophin-induced preparation of the endometrium, with serial serum oestradiol, LH and progesterone measurements. Optimally timed transfers were predefined as those conducted 120 ± 4 h post-ovulation since biopsy and subsequent cryopreservation of full blastocysts which is usually performed at 116-124 h post-oocyte retrieval. This was considered the equivalent of 160 ± 4 h post-hCG trigger in modified-natural cycles (n = 253), as ovulation was assumed to occur ∼40 h after the hCG trigger. For natural cycles (n = 917), this was also considered to be, on average, 160 ± 4 h post the spontaneous LH surge. Thus, study groups were determined as those with optimal timing or not, and additional exploratory and subgroup analyses were performed, varying the time window in terms of onset and width, both overall and per endometrial preparation protocol. Statistical analysis was performed using the generalized estimating equations (GEE) framework to control for the clustered nature of the data while adjusting for potential confounders. Overall, LBRs were significantly higher when the transfer had been performed at 160 ± 4 h post-hCG trigger or LH surge onset compared to when it had been performed outside this window (44.7% vs 36.0%; P = 0.008). A multivariable regression GEE model including the cycle type (natural versus modified-natural), previtrification embryo quality (top versus good quality), embryo stage (fully hatched versus hatching or earlier blastocyst), vitrification day (D5 versus D6) and survival rate (>90% versus <90%) as covariates, confirmed that, overall, embryo transfers conducted 160 ± 4 h post-hCG trigger or LH surge onset (the assumed equivalent of 120 ± 4 h post-ovulation) were associated with a significantly higher LBR (relative risk (RR) 1.21, 95% CI 1.04-1.41). Subgroup exploratory analyses per endometrial preparation protocol demonstrated that these findings were primarily present in the modified-natural cycle group (RR 1.52, 95% CI 1.15-1.99), whilst the natural cycle group showed comparable LBRs across a wider range of time intervals. Moreover, the overall LBR for the natural group (36.8%; 95% CI 33.7-39.9%) was lower than that of the modified-natural group (41.3%; 95% CI 35.4-47.1%), suggesting that there likely remains a greater potential to further optimize the timing of natural cycle embryo transfers. As with all retrospective studies, the presence of residual unknown bias cannot be excluded. Additionally, patients included in this study were a selected group who underwent PGT for specific reasons and hence the results obtained might not be directly applicable to the general population or embryos that have not undergone embryo biopsy. Furthermore, the criteria utilized to interpret hormonal data from natural cycles were specifically adopted for the present study and need to be validated in further studies. The results of this study highlight the significance of embryo-endometrial synchrony for the optimization of frozen embryo transfer outcome. However, it also clearly supports that the implantation window is in most cases wide and the achievement of live birth is possible with relatively high success rates even outside the optimal window of 160 ± 4 h post-trigger for modified-natural cycles and across a range of time intervals for natural cycles. Additionally, this study suggests that implantation rates could be further optimized in natural cycles by improving methods of assessing embryo-endometrial synchrony. C. V. is supported by a National Health and Medical Research Council Early Career Fellowship (GNT1147154). No other funding was received for this study and there are no competing interests. N/A.

Pregnancy outcomes of four different cycle protocols for frozen embryo transfer: a large retrospective cohort study

Objective: To evaluate the pregnancy outcomes of the four endometrial preparation protocols for people undergoing frozen-thawed embryo transfer (FET), including natural cycle (NC), hormone replacement therapy cycle (HRT), gonadotropin-releasing hormone agonist artificial cycle (GAC), and ovarian stimulation cycle (OC). Methods: This retrospective cohort study enrolled 10,333 cycles of frozen embryo transfer performed at Xinan Gynecological Hospital in Sichuan, China, from January 2018 to December 2018. The patient’s baseline characteristics and pregnancy outcomes were extracted from the medical record system. Pregnancy outcomes were compared among the four groups and multiple logistic regression models were used to adjust for the confounding factors. Results: After adjusting for covariates, multiple logistic regression analysis showed no statistical significance in pregnancy outcomes in the HRT group, GAC group, and OC group compared to the NC group in the entire population. The adjusted odds ratio of live birth was 0.976 (95% confidence interval [CI] 0.837–1.138) for the HRT group, 0.959 (95% confidence interval 0.797–1.152) for the GAC group, and 0.909 (95% confidence interval 0.763–1.083) for the OC group. Conclusions: The natural protocol had comparable pregnancy outcomes compared to the other three endometrial preparation protocols in the overall FET population. More high-quality prospective randomized controlled trials are required to assess the efficacy of the four protocols and explore the optimal one.

Comparison of endometrial preparation protocols (natural cycle versus hormone replacement cycle) for frozen embryo transfer (COMPETE): a study protocol for a randomised controlled trial

IntroductionNatural cycle (NC) and hormone replacement treatment (HT) are frequently used endometrial preparation protocols prior to frozen-thawed embryo transfer in ovulatory women. It is not clear which protocol results in...

GnRH-agonist pretreatment in hormone replacement therapy improves pregnancy outcomes in women with male-factor infertility.

ObjectiveThis study aimed to examine the efficacy of HRT with gonadotropin-releasing hormone agonist (GnRH-a) pre-treatment in women with male-factor infertility who underwent a frozen embryo transfer (FET) programme.DesignBetween January 2016 and October 2020, 2733 women with male-factor infertility who underwent the HRT protocol as the endometrial preparation method were enrolled at two Reproductive Medicine Centres. Patients were divided into two groups based on whether they had GnRH-a pre-treatment before HRTs: the GnRHa-HRT group and the HRT group. The inverse probability of treatment weighting (IPTW) method was conducted to balance patient baseline characteristics between treatment cohorts to reduce selection bias. The live birth rate was considered regarded as the primary pregnancy outcome.ResultsMultivariate logistic regression adjusted for confounding factors, the GnRHa-HRT group showed a notably higher rate of live birth (OR 2.154, 95% CI 1.636~2.835, P<0.001) when compared to the HRT group. Additionally, the rate of miscarriage was significantly lower in the GnRHa-HRT group. The GnRHa-HRT group had significantly higher rates of biochemical pregnancy, clinical pregnancy, multiple pregnancy, and term birth.ConclusionThe endometrial preparation protocol of HRT with GnRH-a pre-treatment could obviously increase the live birth rate for women with male-factor infertility undergoing the FET programme.

The impact of different endometrial preparation protocols on obstetric and neonatal complications in frozen-thawed embryo transfer: a retrospective cohort study of 3,458 singleton deliveries

BackgroundFrozen-thawed embryo transfer (FET) is thought to be associated with obstetric and neonatal complications after in vitro fertilization/intracytoplasmic single sperm injection (IVF/ICSI) treatment. The study aimed to determine whether the endometrial preparation protocol is an influencing factor for these complications.MethodsWe conducted a retrospective cohort study of 3,458 women who had singleton deliveries after IVF/ICSI–FET treatment at the Centre for Reproductive Medicine of Shanghai First Maternity and Infant Hospital between July 2016 and April 2021. The women were divided into three groups according to the endometrial preparation protocols: 2,029 women with programmed cycles, 959 with natural cycles, and 470 with minimal ovarian stimulation cycles. The primary outcomes were the incidence rates of obstetric and neonatal complications, namely, hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), placenta previa, preterm rupture of membranes (PROM), preterm delivery, postpartum haemorrhage, large for gestational age (LGA), small for gestational age (SGA), and macrosomia.ResultsAfter adjustments for confounding variables by multivariate logistic regression analysis, the results showed that programmed cycles had an increased risk of HDP (aOR = 1.743; 95% CI, 1.110–2.735; P = 0.016) and LGA (aOR = 1.269; 95% CI, 1.011–1.592; P = 0.040) compared with natural cycles. Moreover, programmed cycles also increased the risk of LGA (aOR = 1.459; 95% CI, 1.083–1.965; P = 0.013) but reduced the risk of SGA (aOR = 0.529; 95% CI, 0.348–0.805; P = 0.003) compared with minimal ovarian stimulation cycles. There were no significant differences between natural cycles and minimal ovarian stimulation cycles.ConclusionsDuring IVF/ICSI–FET treatment, the risk of HDP and LGA was increased in women with programmed cycles. Therefore, for patients with thin endometrium, irregular menstruation or no spontaneous ovulation, minimal ovarian stimulation cycles may be a relatively safer option than programmed cycles.

Programmed frozen embryo transfer cycle increased risk of hypertensive disorders of pregnancy: a multicenter cohort study in ovulatory women

Although live birth rates were comparable between programmed and natural frozen-thawed embryo transfer cycles, recent data showed that pregnancies after programmed cycle were associated with an increased risk of adverse perinatal outcomes, such as hypertensive disorders of pregnancy. Such a difference might be attributed to selection bias because patients with ovulation disorders are more likely to receive programmed endometrial preparation protocol than natural cycle. This study aimed to analyze whether programmed endometrial preparation protocol is associated with an increased risk of adverse perinatal outcomes compared with natural cycle during frozen embryo transfer in ovulatory women. This regional multicenter retrospective cohort study was conducted in 5 reproductive medical centers in Southeast China. Patients with regular cycles (21-35 days), who underwent either programmed or natural cycle blastocyst frozen embryo transfer and delivered singleton live birth babies after 28 weeks of gestation between 2016 and 2019 were analyzed. Each patient only contributed 1 cycle per cohort. The patients' frozen embryo transfer treatment cycles were linked to their obstetrical medication record, and a comprehensive medical record review was conducted to compare the maternal and neonatal outcomes between natural cycle and programmed cycle. Crude and adjusted odds ratios with 95% confidence intervals were calculated, and adjustment was made for relevant confounders. Study samples included 499 natural cycle frozen embryo transfer cases and 900 programmed frozen embryo transfer cases. Pregnancies after programmed cycle were associated with increased odds of hypertensive disorders of pregnancy (adjusted odds ratio, 2.71; 95% confidence interval, 1.59-4.91) and preeclampsia (adjusted odds ratio, 2.71; 95% confidence interval, 1.17-6.23) compared with pregnancies after natural cycle. No significant difference was detected regarding other adverse perinatal outcomes between the 2 endometrial protocols. In subgroup analysis, both the subgroups of hormone replacement therapy and hormone replacement therapy with gonadotrophin-releasing hormone analogue pretreatment had increased odds of developing hypertensive disorders of pregnancy than the natural cycle group. The risk of developing preeclampsia was higher in the hormone replacement therapy with gonadotrophin-releasing hormone analogue pretreatment subgroup than in the other 2 groups (adjusted odds ratio, 4.99; 95% confidence interval, 1.94-12.82) (aOR, 2.47; 95% CI, 1.17-5.18). Pregnancies after programmed frozen embryo transfer were associated with higher risks of hypertensive disorders of pregnancy in ovulatory women. The hormone replacement therapy with gonadotrophin-releasing hormone analogue pretreatment cycle led to the highest risk of preeclampsia among the 3 protocols.

Endometrial preparation and maternal and obstetrical outcomes after frozen blastocyst transfer

Two types of endometrial preparation protocols are used for frozen embryo transfers in current practice: hormone replacement and the natural cycle. Endometrial preparation in the natural cycle reportedly increases the chances of live birth and decreases early pregnancy loss compared with that in the hormone replacement cycle. However, the influence of endometrial preparation on maternal and neonatal health remains unclear. This study aimed to investigate whether the differences between hormone replacement cycle and natural cycle influence perinatal outcomes and risk of congenital anomalies in frozen-thawed blastocyst transfer fetuses or births. Perinatal outcomes and congenital abnormalities were compared between the natural and hormone replacement cycles. According to the timing of ovulation, frozen-thawed blastocyst transfers in the natural cycle were classified into 2 patterns: on day 4.5 (ovulation 4.5) or day 5 (ovulation 5.0) after ovulation. When the serum luteinizing hormone level was not increased on the day of the trigger, a single vitrified-warmed blastocyst transfer was performed on day 7 after the trigger (ovulation 5.0). When the luteinizing hormone level was slightly increased on the day of trigger, single vitrified-warmed blastocyst transfer was performed on day 6 after the trigger (ovulation 5.0). In total, 67,018 cycles (ovulation 4.5, 29,705 cycles; ovulation 5.0, 31,995 cycles; hormone replacement, 5318 cycles) of frozen-thawed blastocyst transfer between January 2008 and December 2017 at Kato Ladies Clinic were retrospectively analyzed. During the study period, embryo cryopreservation was performed using a vitrification method in all cycles. Hormone replacement cycles were associated with a higher occurrence of hypertensive disorders of pregnancy (adjusted odds ratio, 2.16; 95% confidence interval, 1.66-2.81) and placenta accreta (adjusted odds ratio, 4.14; 95% confidence interval, 1.64-10.44) compared with the natural cycle. The risks of cesarean delivery (adjusted odds ratio, 1.93; 95% confidence interval, 1.78-2.18), preterm birth (adjusted odds ratio, 1.55; 95% confidence interval, 1.25-1.93), and low birthweight (adjusted odds ratio, 1.42; 95% confidence interval, 1.18-1.73) were also higher for hormone replacement cycles. No significant difference in the risk of congenital anomalies was observed between the 2 cycles. The risk of hypertensive disorders of pregnancy, placenta accreta, cesarean delivery, preterm delivery, and low birthweight was higher in hormone replacement cycles than in natural cycles, whereas the risk of congenital anomalies was similar between both cycles. Further follow-up is needed to investigate these risks and to explore alternative endometrial preparation methods.

Comparison of different endometrial preparation protocols on frozen embryo transfer pregnancy outcome in patients with normal ovulation

Research questionWhat is the effect of letrozole use in patients undergoing frozen embryo transfer (FET) with normal ovulation? Although the number of FETs is increasing, an optimal protocol for FET (particularly vitrified–warmed embryo transfer) is yet to be determined. The aim of this study was to evaluate letrozole use on patients with normal menstrual cycles compared with hormone replacement therapy (HRT) cycles and natural cycles. DesignThe study involved 2849 patients. Patients were divided into three groups: HRT cycle (n = 2115), letrozole cycle (n = 532) and natural cycle (n = 202). Inverse probability of treatment weighting aimed to equate each group according to measured baseline covariates to achieve a comparison with reduced selection bias and live birth rate as main pregnancy outcome was analysed. ResultsIn the crude analysis, the letrozole group had a higher live birth rate compared with the HRT cycle (OR 1.18, 95% CI 1.06 to 1.33) and natural cycle (OR 1.24, 95% CI 1.11 to 1.41); after adjusting for confounding factors, live birth rate was consistently higher in the letrozole group. Moreover, the biochemical pregnancy, clinical pregnancy, ongoing pregnancy and full-term delivery rates were higher in the letrozole group. ConclusionFor infertile women with normal menstrual cycle undergoing FET, mildly stimulated cycles with letrozole present a relatively large advantage compared with HRT cycle and natural cycle, with higher live birth pregnancy, indicating that letrozole administration could improve pregnancy outcomes in this population.

P-381 A novel natural cycle proliferative phase/progesterone replacement(NC/PR) protocol for endometrial preparation for frozen-thawed embryo transfer(FET) Can it improve pregnancy outcomes : a prospective comparative study

Abstract Study question Can a novel protocol for endometrial preparation- NC/PR-FET, lead to better pregnancy outcomes than artificial cycle (AC)-FET, with similar ease of cycle monitoring and scheduling? Summary answer NC/PR-FET protocol gave comparable clinical pregnancy rates (CPR), significantly less early miscarriage rates (MR) and significantly more live birth rates (LBR) compared to AC-FET protocol. What is known already AC-FET is the most common protocol for endometrial preparation due to flexibility, easy monitoring, and high pregnancy rates albeit with evidence of higher obstetrical risks e.g., miscarriage, pre-eclampsia versus NC-FET. This risk could be due to suboptimal hormonal administration in AC-FET leading to impaired endometrial maturation, predecidualization, and altered endometrial function. Studies indicate, estradiol may have a stronger negative effect(versus progesterone) on the endometrial transcriptome. Hence, we studied a novel protocol with NC-estrogen (but with progesterone similar to AC-FET), for better endometrial maturation, predecidualization along with simple monitoring and flexible ET scheduling. Previously, a proof-of-concept case-series has been reported. Study design, size, duration The prospective comparative study was conducted at a tertiary center (Jan2019-Dec2021) with 126 patients (both autologous [AO] and donor oocytes [DO]):79 (AC-FET) and 47 (NC/PR-FET) with similar ICSI, vitrification, ET protocols. 2 or 3 Grade A cleavage stage embryos were transferred. CPR, implantation rates(IR), early MR (≤13 weeks, miscarriages/clinical pregnancies) and LBR (≥28 weeks, LBs/ETs) were compared. Serum progesterone was studied on day 5 post-ET. Antenatal care and most deliveries were at the same institute. Participants/materials, setting, methods Patients were non-smokers with normal hysteroscopy. In AC-FET, oral estradiol (6-8mg) was initiated from day 1-2 (for 10-17 days). In both groups, when endometrium ≥7mm and S.progesterone&amp;lt;1ng/ml, intramuscular progesterone was initiated(daily till day 4 post-ET, then every 3rd day till week 8). ET was scheduled on day 4 of intramuscular progesterone, and concurrently, vaginal progesterone was added (till week 10). Chi-square, t-tests, and multiple regression was used for statistical analysis and 2-tailed P &amp;lt;.05 indicated statistical significance. Main results and the role of chance Mean age and BMI were comparable in NC/PR-FET and AC-FET groups: 34.48±4.69 years vs. 33.58 ± 5.62 years (P =.35) and 26.27 ± 3.62 kg/m2 vs. 27.34 ± 4.61kg/m2 (P =.18) respectively. Similarly, the source of oocytes (%AO) and % singletons were also comparable in NC/PR-FET and AC-FET groups: 57.4% vs. 46.8% (P = .25), and 78.1% vs. 75% (P= .75) respectively. There were 3 ectopic pregnancies overall. The CPRs and IRs were comparable: 68.09% (NC/PR-FET) vs. 60.76% (AC-FET) (P=.41) and 32.30% (NC/PR-FET) vs. 28.96% (AC-FET) (P=.45) respectively. The early MR was significantly more in AC-FET vs. NC/PR-FET: 29.17% vs. 6.25% (P =.012). Consequently, LBRs were significantly more in NC/PR-FET vs. AC-FET: 59.57% vs. 39.24% (P =.028). After adjusting for age, BMI, AO/DO, this difference remained significant (AOR 2.66; 95% CI 1.21-5.81; P =.014) Mean serum progesterone was comparable in all patients in both groups: 38.50 ± 13.6ng/ml (NC/PR-FET) vs. 40.98 ± 28.64 ng/ml (AC-FET) (P =.57). Serum progesterone levels were also comparable in patients who were pregnant in both groups: 38.51 ± 14.79 (NC/PR-FET) vs. 42.25 ± 32.63 (AC-FET) (P =.53).Also, in the AC-FET group serum progesterone was comparable in patients who aborted,44.23 ± 31.60 vs. those who didn’t, 41.48 ± 33.44 (P =.79). Limitations, reasons for caution This was a single center study. Due to limited sample size, we could not control for many potential confounders (e.g., multiple pregnancies). For the same reason, we could not compare obstetrical risks as a study outcome. Wider implications of the findings This study shows significantly better pregnancy outcomes with a novel NC/PR-FET protocol vs. AC-FET. This needs to be validated in larger studies. Since suboptimal hormone administration in AC-FET could be causal factor for pre-eclampsia, larger studies can test if the NC/PR-FET protocol can lead to better obstetrical outcomes. Trial registration number not applicable

P-391 Early pregnancy complications after frozen-thawed embryo transfer in different cycle regimes: Increased risks for miscarriages and bleedings in Hormone replacement cycles

Abstract Study question What are the associations between cycle regime and early pregnancy complications after frozen-thawed embryo transfers and what are the respective life birth rates per pregnancy? Summary answer Hormone replacement cycles are associated with doubled odd ratios of bleedings and miscarriages &amp;lt;12 weeks leading to lowest life birth rates (LBR) per pregnancy (68.2%). What is known already So far, there are only few studies which analysed both, the associations between cycle regime and early pregnancy complications as well as life birth rates (LBR) per pregnancy after frozen-thawed embryo transfer (FET). In 2017, a Cochrane analysis did not find sufficient evidence to support the use of a specific cycle regimen in preference to another since there were only four direct comparisons. In 2021, a network meta-analysis including 26 RCTs and 113 cohort studies revealed lowest LBR in hormone replacement cycles compared with other endometrial preparation protocols but without stating the reasons for the lowest LBR. Study design, size, duration Retrospective cohort study analyzing a total of 7342 pregnancies after FET that were registered in the Swiss IVF Registry from 2014 to 2019. Participants/materials, setting, methods Women were divided into three groups according to the different cycle regimens: Natural Cycles (NC-FET, n = 998), low-dose Stimulation Cycles (SC-FET, n = 984) and Hormone Replacement Cycles (HRC-FET, n = 5360) leading to pregnancy. Outcomes included early pregnancy complications such as bleedings, miscarriages and ectopic pregnancies, deliveries (including intrauterine deaths) and LBR. Incidences were compared using Fisher exact and Chi-square tests. Multivariate mixed model analysis with pregnancy complications as outcome was performed. Main results and the role of chance The incidences of bleeding in first trimester (NC: 3.5%, SC: 4.3%, HRC: 8.4%; p&amp;lt;.001) and miscarriage &amp;lt;12 weeks (NC: 19.0%, SC: 19.7%, HRC: 29.1%; p&amp;lt;.001) were significantly higher in HRC-FET. Multivariate analysis revealed doubled odds ratio of bleedings in first trimester (aOR 1.92; 95% CI 1.30-2.81; p&amp;lt;.001) and miscarriages &amp;lt;12 weeks (aOR 1.82; 95% CI 1.51-2.19; p&amp;lt;.001) in HRC-FET vs. NC-FET. There were comparable odds ratio in HRC-FET vs. SC-FET and no differences between NC-FET vs. SC-FET. Highest LBR per pregnancy (NC: 78.0%, SC: 77.2%, HRC: 68.2%%; p&amp;lt;.001) was reported in NC-FET. Limitations, reasons for caution The data were drawn from a registry analysis with limited information on patients’ characteristics. Data such as BMI were not available. As the study is based on a register analysis, some errors in data collection cannot be excluded. Wider implications of the findings This is the latest large European register study evaluating early pregnancy complications and LBR per pregnancy after FET by cycle regime. Miscarriage rate was highest in HRC-FET which can be translated into lower LBR. Thus, HRC-FET should be avoided if medically possible, to achieve better pregnancy outcomes. Trial registration number Non required

P-247 Fresh oocyte donation, the use of donor sperm, and the number of usable blastocysts are associated with higher clinical pregnancy rates: results from 1655 cycles

Abstract Study question What are the factors associated with clinical pregnancy in the first single embryo transfer of an oocyte donation treatment? Summary answer The number of blastocysts and the use of donor sperm were positively correlated with clinical pregnancy, while the use of vitrified/warmed oocytes was negatively correlated. What is known already The use of donor oocytes for in vitro fertilization treatments is often necessary to overcome infertility. The number of donor oocytes allocated to each recipient is a key variable to the cumulative success of these treatments. However, time to pregnancy is another key metric in assisted reproduction, and it is important to achieve a better understanding of the factors influencing the success of the first embryo transfer of an oocyte donation treatment. Study design, size, duration A retrospective study was conducted to analyze the outcome of the first single blastocyst transfer of 1665 oocyte donation cycles, from 8 private IVF units, from July 2018 to July 2021. Patients who underwent multiple cycles were only included in the study once, during their first treatment. The endpoint of the study was the clinical pregnancy rate, defined by the presence of a gestational sac confirmed by ultrasound one month after the transfer. Participants/materials, setting, methods All cycles during the study period, using donor oocytes, resulting in a first fresh or frozen single blastocyst transfer were analyzed. Cases that used PGT-A or sperm from testicular biopsy were excluded. Multiple logistic regression was used to determine the association of the variables: patient age, sperm origin, vitrified/warmed oocytes, fertilization and blastocyst development rate, total number of usable blastocysts obtained, fresh/frozen transfer, and embryonic day at transfer. Main results and the role of chance A total of 972 (58.4%) embryo transfers resulted in a clinical pregnancy in the study population. The mean age of the recipient and male partner was 42±4.4 years and 42.1±6.0 years, respectively, and did not differ between positive and negative transfer groups. Statistically significant higher pregnancy rates were observed for day 5 transfers vs. day 6 (59% vs 46%) and fresh vs. vitrified/thawed oocytes (64% vs. 55%). The mean number of zygotes (5.1 vs. 4.8, p = 0.032), the mean fertilization rate (76.3% vs. 72.8%, p = 0.007), the mean usable blastocyst development rate (60.0% vs. 57.7%, p = 0.006) and the mean total number of usable blastocysts (2.9 vs. 2.6, p &amp;lt; 0.001) were higher in clinical pregnancy group. The results of multiple logistic regression showed that the use of sperm donor increased the chances of achieving a clinical pregnancy rate in the first embryo transfer (OR 1.36, 1.04-1.79), and the use of vitrified/thawed oocytes reduced them (OR 0.69, 0.56-0.85). There was a positive association with a higher number of usable blastocysts obtained in a cycle, and higher pregnancy rates (OR 1.16, 1.07-1.26), presumably by allowing for additional morphological embryo selection. Limitations, reasons for caution Certain confounding factors were not accounted for: variability of results between the different IVF units, endometrial preparation protocols, post-warming embryo morphology, sperm analysis diagnostic, as well as variability in recipients’ and donors’ baseline characteristics. Wider implications of the findings Factors of an oocyte donation treatment influencing the outcome of the first embryo transfer were identified. A better understanding of these factors, and interactions amongst them, is key to maximize the efficacy of these treatments, and achieve an optimal use of a limited resource such as donated oocytes. Trial registration number not applicable