Embryo Transfer Treatment Research Articles

Impact of letrozole co-treatment in an antagonist protocol for IVF/ICSI: a retrospective study

ObjectiveThe present study aimed to investigate the impact of combined use of letrozole in an antagonist protocol during IVF on live birth outcomes and to assess the safety of letrozole in terms of maternal and neonatal complications.MethodsThis retrospective cohort study included women undergoing IVF/ICSI and fresh embryo transfer (ET) treatment with and without letrozole co-treatment from 2007 to 2021 at Shanghai Ninth People’s Hospital (Shanghai, China). The primary outcome was the live birth rate, while the incidences of maternal and neonatal complications were secondary outcomes. Logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the analyzed outcomes. Sensitivity analysis was performed using a propensity score-based patient-matching (PSM) model, an inverse probability weighting (IPW) model, logistic regression models with women undergoing their first IVF-ET cycle, and subgroup analysis.ResultsOf the 4780 women enrolled in the study, 3887 underwent an antagonist protocol for ovarian stimulation, while 893 received letrozole co-treatment. In this cohort, letrozole co-treatment demonstrated comparable live birth rates to the use of antagonist protocol alone (logistic regression: aOR, 0.88; 95% CI, 0.71–1.08; PSM: aOR, 0.97; 95% CI, 0.77–1.22; IPW: aOR, 0.88; 95% CI, 0.71–1.10). Notably, individuals with a body mass index (BMI) exceeding 24 and those with high ovarian response experienced higher live birth rates under the letrozole co-treatment regimen (BMI ≥ 24: aOR, 1.85; 95% CI, 1.14-3.00; high response: aOR, 1.60; 95% CI, 1.02–2.50). Letrozole co-treatment was also associated with decreased risks of gestational diabetes (aOR, 0.34; 95% CI, 0.15–0.69) and small for gestational age (SGA) fetuses (aOR, 0.42; 95% CI, 0.22–0.75) in fresh ET cycles. These finding were robust in both PSM and IPW models.ConclusionsOur findings suggested that letrozole co-treatment in antagonist protocol for IVF/ICSI was associated with a comparable live birth rate following fresh ET. Further prospective randomized studies are needed to verify our results.

Dual trigger or hCG alone: A retrospective analysis on patients with diminished ovarian reserve under in vitro fertilization and embryo transfer (IVF-ET) treatment

ObjectiveWith remarkable deficiency in both oocyte stock and competence, the prognosis of IVF-ET in diminished ovarian reserve (DOR) is obstinately poor, underscoring warranted optimization to current procedures. We compared the efficacy of dual-trigger (hCG plus GnRH-a) and hCG alone on the outcomes for DOR patients. Study designA total of 381 couples and 857 controlled ovarian stimulation (COS) cycles, and 222 couples and 366 frozen embryo transfer (FET) ones were included. The intermediate outcomes during oocyte retrieval and in vitro culture were compared based on COS dataset, while outcomes after embryo transfer analyzed based on FET dataset. The marginal effect of all study factors and covariates were evaluated with a cluster-weighted GEE model. Results and conclusionNeither the intermediate nor implantation outcomes were improved by dual-trigger. The OR values were 1.08 (95 % CI: 0.41–2.78) for retrieval cancellation, 1.33 (95 % CI: 0.89–2.00) for oocyte harvest, 1.04(95 %CI: 0.94–1.15) for viable embryo and 1.03(95 %CI: 0.88–1.19) for top-quality embryo. Similarly, the ORs were 0.90 (95 %CI: 0.62–1.30) for implantation and 0.97 (95 %CI: 0.56–1.69) for clinical pregnancy. This equivalence remained unchanged after adjusting for the covariates such as age, BMI, controlled ovarian stimulation protocols, etc. Thus, dual-trigger cannot provide significant advantage over hCG in related to immediate or clinical outcomes of IVF-ET treatments in DOR patients.

The impact of intracytoplasmic sperm injection versus conventional in vitro fertilization on the reproductive outcomes of couples with non-male factor infertility and frozen-thawed embryo transfer cycles

This study was aimed to investigate the impact of intracytoplasmic sperm injection (ICSI) on reproductive outcomes in couples with non-male factor infertility and frozen-thawed embryo transfer (FET) treatment. This retrospective cohort study involved a total of 10,143 cycles from 6206 couples who underwent FET at the Third Affiliated Hospital of Zhengzhou University between January 2016 and September 2022. Patients were categorized into two groups based on the insemination methods of transferred embryos. Clinical and neonatal outcomes were compared between ICSI and conventional in vitro fertilization (cIVF) groups. The results showed that ICSI was not associated with improved clinical outcomes compared to cIVF. However, ICSI was associated with lower birthweight when twins were born. In conclusion, although subgroup analysis showed that ICSI was associated with slightly improved live birth rate for infertile couples with non-male factor infertility compared to cIVF, the regression analysis showed that ICSI did not demonstrate any improvement of the reproductive outcomes. The infertile women with twin pregnancies should be further informed of the lower birthweight and lower birth length when their oocytes were inseminated with ICSI. The findings of this study provide valuable insights for clinicians when discussing the benefits and risks of ICSI in patients with non-male factor infertility.

Effect of pre-treatment with deslorelin on the ovarian response of ewes superovulated with FSH.

This study evaluated the use of the GnRH agonist hormone, deslorelin, to control the follicular population before initiating multiple ovulation and embryo transfer (MOET) treatment. Twenty-four cross-bred Santa Inês ewes, aged between 2 and 4 years, were randomly assigned to either a control group (n = 11) or a treated group (n = 13). All ewes received an intravaginal device containing 60 mg of medroxyprogesterone acetate on day 0, and a new device on day 7, which remained in place until day 14. Additionally, the ewes were administered 125 μg of cloprostenol on day 7. The superovulatory treatment involved administering 200 mg of pFSH, divided into eight decreasing doses at 12-h intervals starting on day 12. On day 14, 300 IU of eCG was administered. In the deslorelin group, three doses of 100 μg of deslorelin were administered starting on day 3 after the insertion of the vaginal device, with subsequent doses given at 72-h and 144-h intervals. Natural mating was performed 36 h after the removal of the progesterone implant using males with proven fertility. Embryo collection took place on the 6th day after mating, and the recovered structures were quantified and evaluated for quality and developmental stage. Transrectal ultrasonography was conducted on days 12, 16 and 21 to evaluate the ovaries, specifically to assess the ovarian follicular population and the presence of the corpus luteum. Ewes in the control group had higher embryo recovery rates (p < .01) compared to the treated group (5.2 ± 0.8 vs. 1.1 ± 0.8), with differences observed primarily in the number of morulae. The number of corpus luteum observed during the laparotomy on day 21 was significantly higher (p < .01) in the control group (10.44 vs. 4.5 corpus luteum per ewe). Yet, the treated group had a significantly higher number of follicles (p < .05) on the first day of pFSH application (5.5 vs. 3.0 follicles per ewe). In conclusion, although the inclusion of deslorelin in the superovulation protocol resulted in increased synchronization of oestrus and follicle number, it did not lead to an increase in the number of corpus luteum or harvested embryos.

P-126 The impact of ICSI versus IVF on the reproductive outcomes of couples with non-male factor infertility and frozen-thawed embryo transfer cycles

Abstract Study question Does Intracytoplasmic Sperm Injection (ICSI) improve reproductive outcomes in patients with non-male factor infertility undergoing Frozen-Thawed Embryo Transfer (FET) treatment? Summary answer ICSI showed slightly improved clinical outcomes compared to IVF, but was associated with higher preterm birth rates and low birthweight when twins were born. What is known already The use of ICSI has seen a significant surge globally, particularly in Europe and the USA, as a solution for fertilization failure resulting from male factor infertility. FET presents a viable option for those considering additional children. Numerous studies have investigated the effectiveness of ICSI in couples with non-male factor infertility undergoing fresh embryo transfer in ovarian stimulation cycles. However, there is a dearth of evidence demonstrating whether ICSI, compared to conventional IVF (cIVF), could influence reproductive outcomes in couples with non-male factor infertility undergoing FET treatment. Study design, size, duration This retrospective cohort study included 10,143 cycles from 6,206 couples who underwent FET at the Third Affiliated Hospital of Zhengzhou University between January 2016 and September 2022. Participants/materials, setting, methods Patients were categorized into two groups based on the insemination methods used for the transferred embryos. Patients were excluded if : 1) Embryos were biopsied and tested; 2) Oocytes had been vitrified; 3) Embryos were derived from donor oocytes, AOA treatment, or rescue ICSI; 4) Embryos that were not transferred; and 5) They had undergone fresh embryo transfer. PSM at a ratio of 1:1 was utilized to ensure comparability of reproductive outcomes. Main results and the role of chance Post-PSM, the general characteristics were comparable across both groups. The clinical pregnancy rates (37.6% vs 40.0%, P = 0.311), miscarriage rates (21.4% vs 23.1%, P = 0.597), and live birth rates (28.2% vs 30.4%, P = 0.329) exhibited no significant disparity post-PSM between the two groups. Notably, a marginally elevated live birth rate was observed in the ICSI group when blastocysts were transferred to the women (39.8% vs 48.3%, P = 0.050). However, the GEE models indicated that ICSI did not enhance the likelihood of clinical pregnancy, miscarriage, and live birth relative to IVF in women with non-male factor infertility. Following adjustments for variables, ICSI yielded consistent OR values [1.14(0.92-1.42), P = 0.241; 1.08(0.72-1.61), P = 0.703; and 1.16(0.92-1.46), P = 0.220, respectively]. The perinatal outcomes were similar between the two grousps. However, a significantly higher incidence of preterm birth was observed in the ICSI group compared to the cIVF group (20.0% vs 12.5%, P = 0.026). While pregnancy complications were comparable between the two groups, neonates born as twins in the ICSI group exhibited significantly reduced live birth-weight [2520.8(572.9) vs 2691.9(423.7), P = 0.043] and birth length [47.5(2.8) vs 48.5(2.3), P = 0.031]. Correspondingly, the rate of low birthweight was significantly higher in the ICSI group (38.9% vs 21.0%, P = 0.025). Limitations, reasons for caution The retrospective design may lead to selection bias among the included patients. The use of ICSI in ART has been strictly regulated in our country, limiting the sample size and potentially reducing the statistical power. Wider implications of the findings The value of ICSI should be thoroughly discussed with patients with non-male factor infertility before ovarian stimulation. Further research is needed to better understand the impact of ICSI on reproductive and neonatal outcomes in this population. Trial registration number 2021YFC2700602

Autologous PRP therapy for thin endometrium: A self-controlled case series study across menstrual cycles

ObjectivesThin endometrium (TE) compromises endometrial receptivity, often leading to implantation failure and lower clinical pregnancy rates. As autologous platelet-rich plasma (PRP) emerges as a potential remedy, the present study focused on its therapeutic effects on TE in infertile women who underwent frozen embryo transfer. Study designPatients with TE who underwent frozen embryo transfer treatment in our hospital were included. To diminish individual variability, a self-controlled series approach was used. Two menstrual study cycles were arranged for each participant before the actual embryo transfer cycle; PRP treatment was conducted in the second cycle. Key metrics analyzed included endometrial thickness and the expression of specific endometrial biomarkers including HOXA-10, Ki67, and αvβ3 integrin. Transvaginal ultrasound was employed to measure endometrial thickness on Days 11 and 14, and an endometrial biopsy was conducted on progesterone Day 5 of the first two cycles. Pregnancy outcomes were observed after the embryo transfer cycle. ResultsPRP treatment significantly increased the median endometrial thickness, from 5.8 mm to 6.5 mm (P = 0.0066). Additionally, PRP treatment resulted in a statistically significant increase in the H-score for all endometrial markers. Importantly, during the subsequent embryo transfer cycle with PRP treatment, two patients successfully achieved pregnancies, both culminating in live births. ConclusionsThese findings emphasize the potential of PRP in improving endometrial conditions, especially for individuals grappling with thin endometrium issues, as underscored by this self-comparison methodology.

Intracytoplasmic Sperm Injection Versus In vitro Fertilization in Infertile Women with Thyroid Autoimmunity.

Background: It has been reported that intracytoplasmic sperm injection (ICSI) may be the preferred fertilization method for women with thyroid autoimmunity (TAI) seeking assisted reproduction. We compared the reproductive outcomes of women with TAI who were treated with ICSI compared with in vitro fertilization (IVF). Methods: In this retrospective cohort study, we included women with infertility who were referred to the Reproductive Centre of Peking University Third Hospital for their first IVF/ICSI and embryo transfer (ET) treatment cycle from January 2019 to February 2021. In total, 2171 and 743 women with TAI underwent IVF and ICSI, respectively, while 8702 and 2668women without TAI underwent IVF and ICSI, respectively. We examined the cumulative live birth rate (primary outcome) from the initiated stimulative cycle as well as the secondary outcomes of fertilization rate, rates of clinical pregnancy, and live birth after the first ET cycle. We compared the reproductive outcomes of women treated with IVF and ICSI according to TAI status. Multivariable logistic regression analyses were performed to adjust for relevant confounders. Results: Women who underwent ICSI had significantly higher fertilization rates than those who underwent IVF (median [interquartile range]: 0.6 [0.5-0.8] in the TAI-positive and IVF group vs. 0.7 [0.5-0.8] in the TAI-positive and ICSI group vs. 0.6 [0.5-0.8] theTAI-negative and IVF group vs. 0.7 [0.5-0.8] in the TAI-negativeand ICSI group, p < 0.001). However, the rates of cumulative live births, clinical pregnancies, and live births were significantly lower among women with TAI who underwent ICSI than those who underwent IVF (cumulative live birth: 51.8% vs. 47%, adjusted odds ratio [aOR]: 0.80 [confidence interval, CI: 0.67-0.97]; clinical pregnancy: 43.0% vs. 38.8%, aOR: 0.81 [CI: 0.67-0.97]; live birth: 36.2% vs. 32.4%, aOR: 0.81 [CI: 0.66-0.98]). Conclusion: We observed that the use of ICSI in women with TAI was not associated with better assisted reproductive outcomes compared with IVF. Further prospective clinical trials are needed to confirm our findings.

A sonographic endometrial thickness

BackgroundThe prevalence of placenta accreta spectrum (PAS), a potentially life-threatening condition, has exhibited a significant global rise in recent decades. Effective screening methods and early identification strategies for PAS could enable early treatment and improved outcomes. Endometrial thickness (EMT) plays a crucial role in successful embryo implantation and favorable pregnancy outcomes. Extensive research has been conducted on the impact of EMT on assisted reproductive technology cycles, specifically in terms of pregnancy rates, live birth rates, and pregnancy loss rates. However, limited knowledge exists regarding the influence of EMT on PAS. ObjectiveThis study aims to evaluate association between pre-implantation EMT and the occurrence of PAS in women undergoing assisted reproductive technology cycles. Study DesignA total of 4637 women who had not undergone prior caesarean section, conceived by in vitro fertilization or intracytoplasmic sperm injection embryo transfer treatment and subsequently delivered at the Third Affiliated Hospital of Guangzhou Medical University between January 2008 to December 2020 were included in this study. To explore the relationship between EMT and PAS, we employed smooth curve fitting, threshold effect, and saturation effect analysis. Multivariate logistic regression analysis was performed to evaluate the independent association between EMT and PAS while adjusting for potential confounding factors. Propensity score matching (PSM) was performed to reduce the influence of bias and unmeasured confounders. Furthermore, we employed causal mediation effect analysis to investigate the mediating role of EMT in the relationship between gravidity and ovarian stimulation protocol and the occurrence of PAS. ResultsAmong the 4637 women included in this study, pregnancies with PAS (159, 3.4%) had significantly thinner EMT (non-PAS 10.08±2.04 vs PAS 8.88±2.21 mm，P<0.001) during the last ultrasound before embryo transfer. By smooth curve fitting, the saturated effect was found on EMT and PAS, with an inflection point at 10.9mm. Then the EMT was divided into four groups: ≤7mm, >7 to≤10.9mm, >10.9 to≤13mm, >13mm, and the absolute rates of PAS in each group was 11.91%, 3.73%, 1.35%, and 2.54%, respectively. When compared to women with an EMT ranging from between 10.9-13mm, the odds of PAS increased from adjusted odds ratio (aOR) of 2.27 (95% CI, 1.33-3.86) for EMT ranging from 7-10.9mm to aOR of 7.15 (95% CI, 3.73-13.71) for EMT <7mm after adjusting for potential confounding factors. Placenta previa remained as an independent risk factor for PAS (aOR, 11.80; 95% CI, 7.65-18.19). Moreover, EMT <7mm was still an independent risk factor for PAS (aOR, 3.91; 95% CI, 1.57-9.73) in the matched cohort after PSM. Causal mediation analysis revealed that approximately 63.9% of the total effect of gravidity and 18.6% of the total effect of ovarian stimulation protocol on PAS were mediated by the EMT. ConclusionsThe findings from our study indicate that thin EMT is an independent risk factor for PAS in women without prior caesarean section undergoing assisted reproductive technology treatment. The clinical significance of this risk factor is slightly lower than placenta previa. Furthermore, our results demonstrate that EMT plays a significant mediating role in the relationship between gravida or ovarian stimulation protocol and PAS.

#130 : Food Intolerance and Conception in Women Suffering Repeated Implantation Failure

Background and Aims: Food-specific immunoglobulins, in combination with the elevated reactive oxygen species and other inflammatory components, have been indicated to represent immunological response to food consumed. This study aimed to investigate the relationship of food intolerance and conception in women receiving IVF treatments. Method: Infertile women who had experienced at least two failed embryo transfer treatments were investigated between June 2017 and August 2021 in TUBE Fertility Clinic. The whole blood 20 mL was taken from cubital vein and complete food panel examination employing ELISA analyses were designed to assay food-specific IgG and IgE antibodies. The levels of IgG antibodies were presented through spectrophotometric analysis (Table 1). The IgG tests included 5 dairy components, 25 grains/legumes/nuts, 18 vegetables, 9 egg/meat/poultry, 21 fruits, 9 herbs/spices, 18 fish/crustacea/mollusk, and 9 miscellaneous foods including baker’s yeast. Infertile women were asked to refrain from those foods according to the level of hypersensitivity, six months were required for those with reaction class III to IV, and three months for those with reaction class II. Further IVF and embryo transfer cycles were then carried out afterwards. Results: In total, 67 infertile women enrolled in this study. Their mean age was 38.2 ± 4.3 years old. They had received 2.7 ± 1.6 previous IVF/ET cycles. All 67 women showed positive IgG and 14 (21%) women with positive IgE investigated. Grains/legumes/nuts (90%) and dairy products (86.6%) were the most common hypersensitive foods (Table 2). Thirty-one (46.3%) women conceived in their successive ET cycles after refraining from hypersensitive foods. Lower pregnancy rates were noted in those with hypersensitivity to fish/crustacea/mollusk and eggs/meat/poultry, even after refraining from those foods. Conclusion: High percentage of infertile women suffering repeated failed IVF/ET cycles presented with different levels of hypersensitivity to foods. Avoidance of hypersensitive foods may help them achieve future conception.

The low birth weights of newborns conceived using assisted reproduction technology.

Couples are increasingly using assisted reproduction technology (ART) to facilitate having children. This raises the question of whether using ART leads to the same health outcomes as spontaneous conception.One of the major health outcome factors concerns the weight of the newborn. Many foreign studies have proved that newborns conceived via ART evince lower birth weights than newborns that were conceived spontaneously. The purpose of this study is to determine whether the risk of low birth weight differs according to the ART method selected (in-vitro fertilisation with fresh embryo transfer, frozen embryo transfer, oocyte receipt), and which of these methods is associated with the lowest risk of alow birth weight. Anonymised individual data on all deliveries that took place in Czechia between 2013 and 2018 was used for the analysis. The dataset was obtained from the National Registry of Reproduction Health (administered by IHIS CR).The binary logistic regression revealed that concerning many of the covariates controlled, women who underwent IVF had ahigher risk (30 %) of giving birth to achild with alow birth weight than women who received frozen embryo transfer treatment (CI 1.15-1.48). Women who underwent oocyte receipt treatment were found to have an even higher (52 %, CI 1.17-1.97) risk than women who received frozen embryo transfer. This study supports existing international knowledge of the specifics of the health outcomes of women who use ART (Tab. 1, Fig. 3, Ref. 32). Keywords: Low birth weight, assisted reproduction technology, in-vitro fertilisation, frozen embryo transfer, oocyte receipt.

Hyperbaric oxygen therapy: a possible choice for patients with resistant thin endometrium during frozen embryo transfer treatments

BackgroundThin endometrium is considered suboptimal for embryo implantation, leading to compromised pregnancy rates without effective therapies. While some studies have reported promoted endometrial growth after a period of hyperbaric oxygen therapy (HBOT) in patients with intrauterine adhesion, there have been no reports in patients with resistant thin endometrium. The purpose of this study was to investigate the impact of HBOT on endometrium growth and pregnancy outcomes in patients with resistant thin endometrium during frozen embryo transfer (FET) treatments.MethodsThis prospective pre-post cohort study was conducted at a university-affiliated assisted reproductive medical center between October 2021 and December 2022. Patients who had experienced at least one canceled transfer cycle due to a thin endometrium(< 7 mm) on the endometrium transformation day, despite the use of standard therapies as well as adjuvant therapies, were enrolled in the study. Patients were assigned voluntarily to either the HBOT group or the concurrent control group. The HBOT group received daily HBOT for at least 10 days during the proliferative phase, in addition to the routine endometrium preparation methods and the concurrent control group underwent cycles without HBOT. Propensity score matching (PSM) was used to ensure comparability between the groups. Both self-control and case-control comparisons were conducted. The primary outcome measured was endometrial thickness (ET) on the day of endometrium transformation. Secondary outcomes included intrauterine pregnancy rate (IPR), embryo implantation rate (IR), miscarriage rate, and others.ResultsPatients in the HBOT group demonstrated a significantly thicker endometrial thickness on the day of endometrium transformation after undergoing therapy (5.76 ± 1.66 vs. 6.57 ± 1.23, P = 0.002). This improvement was accompanied by a decreased rate of cycle cancellations. Baseline parameters and endometrial thickness were comparable between the HBOT group and the concurrent control group during the cycle. The IPR was similar in patients who received cleavage-stage embryos (0.0% vs. 6.7%, P = 1.00), but significantly higher in patients in the HBOT group who received blastocysts (53.8% vs. 18.2%, P = 0.017).ConclusionsA period of HBOT prior to endometrium transformation contributes to increased endometrial thickness and facilitates blastocyst implantation in patients with resistant thin endometrium during FET treatments.Trial registrationThe trial was registered on the Chinese Clinical Trial Registry (registration no. ChiCTR2300072831, retrospectively registered).

Multicenter, 2-dose single-group controlled trial of tacrolimus for the severe infertility patients.

Infertility is estimated to affect 8% to 12% of reproductive-aged couples worldwide. While approximately 85% of infertile couples have an identified cause, the remaining 15% suffer physically and emotionally from unexplained intractable infertility. In recent years, maternal-to-fetal immunological abnormalities have attracted attention as mechanisms that differ from the conventional factors contributing to infertility and pregnancy loss. A T-helper 2 (Th2)-dominant immune state has been proposed as a maternal immune alteration to eliminate rejection and induce tolerance to a semi-allogeneic fetus. An imbalance in Th1 responses would not induce adequate maternal immune tolerance to the fetus or early embryos. Tacrolimus, widely used as an immunosuppressant agent in solid organ transplant recipients, is expected to suppress maternal rejection and promote tolerance to early embryos after assisted reproductive technology by modulating the immunological environment of the preimplantation endometrium. We planned an exploratory clinical trial to determine the efficacy, safety, and dosage of tacrolimus in women with intractable infertility. This is a multicenter, 2-dose, single-group controlled trial in infertile women who failed to achieve a chemical pregnancy despite multiple in vitro fertilization (IVF) and embryo transfer (ET) treatment cycles. The following 2 key selection criteria were set: no underlying factors of infertility despite appropriate evaluation and presence of Th1-dominant immune state, defined as a Th1/Th2 cell ratio ≥ 10.3 in the peripheral blood. A total of 26 eligible participants are randomly assigned (in a 2:1 ratio) to receive immunosuppressive therapy with oral tacrolimus at a daily dose of 2 mg or 4 mg. Tacrolimus is administered for 16 days starting from 2 days before ET. The primary endpoint is the presence of clinical pregnancy 3 weeks after IVF/ET treatment, and the secondary endpoint is the presence of biochemical pregnancy 2 weeks after IVF/ET treatment. Safety evaluation and biomarker discovery for tacrolimus treatment in infertile women will be conducted simultaneously. Japan Registry of Clinical Trials (jRCT; jRCTs031220235).

P-469 Body mass index impacts ectopic pregnancy during in vitro fertilization: are we jumping the gun? An analysis of 42,362 clinical pregnancy cycles

Abstract Study question Does female body mass index (BMI) have impact on ectopic pregnancy (EP) in women undergoing in vitro fertilization (IVF) and embryo transfer (ET) treatment? Summary answer EP rate is higher in underweight patients in fresh cycles. However, BMI is not a risk factor for EP after controlling confounders. What is known already It has been shown that tubal factor infertility, stage of embryos transferred (cleavage stage or blastocyst stage), high estrogen levels during ovarian stimulation, and endometrial thickness, have impact on EP rate in IVF cycles. In addition, other potential factors including ovarian stimulation protocols, number of embryos transferred, and type of embryos (fresh or frozen thawed) are also seemed to be associated with EP rate. However, BMI has interactions with these confounding factors mentioned above. Study design, size, duration This was a retrospective cohort study. From January 2010 to June 2022, patients between the ages of 20 and 45 years who had their first fresh/frozen thawed ET cycles, and reported as clinical pregnant were included. BMI was categorized into three groups: underweight (&amp;lt; 18.5 Kg/m2), normal weight (18.5–23.9 Kg/m2), overweight and obesity (≥ 24 Kg/m2). Participants/materials, setting, methods A total of 42,362 cycles were included in the final analysis. The overall ectopic pregnancy rate was 2.57% (1,089/42,362). Firstly, possible factors affecting ectopic pregnancy were screened in both fresh and frozen thawed ET cycles. Then, multivariate logistic regression analysis was used to adjust confounding risk factors. Main results and the role of chance EP rates in fresh, and frozen thawed transfer cycles were 2.43% (672/27,600) and 2.82% (417/14,762), respectively. In fresh ET cycles, the ectopic pregnancy rate was significantly higher in underweight patients when compared with that in normal and overweight/obesity patients (3.29% vs. 2.29% vs. 2.54%; P = 0.029). However, the ectopic pregnancy rate was not differ among patients with different BMI (2.72% vs 2.76% vs 2.96%; P = 0.782) in frozen thawed cycles. In fresh ET cycles, secondary infertility, tubal infertility, elevated estrogen level, thin endometrial thickness, and cleavage stage embryo transfer were risk factors with ectopic pregnancy. However, female BMI was not associated with ectopic pregnancy (adjusted OR: 0.98, P = 0.894, for BMI 18.5-23.9 Kg/m2; adjusted OR: 0.89, P = 0.205, for BMI ≥ 24 Kg/m2. Reference = BMI &amp;lt; 18.5 Kg/m2). In frozen thawed embryo transfer cycles, only thin endometrial thickness, and cleavage stage embryo transfer were risk factors with ectopic pregnancy. Female BMI was not predictable for ectopic pregnancy, either (adjusted OR: 1.15, P = 0.513, for BMI 18.5-23.9 Kg/m2; adjusted OR: 1.24, P = 0.367, for BMI ≥ 24 Kg/m2. Reference = BMI &amp;lt; 18.5 Kg/m2). Limitations, reasons for caution This is a retrospective study with 12 years period. New embryo culture methods and embryo transfer strategy emerged. It is possible that not all confounders have been controlled. Meanwhile, the definition of tubal infertility and pelvic disease need more caution as the lack of laparoscopic examination in some cases. Wider implications of the findings Understanding the impact of BMI on EP during IVF treatment may be useful for predicting results. At the first glance, underweight patients are more likely to encounter with EP during fresh ET. However, it is the high estrogen level, but not low BMI, that contributes to this phenomenon. Trial registration number N/A

P-656 Machine learning algorithm automatically manages and accurately predicts ovulation in natural frozen-thawed embryo transfer cycles.

Abstract Study question Can an Artificial Intelligence (AI) algorithm automatically manage frozen-thawed embryo transfer (NC-FET) treatment cycles and give an accurate prediction of ovulation day. Summary answer An AI algorithm automatically managed and predicted the ovulation of NC-FET treatment cycles with 94.8% accuracy using an average of 3.01 test days. What is known already Today the preferred method for frozen embryo transfer is natural cycle based on ovulation detection. Currently, there is no software capable of managing the treatment cycle automatically and identifying the time of ovulation to support doctor decisions. The aim of this study is to develop a physician support AI software for determining ovulation time reliably with high accuracy. Study design, size, duration 2083 NC-FET cycles from September 2018 to June 2021 were used to develop the ovulation detection and treatment management algorithms. Each cycle had data from at least 2 visits including: hormonal levels (Estrogen/Progesterone/LH) and follicle sizes. The dataset was divided into a train set and two test sets. In the 1st test set ovulation was determined by experts’ opinions and the 2nd test set included cycles in which follicle rupture was documented in consecutive ultrasounds. Participants/materials, setting, methods Two algorithms were developed, an ovulation prediction algorithm based on an NGBoost model and a treatment management algorithm that used the model to determine if and when to call for a new test or declare the ovulation day. Both algorithms were jointly tuned to reach the highest success rate, defined as providing the correct day of ovulation using the available cycle data, with as few test days as possible. Main results and the role of chance On the first test set, which consisted of 176 cycles in which ovulation was determined through the majority decision of 2 independent experts and the attending physician, the treatment management algorithm required on average 3.01 tests to reach a prediction and successfully predicted the ovulation day in 94.8% of cycles. In the second test set, which consisted of 29 cycles in which ovulation was determined through the follicular rupture in two consecutive ultrasounds, only the ovulation prediction model was tested. To ensure that the model provides a reliable answer and does not rely solely on the follicular disappearances, examined cycles were tested twice: Once using the ovulation day without the day prior to it, and again using only the day prior to ovulation without the ovulation day itself. The algorithm accurately predicted ovulation in 28 out of 29 instances (96.6%) using the day of ovulation and in 28 out of 29 instances (96.6%) using the day before ovulation. Limitations, reasons for caution The main drawback is this being a retrospective study: while the algorithm was trained to maximize accuracy when it selects the test days, the dataset test days were selected by the attending physicians. Statistical methods were used to overcome this, however further prospective trials are needed to validate the results. Wider implications of the findings This is the first AI algorithm designed to automatically manage NC-FET IVF treatment cycles and predict ovulation. The high accuracy and low average tests count might improve treatment outcomes, reduce the patients’ life disruption, and allow physicians to spend less time monitoring their patients’ treatments. Trial registration number not applicable

RNA sequencing-based transcriptome analysis of granulosa cells from follicular fluid: Genes involved in embryo quality during in vitro fertilization and embryo transfer.

Granulosa cells play an important role in folliculogenesis, however, the role of RNA transcripts of granulosa cells in assessing embryo quality remains unclear. Therefore, we aims to investigate that RNA transcripts of granulosa cells be used to assess the probability of the embryonic developmental capacity. This prospective cohort study was attempted to figure out the probability of the embryonic developmental capacity using RNA sequencing of granulosa cells. Granulosa cells were collected from 48 samples in good-quality embryo group and 79 in only poor- quality embryo group from women undergoing in vitro fertilization and embryo transfer treatment. Three samples from each group were used for RNA sequencing. 226 differentially expressed genes (DEGs) were related to high developmental competence of embryos. Gene Ontology enrichment analysis indicated that these DEGs were primarily involved in biological processes, molecular functions, and cellular components. Additionally, pathway analysis revealed that these DEGs were enriched in 13 Kyoto Encyclopedia of Genes and Genomes pathways. Reverse transcription quantitative polymerase chain reaction verified the differential expression of the 13 selected DEGs. Among them,10 genes were differently expressed in the poor-quality embryo group compared to good-quality embryo group, including CSF1R, CTSH, SERPINA1, CYP27A1, ITGB2, IL1β, TNF, TAB1, BCL2A1, and CCL4. RNA sequencing data provide the support or confute granulosa expressed genes as non-invasive biomarkers for identifying the embryonic developmental capacity.

Decreased GDF9 and BMP15 in follicle fluid and granulosa cells and outcomes of IVF-ET among young patients with low prognosis.

To analyze the level of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) in follicle fluid (FF) and granulosa cells (GCs) derived from young patients with low prognosis for in vitro fertilization and embryo transfer (IVF-ET) treatment. A prospective cohort study was carried out by enrolling 52 young patients with low prognosis according to the POSEIDON classification group 3 (low prognosis group) and 51 young patients with normal ovarian reserve (control group). The concentration of the GDF9 and BMP15 proteins in FF was determined by enzyme-linked immunosorbent assay. The mRNA level of the GDF9 and BMP15 in the GCs was measured by quantitative real-time PCR. The concentration of GDF9 (1026.72 ± 159.12 pg/mL vs. 1298.06 ± 185.41 pg/mL) and BMP15 (685.23 ± 143.91 pg/mL vs. 794.37 ± 81.79 pg/mL) in FF and the mRNA level of GDF9 and BMP15 in the GCs and the live birth rate per treatment cycle started (30.77% vs. 50.98%) and oocytes retrieved (4.25 ± 1.91 vs.12.04 ± 4.24) were significantly lower, whereas the canceled cycle rate was significantly higher (9.62% vs. 0) in the low prognosis group compared with the control group (P < 0.05). The expression of GDF9 and BMP15 in the ovary was positively correlated with live birth (P < 0.05). The expression of GDF9 and BMP15 in the ovary was decreased in young patients with low prognosis accompanied by a poorer outcome of IVF-ET treatment. ChiCTR1800016107 (Chinese Clinical Trial Registry), May 11, 2018. ( http://www.chictr.org.cn/edit.aspx?pid=27216&htm=4 ).

Progesterone levels on the day of embryo transfer using a single pessary of 400mg of vaginal progesterone vs. 200mg x2 pessaries in hormonal replacement cycles.

Does the use of 400mg pessaries of micronized progesterone provide comparable results as pessaries of 200mg x2, in terms of progesterone levels in hormonal replacement cycles for embryo transfer?. Retrospective cohort study based on 299 embryo transfer treatments under artificial endometrial preparation carried out at Instituto Bernabeu. 131 patients received 1 pessary of 400 mg b.i.d. (group A) and 168 received 2 pessaries of 200 mg b.i.d. (group B). Mean serum progesterone levels were similar between groups (A: 13.64±4.47ng/mL vs. B: 13.88±7.17ng/mL). There were no differences in suboptimal progesterone levels between groups (A: 11.5% vs. B: 16.8%). In terms of patients receiving additional progesterone supplementation, there were no differences between groups (A: 26% vs. B: 35.3%.). No differences between groups were observed in clinical outcomes: pregnancy rate (PR) (A: 55% vs. B: 54.8%), biochemical pregnancy loss rate (BPLR) (A: 13.4% vs. B: 17.6%), miscarriage rate (MR) (A: 17.9% vs. B: 19.8%) and ongoing pregnancy rate (OPR) (A: 36.5% vs. B: 34.1%). One progesterone pessary of 400mg (Cyclogest®) twice daily appears to be non-inferior to the use of two-200mg pessaries twice daily in terms of progesterone levels in HRT cycles.

Status of maternal serum B vitamins and pregnancy outcomes: New insights from in vitro fertilization and embryo transfer (IVF-ET) treatment.

The influence of B vitamins on human fertility and infertility treatments remains elusive. Therefore, this study investigated the association of most B vitamins with IVF-ET outcomes. A total of 216 subjects aged <35 year in their first oocyte retrieval cycle were recruited. Blood samples from the participants were collected before the oocyte pick-up procedure, and serum levels of riboflavin, niacin, pantothenic acid, vitamin B6 (including PA and PLP), folate, and methylmalonic acid (MMA) were detected using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Endpoints were classified into three groups according to tertiles (lower, middle, and upper) of each vitamin index, and the association of the serum vitamin status with intermediate and clinical outcomes was analyzed using a generalized estimating equation model. Higher riboflavin levels were associated with elevated probabilities of high-quality embryos, as well as clinical pregnancy after embryo transfer. A greater likelihood of transferable embryos was found in the middle tertile of serum folate. Similarly, a negative correlation of serum MMA, a marker of vitamin B12 deficiency, with high-quality embryos was identified. No significance was observed for other vitamins in terms of all endpoints. Therefore, sufficient levels of pre-conception riboflavin, folate, and vitamin B12 are recommended for successful infertility treatment and pregnancy planning; further evidence is needed to confirm our conclusion.

PAIN, SATISFACTION, AND SPOTTING: COMPARING OF DAILY INTRAMUSCULAR (IM) PROGESTERONE AND VAGINAL PLUS INTERMITTENT IM PROGESTERONE (VIM) FOR FROZEN EMBRYO TRANSFER (FET)

Programmed frozen embryo transfer treatment (FET) protocols are widely utilized. After a prospective randomized study found comparable live-birth outcomes utilizing either daily intramuscular progesterone (IM) or twice daily vaginal progesterone plus IM progesterone every 3 days (VIM), we incorporated these protocols into our programmed FET cycles and allowed patient choice. Since there are no studies comparing pain, spotting, and patient satisfaction comparing IM and VIM progesterone, we initiated an IRB approved prospective observational registry to assess these outcomes. Our hypothesis was that spotting would be more prevalent with VIM but satisfaction would be higher, and pain would be greater with IM progesterone.

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.