Fresh Embryo Transfer Cycles Research Articles

P-645 standard- and low-dose dual trigger compared with human chorionic gonadotropin trigger in preimplantation genetic testing cycles

Abstract Study question Standard-dose dual trigger (SDT) and low-dose dual trigger (LDT) could improve the number of oocytes, blastocysts and euploid blastocysts or not compared with hCG trigger. Summary answer LDT increased the number of oocytes and blastocysts but not euploid blastocysts among high ovarian responders, while SDT cannot help poor to normal ovarian responders. What is known already For low and normal responders, hCG trigger was recommended by the ESHRE guidelines for ovarian stimulation for in vitro fertilization (IVF) /intracytoplasmic sperm injection (ICSI) in 2020. For high responders, this guideline recommended gonadotropin-releasing hormone agonist (GnRH-a) as the first-choice treatment. While recent studies showed that SDT could increase the number of oocytes and blastocysts to achieve equivalent or better pregnancy outcomes among poor and normal ovarian responders. And LDT was designed to prevent severe ovarian hyperstimulation syndrome (OHSS) while guaranteeing embryo quality among high responders by previous studies. Study design, size, duration This retrospective cohort study was performed at the Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital from July 2018 to December 2021. A total of 2,649 IVF-PGT cycles involving 2,275 patients were analyzed, of which 2,270 cycles had complete baseline data. A total of 1,131, 715, and 424 cycles were included in the hCG trigger, SDT, and LDT groups, respectively. Participants/materials, setting, methods Patients who were triggered by SDT(triptorelin acetate 0.2 mg and rhCG 250 µg), LDT(triptorelin acetate 0.2 mg and rhCG 125 µg or hCG 2,000 IU), and hCG (rhCG 250 µg) with GnRH-antagonist stimulation protocol in IVF-PGT cycles were enrolled. The number of oocytes retrieved, blastocysts, and euploid blastocysts were compared as primary endpoints. Propensity score matching (PSM) was used to control for confounding factors of retrospective study. Main results and the role of chance The SDT and hCG groups had a comparable number of oocytes retrieved (11.0 [7.0, 16.0] vs. 11.0 [7.0, 15.0], p = 0.580), blastocysts (2.0 [1.0, 3.0] vs. 2.0 [1.0, 3.0], p = 0.517), and euploid blastocysts (1.0 [0.0, 2.0] vs. 1.0 [0.0, 2.0], p = 0.383) after PSM. LDT increased the number of oocytes retrieved (19.0 [14.0, 25.0] vs. 16.0 [12.0, 21.0], p < 0.001) and blastocysts (3.0 [2.0, 6.0] vs. 3.0 [2.0, 5.0], p = 0.001), but not euploid blastocysts (2.0 [1.0, 3.0] vs. 1.0 [1.0, 3.0], p = 0.111), compared with the hCG trigger after PSM. Limitations, reasons for caution This was a single-center retrospective cohort study. The baseline characteristics of SDT and LDT differed from those of the hCG group because of clinical decision preferences. PSM was used to control for these effects and generate a balanced cohort. Pregnancy outcomes after embryo transfer has not been assessed yet. Wider implications of the findings The hormone change curve induced by LDT is more similar to the natural cycle. Probably LDT could also benefit poor to normal ovarian responders in IVF/ICSI cycles. And LDT might help in fresh embryo transfer cycles because of its advantage on endometrial receptivity. Trial registration number the National Natural Science Foundation of China (Grant No.82171626)

P-551 Association between the length of in vitro culture and mode of ART and the initial se-hCG rise in ongoing singleton pregnancy

Abstract Study question Does the length in vitro and mode of ART (fresh and frozen cycles) impact the se-hCG rise in cycles with ongoing single implantation pregnancy? Summary answer Length in vitro and mode of ART alter the hCG. Blastocysts in FET induced higher hCG than FET clevage stage embryos and fresh blastocyst transfers. What is known already Human chorionic gonadotropin (hCG) is produced by placental trophoblasts providing the first measurable sign of pregnancy. Factors, such as multiple pregnancies, advanced maternal age and gender of the fetus are known to influence hCG levels. Other factors such as mode of ART and length in vitro have been considered to alter the hCG kinetics but with conflicting results. Some studies have shown that hCG levels are higher after fresh blastocyst transfer compared with fresh cleavage stage embryo transfer (ET). Other studies found frozen-thawed embryo transfer (FET) results in higher hCG compared with fresh ET, other studies concluded the opposite. Study design, size, duration Multicenter historical cohort study based on clinical data. The study included 5271 women undergoing in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), insemination (IUI) or FET with single ET followed by hCG measurement day 15-19 after ovulation induction (IVF/ICSI/IUI/natural cycle FET) or progesterone administration (estrogen/progesterone substituted FET cycles). All included cycles resulting in single implantation and ongoing pregnancy verified by ultrasound in week 7-8. Data was collected between January 2014 and December 2021. Participants/materials, setting, methods Data was prospectively collected from the Danish Medical Data Centre used by three public fertility clinics, Copenhagen University hospitals. The association between length in vitro (no in vitro period (IUI), day2/3, day5, day6) and mode of ART (IVF/ICSI, FET) and the initial hCG rise was tested both with linear regression and multivariable regression. The results were based on mean serum hCG and presented in percentage with the corresponding 95% confidence interval (CI). Main results and the role of chance After accounting for the pre-defined exclusion criteria (i.e. oocyte donation, pre-implantation genetic testing, more than one gestational sac), 5251 cycles were included in the study. 2122 were FET, 2521 were fresh ET and 608 were IUI. The initial hCG rise was overall lower for fresh ET compared to IUI (no in vitro period). For cleavage stage ET, hCG was 18% (95% CI: 13% - 23%, p < 0.001) lower, and for blastocyst transfer 23% (95% CI: 18% - 28%, p < 0.001) lower. In FET, hCG was 26% (95% CI: 13% - 40%, p < 0.001) higher for blastocyst transfer compared to cleavage stage ET. When comparing blastocyst transfer in FET vs. fresh ET cycles, hCG was 33% (95% CI: 27% - 45%, p < 0.001) higher in FET cycles. Stratifying FET cycles in natural and substituted cycle did not alter the result. All results remained significant after adjusting for referral diagnosis, women age and treatment center. Limitations, reasons for caution It cannot be excluded that the higher level of hCG in IUI pregnancies is due to an additional vanished implantation. Wider implications of the findings The mechanisms in the embryo and endometrial interplay are far from understood. The present data add to the knowledge regarding this, pointing towards alteration in the implantation window in fresh stimulated cycles. Studies following the more detailed hCG rise are needed for further elucidating how ART affect the early implantation. Trial registration number Journal-nr.: 21019857

P-222 Early blastulation on day 4 predicts ongoing pregnancy in fresh transfer cycles

Abstract Study question Do embryos with early blastulation (EB) on D4 show higher implantation potential compared to top D5 blastocysts in fresh elective single embryo transfer (eSET) cycles? Summary answer Fresh EB transfer with time start to blastulation (tSB)<96.6h and time of expanded blastocyst (tEB)<100h post-insemination is predictive of ongoing pregnancy for patients <35. What is known already Expansion and hatching of blastocysts are correlated to implantation potential in fresh single transfers. Thanks to time-lapse morphokinetics, several time-points can be analyzed during embryonic growth. Embryos with faster growing speed are correlated to euploid status. The tSB of < 96.6h, day 4 post-insemination, is reported to have significant predictive value of euploid embryos, which are found to be associated not only with higher expansion scores, but also with shorter tSB, full expansion, and hatching. A study reported that significantly more embryos that reached the tSB by 100h implanted compared to those that did not. Study design, size, duration Prospective observational study in a single private hospital during 2022. In 160 cycles (n = 81 cIVF and n = 79 ICSI) an EB on D4 was observed. 48 patients (n = 28 ICSI and n = 20 cIVF) underwent a fresh eSET with an embryo showing EB on day 4. Participants/materials, setting, methods Patients with EB on D4 (tSB<96.6h, tEB<100h post-insemination) were enrolled regardless of indication, female age, attempt’s rank or technique. Those with a fresh eSET on D4 were included in this study. Gardner’s classification was used to rate the blastocysts in Embryoscope + (Vitrolife). The outcome data of transfer for D4 blastocysts (B3/B4 AA-AB-BA) were compared to eSET with top D5 (B4/B5 AA) of reference group (female age ≤35). The statistical analyses were performed by SPSS software. Main results and the role of chance In the study group, all the transferred embryos were graded according to Gardner’s classification as B3AA, or B3AB, or B3BA, or B4AA, or B4AB, or B4BA. In the reference group, we chose only the fresh transfer cycles with ultra-top grade D5 embryos classified as B4AA or B5AA. The results obtained in the overall population (n = 48) were compared to those obtained in the reference group (n = 92): age 34.0 ± 3.8 vs 31.8 ± 2.3, oocyte maturity (OM) 79.8% vs 80.3%, fertilization rate (FR) 80.0% vs 77.0%, overall blastulation rate (OBR) 78.1% vs 74.3%, top blastulation rate (TBR) 59.1% vs 54.4%, total pregnancy rate (PR) 75.5% vs 61.4%, implantation rate (IR) 58.3 vs 51.2% and ongoing pregnancy rate (OPR) 58.6% vs 47.1%, and showed a statistical difference only in PR (p<0.05). The results obtained in younger patients with age 32.1 ± 3.2 (n = 34) were also compared to reference group: OM 75.1% vs 80.3%, FR 85.0% vs 77.0%, OBR 78.1% vs 74.3%; TBR 58.7% vs 54.4% were comparable between the groups. A statistical difference was observed for PR (88.0% vs 61.4%, p<0.01) IR (70.6% vs. 51.2%, p<0.05) and OPR (70.6% vs 47.1%, p<0.05). Limitations, reasons for caution The small size of the sample needs to be expanded in order to confirm the encouraging findings in a larger population, especially in older patients yielding more aneuploid embryos. The study will continue during 2023 and will compel the live birth rate. Wider implications of the findings When a D4 embryo with EB is available, the best option is the fresh transfer on D4. The increased implantation with EB seems to correlate with embryo euploidy and the advanced endometrial receptivity in stimulated cycles. Higher IR and OPR are reported even in patients with lower rate of aneuploidy. Trial registration number not applicable

O-162 Fresh or frozen Day 6 blastocyst transfer : Is there still a question?

Abstract Study question Whether slow developing expanded day 6 (D6) blastocysts should be either transferred during fresh cycle or systematically vitrified at D6 Summary answer Fresh D6 blastocyst transfer is independently associated with reduced live birth rate compared to frozen thawed D6 transfer What is known already Live birth rate (LBR) after D5 blastocyst transfers are significantly higher when compared with D6 embryos in both fresh and frozen-vitrified embryo transfer cycles according to the last published meta-analyses. Therefore, for women obtaining only D6 blastocysts, chances of pregnancy may be lower but still persist and these embryos should be transferred. The question of the best strategy for transfer (i.e. in fresh or frozen cycles) remains unclear while data on this subject are scarce. Study design, size, duration Retrospective observational cohort study. Patients having only embryos reaching blastocyst stage at D6 were included between January 2018 and May 2021. Two groups were compared : patients having a fresh D6 transfer (D6 fresh transfer group) and patients having a frozen thawed D6 transfer ( D6 frozen transfer group). Participants/materials, setting, methods 830 D6 single blastocyst transfers (736 frozen blastocysts and 94 fresh blastocysts) were analyzed. LBR and neonatal outcome were compared between groups, as well as the influence of clinical characteristics and data related to COS protocols. Correlation between D6 blastocyst morphology according to Gardner’s classification and livebirth occurrence was also evaluated. Statistical analysis of the data was carried out using univariate and multivariate logistic regression models. Main results and the role of chance LBR was significantly lower after D6 fresh blastocyst transfer compared to D6 frozen thawed blastocyst transfer [5.3% (5/96) vs 12.2% (90/736), p < 0.05]. Moreover, when comparing a subgroup of 68 first D6 frozen embryo transfers (1st D6 frozen transfer group) to the 94 fresh D6 blastocyst transfers (D6 fresh elective group), the superiority of D6 frozen blastocyst transfers regarding LBR was also confirmed (17.6% vs 5.3% p < 0.001, respectively). Concerning neonatal outcomes, the mean birth weight was comparable between the two groups. Univariate logistic regression analysis taking into account blastocyst morphology parameters showed that TE grade was the only parameter significantly associated with LBR after D6 embryo transfer (p < 0.001). Multiple logistic regression revealed that D6 embryo fresh transfer was independently associated with reduced LBR compared to frozen thawed D6 transfer (OR 0.367; 95%IC 0.143-0.945; p = 0.038). Moreover, our results showed that transferring a good or top quality D6 blastocyst increases 3 fold chances of live birth. Limitations, reasons for caution The number of fresh cycles seems relatively small, but the consistency of our results was guaranteed by the homogeneity of the 2 subgroups, standardization of all biological and clinical procedures and the robust statistical analysis methodology used in this study. Wider implications of the findings Despite their lower potential, D6 blastocysts have to be transferred with the objective to improve LBR, especially in women obtaining only these type of embryos. Our results recommend to transfer D6 blastocysts in frozen cycles. However, these findings have to be confirmed on larger series in prospective randomized trials. Trial registration number not applicable

O-297 Contribution of Frozen Embryo Transfer Cycles to ICSI Clinical Outcomes in Male Factor Infertility

Abstract Study question What is the benefit of adding frozen embryo transfer (FET) cycles to ICSI clinical outcomes in male factor infertility? Summary answer FET carried out on spare embryos that reached blastocyst stage remarkably contributed to additional clinical pregnancies in ICSI cycles for male factor infertility. What is known already Current trends in reproductive medicine lean toward full-preimplantation development and eventually to PGT-A to select a single euploid embryo for transfer. The utilization of this approach, while beneficial in most couples, is not ideal for male factor infertility due to the tendency of being characterized by impaired embryo development. So, we wonder if the utilization in FET cycles of leftover embryos that reached to blastocyst stage or those that eventually reached day 5 for aneuploidy testing contributed to the clinical outcomes. Study design, size, duration In the past 7 years, we included 22,289 couples who underwent ICSI while the large majority (84.8%) received a fresh embryo transfer, of which 70.9% were transferred at day 3. Leftover embryos, together with those euploid after PGT-A at blastocyst stage, were replaced in subsequent FET cycles. The clinical outcomes including clinical pregnancy rate (CPR) and deliveries were compared between the fresh embryo transfer and those after FET in total and after PGT-A. Participants/materials, setting, methods Couples with male factor underwent ICSI in standard fashion using exclusively ejaculated sample. For fresh embryo transfer cycles, embryos were transferred either at day 3 or at day 5. For FET cycles, embryos were cultured up to exclusively blastocyst stage and cryopreserved by vitrification. For aneuploidy, NGS was carried out for PGT-A. FET was carried out in natural or programmed cycles. Main results and the role of chance In the cohort underwent fresh embryo transfer, 18,896 couples underwent 37,751 ICSI cycles, where 322,916 oocytes were injected and 243,768 (75.5%) fertilized. Additionally, 3,393 patients received 4,712 FET in total with a fertilization of 69.8% (46,163/66,171) that did not differ from the fresh transfer group. The number of average embryos transferred in fresh cycles was 2.4±2 while FET was carried out exclusively on single embryo. Fresh transfer yielded 37.3% (14,087/37,751) CPR, while overall FET cycles achieved a higher CPR at 52.2% (2,462/4,712, P<0.0001). Similarly, the delivery rate in fresh cycles was 31.8% (12004/37751) and became 45.5% (2145/4712) in the FET (P<0.0001). To identify the advantage of selecting a single euploidy embryo, we compared FET on leftover unscreened blastocyst to those that were planned for PGT-A. Spare embryo transfers involved 1774 patients in 2282 cycles with a fertilization rate of 67.7% (18,905/27,937). For the PGT-A cycles, 1619 couples in 2430 cycles achieved a comparable fertilization rate of 71.3% (27,258/38,234), In this comparison, the FET on spare unscreened embryos achieved a CPR at 47.0% (1,072/2,282) while in the PGT-A group reached CPR at 57.2% (1390/2430, P<0.0001). Similarly, the delivery rate was 37.6% (857/2,282) in the FET and PGT-A was 53.0% (1,288/2,430) (P<0.0001). Limitations, reasons for caution The comparison is retrospective and is carried out on male factor infertility where day 3 embryo transfer were performed almost exclusively on fresh cycle to overcome poor embryo development. Nonetheless, those spare embryos that reached blastocyst stage and those that electively underwent aneuploidy testing significantly contributed to enhance clinical outcomes. Wider implications of the findings ICSI can overcome most of male infertility; however, the risk of impaired embryo development proposes a transfer at cleavage stage. The advanced embryo culture condition together with time-lapse allowed us to monitor embryos up to the blastocyst stage that once transferred, improving clinical outcomes, especially for embryos with confirmed euploidy. Trial registration number N/A

High anti-Mullerian hormone level is adversely associated with cumulative live birth rates of two embryo transfers after the first initiated cycle in patients with polycystic ovary syndrome.

Anti-Mullerian hormone (AMH) has been recently identified as a potential predictor of live birth rates (LBRs) following assisted reproductive technology (ART) treatment. This study aimed to investigate the association between AMH levels and the outcomes of in vitro fertilization (IVF) in patients with polycystic ovary syndrome (PCOS). Patients with PCOS initiating their first ovarian stimulation under the gonadotropin-releasing hormone antagonist protocol at the Guangdong Women and Children Hospital, China, were enrolled from November 2014 to September 2018.A total of 157 patients who underwent fresh embryo transfer (ET) cycles were included in group A, whereas 187 patients who underwent frozen-thawed ET cycles were included in group B. After the failure of the first ET cycle, 94 patients underwent the second ET cycle with frozen-thawed embryos. Of these 94 patients, 52 had failed the first fresh ET cycle (group C) and 42 had failed the first frozen-thawed ET cycle (group D). Successful embryo transfer was defined as live birth. This retrospective cohort study addressed the association between AMH levels and pregnancy outcomes using logistic regression approaches. After adjusting for age, body mass index, antral follicle counts, baseline follicle-stimulating hormone levels and baseline progesterone levels, LBRs were compared among the four groups and the cumulative live birth rate after two embryo transfers (TCLBR) was calculated. The LBRs showed no differences among the four groups. Higher serum AMH levels were found to be associated with a lower TCLBR [adjusted OR 0.937 (0.888-0.987), P = 0.015]. In patients who underwent the second ET cycle, LBRs were inversely proportional to AMH levels [crude OR 0.904 (0.828-0.986), P = 0.022 versus adjusted OR 0.845 (0.754-0.946), P = 0.004, respectively]. In addition, the LBR was approximately 61%-78% lower in the group with AMH levels of >12 ng/mL [crude OR 0.391 (0.168-0.912), P = 0.030 versus adjusted OR 0.217 (0.074-0.635), P = 0.005, respectively]. Among PCOS patients high AMH level (>12 ng/ml) is found to be associated with low TCLBR and low LBR of the second embryo transfer cycles. The results provide limited clinical inferences and warrant further investigation.

Low Molecular Weight Heparin-Aspirin-Prednisolone Combination Does Not Increase the Live Birth Rate in Recurrent Implantation Failure: A Retrospective Cohort Study.

This study investigates the triple combination of adjuvants (low molecular weight heparin (LMWH)-aspirin-prednisolone) whether it improves the live birth rates of IVF&ICSI patients with previous implantation failure. This retrospective study included 1095 patients with >2 failed either fresh or frozen single embryo transfer cycles between 2014 Jan and 2021 Jan. Patients were divided into two subgroups. Group A consisted of patients with only vaginal progesterone for luteal phase support. Group B consisted of patients with triple (daily subcutaneous LMWH, daily 150 mg aspirin, and daily 16 mg prednisolone) luteal phase supplementation to vaginal progesterone. Demographic parameters, cycle characteristics, embryology, and pregnancy outcomes were compared, and the study's primary outcome was the live birth rate. Demographic parameters were similar between the groups. Positive b-hCG, miscarriage, and live birth rates were similar between groups as Group A vs. Group B, positive b-hCG 30.8% (190/617) vs. 35.4% (169/478), miscarriage rates 4.4% (27/617) vs. 6.7% (32/478), and live birth rates 20.4% (126/617) vs. 23.8% (114/478), respectively. When patients were stratified according to previous failures, live birth rates were still similar. Pregnancy outcomes were significantly improved in only patients with diminished ovarian reserve (Group A vs. Group B, positive b-hCG 24.2% vs. 34.3%, live birth rate 12.1% vs. 21.9%, p < 0.01). Whether the embryo transfer was fresh or frozen-thawed did not affect the results. A combined supplementation of LMWH, aspirin, and prednisolone in the luteal phase does not improve live birth rates of IVF&ICSI patients with previous implantation failure except potentially for patients with diminished ovarian reserve.

Impact of having surplus blastocysts cryopreserved on the ongoing pregnancy rate following a fresh transfer

Purpose This study aimed to investigate whether a surplus of vitrified blastocysts correlated with ongoing pregnancy by analyzing the clinical outcomes of fresh transfer cycles with/without a surplus of vitrified blastocysts. Methods This was a retrospective analysis carried out in the Reproductive Medicine Center of Guizhou Medical University Affiliated Hospital between January 2020 and December 2021. Overall, 2482 fresh embryo transfer cycles were included in this study, including 1731 cycles with a surplus of vitrified blastocysts (group A) and 751 cycles with no surplus of vitrified blastocysts (group B). The clinical outcomes of fresh embryo transfer cycles were analyzed and compared between the two groups. Results In total, the clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR) after fresh transfer in group A were significantly higher than those in group B (59% vs. 34.1%, p < .001; 51.9% vs. 27.8%, p < .001, respectively). Moreover, the miscarriage rate was significantly lower in group A when compared to that in group B (10.8% vs. 16.8%, p = .008). When grouped by either female age or the number of good-quality embryos transferred, the same trends for CPR and OPR were seen in all subgroups. After adjusting for potential confounding factors in multivariate analysis, a surplus of vitrified blastocysts remained significantly associated with a higher OPR (OR: 1.52; 95% CI:1.21–1.92). Conclusion Ongoing pregnancy outcome increases significantly in fresh transfer cycle with a surplus of vitrified blastocysts.

Association Between Uterine Volume and In Vitro Fertilization (IVF) Reproductive Outcomes of Infertile Patients with Adenomyosis

To explore the association between uterine volume and in vitro fertilization (IVF) reproductive outcomes of infertile patients with adenomyosis, we performed a retrospective cohort study of infertile patients with adenomyosis who underwent IVF from January 2009 to December 2019 in our clinical center. Patients were divided into five groups according to the uterine volume before the IVF cycle. A line graph was drawn to demonstrate the linear trend of IVF reproductive outcomes with uterine volume. Univariate and multivariate analyses were used to explore the association between uterine volume of adenomyosis patients and IVF reproductive outcomes in first fresh embryo transfer (ET) cycle, first frozen-thawed embryo transfer (FET) cycle, and per ET cycle. Kaplan–Meier curves and Cox regression were conducted to evaluate the association between uterine volume and cumulative live birth. A total of 1155 infertile patients with adenomyosis were included. Clinical pregnancy rate showed no significant correlation with uterine volume in first fresh ET cycle, first FET cycle, and per ET cycle; miscarriage rate showed an upward trend with uterine volume increasement, in which the uterine volume turning point was 8 weeks of gestation; live birth rate showed a downward trend with turning point of 10 weeks of gestation. Subsequently, patients were divided into two groups (uterine volume ≤ 8 weeks of gestation vs. uterine volume > 8 weeks of gestation). Univariate and multivariate analyses showed that patients with a uterus larger than 8 weeks of gestation had a higher miscarriage rate and a lower live birth rate in all ET cycles. Kaplan–Meier curves and Cox regression demonstrated lower cumulative live birth rate in patients with a uterine volume larger than 8 weeks of gestation. IVF reproductive outcome gets worse as uterine volume increases in infertile patients with adenomyosis. Adenomyosis patients with a uterus larger than 8 weeks of gestation had a higher miscarriage rate and a lower live birth rate.

Blood metal/metalloid concentration of male subjects undergoing IVF/ICSI treatment outcomes: A prospective cohort study

BackgroundPrevious epidemiology studies reported that heavy metal/metalloid exposure is associated with the impairment of semen quality. However, it is still not clear whether the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment outcome will be affected after the heavy metal/metalloid exposure of the male partners. MethodsA prospective cohort study with a 2-year followed-up was conducted in a tertiary IVF center. A total of 111 couples undergoing IVF/ICSI treatment were initially recruited from November 2015 to November 2016. Male blood concentrations of heavy metal/metalloid including Ca, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Mo, Cd, Hg, and Pb were measured by inductively coupled plasma mass spectrometry, and the lab and pregnancy outcome data were followed up. The associations between male blood heavy metal/metalloid concentration and the clinical outcomes were analyzed by Poisson regression analysis. ResultsOur results showed that none of the heavy metal/metalloid of male partners we investigated are significantly associated with the oocyte fertilization and good embryo (P ≥ 0.05); however, antral follicle count (AFC) was a protective factor for the oocyte fertilization (RR: 1.07, 95 % CI: 1.04–1.10). The blood Fe concentration of the male partner was positively associated (P < 0.05) with pregnancy in the first fresh cycle (RR:170.93, 95 % CI: 4.13–7082.04), cumulative pregnancy (RR: 23.61, 95 % CI: 3.25–171.64) and cumulative live birth (RR: 36.42, 95 % CI: 1.21–1092.54). In the first frozen embryo cycles, pregnancy was significantly associated (P < 0.05) with the blood Mn (RR: 0.01, 95 % CI:0.00–0.11) and Se concentration (RR: 0.01, 95 % CI:8.25 E-5–0.47) and female age (RR: 0.86, 95 % CI:0.75–0.99); live birth was significantly associated (P < 0.05) with the blood Mn concentration (RR: 0.00, 95 % CI: 1.14E-7–0.51). ConclusionsOur results suggested that the higher male blood Fe concentration was positively associated with pregnancy in the fresh embryo transfer cycle, cumulative pregnancy, and cumulative live birth, whereas the higher male blood Mn and Se concentration were associated with lower chance of pregnancy and live birth in the frozen embryo transfer cycle. However, the underline mechanism of this finding still needs further investigation.

Association between PM2.5 exposure and the outcomes of ART treatment: A prospective birth cohort study

Exposure to fine particulate matter (PM2.5) has been reported to be adversely associated with reproductive health. However, current evidence on PM2.5 exposure adversely influencing pregnancy outcomes remains inconclusive. Women receiving assisted reproductive technology (ART) treatment are under close monitoring with regards to their treatment process, which make them great study population to assess the impact of PM2.5 in the post-implantation period. Therefore, within a prospective cohort study in Jiangsu, China, we assessed the associations between exposure to ambient PM2.5 and the outcomes of ART treatment, including implantation failure, biochemical pregnancy loss, clinical pregnancy and live birth, in 2431 women who underwent the first fresh embryo transfer or frozen embryo transfer cycle. High-performance machine-learning model was performed to estimate daily PM2.5 exposure concentrations at 1 km spatial revolution. Exposure windows were divided into seven periods according to the process of follicular and embryonic development in ART. Generalized estimation equations (GEE) was used to assess the association between PM2.5 and ART outcomes. Higher PM2.5 exposure was associated with decreased probability of clinical pregnancy (RR: 0.98, 95 % CI: 0.96–1.00). Each 10 μg/m3 increase in PM2.5 exposure in the duration from hCG test to 30 days after embryo transfer (Period 7) was positively associated with the risk of biochemical pregnancy loss (RR: 1.06, 95 % CI: 1.00–1.13), and more prominent effects were observed in women undergoing fresh embryo transfer. Null associations were observed between PM2.5 exposure and implantation failure or live birth at any exposure window. Collectively, our study suggested that exposure to PM2.5 increased the risk of adverse treatment outcomes in the ART population. Thus, for women opting for ART treatment, particularly those who select fresh embryo transfer cycles, additional evaluation of PM2.5 exposure before treatment might be of value in decreasing the risk of adverse pregnancy outcomes.

Impact of thyroid autoimmunity on pregnancy outcomes in euthyroid women following fresh/frozen-thawed embryo transfer.

To investigate whether thyroid autoimmunity (TAI) is associated with assisted reproductive technology (ART) outcomes in euthyroid women undergoing fresh embryo transfer (ET) and frozen-thawed embryo transfer (FET). A retrospective cohort study. Pregnancy and neonatal outcome after freshETor FETwere compared between the positive and negative thyroid autoimmune antibody groups. A total of 5439 euthyroid women who started their ART cycle at our centre between 2015 and 2019 were included. The thyroid antibody positive group had a greater mean age than the thyroid antibody negative group (32(29,35) vs. 31(28,34), p < .001). Women with positive thyroid antibody presented with a higher prevalence of diminished ovarian reserve (DOR) (9.1% vs. 7.1%, p = .026) and lower number of oocyte retrieved (9(5,15) vs. 10(6,15), p = .020), but difference was not significant after adjusting for age. The pregnancy rate, live birth rate, pregnancy loss rate, preterm delivery rate and low birthweight rate between the thyroid antibody positive and thyroid antibody negative groups were comparable both in fresh ET cycles and FET cycles. Subanalysis of the treatment outcomes when using a stricter threshold of TSH of 2.5 mIU/L showed no difference to that achieved when using an upper limit of 4.78 mIU/L. The present study reveals that patients with anti-thyroid peroxidase antibodies (TPOAbs) and/or antithyroglobulin antibodies (TgAbs) showed no significant differences in pregnancy outcomes following fresh ET and FET when compared with patients with negative thyroid antibodies.

Diminished ovarian reserve may not be associated with a poorer fresh cycle outcome in women < 38 years

BackgroundPrevious studies have discussed the pregnancy outcomes of diminished ovarian reserve (DOR) patients. However, data on embryonic development potential, neonatal outcomes, and maternal complications of DOR patients still remained unknown. This is the first study to investigate the risk of DOR on pregnancy and perinatal outcomes among women < 38 years.MethodsRetrospective cohort study was conducted. Patients (< 38 years of age) undergoing their first oocyte retrieval cycle were included. Patients were divided into DOR group and non-DOR group. Pregnancy outcomes of fresh cycle and cumulative live birth rate and perinatal outcomes after one oocyte retrieved cycle were compared between DOR and non-DOR group.Result(s)From January 2016 to September 2020, there were 8,179 patients involved: 443 patients in the DOR group and 7,736 patients in the non-DOR group. The incidences of live birth and clinical pregnancy did not differ significantly between patients with or without DOR after fresh cycle transfer, but the cumulative live birth rate was significantly lower in DOR group. Among women who had singleton live births, after binary logistic regression, the rates of maternal complications and neonatal outcomes were comparable in the two groups.Conclusion(s)DOR patients (< 38 years of age) showed similar pregnancy outcomes in the first fresh embryo transfer cycle but a lower chance of live birth after a whole oocyte retrieval cycle to non-DOR patients and DOR is not associated with adverse perinatal outcomes.

Comparison of the efficacy of depot GnRH agonist protocol and the GnRH antagonist protocol in patients with repeated IVF failure: a retrospective cohort study

The aims of the research were (i) to compare the clinical outcome of IVF using follicular-phase depot gonadotropin-releasing hormone (GnRH) agonist (depot agonist) protocol and GnRH antagonist protocol in patients with repeated IVF failure (RIF), (ii) to discover the optimal ovarian stimulation protocol for this group of low prognosis patients. 801 RIF patients with normal ovarian reserve receiving in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) were included in this retrospective study. Among them, 492 patients were treated with the depot agonist protocol, and the remaining 309 patients with the antagonist protocol. Multivariable logistic regression analysis was used to find the predictor(s) of the chance of live birth. Higher live birth rate (LBR) and clinical pregnancy rate (CPR) in fresh embryo transfer (ET) cycles were associated with the use of depot agonist compared with the antagonist protocols (44.81% vs. 27.27%, 54.64% vs. 34.93%, respectively; both p < 0.01) and depot agonist protocol was a strong predictor of live birth (OR = 2.182, 95% CI 1.355–3.514, p < 0.01). The CPR in thawed ET cycles was not significantly different between the two groups (38.12% vs. 45.26%, p > 0.05). A higher cumulative live birth rate (CLBR) was achieved in the depot agonist group (46.59% vs. 35.21%, p < 0.01). Beneficial endometrial receptivity in the depot agonist protocol contributed to a higher LBR in fresh ET cycles, rendering this protocol the preferred option in the treatment of RIF patients.

Pregnancy incidence and associated risk factors of dichorionic triamniotic triplet under assisted reproduction: A large sample of clinical data analysis.

Dichorionic triamniotic (DCTA) triplet pregnancies are rare in spontaneous pregnancy. The aim was to characterize the incidence and risk factors of DCTA triplet pregnancies after assisted reproductive technology (ART). A retrospective analysis of 10,289 patients, including 3,429 fresh embryo transfer (ET) cycle and 6,860 frozen ET cycle, was performed from January 2015 to June 2020. The effect of different ART parameters on the incidence of DCTA triplet pregnancies was evaluated by multivariate logistic regression analyses. Among all clinical pregnancies after ART, the incidence of DCTA was 1.24%. 1.22% occurred in the fresh ET cycle, while 1.25% occurred in the frozen ET cycle. The number of ET and cycle type has no effect on the occurrence of DCTA triplet pregnancies (p = 0.987; p = 0.056, respectively). There were significant differences in DCTA triplet pregnancies rate among receiving intracytoplasmic sperm injection (ICSI) and receiving in vitro fertilization (IVF) [1.92% vs. 1.02%, p < 0.001, OR = 0.461, 95% confidence interval (CI) 0.315-0.673], blastocyst transfer (BT) versus cleavage-ET (1.66% vs. 0.57%, P < 0.001, OR = 0.329, 95% CI 0.315-0.673), and maternal age ≥ 35 years versus maternal age < 35 years (1.00% vs. 1.30%, P = 0.040, OR = 1.773, 95% CI 1.025-3.066). Based on the regression analysis of cycle type, DCTA triplet pregnancies rate was higher in maternal age < 35 years than in maternal age ≥ 35 years (1.35% vs. 0.97%, P < 0.001, OR = 5.266, 95% CI 2.184-12.701), BT versus cleavage-ET (1.47% vs. 0.94%; P = 0.006, OR = 0.346, 95% CI 0.163-0.735), and receiving ICSI was higher than receiving IVF (3.82% vs. 0.78%, p < 0.001, OR = 0.085, 95% CI 0.039-0.189) in fresh ET cycle. However, DCTA triplet pregnancies rate did not show difference in maternal age, insemination methods, and number of ET, and only BT was found to be associated with a higher DCTA triplet pregnancies rate in the frozen ET cycle (1.73% vs. 0.30%, p < 0.001, OR = 0.179, 95% CI 0.083-0.389). The prevalence of DCTA triplet pregnancies has increased after ART. Maternal age < 35 years, BT, and receiving ICSI are risk factors for DCTA triplet pregnancies, also in fresh ET cycle. However, in frozen ET cycle, BT is an independent risk factor for increased DCTA triplet pregnancies rate.

Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen–thawed embryo transfer cycle: a retrospective cohort study

BackgroundGnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression.MethodsThe retrospective cohort study included a total of 350 patients undergoing GnRHa-HRT FET cycles. The study group included 179 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 171 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups.ResultsBaseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 2.04, 95% CI 1.20–3.47, P = 0.008) and live birth (OR 2.03, 95% CI 1.20–3.45, P = 0.009). When the subgroup of patients with recurrent implantation failure was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 4.55, 95% CI 1.69–12.30, P = 0.003) and live birth (OR 4.30, 95% CI 1.59–11.65, P = 0.004).ConclusionsOur data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol.

Cycle Characteristics and Pregnancy Outcomes of Early Rescue Intracytoplasmic Sperm Injection Cycles in Normal and Hyper-Ovarian Response Women: A Six-Year Retrospective Study

This study aims to analyze the cycle characteristics, pregnancy, and neonatal outcomes in early rescue intracytoplasmic sperm injection (r-ICSI) cycles in normal and hyper-ovarian response women in their first IVF/ICSI attempts. Data from short-term in vitro fertilization (IVF, N = 7148), early r-ICSI (N = 618), and ICSI (N = 1744) cycles were retrospectively analyzed from normal and hyper-ovarian women who underwent their first IVF/ICSI cycles at our center from October 2015 to October 2021. The r-ICSI group was subdivided into partial r-ICSI (N = 451) and total r-ICSI (N = 167) based on the number of fertilized oocytes in the IVF part. Cyclic characteristics, pregnancy, delivery and neonatal outcomes in the fresh cycle were compared among the four groups; pregnancy, delivery and neonatal outcomes in frozen-thawed cycles were compared regarding cleavage and blastocyst transfers derived from r-ICSI cycles. Partial r-ICSI cycles showed different cyclic characteristics compared to total r-ICSI cycles, presenting as elevated AMH and estradiol levels on trigger day and an increased number of oocytes retrieved. Early r-ICSI delayed blastocyst development as seen by the increase in the number of day 6 blastocysts. There was no significant difference among the groups in clinical pregnancy, pregnancy loss, and live birth in fresh cleavage-stage embryo transfer cycles. However, early r-ICSI groups showed a reduction in clinical pregnancy and live birth rates in fresh blastocyst transfer cycles but not in the frozen-thawed cycles. For pregnant women, early r-ICSI did not show a negative effect on the risk of preterm birth, Cesarean section, neonatal birth weight, and sex ratio. In conclusion, early r-ICSI had comparable pregnancy, delivery, and neonatal outcomes when compared with short-term IVF and ICSI groups in fresh cleavage-stage embryo transfer cycles, but early r-ICSI did result in reduced pregnancy outcomes in fresh blastocyst embryo cycles, possibly due to delayed blastocyst development and asynchronization with the endometrium.

GnRHa trigger—the story of the ugly duckling

The objective of this invited review is to describe the introduction and development of the GnRH agonist (GnRHa) trigger protocol in modern invitro fertilization, focusing on ovarian hyperstimulation syndrome (OHSS) prevention and, equally important on the role of GnRHa trigger as an opener of the luteal phase "black box." The GnRHa trigger and freezing of all embryos is the ultimate weapon against OHSS in the OHSS-risk patient. In the non OHSS-risk patient, GnRHa trigger followed by a modified luteal phase support with lutein hormone activity and subsequent fresh embryo transfer results in excellent reproductive outcomes. Thus, the GnRHa trigger has paved the way for a virtually OHSS-free clinic, and equally important is the fact that the early lessons learned from studying the GnRHa trigger opened the "black box" of the luteal phase enabling improved reproductive outcomes in both fresh and frozen embryo transfer cycles.

Growth of twins conceived using assisted reproductive treatments up to 5 years old: a national growth cohort.

Do twins conceived through assisted reproductive treatments (ART) grow differently from naturally conceived (NC) twins in early life? Assessments at 6-8 weeks old and at school entry show that ART twins conceived from frozen embryo transfer (FET) grow faster than both NC twins and ART twins conceived from fresh embryo transfer (ET). Singletons born from fresh ET grow more slowly in utero and in the first few weeks of life but then show postnatal catch-up growth by school age, compared to NC and FET babies. Evidence on early child growth of ART twins relative to NC twins is inconsistent; most studies are small and do not distinguish FET from fresh ET cycles. This cohort study included 13528 live-born twin babies conceived by ART (fresh ET: 2792, FET: 556) and NC (10180) between 1991 and 2009 in Scotland. The data were obtained by linking Human Fertilisation and Embryology Authority ART register data to the Scottish Morbidity Record (SMR02) and Scottish child health programme datasets. Outcome data were collected at birth, 6-8 weeks (first assessment), and school entry (4-7 years old) assessments. The primary outcome was growth, measured by weight at the three assessment points. Secondary outcomes were length (at birth and 6-8 weeks) or height (at school entry), BMI, occipital circumference, gestational age at birth, newborn intensive care unit admission, and growth rates (between birth and 6-8 weeks and between 6-8 weeks and school entry). All twins in the linked dataset (born between 1991 and 2009) with growth data were included in the analysis. To determine outcome differences between fresh ET, FET, and NC twins, linear mixed models (or analogous logistic regression models) were used to explore the outcomes of interest. All models were adjusted for available confounders: gestational age/child age, gender, maternal age and smoking, Scottish Index of Multiple Deprivation, year of treatment, parity, ICSI, and ET stage. In the primary birth weight models, the average birth weight of fresh ET twins was lower [-35 g; 95% CI: (-53, -16)g] than NC controls, while FET twins were heavier [71 g; 95% CI (33, 110) g] than NC controls and heavier [106 g; 95% CI (65, 146) g] than fresh ET twins. However, the difference between FET and NC twins was not significant when considering only full-term twins (≥37 weeks gestation) [26 g; 95% CI (-30, 82) g], while it was significantly higher in preterm twins [126 g; 95% CI (73, 179) g]. Growth rates did not differ significantly for the three groups from birth to 6-8 weeks. However, FET twins grew significantly faster from 6 to 8 weeks than NC (by 2.2 g/week) and fresh ET twins (by 2.1 g/week). By school entry, FET twins were 614 g [95% CI (158, 1070) g] and 581 g [95% CI (100, 1063) g] heavier than NC and fresh ET twins, respectively. Length/height and occipital frontal circumference did not differ significantly at any time point. Although the differences between ART and NC reflect the true ART effects, these effects are likely to be mediated partly through the different prevalence of mono/dizygotic twins in the two groups. We could not explore the mediating effect of zygosity due to the unavailability of data. The confounding variables included in the study were limited to those available in the datasets. Live-born twins from FET cycles are heavier at birth, grow faster than their fresh ET and NC counterparts, and are still heavier at school entry. This differs from that observed in singletons from the same cohort, where babies in the three conception groups had similar weights by school entry age. The results are reassuring on known differences in FET versus fresh ET and NC twin outcomes. However, FET twins grow faster and are consistently larger, and more ART twins depict catch-up growth. These may lead to an increased risk profile for non-communicable diseases in later life. As such, these twin outcomes require careful evaluation using more recent and comprehensive cohorts. This study was funded by the EU H2020 Marie Sklodowska-Curie Innovative Training Networks (ITN) grant Dohartnet (H2020-MSCA-ITN-2018-812660). The authors have no competing interests to declare. N/A.

The homeostasis model assessment of insulin resistance is a judgment criterion for metformin pre-treatment before IVF/ICSI and embryo transfer cycles in patients with polycystic ovarian syndrome.

The aim of this study was to explore the value of the homeostasis model assessment of IR (HOMA-IR) as a judgment criterion for metformin pre-treatment before in vitro fertilization/intracellular sperm injection (IVF/ICSI) and embryo transfer (ET) for polycystic ovarian syndrome (PCOS) patients. The clinical and laboratory information of PCOS patients who received IVF/ICSI-ET from January 2017 to September 2021 was retrospectively analyzed. We compared the clinical pregnancy rate (primary outcome) and controlled ovarian stimulation (COS)-related parameters (secondary outcomes) between patients with and without metformin pre-treatment for all PCOS patients not grouped by HOMA-IR, PCOS patients with HOMA-IR < 2.71, and PCOS patients with HOMA-IR ≥ 2.71. A total of 969 PCOS patients who received the GnRH-antagonist protocol were included in this study. For all PCOS patients, the metformin group showed comparable clinical pregnancy rates in fresh ET cycles and frozen ET cycles compared with the control group (55.9% vs. 57.1%, p = 0.821 and 63.8% vs. 60.9%, p = 0.497). For PCOS patients with HOMA-IR < 2.71, the clinical pregnancy rates in both fresh ET cycles and frozen ET cycles were statistically similar between the two groups (61.5% vs. 57.6%, p = 0.658 and 70.6% vs. 66.7%, p = 0.535). For PCOS patients with HOMA-IR ≥ 2.71, the clinical pregnancy rate in fresh ET cycles was comparable between the two groups (51.5% vs. 56.3, p = 0.590), but it was statistically higher in the metformin group than in the control group in frozen ET cycles (57.1% vs. 40.0%, p = 0.023). The metformin group had less oocytes retrieved, a lower cleaved oocyte rate, a lower available D3 embryo rate, a lower blastocyst formation rate, and a lower available blastocyst rate than the control group. HOMA-IR is a judgment criterion for metformin pre-treatment before IVF/ICSI-ET in patients with PCOS. Metformin pre-treatment could be added for PCOS patients with HOMA-IR ≥ 2.71 during frozen IVF/ICSI-ET cycles to improve the clinical pregnancy rate.