Assisted reproductive technology use and outcomes in childhood cancer survivors.

BACKGROUND: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. METHODS: Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. RESULTS: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0-20 years]; median years of follow-up after age 18 years, 11 years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p = .39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p = .33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). CONCLUSIONS: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Assessment of artificial intelligence model and manual morphokinetic annotation system as embryo grading methods for successful live birth prediction: a retrospective monocentric study.

PURPOSE: The introduction of the time-lapse monitoring system (TMS) and the development of predictive algorithms could contribute to the optimal embryos selection for transfer. Therefore, the present study aims at investigating the efficiency of KIDScore and iDAScore systems for blastocyst stage embryos in predicting live birth events. METHODS: The present retrospective study was conducted in a private IVF Unit setting throughout a 10-month period from October 2021 to July 2022, and included the analysis of 429 embryos deriving from 91 IVF/ICSI cycles conducted due to infertility of various etiologies. Embryos incubated at the Embryoscope+ timelapse incubator were analyzed through the established scoring systems: KIDScore and iDAScore®. The main outcome measure was the comparison of the two scoring systems in terms of live birth prediction. Embryos with the higher scores at day 5 (KID5 score/iDA5 score) were transferred or cryopreserved for later use. RESULTS: Embryos with high KID5 and iDA5 scores positively correlated with the probability of successful live birth, with KID5 score yielding a higher efficiency in predicting a successful reproductive outcome compared to a proportionally high iDA5 score. KID5 demonstrated conservative performance in successfully predicting live birth compared to iDA5 score, indicating that an efficient prediction can be either provided by a relatively lower KID5 score or a relatively higher iDA5 score. CONCLUSION: The developed artificial intelligence tools should be implemented in clinical practice in conjunction with the conventional morphological assessment for the conduction of optimized embryo transfer in terms of a successful live birth.

Human papillomavirus infection in women undergoing in-vitro fertilization: effects on embryo development kinetics and live birth rate.

BACKGROUD: Several studies showed that human papillomavirus (HPV) affects male fertility, but its impact on female fertility and in vitro fertilization (IVF) outcome is not yet clear. METHODS: Objective of this observational, prospective, cohort study was to evaluate the prevalence of HPV infection in women candidate to IVF, and the effects of HPV infection on the kinetic of embryonic development and on IVF outcome. A total number of 457 women candidate to IVF were submitted to HR-HPV test; among them, 326 underwent their first IVF cycle and were included in the analysis on IVF results. RESULTS: 8.9% of women candidate to IVF were HPV-positive, HPV16 being the most prevalent genotype. Among the infertility causes, endometriosis was significantly more frequent in HPV-positive than in negative women (31.6% vs. 10.1%; p < 0.01). Granulosa and endometrial cells resulted HPV-positive in 61% and 48% of the women having HPV-positive cervical swab, respectively. Comparing HPV-positive and negative women at their first IVF cycle, no significant difference was observed in the responsiveness to controlled ovarian stimulation (COS) in terms of number and maturity of retrieved oocytes, and of fertilization rate. The mean morphological embryo score was comparable in the two groups; embryos of HPV-positive women showed a quicker development in the early stages, with a significantly shorter interval between the appearance of pronuclei and their fusion. In the following days, embryo kinetic was comparable in the two groups until the early blastocyst stage, when embryos of HPV-positive women became significantly slower than those of HPV-negative women. Overall, these differences did not affect live birth rate/started cycle, that was comparable in HPV-positive and negative women (22.2 and 28.1%, respectively). CONCLUSIONS: (a) the prevalence of HPV infection in women candidate to IVF is similar to that observed in the general female population of the same age range; (b) HPV infection migrates along the female genital apparatus, involving also the endometrium and the ovary, and perhaps participates in the genesis of pelvic endometriosis; (c) HPV slightly affects the developmental kinetic of in vitro-produced embryos, but does not exert an effect on live birth rate.

ART outcomes in lean compared to obese phenotypes of polycystic ovarian syndrome.

RESEARCH QUESTION: To investigate differences in reproductive outcomes among IVF patients with lean compared to obese polycystic ovarian syndrome (PCOS) phenotypes. DESIGN: A retrospective cohort study of patients with PCOS who underwent IVF in a single, academically affiliated infertility center in the USA between December 2014 and July 2020. The diagnosis of PCOS was assigned based on Rotterdam criteria. Patients were designated as lean (< 25) or overweight/obese (≥ 25) PCOS phenotype based on BMI (kg/m2) at cycle start. Baseline clinical and endocrinologic laboratory panel, cycle characteristics, and reproductive outcomes were analyzed. The cumulative live birth rate included up to 6 consecutives cycles. A Cox proportional hazards model and Kaplan-Meier curve for estimating live birth rates were used to compare the two phenotypes. RESULTS: A total of 1395 patients who underwent 2348 IVF cycles were included. The mean (SD) BMI was 22.7 (2.4) in the lean and 33.8 (6.0) in the obese group (p < 0.001). A number of endocrinological parameters were similar between lean and obese phenotypes: total testosterone 30.8 ng/dl (19.5) vs 34.1 (21.9), p > 0.02 and pre-cycle hemoglobin A1C 5.33% (0.38) vs 5.51% (0.51) p > 0.001, respectively. The CLBR was higher in those with a lean PCOS phenotype: 61.7% (373/604) vs 54.0% (764/1414) respectively. Miscarriage rates were significantly higher for O-PCOS patients (19.7% (214/1084) vs 14.5% (82/563) p < 0.001) and the rate of aneuploids was similar (43.5%, 43.8%, p = 0.8). A Kaplan-Meier curve estimating the proportion of patients with a live birth was higher in the lean group (log-rank test p = 0.013). After adjusting for potential confounders, the lean phenotype was associated with an increased hazard ratio for live birth: HR = 1.38 p < 0.001. CONCLUSIONS: Lean PCOS phenotype is associated with a significantly higher CLBR compared to their obese counterparts. Miscarriage rates were significantly higher among obese patients, despite comparable pre-cycle HBA1C and similar aneuploidy rates in patients who underwent PGT-A.

Investigating the impact of SARS-CoV-2 infection on basic semen parameters and in vitro fertilization/intracytoplasmic sperm injection outcomes: a retrospective cohort study.

BACKGROUND: This study aimed to evaluate the influences of SARS-CoV-2 infection on semen parameters and investigate the impact of the infection on in vitro fertilization (IVF) outcomes. METHODS: This retrospective study enrolled couples undergoing IVF cycles between May 2020 and February 2021 at Tongji Hospital, Wuhan. Baseline characteristics were matched using propensity score matching. Participants were categorized into an unexposed group (SARS-COV-2 negative) and exposed group (SARS-COV-2 positive) based on a history of SARS-CoV-2 infection, and the populations were 148 and 50 after matching, respectively. IVF data were compared between the matched cohorts. Moreover, semen parameters were compared before and after infection among the infected males. The main measures were semen parameters and IVF outcomes, including laboratory and clinical outcomes. RESULTS: Generally, the concentration and motility of sperm did not significantly differ before and after infection. Infected males seemed to have fewer sperm with normal morphology, while all values were above the limits. Notably, the blastocyst formation rate and available blastocyst rate in the exposed group were lower than those in the control group, despite similar mature oocytes rates, normal fertilization rates, cleavage rates, and high-quality embryo rates. Moreover, no significant differences were exhibited between the matched cohorts regarding the implantation rate, biochemical pregnancy rate, clinical pregnancy rate, or early miscarriage rate. CONCLUSIONS: The results of this retrospective cohort study suggested that the semen quality and the chance of pregnancy in terms of IVF outcomes were comparable between the males with a history of SARS-CoV-2 infection and controls, although a decreased blastocyst formation rate and available blastocyst rate was observed in the exposed group, which needs to be reinforced by a multicenter long-term investigation with a larger sample size.

The use of frozen embryos and frozen sperm have complementary IVF outcomes: a retrospective analysis in couples experiencing IVF/Donor and IVF/Husband.

BACKGROUND: The cryopreservation of sperm or embryos has been an important strategy in the treatment of infertility. Recently studies have revealed the outcomes after IVF (in vitro fertilization) treatment for single-factor exposure either to frozen sperm or embryos. METHODS: This retrospective study was to uncover the exposure to both frozen sperm and embryo effects using IVF/H (in vitro fertilization using husbands' fresh sperm) or IVF/D (in vitro fertilization using donors' frozen sperm) treatment. RESULTS: The results showed the clinical pregnancy rate (CPR), live birth rate (LBR) and low birth weight rate (LBW) increased to 63.2% (or 68.1%), 61.1% (or 66.4%) and 15.8% (or 16.2%) after using frozen embryo transfer within Group IVF/H (or Group IVF/D). After using frozen sperm, the high-quality embryo rate (HER) increased to 52% and baby with birth defect rate (BDR) reduced to 0% in subgroup D/ET comparing to subgroup H/ET. While the fertilization rate (FER), cleavage rate (CLR), HER and multiple pregnancy rate (MUR) reduced to 75%, 71%, 45% and 9.2% in subgroup D/FET comparing to subgroup H/FET. Finally, our study found accumulative frozen gamete effects, including both sperm and embryos, led to the significantly increasing in the HER (p < 0.05), CPR (p < 0.001), LBR (p < 0.001) and LBW (p < 0.05) in subgroup D/FET comparing to subgroup H/ET. CONCLUSION: The use of frozen embryos and frozen sperm have complementary IVF outcomes. Our findings highlighted the parent's distinguished frozen effect not only for clinical studies but also for basic research on the mechanism of cellular response adaptations to cryopreservation.

The optimal period for oocyte retrieval after the administration of recombinant human chorionic gonadotropin in in vitro fertilization.

BACKGROUND: Our objective was to investigate the existence of an optimal period for oocyte retrieval in regards to the clinical pregnancy occurrence after the administration of recombinant human chorionic gonadotropin (rhCG) (Ovitrelle®). METHODS: We studied the digital records of 3362 middle eastern couples who underwent in vitro fertilization (IVF) treatment between 2019 and 2021. RESULTS: Through statistical testing, we found that there is a significant positive correlation between the oocyte retrieval period and the clinical pregnancy occurrence up to the 37th hour, where retrieval at the 37th hour was found to provide the most optimal outcome, especially in the case of gonadotropin-releasing hormone agonist (GnRHa) long protocol. CONCLUSIONS: This cohort study recommends retrieval at hour 37 after ovulation triggering under the described conditions.

Assessment of in vitro fertilization outcomes after hysteroscopic isthmoplasty in recurrent implantation failure.

AIM: The aim of this study was to assess the in vitro fertilization (IVF) treatments outcomes of women with recurrent implantation failure (RIF) after hysteroscopic isthmoplasty for isthmocele. METHODS: This retrospective, observational study included 61 patients with RIF and isthmocele who presented to IVF Unit of Hüma Obstetrics and Gynecology Hospital between January, 2018 and December, 2020. Thirty-one patient who underwent hysteroscopic isthmoplasty-before IVF procedure-were included. Remaining 30 patients underwent IVF without hysteroscopic isthmoplasty were included as controls. The fertility outcome were compared between groups. RESULTS: After 3 months, spontaneous pregnancy was achieved in 18.4% (7/38) of patients with isthmocele who underwent hysteroscopic isthmoplasty. In the isthmoplasty group, implantation rate, clinical pregnancy rate, biochemical pregnancy rate, and the miscarriage rate were 41.9% (13/31), 35.5% (11/31), 6.5% (2/31), and 9.7% (3/31), respectively. The live birth rate after in vitro fertilization was 25.8% (8/31) in the isthmoplasty group and 3.3% (1/30) in the control group (p < 0.05). There were no significant differences in the IVF outcomes such as the biochemical pregnancy rate and miscarriage rate between the isthmoplasty and control groups. CONCLUSION: This study demonstrated that hysteroscopic isthmoplasty improves pregnancy and live birth rates for women with a history of RIF and isthmocele. Reproductive results of the IVF cycles after hysteroscopic correction of isthmocele were comparable to those of the patients without any uterine abnormalities and those with diagnosis of unexplained infertility.

Cytokines in culture media of preimplantation embryos during in vitro fertilization: Impact on embryo quality.

Cytokine support of embryonic development includes promotion of implantation and protection of blastomeres from cell stress and apoptosis. Correlations between embryo quality and concentrations of specific cytokines in culture media of human embryos have been investigated for many years. The aim of this study was to assess the concentrations of cytokines in preimplantation embryo culture media and to investigate their relationships with embryo quality and in vitro fertilization (IVF) outcomes. Seventy-two samples were obtained from 39 infertile couples undergoing IVF or intracytoplasmic sperm injection treatment between October 2018 and May 2019. Each embryo was cultured separately, and the embryo culture medium was collected 72 h after fertilization. Before embryo transfer on day 3, a morphological evaluation of each embryo was performed. Cytokine concentrations of each culture medium were analyzed for 23 selected cytokines using the Multiplex Cytokine/Chemokine Panel II Assay (Merck Millipore®). The results were categorized into two groups (top-quality and non-top-quality embryos). The median age of the 39 patients was 34 years. Nine of 23 cytokines were quantified and compared between the top-quality embryo group and non-top-quality embryo group. Among the nine cytokines, CCL15, CCL27, and CXCL-12 were significantly elevated in the top-quality embryo group. These results suggested that specific cytokines measured in human embryo culture media can be used to predict embryo quality and IVF outcomes.

Kallistatin in follicular fluid of women with endometriosis and its correlation with IVF outcome.

BACKGROUND: Endometriosis (EM) affects 10% women of reproductive age and alters fertility. Its management is still debated notably the timing of surgery and ART in infertility. Kallistatin (KS) is an endogenous protein that regulates differential signaling pathways and biological functions. However, the function and the underlying molecular mechanism in EM and its correlation with in vitro fertilization (IVF) outcome have not been determined. The purpose of this study was to evaluate KS concentrations in follicular fluid (FF) of women with EM and controls women without EM who underwent IVF with embryo transfer (IVF-ET). METHODS: FF KS concentrations from 40 patients with EM and 40 non-EM patients were measured by ELISA. RESULTS: Compared with the non-EM patients, patients with EM had lower KS levels in FF (281.67 ± 104.60 vs. 490.70 ± 216.33 pg/ml). The rates of fertilization (61.64 ± 22.42 vs. 71.00 ± 24.39%), available embryo (45.96 ± 19.83 vs. 50.61 ± 26.26%), and top-quality embryo (12.71 ± 21.01 vs. 16.04 ± 16.87%) were significantly lower in the EM group than in the control group. The KS concentrations in the FF of women who conceived consequent to the treatment were significantly higher than those from women who did not in the combined EM and control groups. CONCLUSIONS: These results indicate that the KS concentration in FF could be used as a predictor for IVF-ET outcomes. This may contribute to the pathologic mechanism responsible for the poor outcome of IVF in patients with EM.

Ambient air pollutant exposure and in vitro fertilization treatment outcomes in Zhengzhou, China.

OBJECTIVE: To study the association between ambient air pollutant exposure during the follicular phase and in vitro fertilization (IVF) outcomes. DESIGN: A single-center retrospective analysis. SETTING: Henan Province, China. PATIENTS: Patients (n = 6659) living in Zhengzhou, Henan Province in central China who underwent their first IVF cycle at the First Affiliated Hospital of Zhengzhou University between 2013 and 2019 were included for analysis. INTERVENTION: None. MAIN OUTCOME MEASURE: The relationships between PM2.5, PM10, and AQI (Air Quality Index) with IVF outcomes during the follicular phase (period I, 85 days before oocyte retrieval; period II, gonadotrophin start to oocyte retrieval). RESULTS: Compared with the bottom tertile, exposure to the top PM2.5 and PM10 tertiles during period I was associated with decreased clinical pregnancy (PM2.5: adjusted odds ratio [OR], 0.838%, and 95% confidence interval [CI], 0.723 and 0.971; PM10: adjusted OR, 0.818%, and 95% CI, 0.705 and 0.950), and decreased live birth rate (PM2.5: adjusted odds ratio [OR], 0.852%, and 95% confidence interval [CI], 0.736 and 0.987; PM10: adjusted OR, 0.850%, and 95% CI, 0.733 and 0.986), and exposure to the top PM2.5 tertile during period II adversely affected clinical pregnancy and the live birth rate (adjusted OR, 0.824%, and 95% CI, 0.711 and 0.955; adjusted OR, 0.817%, and 95% CI, 0.706 and 0.945). Compared with the bottom PM10 tertile, exposure to the middle PM10 tertile in period II showed decreased clinical pregnancies and live births (adjusted OR, 0.844; 95% CI, 0.729 and 0.978, adjusted OR, 0.846; 95% CI, 0.731 and 0.979). The PM10 level during period II of the follicular phase tend to adversely affect live birth rate, but the tendency did not reach significance (P = 0.051). CONCLUSION: Exposure to PM2.5 and PM10 before oocyte retrieval has an adverse effect on IVF outcomes. CAPSULE: Exposure to PM2.5 and PM10 before oocyte retrieval has an adverse effect on IVF outcomes.

Three-dimensional ultrasound diagnosis of adenomyosis is not associated with adverse pregnancy outcome following single thawed euploid blastocyst transfer: prospective cohort study.

OBJECTIVES: The objectives of this study were (1) to assess the prevalence of ultrasound (US) features of adenomyosis in an infertile population undergoing in-vitro fertilization (IVF), (2) to define the inter- and intrarater agreement of three-dimensional (3D) US assessment of adenomyosis, and (3) to evaluate sonographic features of adenomyosis with respect to pregnancy outcome following transfer of a single thawed euploid blastocyst. METHODS: This was a prospective cohort study. Subjects scheduled to undergo a single thawed euploid blastocyst transfer between April and December 2017 at a large IVF center were eligible for inclusion. Enrolled subjects underwent endometrial preparation for frozen embryo transfer. 3D-US was performed on the day prior to embryo transfer, with images stored for subsequent evaluation. Subjects then underwent transfer of a single thawed euploid blastocyst, and pregnancy outcomes were collected. All 3D-US volumes were de-identified and reviewed independently by five reproductive endocrinologists/infertility specialists with expertise in gynecological US for the presence of seven sonographic features of adenomyosis: global uterine enlargement, myometrial wall asymmetry, heterogeneous echogenicity, irregular junctional zone, myometrial cysts, fan-shaped shadowing and ill-defined myometrial lesions. Adenomyosis was considered to be present if the majority of the reviewers noted at least one of the seven sonographic features. Inter- and intrarater agreement was evaluated using Fleiss's kappa. Clinical and cycle characteristics of subjects with and those without adenomyosis were compared. The primary outcome of interest was live birth rate. Secondary outcomes included clinical pregnancy rate and miscarriage rate. Logistic regression analysis was performed to account for potential confounders. RESULTS: A total of 648 subjects were included. The prevalence of adenomyosis on US was 15.3% (99/648). On retrospective chart review, very few patients with adenomyosis had symptoms. The inter- and intrarater agreement amongst five independent specialists conducting the 3D-US assessments of adenomyosis were poor (κ = 0.23) and moderate (κ = 0.58), respectively. Subjects with adenomyosis were older (37.1 vs 35.9 years, P = 0.02) and more likely to undergo a gonadotropin-releasing hormone agonist downregulation protocol when compared with those without adenomyosis (12.1% vs 5.1%, P = 0.02). Clinical pregnancy (80.0% vs 75.0%) and live birth (69.5% vs 66.5%) rates were similar between the groups. When adjusting for potential confounders, there was no difference in the rate of clinical pregnancy (adjusted odds ratio (aOR), 1.47 (95% CI, 0.85-2.56)), miscarriage (aOR, 1.3 (95% CI, 0.62-2.72)) or live birth (aOR, 1.28 (95% CI, 0.78-2.08)) between subjects with and those without adenomyosis. No individual sonographic marker of adenomyosis was predictive of pregnancy outcome. CONCLUSIONS: The inter-rater agreement of 3D-US assessment of adenomyosis is poor. Furthermore, sonographic markers of adenomyosis in asymptomatic patients may not be associated with altered pregnancy outcome following transfer of a single thawed euploid blastocyst. These findings suggest that routine screening for asymptomatic adenomyosis in an unselected infertile patient population undergoing frozen embryo transfer may not be warranted. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Trends in primeval ß-hCG level increment after fresh and frozen-thawed IVF embryo transfer cycles.

Mid-trimester beta-human chorionic gonadotropin (BHCG) levels are considerably higher in pregnancies resulting from frozen embryo transfer (FET) compared with fresh (FRET), leading to a higher false positive rate in aneuploidy screening tests. We aimed to investigate the dynamics of BHCG increment and its predictive value for cycle outcome. A retrospective analysis of FRET and FET cycles. BHCG values on days 14 and 16 post embryo transfer were compared and stratified according to the number of sacs demonstrated on US scan at six weeks gestation, and pregnancy outcome (biochemical pregnancy, ectopic pregnancy, spontaneous abortion, and a singleton or twin birth). A prediction model for live birth was built. A total of 430 treatment cycles were analyzed. The average BHCG levels were significantly higher in FET compared with FRET group in nonviable pregnancies on day 14, 450 vs. 183 IU/L, p < .05 and day 16, 348 vs. 735 IU/L, p < .05, respectively. The increment of BHCG was significantly steeper in the FET compared with FRET group in biochemical pregnancies (F = 6.485, p = .012*). Optimal cutoff level for live birth prediction in the FRET group was 211 IU/L (sensitivity 84%, specificity 76.2%) for day 14 and 440 IU/L (sensitivity 86.0% and specificity 72.5%) for day 16. The increment in BHCG differed significantly between the FRET and FET cycles in nonviable pregnancies. Nevertheless, the difference in BHCG levels observed in the second trimester in pregnancies conceived after FRET and FET cycle may begin as early as the fourth week of pregnancy.

Testosterone therapy for women with poor ovarian response undergoing IVF: a meta-analysis of randomized controlled trials.

PURPOSE: The aim of the present systematic review and meta-analysis was to summarize evidence on the effectiveness of testosterone supplementation for poor ovarian responders (POR) on IVF outcomes. The primary outcome was live birth rate (LBR); secondary outcomes were clinical pregnancy rate (CPR), miscarriage rate (MR), total and MII oocytes, and total embryos. METHODS: This meta-analysis of randomized controlled trials (RCTs) evaluates the effects of testosterone administration before/during COS compared with a control group in patients defined as POR. The primary outcome was live birth rate (LBR); secondary outcomes were clinical pregnancy rate (CPR), miscarriage rate (MR), total and MII oocytes, and total embryos. Pooled results were expressed as risk ratio (RR) or mean differences (MD) with 95% confidence interval (95% CI). Sources of heterogeneity were investigated through sensitivity and subgroup analysis. All analyses were performed by using the random-effects model. RESULTS: Women receiving testosterone showed higher LBR (RR 2.29, 95% CI 1.31-4.01, p = 0.004), CPR (RR 2.32, 95% CI 1.47-3.64, p = 0.0003), total oocytes (MD = 1.28 [95% CI 0.83, 1.73], p < 0.00001), MII oocytes (MD = 0.96 [95% CI 0.28, 1.65], p = 0.006), and total embryos (MD = 1.17 [95% CI 0.67, 1.67], p < 0.00001) in comparison to controls, with no difference in MR (p = ns). Sensitivity and subgroup analysis did not provide statistical changes to the pooled results. CONCLUSIONS: Testosterone therapy seems promising to improve the success at IVF in POR patients. Further RCTs with rigorous methodology and inclusion criteria are still mandatory.

The number of oocytes retrieved during IVF: a balance between efficacy and safety.

STUDY QUESTION: What is the relationship between the number of oocytes collected in fresh IVF treatments and the likelihood of cumulative delivery rate (fresh and frozen) per oocyte aspiration, severe ovarian hyperstimulation syndrome (OHSS) and thromboembolic events? SUMMARY ANSWER: Cumulative delivery rate per aspiration increases up to 20 oocytes retrieved and then evens out while the incidence of severe OHSS increases more rapidly from around 18 oocytes and thromboembolic events, although rare, occurs in particular if 15 or more oocytes are retrieved. WHAT IS KNOWN ALREADY?: Previous studies have shown that the number of oocytes retrieved for IVF is a positive predictor of live birth in fresh cycles. Few studies have investigated cumulative live birth rates and OHSS in relation to the number of aspirated oocytes. STUDY DESIGN, SIZE, DURATION: Retrospective population-based registry study including 39 387 women undergoing 77 956 fresh IVF cycles in the period 2007-2013 and 36 270 consecutive transfers of frozen/thawed embryos in the period 2007-2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from The Swedish National Quality Registry of Assisted Reproduction (Q-IVF) including all IVF cycles with oocyte retrieval performed in public or private infertility clinics during the study period, was cross-linked to the National Patient Register regarding diagnostic codes (ICD 10) for severe (OHSS) and thromboembolic events. Oocyte donation cycles were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth delivery rate in fresh cycles increased up to 11 oocytes retrieved and then evened out, where the live birth rate was 30.3% for a 34-year-old woman. The cumulative delivery rate per aspiration, including fresh transfer and all subsequent transfers of frozen-thawed embryos (FET cycles) per oocyte retrieval, increased up to approximately 20 oocytes where it reached 45.8%. The adjusted odds ratio (AOR) for live birth by the number of oocytes was 1.064 (95% CI: 1.061; 1.067). The incidence of severe OHSS increased significantly by the number of oocytes, particularly if more than 18 oocytes were retrieved. The AOR for OHSS by the number of oocytes was 1.122 (95% CI: 1.08; 1.137). Thromboembolic events were rare, a total of 16 events in 14 patients were observed, and occurred in particular if 15 or more oocytes were retrieved. LIMITATIONS, REASONS FOR CAUTION: All FET cycles might not be included. Some embryos cryopreserved between 2010 and 2013 might still result in additional births until 2018. Furthermore the gonadotrophin dose was not included in the Q-IVF Registry in the study period, thus adjustment for dose was not possible. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest a shift at approximately 18-20 oocytes where the cumulative delivery rate per aspiration levels off and, at the same time, the incidence of severe OHSS increases more rapidly. Thromboembolic events, although rare, should also be taken into consideration at stimulation regimes for IVF. Evaluating data taking both efficacy and the most serious safety aspects into account, is a new approach and of crucial importance both for patients undergoing IVF and their physicians. STUDY FUNDING/COMPETING INTEREST: Financial support was received through an agreement relating to research and the education of doctors (ALFGBG-70 940) and grant from the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest.

Ultrasound-guided embryo transfer: summary of the evidence and new perspectives. A systematic review and meta-analysis.

Despite the purported advantages of ultrasound guidance during embryo transfer, and the large number of clinical trials published on this topic, recommendations for the use of this technique in daily clinical practice are still under debate. We designed a meta-analysis based exclusively on evidence from published randomized controlled trials, with the aim of analysing the effect of trans-abdominal ultrasound guidance during embryo transfer versus clinical touch and of transvaginal ultrasound guidance (TV-US) versus the trans-abdominal approach on IVF outcomes. On the basis of 14 randomized trials, we found a moderate quality of evidence supporting the beneficial effects of transabdominal guidance during embryo transfer compared with conventional clinical touch in clinical pregnancy and ongoing or live birth rates. No significant differences were found in miscarriage and ectopic pregnancy rate, with low or very low quality of evidence, respectively. On the basis of three randomized trials, we found the quality of evidence supporting the equivalence of transvaginal versus transabdominal approach in clinical pregnancy and ongoing or live birth rates to be low. Finally, larger randomized controlled trials are necessary to explore the possible benefits of TV-US, three-dimensional ultrasound imaging modality, and uterine length measurement before transfer.

Relationship between follicular volume and oocyte competence, blastocyst development and live-birth rate: optimal follicle size for oocyte retrieval.

OBJECTIVE: To analyze oocyte competence in gonadotropin-releasing hormone agonist (GnRHa) stimulation cycles with regard to maturity, fertilization and blastocyst rate, as well as clinical outcome (pregnancy and live-birth rate), in relation to follicular volume, measured by three-dimensional transvaginal sonography (3D-TVS), and follicular fluid composition. METHODS: This was a prospective single-center study conducted between June 2012 and June 2014, including 118 ovum pick-ups with subsequent embryo transfer. Ovarian stimulation was performed using the GnRHa long protocol. Of 1493 follicles aspirated individually, follicular volume was evaluated successfully in 1236 using automated 3D-TVS during oocyte retrieval. Oocyte maturity and blastocyst development were tracked according to follicular volume. Intrafollicular concentrations of estradiol, testosterone, progesterone, luteinizing hormone, follicle-stimulating hormone and granulocyte-colony stimulating factor were quantified by immunoassay. Clinical outcome, in terms of implantation rate, (clinical) pregnancy rate, miscarriage and live-birth rate (LBR), was evaluated. RESULTS: Follicles were categorized, according to their volume, into three arbitrary groups, which included 196 small (8-12 mm/0.3-0.9 mL), 772 medium (13-23 mm/1-6 mL) and 268 large (≥ 24 mm/> 6 mL) follicles. Although oocyte recovery rate was significantly lower in small follicles compared with medium and large ones (63.8% vs 76.6% and 81.3%, respectively; P < 0.001), similar fertilization rates (85.1% vs 75.3% and 81.4%, respectively) and blastocyst rates (40.5% vs 40.6% and 37.2%, respectively) per mature metaphase II oocyte were observed. A trend towards higher LBR after transfer of blastocysts derived from small (< 1 mL) follicles compared with medium (1-6 mL) or large (> 6 mL) follicles (54.5% vs 42.0%, and 41.7%, respectively) was observed. No predictive value of follicular fluid biomarkers was identified. CONCLUSIONS: Our data indicate that the optimal follicular volume for a high yield of good quality blastocysts with good potential to lead to a live birth is 13-23 mm/1-6 mL. However, oocytes derived from small follicles (8-12 mm/0.3-0.9 mL) still have the capacity for normal development and subsequent delivery of healthy children, suggesting that aspiration of these follicles should be encouraged as this would increase the total number of blastocysts retrieved per stimulation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

A prospective investigation of perceived stress, infertility-related stress, and cortisol levels in women undergoing in vitro fertilization: influence on embryo quality and clinical pregnancy rate.

INTRODUCTION: Women undergoing fertility treatment experience high levels of stress. However, it remains uncertain if and how stress influences in vitro fertilization (IVF) cycle outcome. This study aimed to investigate whether self-reported perceived and infertility-related stress and cortisol levels were associated with IVF cycle outcomes. MATERIAL AND METHODS: A prospective cohort of 485 women receiving fertility treatment was recruited from September 2011 to December 2013 and followed until December 2014. Data were collected by online questionnaire prior to IVF start and from clinical charts. Salivary cortisol levels were measured. Associations between stress and cycle outcomes (clinical pregnancy and indicators of oocyte and embryo quality) were measured by logistic or linear regression, adjusted for age, body mass index, education, smoking, alcohol and caffeine consumption, shiftwork and night work. RESULTS: Ultrasound verified pregnancy rate was 26.6% overall per cycle started and 32.9% per embryo transfer. Stress measures were not associated with clinical pregnancy: when compared with the lowest categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest categories of the perceived stress score was 1.04 (95% CI 0.58-1.87), infertility-related stress score was OR = 1.18 (95% CI 0.56-2.47), morning and evening cortisol was OR = 1.18 (95% CI 0.60-2.29) and OR = 0.66 (95% CI 0.34-1.30), respectively. CONCLUSIONS: Perceived stress, infertility-related stress, and cortisol levels were not associated with IVF cycle outcomes. These findings are potentially reassuring to women undergoing fertility treatment with concerns about the influence of stress on their treatment outcome.

Comparison of effects of thawing entire donor sperm vial vs. partial thawing (shaving) on sperm quality.

PURPOSE: Partial thawing of a vial of cryopreserved sperm (shaving) is sometimes applied as a measure to preserve sperm for further use, particularly in cases of very restricted sperm quantity. However, mechanical violence may disrupt the sperm-wall and lead to impaired in-vitro fertilization (IVF) outcomes. MATERIAL AND METHODS: In a retrospective case-control study at a tertiary, university-affiliated medical center, we compared the IVF/intracytoplasmic sperm injection (ICSI) outcomes of patients who used donor sperm following partial thawing (shaving) of the vial of cryopreserved sperm (n = 99) to a control group consisting of patients for whom the vial of sperm was completely thawed before use (n = 99). RESULTS: While no differences were observed in the rates of oocyte fertilization, the mean number of top-quality embryos (TQE) was significantly lower in the shaving group than in the complete thawing group (1.33 ± 0.17 vs. 1.87 ± 0.17, p < 0.02). Experimental analysis of aliquots from the same donors revealed significantly reduced motility in sperm samples that were shaved vs. fully thawed (6.5 vs. 37.1%, p < 0.001). CONCLUSIONS: In cases in which available cryopreserved sperm samples are limited, shaving of the vial without thawing can be used but with caution and only when absolutely necessary. Further, large prospective studies are needed to better clarify whether there is post-thawing sperm damage and to compare IVF outcomes after these two thawing methods.

Randomized, open trial comparing a modified double-lumen needle follicular flushing system with a single-lumen aspiration needle in IVF patients with poor ovarian response.

Study question: Is a modified double-lumen aspiration needle system with follicular flushing able to increase the mean oocyte yield by at least one in poor response IVF patients as compared to single-lumen needle aspiration without flushing? Summary answer: Follicular flushing with the modified flushing system did not increase the number of oocytes, but increased the procedure duration. What is known already: Most studies on follicular flushing were performed with conventional double-lumen needles in patients who were normal responders. Overall, these studies indicated no benefit of follicular flushing. Study design size, duration: Prospective, single-centre, randomized, controlled, open, superiority trial comparing the 17 G Steiner-Tan Needle® flushing system with a standard 17 G single-lumen aspiration needle (Gynetics®); time frame February 2015-March 2016. Participants/materials setting methods: Eighty IVF patients, 18-45 years, BMI >18 kg/m2 to <35 kg/m2, presenting with ≤ five follicles >10 mm in both ovaries at the end of the follicular phase were randomized to either aspirating and flushing each follicle 3× with the Steiner-Tan-Needle® automated flushing system (n = 40) or a conventional single-lumen needle aspiration (n = 40). Primary outcome was the number of cumulus-oocyte-complexes (COCs). Procedure duration, burden (Depression Anxiety and Stress Scale; DASS-21) and post-procedure pain were also assessed. Main results and the role of chance: Flushing was not superior with a mean (SD) number of COCs of 2.4 (2.0) and 3.1 (2.3) in the Steiner-Tan Needle® and in the Gynectics® group, respectively (mean difference -0.7, 95% CI: 0.3 to -1.6; P = 0.27). Likewise no differences were observed in metaphase II  oocytes, two pronuclear oocytes, number of patients having an embryo transfer and DASS 21 scores. The procedure duration was significantly 2-fold increased. Limitations reasons for caution: Testing for differences in the number of patients achieving an embryo transfer or differences in pregnancy rate would require a much larger sample size. Wider implications of the findings: The use of follicular flushing is unlikely to benefit the prognosis of patients with poor ovarian response. Study funding/competing interest(s): The Steiner-Tan Needles® and the flushing system were provided for free by the manufacturer. K.v.H. has received personal fees from Finox and non-financial support from Merck-Serono; M.D. has received personal fees from Finox and non-financial support from Merck-Serono. A.S.-M. has received personal fees and non-financial support from M.D., Ferring, Merck-Serono, Finox, TEVA. G.G. has received personal fees and non-financial support from M.D., Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, as well as personal fees from VitroLife, NMC Healthcare LLC, ReprodWissen LLC and ZIVA LLC. Trial registration number: NCT 02365350 (clinicaltrials.gov). Trial registration date: Sixth of February 2015. Date of first patient's enrolment: Ninth of February 2015.