Embryology with precision: effective quality control in the in vitro fertilization laboratory.

The purpose of this review is to address the critical need for standardization and clarity in the use of key performance indicators (KPIs) within the realm of in vitro fertilization (IVF), particularly emphasizing the integration of preimplantation genetic testing (PGT) processes. This review is timely and relevant given the persistently modest success rates of IVF treatments, which stand at approximately 30%, and the growing complexity of IVF procedures, including PGT practices. The review synthesizes recent findings across studies focusing on technical and clinical KPIs in embryology and genetic laboratories, identifying gaps in current research and practice, particularly the lack of standardized KPIs and terminology. Recent findings highlighted include the critical evaluation of technical KPIs such as Intracytoplasmic Sperm Injection (ICSI) fertilization rates, embryo development rates, and laboratory performance metrics, alongside clinical KPIs like the proportion of mature oocytes and clinical pregnancy rates. Notably, the review uncovers a significant gap in integrating and standardizing KPIs for PGT applications, which is essential for improving IVF outcomes and genetic diagnostic accuracy. The implications of these findings are profound for both clinical practice and research. For clinical practice, establishing a standardized set of KPIs, especially for PGT, could significantly enhance the success rates of IVF treatments by providing clearer benchmarks for quality and performance. For research, this review underscores the necessity for further studies to close the identified gaps, promoting a more integrated and standardized approach to KPIs in IVF and PGT processes. This comprehensive approach will not only aid in improving clinical outcomes but also in advancing the field of reproductive medicine.

PIEZO-ICSI increases fertilization rates compared with standard ICSI: a prospective cohort study.

RESEARCH QUESTION: Is PIEZO-intracytoplasmic sperm injection (ICSI) coupled with a new novel operational fluid (perfluoro-n-octane) superior to standard ICSI? DESIGN: A cohort of patients (n = 69) undertaking microinjection were recruited between January and November 2019 and were then prospectively case-matched. Patients required six or more mature oocytes for inclusion in the study. PIEZO-ICSI uses high-speed microinjection drilling to penetrate the zona and oolemma and deposit the spermatozoa into the cytoplasm, compared with the traditional 'cutting' action of ICSI. The primary outcome was fertilization, with secondary outcomes including oocyte degeneration, abnormal fertilization, embryo cryopreservation and embryo utilization. RESULTS: PIEZO-ICSI resulted in significantly higher fertilization rates (80.5 ± 2.4% vs 65.8 ± 2.3%, P < 0.0001) and lower oocyte degeneration rates (4.4 ± 1.3% vs 8.6 ± 1.2%, P = 0.019) and abnormal fertilization rates (2.9 ± 1.1% vs 7.4 ± 1.1%; P = 0.003) compared with standard ICSI. This improvement in fertilization was of most benefit in patients aged ≥38 years. This increase in fertilization increased the number of good quality embryos that were available for cryopreservation/transfer (3.8 ± 0.2 vs 3.1 ± 0.2; P = 0.038), such that patients on average had one extra usable embryo per cycle compared with standard ICSI. There were no differences to Day 5 embryo development or clinical pregnancy from fresh embryo transfer (57.1% PIEZO-ICSI vs 60.0% ICSI) between microinjection methods, although pregnancy outcomes were underpowered. CONCLUSIONS: PIEZO-ICSI significantly increased fertilization rates, thereby increasing the number of embryos available for cryopreservation compared with standard ICSI. Further prospective studies assessing cumulative pregnancy rates are warranted.

What is the optimal timing of intracytoplasmic sperm injection (ICSI) after EGG retrieval? A randomized controlled trial.

PURPOSE: To determine if oocyte denudation and ICSI at 36.5 versus 39 h post HCG and/or Lupron trigger (2.5 h versus 5 h post-oocyte retrieval) influences fertilization and blastulation rates in good prognosis couples METHODS: We performed a prospective, randomized controlled trial of 12 patients undergoing IVF with ICSI at an academic fertility center, resulting in 206 MII oocytes analyzed. At time of retrieval, patients with more than 10 oocytes retrieved had their oocytes randomized into two groups-one group for oocyte denudation and ICSI at 36.5 h post HCG and/or Lupron trigger and the other group for these procedures at 39 h post HCG and/or Lupron trigger (2.5 and 5 h after oocyte retrieval). Primary outcomes were fertilization and blastulation rates. RESULTS: No difference was observed in fertilization rate, total blastulation rate, or day of blastulation based on timing of denudation and ICSI (all p > 0.05). Multiple regression analyses for fertilization and blastulation controlling for age and BMI revealed no difference in fertilization based on time of ICSI (p = 0.38, 0.71, respectively). A conditional logistic regression to account for multiple oocytes derived from each patient also found no difference in fertilization or blastulation based on timing of ICSI, even when controlling for age and BMI (p = 0.47, 0.59, respectively). CONCLUSION(S): In good prognosis couples, we observed no difference in fertilization or blastulation rates based on timing of ICSI within the currently accepted 2- to 6-h window post-retrieval based on a 34-h trigger. The oocyte appears to have a physiological tolerance for fertilization during this window of time, and variability in the timing of ICSI during this window is unlikely to have an impact on cycle outcome.

The outcome of intra-cytoplasmic sperm injection (ICSI): do the sperm concentration and motility matter?

OBJECTIVES: The male-factor subfertility was reported to be 30% globally; thus, the intracytoplasmic sperm injection (ICSI) procedure was implemented to improve the overall in vitro fertilization (IVF) rates. Nevertheless, at least 10% of fertilization failure still occurs. Concerning this issue, we explored the association of sperm concentration and motility with the quality of embryo development and pregnancy outcome in IVF-ICSI cycles. METHODS: Retrospective analysis of 109 couples with male factor were done over 14 months in a tertiary university hospital in Malaysia. The data were divided into four groups; Group I: normal sperm parameters, Group II: normal sperm concentration but reduced total sperm motility, Group III: reduced sperm concentration and motility, Group IV: reduced sperm concentration but normal sperm motility. Only fresh semen samples and fresh embryo transfers were included. The fertilization, cleavage rate, embryo quality and pregnancy outcome were assessed. RESULTS: Overall, group I had the highest oocytes yield and ICSI attempted; (10.12 + 6.50), whereas the lowest was in group IV; (7.00 + 2.82). Group II revealed the highest fertilization and cleavage rates; (54.14 + 25.36), (55.16 + 26.06), thus not surprisingly resulting in the highest number of good embryos and highest clinical pregnancy rates. The lowest cleavage and pregnancy rates were seen in group IV. However, all the outcomes were not statically significant (p>0.05). CONCLUSIONS: Similar fertilization rate and comparable pregnancy outcome was seen among couples with normal and reduced sperm concentration and motility.

Clinical outcomes analysis of infertile women with unicornuate uterus in IVF-ET.

PURPOSE: To explore the pregnancy outcomes, and neonatal status, arising from embryo transfer in unicornual uterine infertility patients. METHODS: We analyzed 2499 cycles of clinical data from in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) from 1st May 2016 to 1st May 2018 in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University, including 109 women with unicornuate uterus (the observation group) and 2390 women with normally shaped uterus (the control group). RESULTS: There were no significant differences in embryo implantation rate, clinical pregnancy rate or miscarriage rate (41.88 % VS 42.36 %, P = 0.904; 48.62 % VS 55.94 %, P = 0.133; 11.01 % VS 8.99 %, P = 0.474) between the two groups. The live birth rate in the observation group was lower than that in the control group (35.78 % VS 45.82 %, P = 0.040). The fetal birth weight of the observation group was lower than that of the control group among single-born live births (3009.12 ± 430.59 g VS 3413.40 ± 492.25 g, P = 0.017), but the differences were not observed in the sex ratio at birth, premature birth rate, low birth weight infant (LBW) rate and macrosomia rate (P > 0.05). The fetal birth weight of the observation group was lower than that of the control group among twins live births (2480.00 ± 190.32 g VS 2606.02 ± 471.59 g), but the difference between the groups did not reach statistical significance (P > 0.05)．Logistic regression analysis showed that age, number of embryos transplanted and uterine morphology were independent influencing factors of live birth. CONCLUSION: Compared with women with normal uterus, the live birth rate of women with unicornuate uterus is low, and the birth weight of newborns with single birth is reduced.

Live birth in a complete zona-free patient: a case report.

OBJECTIVE: To report a live birth from a patient with complete zona-free oocytes due to abnormal zona production and to reveal full time-lapse blastocyst development footage of its originating embryo. METHODS: A 34-year-old woman presented with a history of failed fertilization via standard in vitro fertilization insemination and a potential absence of zona pellucida. A total of 3 intracytoplasmic sperm injection cycles were undertaken with all oocytes collected being zona-free. Embryos created in the initial 2 cycles were cultured in the G1+/G2+ sequential media in a benchtop incubator. During the final successful cycle, the culture strategy was shifted to single step media (G-TL) in an Embryoscope+ incubator. RESULTS: The first 2 attempts led to a biochemical pregnancy or no blastocyst available for transfer. In the third cycle, 13 out of 24 collected oocytes were subjected to injection, with 4 being normally fertilized. Two blastocysts were subsequently formed, in which one was cryopreserved and the other transferred. A live baby girl (1570g) was subsequently delivered at 34 weeks of gestation by cesarean section. CONCLUSION: Live birth can be achieved for patients with zona production deficiency. Adjustment in ovarian stimulation and subsequent embryo culture strategies may have potentially contributed to the success of the 3rd cycle.

Influence of sperm morphology on pregnancy outcome and offspring in in vitro fertilization and intracytoplasmic sperm injection: a matched case-control study.

Sperm morphology was once believed as one of the most predictive indicators of pregnancy outcome in assisted reproductive technology (ART). However, the impact of teratozoospermia on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes and its offspring remains inconclusive. In order to evaluate the influence of teratozoospermia on pregnancy outcome and newborn status after IVF and ICSI, a retrospective study was conducted. This was a matched case-control study that included 2202 IVF cycles and 2574 ICSI cycles and was conducted at the Reproductive and Genetic Hospital of CITIC-Xiangya in Changsha, China, from June 2013 to June 2018. Patients were divided into two groups based on sperm morphology: teratozoospermia and normal sperm group. The pregnancy outcome and newborn outcome were analyzed. The results indicated that couples with teratozoospermia had a significantly lower optimal embryo rate compared to those with normal sperm morphology in IVF (P = 0.007), while there were no statistically significant differences between the two groups in terms of the fertilization rate, cleavage rate, implantation rate, and pregnancy rate (all P > 0.05). Additionally, teratozoospermia was associated with lower infant birth weight in multiple births after IVF. With regard to ICSI, there was no significant difference in both pregnancy outcome and newborn outcome between the teratozoospermia and normal groups (both P > 0.05). Furthermore, no increase in the risk of birth defects occurred in the teratozoospermia group after IVF/ICSI. Consequently, we believe that teratozoospermia has limited predictive value for pregnancy outcomes in IVF/ICSI, and has little impact on the resulting offspring if multiple pregnancy is avoided.

Reproductive outcomes of intracytoplasmic sperm injection using testicular sperm and ejaculated sperm in patients with AZFc microdeletions: a systematic review and meta-analysis.

Studies have explored the assisted reproductive technology (ART) outcomes of Y-chromosome azoospermia factor c (AZFc) microdeletions, but the effect of sperm source on intracytoplasmic sperm injection (ICSI) remains unknown. To determine the ART results of ICSI using testicular sperm and ejaculated sperm from males with AZFc microdeletions, we searched Embase, Web of Science, and PubMed to conduct a systematic review and meta-analysis. The first meta-analysis results for 106 cycles in five studies showed no significant differences in the live birth rate between the testicular sperm group and the ejaculated sperm group (risk ratio: 0.97, 95% confidence interval [CI]: 0.73-1.28, P = 0.82). The second meta-analysis of 106 cycles in five studies showed no difference in the abortion rate between the testicular sperm group and ejaculated sperm group (risk ratio: 1.06, 95% CI: 0.54-2.06, P = 0.87). The third meta-analysis of 386 cycles in seven studies showed no significant difference in clinical pregnancy rates between the testicular sperm group and the ejaculated sperm group (risk ratio: 1.24, 95% CI: 0.66-2.34, P = 0.50). Inevitable heterogeneity weakened our results. However, our results indicated that testicular sperm and ejaculated sperm yield similar ART outcomes, representing a meaningful result for clinical treatment. More properly designed studies are needed to further confirm our conclusions.

Abnormal fertilization in ICSI and its association with abnormal semen parameters: a retrospective observational study on 1855 cases.

Intracytoplasmic sperm injection (ICSI) efficiently addresses male factor infertility. However, the occurrence of abnormal fertilization, mainly characterized by abnormal pronuclei (PN) patterns, merits investigation. To investigate abnormal fertilization patterns following ICSI and identify their respective associations with abnormal parameters in semen analysis (SA), a retrospective observational study including 1855 cycles was performed. Male infertility diagnosis relied on the 2010 WHO criteria. The population was divided into groups based on their SA results. The presence of 2PNs and extrusion of the second polar body (PB) indicated normal fertilization. A Kruskal-Wallis test along with a Wilcoxon post hoc evaluation and Bonferroni correction was employed for comparison among the groups. For the pregnancy rate, logistic regression was employed. No correlation was established between the SA abnormalities and the 1PN or 3PN formation rates. The highest and lowest 0PN rates were reported for the oligoasthenoteratozoospermic and normal groups, respectively. The lowest cleavage formation rates were identified in the oligoasthenozoospermic and oligoasthenoteratozoospermic groups. The aforementioned groups along with the oligoteratozoospermic group similarly presented the lowest blastocyst formation rates. For the clinical pregnancy rate, no statistically significant difference was observed. In conclusion, the incidence of two or more abnormal SA parameters - with the common denominator being oligozoospermia - may jeopardize normal fertilization, cleavage, and blastocyst rates. Once the developmental milestone of achieving blastocyst stage status was achieved, only oligoasthenozoospermia and oligoasthenoteratozoospermia were associated with lower rates. Interestingly, following adjustment for the number of blastocysts, no statistically significant differences were observed.

Diagnosis and treatment of infertility in men: AUA/ASRM guideline part II.

PURPOSE: The summary presented herein represents Part II of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part II outlines the appropriate management of the male in an infertile couple. Medical therapies, surgical techniques, as well as use of intrauterine insemination (IUI)/in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) are covered to allow for optimal patient management. Please refer to Part I for discussion on evaluation of the infertile male and discussion of relevant health conditions that are associated with male infertility. MATERIALS/METHODS: The Emergency Care Research Institute Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January 2000 through May 2019. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. (Table 1) This summary is being simultaneously published in Fertility and Sterility and The Journal of Urology. RESULTS: This Guideline provides updated, evidence-based recommendations regarding management of male infertility. Such recommendations are summarized in the associated algorithm. (Figure 1) CONCLUSION: Male contributions to infertility are prevalent, and specific treatment as well as assisted reproductive techniques are effective at managing male infertility. This document will undergo additional literature reviews and updating as the knowledge regarding current treatments and future treatment options continues to expand.

Conventional IVF revisited: Is ICSI better for non-male factor infertility? Randomized controlled double blind study.

STUDY QUESTION: Is ICSI better than conventional IVF for non-male factor infertility? SUMMARY ANSWER: IVF should be the choice of assisted reproductive technique in non-male factor infertility cases. WHAT IS ALREADY KNOWN: Although total fertilization failure is a major concern for patients and professionals, the overall risk/benefit analysis favors conventional IVF in non-male factor infertility cases. However, according to the ESHRE EIM database pertaining to 1997-2012, the use of IVF has been continuously decreasing in favor of ICSI. STUDY DESIGN, SIZE, DURATION: Randomized controlled double-blind study involving 138 women undergoing ART in a private Center. PARTICIPANTS/MATERIALS, SETTING, METHODS: All couples with a female partner ≤42 years of age and without severe male factor (total progressive motile sperm with normal morphology >10.000) were included in the study. Exclusion criteria were: history of total fertilization failure, less than 6 cumulus oocyte complexes (COC) available for fertilization, prenatal genetic testing (PGT) cycles, unwillingness to participate and couples undergoing total cryopreservation for any indication. On the day of oocyte pick up, sibling COCs were randomly allocated to fertilization with IVF or denudation followed by ICSI to MII oocytes. The decision to transfer IVF or ICSI embryo(s) depended on embryo quality. Women receiving two embryos were given only IVF or ICSI embryos. Neither the clinician performing the transfer nor the patients were aware of the fertilization method used to generate the embryos transferred. Main outcome parameters were fertilization, clinical pregnancy, implantation and miscarriage rates. MAIN RESULTS AND THE ROLE OF CHANCE: Demographic variables, ovarian reserve and infertility etiology, duration of stimulation, total gonadotropin consumption, peak estradiol levels were similar for IVF-ET and ICSI-ET groups. Mean number of COCs (18.95 vs 19.24), number of embryos transferred (1,81 vs 1,81), the ratio of good quality embryos/total embryos (56.89 % and 55.97 %), clinical pregnancy rates (63 % vs 49 %), implantation rates (31 % vs 28 %), and abortion rates (12,5 % vs 8,1 %) were also similar. A total of 1306 COCs were allocated for IVF while 1331 COCs were denuded for ICSI. Fertilization rate per inseminated oocyte was significantly higher in ICSI group (56,20 % vs 63,78 %). There were ten cases of total fertilization failure, all in the IVF group. Although overall fertilization rate was higher for ICSI, it was similar in both groups when cases with total fertilization failure were excluded. LIMITATIONS, REASONS FOR CAUTION: The non-availability of live birth rates is a limitation. Randomization of sibling oocytes, not patients requires careful interpretation of pregnancy and implantation rates. WIDER IMPLICATIONS OF THE FINDINGS: Lower cost, ease of application and similar clinical outcome makes IVF the choice of fertilization method in non-male factor infertility cases.

Intracytoplasmic sperm injection (ICSI) for non-male factor indications: a committee opinion.

Intracytoplasmic sperm injection, while typically effective for overcoming low or absent fertilization in couples with a clear abnormality of semen parameters, is frequently used in combination with assisted reproductive technologies for other etiologies of infertility in the presence of semen parameters that meet the World Health Organization 2010 normative reference values. This committee opinion provides a critical review of the literature, where available, to identify situations where this may or may not be of benefit. This document replaces the previously published document of the same name, last published in 2012 (Fertil Steril 2012;98:1395-9).

A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens.

PURPOSE: Cystic fibrosis transmembrane conductance regulator (CFTR) and adhesion G protein-coupled receptor G2 (ADGRG2) have been identified as the main pathogenic genes in congenital bilateral absence of the vas deferens (CBAVD), which is an important cause of obstructive azoospermia. This study aimed to identify the disease-causing gene in two brothers with CBAVD from a Chinese consanguineous family and reveal the intracytoplasmic sperm injection (ICSI) outcomes in these patients. METHODS: Whole-exome sequencing and Sanger sequencing were used to identify the candidate pathogenic genes. Real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence were used to assess the expression of the mutant gene. Moreover, the ICSI results from both patients were retrospectively reviewed. RESULTS: A novel hemizygous loss-of-function mutation (c.G118T: p.Glu40*) in ADGRG2 was identified in both patients with CBAVD. This mutation is absent from the human genome databases and causes an early translational termination in the third exon of ADGRG2. Expression analyses showed that both the ADGRG2 mRNA and the corresponding protein were undetectable in the proximal epididymal tissue of ADGRG2-mutated patients. ADGRG2 expression was restricted to the apical membranes of non-ciliated epithelia in human efferent ducts, which was consistent with a previous report in mice. Both ADGRG2-mutated patients had normal spermatogenesis and had successful clinical outcomes following ICSI. CONCLUSIONS: Our study verifies the pathogenic role of ADGRG2 in X-linked CBAVD and broadens the spectrum of ADGRG2 mutations. In addition, we found positive ICSI outcomes in the two ADGRG2-mutated CBAVD patients.

The complex microbiome from native semen to embryo culture environment in human in vitro fertilization procedure.

BACKGROUND: Only a few microbial studies have conducted in IVF (in vitro fertilization), showing the high-variety bacterial contamination of IVF culture media to cause damage to or even loss of cultured oocytes and embryos. We aimed to determine the prevalence and counts of bacteria in IVF samples, and to associate them with clinical outcome. METHODS: The studied samples from 50 infertile couples included: raw (n = 48), processed (n = 49) and incubated (n = 50) sperm samples, and IVF culture media (n = 50). The full microbiome was analyzed by 454 pyrosequencing and quantitative analysis by real-time quantitative PCR. Descriptive statistics, t-, Mann-Whitney tests and Spearman's correlation were used for comparison of studied groups. RESULTS: The study involved normozoospermic men. Normal vaginal microbiota was present in 72.0% of female partners, while intermediate microbiota and bacterial vaginosis were diagnosed in 12.0 and 16.0%, respectively. The decreasing bacterial loads were found in raw (35.5%), processed (12.0%) and sperm samples used for oocyte insemination (4.0%), and in 8.0% of IVF culture media. The most abundant genera of bacteria in native semen and IVF culture media were Lactobacillus, while in other samples Alphaproteobacteria prevailed. Staphylococcus sp. was found only in semen from patients with inflammation. Phylum Bacteroidetes was in negative correlation with sperm motility and Alphaproteobacteria with high-quality IVF embryos. CONCLUSION: Our study demonstrates that IVF does not occur in a sterile environment. The prevalent bacteria include classes Bacilli in raw semen and IVF culture media, Clostridia in processed and Bacteroidia in sperm samples used for insemination. The presence of Staphylococcus sp. and Alphaproteobacteria associated with clinical outcomes, like sperm and embryo quality.

Update on advanced semen-processing technologies and their application for in vitro embryo production in horses.

The increased commercialisation of intracytoplasmic sperm injection (ICSI) in horses creates more opportunities to incorporate advanced reproductive technologies, such as sex-sorted, refrozen and lyophilised spermatozoa, into a breeding program. This paper reviews the status of these semen-handling technologies in light of their use in equine ICSI programs. Pregnancies have been achieved from each of these advanced technologies when combined with ICSI in horses, but refinements in the semen-handling processes underpinning these technologies are currently being explored to produce more reliable and practical improvements in the results from equine ICSI.

Types and frequency of non-conformances in an IVF laboratory.

STUDY QUESTION: How many non-conformances occur in an ART laboratory and how often do they occur? SUMMARY ANSWER: The limited data to date demonstrate that IVF laboratories have a very low non-conformance rate compared with reported non-conformances in other medical laboratories, especially when one considers the high-complexity of procedures performed. WHAT IS KNOWN ALREADY: ART involves a series of very complex patient and laboratory procedures. Although it is assumed that strict measures control ART laboratories, there is very little published data on non-conformances. STUDY DESIGN, SIZE, DURATION: In accordance with the ISO 9001:2008 standard, Boston IVF has created an electronic database to record non-conformances in the IVF laboratory. We reviewed the non-conformances reported between March 2003 and December 2015. The non-conformances were categorized into four grades largely based upon their impact on the outcome or continuation of an IVF treatment cycle: None/Minimal (not measurably decreasing the likelihood of success), Moderate (a negative impact but not loss of a cycle), Significant (loss of a cycle or majority of gametes or embryos) and Major (infrequent errors that have an extreme impact on a patient or patients such as a confirmed pregnancy or birth involving misidentification of sperm, egg or embryo, or an extreme equipment or documentation failure that affects numerous patients). The category of problem or error associated with the Non-conformance Report was also noted. PARTICIPANTS/MATERIALS, SETTING, METHOD: Retrospective analysis of an electronic database registering non-conformances at a large IVF laboratory. MAIN RESULTS AND THE ROLE OF CHANCE: During the study period, a total of 36 654 IVF treatment cycles (fresh and frozen embryo transfer cycles) were conducted which involved a total of 181 899 individual laboratory procedures encompassing egg retrievals, sperm preparations, inseminations, embryo transfers, etc. When combining both moderate and significant non-conformances, 99.96% of procedures and 99.77% of cycles proceeded with no non-conformances. No Major grade non-conformances were reported. LIMITATIONS, REASONS FOR CAUTION: A comparison of non-conformances between IVF clinics is difficult because of different classifications. WIDER IMPLICATIONS OF THE FINDINGS: Errors are inevitable and it is incumbent on all IVF centers to be honest and transparent, both within the organization and with patients when errors occur. Robust systems for identifying, documenting, analyzing and implementing improvements should be established and maintained. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. The authors have no conflicts of interest.

External validation of a prediction model to select the best day-three embryo for transfer in in vitro fertilization or intracytoplasmatic sperm injection procedures.

OBJECTIVE: To evaluate the multivariate embryo selection model by van Loendersloot et al. (2014) (VL) in a different geographical context. DESIGN: This is a retrospective external validation study of a 5-year cohort of women undergoing in vitro fertilization or intracytoplasmatic sperm injection. SETTING: Two outpatient fertility clinics. PATIENT(S): A total of 1,197 women who underwent 1,610 fresh in vitro fertilization or intracytoplasmatic sperm injection cycles with single embryo transfer were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The area under the receiver operating characteristics curve for diagnostic efficacy was used to assess the discriminative value of the model. Calibration for testing the validity of the VL model was performed using the Hosmer-Lemeshow goodness-of-fit test and a calibration plot. RESULT(S): Three hundred thirty-three patients (21%) achieved a viable pregnancy of at least 11 weeks. The area under the receiver operating characteristics curve using the VL model was 0.68. No significant difference between the predicted implantation rate and the observed implantation rates was showed using the Hosmer-Lemeshow (X2= 6.70). The calibration plot showed an intercept of the regression line of 0.34 and the estimated slope was 0.72. CONCLUSION: The investigated VL model was able to distinguish between higher and lower implantation potential of embryos in our clinical setting.

Hysteroscopy after repeated implantation failure of assisted reproductive technology: A meta-analysis.

We conducted this meta-analysis to explore the prognostic value of outpatient (or office) hysteroscopy (OH) preceding in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles in women who had experienced repeated implantation failure (RIF), particularly in regard to the conflicting evidence reported by previous studies. Two reviewers independently searched Pubmed, MEDLINE, Web of Science, Cochrane Library and Embase to identify all publications of clinical trials of hysteroscopy with or without endometrial biopsy in RIF patients. The primary outcome measures were clinical pregnancy rate (CPR) and live birth rate (LBR). Pooled relative ratios (RRs) with 95% confidence intervals (CIs) were calculated. Publication bias was detected using funnel plots and Egger's regression tests. Six eligible studies comprising 4143 patients were included. The CPR and LBR were both significantly higher in RIF patients with OH than RIF patients without OH (CPR: RR 1.34, 95% CI 1.14-1.57, P < 0.05; LBR: RR 1.29, 95% CI 1.03-1.62, P < 0.05). Subgroup analysis revealed a significant association between OH and CPR in Asia (CPR: RR 1.49, 95% CI 1.31-1.69; P < 0.05) rather than in Europe (CPR: RR 1.08, 95% CI 0.93-1.26; P = 0.291). However, there was no evidence of a significant difference in either CPR or LBR between the normal and abnormal OH groups (CPR: RR 0.92, 95% CI 0.83-1.02, P = 0.12; LBR: RR 0.76, 95% CI 0.37-1.56, P = 0.450). Hysteroscopy may potentially improve pregnancy outcomes in patients with RIP.

Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF/ICSI cycles.

Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a "freeze-all" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p<0.01) and progesterone levels at ovulation triggering (p = 0.01) were the only two variables that significantly predicted top quality blastocyst formation rate after adjusting for relevant factors including female age, BMI, basal AMH and total dose of FSH used for COS. More specifically, progesterone levels at induction showed an inverse relation with top quality blastocyst formation (correlation coefficient B = -1.08, 95% CI -1.9 to -0.02) and ROC curve analysis identified P level >1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p<0.01). Our study is the first to investigate the top quality blastocyst formation rate in relation to progesterone levels in IVF/ICSI cycles, showing that increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are observed. This observation extends the results of two recent studies focused on day-3 embryos and deserves further research.

Value of Post-transfer Day-12 Beta Human Chorionic Gonadotropin Levels for Pregnancy Outcome Prediction of Intracytoplasmic Sperm Injection Cycles.

BACKGROUND: Several markers were studied previously in order to predict the pregnancy outcome of assisted reproductive techniques; however, serum beta human chorionic gonadotropin was found to be the most predictive marker. AIMS: To evaluate the value of serum beta human chorionic gonadotropin levels in discriminating biochemical and clinical pregnancies 12 days after embryo transfer, while determining the factors predicting ongoing pregnancy was established as the secondary aim. STUDY DESIGN: Retrospective cross-sectional study. METHODS: A total of 445 pregnant cycles were retrospectively analysed in 2359 embryo transfer cycles. Patients were divided into two groups according to the outcome of pregnancy: biochemical and clinical. RESULTS: The cut-off value of beta human chorionic gonadotropin levels on day 12 in predicting clinical pregnancies was 86.8 IU/mL with 65.1% sensitivity and 74.7% specificity [CI: 0.76 (0.71-0.81). Receiver operating characteristic curve analysis revealed different cut-off values for embryo transfer days (57 mIU/mL for day 3 embryo transfer CI: 0.59-0.79 and 87 mIU/mL for day 5 embryo transfer, CI: 0.74-0.86). Subgroup analysis of clinical pregnancies revealed a significant difference between ongoing pregnancies and early fetal losses regarding duration of infertility (81.3±54.4 vs. 100.2±62.2 months), serum oestradiol on hCG day (2667.4±1276.4 vs. 2094.6±1260.5 pg/mL), number of transferred embryos (1.9±0.8 vs. 1.5±0.7) and the prevalence of diminished ovarian reserve as an indication (2.3% vs 12.2%). CONCLUSION: Beta human chorionic gonadotropin levels on day 12 following embryo transfer provide an important parameter for the prediction of clinical pregnancy; however, other stimulation parameters are indicated in the prediction of ongoing pregnancies.