In vitro maturation (IVM) of human immature oocytes: is it still relevant?

In vitro maturation (IVM) of human immature oocytes has been shown to be a viable option for patients at risk of ovarian hyperstimulation syndrome (OHSS), those seeking urgent fertility preservation and in circumstances where controlled ovarian stimulation is not feasible. Moreover, IVM techniques can be combined with ovarian tissue cryobanking to increase the chances of conception in cancer survivors. The clinical applications of IVM in the field of reproductive medicine are rapidly expanding and the technique is now classified as non-experimental. In contrast to conventional IVF (in vitro fertilization), IVM offers several advantages, such as reduced gonadotropin stimulation, minimal risk of ovarian hyperstimulation syndrome (OHSS), reduced treatment times and lower costs. However, the technical expertise involved in performing IVM and its lower success rates compared to traditional IVF cycles, still pose significant challenges. Despite recent advances, such as innovative biphasic IVM systems, IVM is still an evolving technique and research is ongoing to refine protocols and identify techniques to improve its efficiency and effectiveness. A comprehensive understanding of the distinct mechanisms of oocyte maturation is crucial for obtaining more viable oocytes through in vitro methods, which will in turn lead to significantly improved success rates. In this review, the present state of human IVM programs and future research directions will be discussed, aiming to promote a better understanding of IVM and identify potential strategies to improve the overall efficiency and success rates of IVM programs, which will in turn lead to better clinical outcomes.

MYO10 promotes transzonal projection-dependent germ line-somatic contact during mammalian folliculogenesis†.

Granulosa cells of growing ovarian follicles elaborate filopodia-like structures termed transzonal projections (TZPs) that supply the enclosed oocyte with factors essential for its development. Little is known, however, of the mechanisms underlying the generation of TZPs. We show in mouse and human that filopodia, defined by an actin backbone, emerge from granulosa cells in early stage primary follicles and that actin-rich TZPs become detectable as soon as a space corresponding to the zona pellucida appears. mRNA encoding Myosin10 (MYO10), a motor protein that accumulates at the base and tips of filopodia and has been implicated in their initiation and elongation, is present in granulosa cells and oocytes of growing follicles. MYO10 protein accumulates in foci located mainly between the oocyte and innermost layer of granulosa cells, where it colocalizes with actin. In both mouse and human, the number of MYO10 foci increases as oocytes grow, corresponding to the increase in the number of actin-TZPs. RNAi-mediated depletion of MYO10 in cultured mouse granulosa cell-oocyte complexes is associated with a 52% reduction in the number of MYO10 foci and a 28% reduction in the number of actin-TZPs. Moreover, incubation of cumulus-oocyte complexes in the presence of epidermal growth factor, which triggers a 93% reduction in the number of actin-TZPs, is associated with a 55% reduction in the number of MYO10 foci. These results suggest that granulosa cells possess an ability to elaborate filopodia, which when directed toward the oocyte become actin-TZPs, and that MYO10 increases the efficiency of formation or maintenance of actin-TZPs.

Is There an Association Between Sperm Parameters and Sexual Orientation? A Cross Sectional Study.

OBJECTIVE: To evaluate whether sexual orientation affects sperm parameters. METHODS: This was a cross-sectional study using existing data from an academic reproductive centre for the period of April 01, 2009, to March 31, 2021. We compared the results of sperm analysis from male patients who were in same-sex relationships (study group) with those of men in heterosexual relationships who did not have male-factor infertility (control group). A subsequently comparison of both groups with World Health Organization (WHO) reference values was also performed. RESULTS: Thirty-nine samples from the study group were compared with 494 samples from the control group. All parameters, apart from morphology, were comparable. The median sperm concentrations were 64 (interquartile range [IQR] 32.1-102.9) million/mL and 50.1 (IQR 25.3-92.5) million/mL in the study and control groups, respectively (P = 0.252), whereas the median percentage of progressive motile sperm was 50% (IQR 34-65) in the study group and 52% (IQR 33-65) in the control group (P = 0.198). The median percentage of morphologically normal sperm was higher in the control group than in the study group (6% vs. 5%; P = 0.019). However, no significant difference was found when sperm morphology was dichotomized with the cut-off of ≥4% (74.1% and 74.4%, respectively; P = 0.966). When compared with the WHO reference group, the percentage of men with total motile sperm counts ≥10 million and the percentage of men with normal morphology were significantly lower in both groups. CONCLUSION: Our study suggests that there is no relationship between sexual orientation and sperm parameters.

Among high responders, is oocyte development potential different in Rotterdam consensus PCOS vs non-PCOS patients undergoing IVF?

PURPOSE: To evaluate the oocyte potential to develop to blastocyst in Rotterdam consensus PCOS in women with hyper-responses requiring freeze-all embryos. METHODS: Retrospective, single-academic center, cohort study of 205 patients who underwent freeze-all antagonist IVF cycles for OHSS risk between 2013 and 2019. Women in the PCOS group (n = 88) were diagnosed per the 2003 Rotterdam criteria. Control patients (n = 122) had no evidence of hyperandrogenism or menstrual disturbance. Data was compared by t-tests, chi-squared tests, or multivariate logistic regression (SPSS). Frozen blastocysts were Gardner's grade BB or better. RESULTS: There was no difference in terms of number of oocytes collected (PCOS vs non-PCOS 27.7 ± 9.4 vs 25.9 ± 8.2, p = 0.157), number of MII (20.7 ± 8.0 vs 19.1 ± 6.6, p = 0.130), number of 2PN fertilized (15.6 ± 7.4 vs 14.4 ± 5.9, p = 0.220), and number of frozen blastocysts (7.8 ± 4.9 vs 7.1 ± 3.8, p = 0.272). In addition, fertilization rates (74 ± 17% vs 75 ± 17%, p = 0.730), blastulation rates per 2PN (51 ± 25% vs 51 ± 25%, p = 0.869), and blastulation rates per mature oocytes (37 ± 18% vs 37 ± 15%, p = 0.984) were all comparable between PCOS and controls, respectively. Moreover, there was no difference when comparing PCOS and controls in pregnancy rates (45/81 vs 77/122, p = 0.28) and clinical pregnancy rates (34/81 vs 54/122, p = 0.75), respectively. Multivariate logistic regression controlling for confounders failed to alter these results. CONCLUSION: PCOS subjects do not seem to have altered oocyte potential as measured by number of MII oocytes collected, fertilization, and blastulation rates when compared to high-responder controls, with similar magnitude of stimulation.

The biochemical pregnancy loss rate remains stable up irrespective of age and differs in pattern from clinical miscarriages.

INTRODUCTION: As women age, the increasing rate of aneuploidy lead to an augmentation in the incidence of clinical miscarriages. It was anticipated that biochemical pregnancy rates would also rise with maternal age. However, no study has previously evaluated the effect of maternal age on biochemical pregnancy rates. MATERIAL AND METHODS: A retrospective cohort study of 2177 subjects who underwent single embryo transfer (SET) as part of a fresh or thawed IVF cycle were recruited from 2008 through 2012, resulting in 952 pregnancies. Data was stratified for age and compared using analysis of variance (continuous data) and chi-squared tests (categorical data). RESULTS: The likelihood of a clinical miscarriage increased with age (p < .001). Surprisingly, advancing age had no effect on the biochemical pregnancy loss rate (p = .72) (Age 21-30 y: 10.7%, Age 31-35 y:9.8%, Age 36-40y:11.5%, Age 41-42 y:13.6%). CONCLUSIONS: Biochemical pregnancy loss rate did not increase as a function of age in women 21 to 42 years of age.

Hope for male fecundity: clinically insignificant changes in semen parameters over 10 years at a single clinic while assessing an infertility population.

PURPOSE: What is the trend in sperm parameters in a group of men attending a single reproductive center, over a 10-year period? METHODS: A retrospective study was conducted on 12,188 semen samples obtained from unique individuals who attended a university reproductive clinic from 2009 to 2018, inclusively. Semen analysis was done using computer-assisted sperm analysis and verified by an andrologist. Analysis was done after dividing the dataset into two groups: above WHO 2010 lower reference limits (ARL) (N = 6325) and below the reference limits (BRL) (N = 5521). RESULTS: Volume increased slightly (ARL, p = 0.049) before returning to baseline or was stable (BRL, p = 0.59). Sperm concentration and total count of the BRL and ARL group declined initially and then recovered slightly (p < 0.0001, in all cases). Although these changes were statistically significant, this was due to the large study population; clinically, these changes were quite mild and would not have been significant for fertility. Sperm total motility and progressive motility of both the BRL group and the ARL group increased slightly from 2009 until 2015 and then decreased back to baseline (p < 0.0001). This change offset the decrease in count seen in those years. A spurious change was observed with sperm morphology that declined after the first 2 years and remained stable thereafter (p < 0.0001, in both groups). However, this change was attributed to a contemporaneous change in the method of analyzing strict morphology which happened when the change occurred. CONCLUSION: While statistically significant changes were found, clinically, these changes were quite mild and would not have been significant for fertility.

An age-based sperm nomogram: the McGill reference guide.

STUDY QUESTION: How does age affect various semen parameters? SUMMARY ANSWER: For most semen parameters, the nomogram of the entire population was biphasic, peaking around the fourth decade of life. WHAT IS KNOWN ALREADY: In clinical practice, semen quality is examined by using the WHO 2010 reference limits but these limits do not account for male age. A percentile-based, large-scale nomogram describing how different semen parameters change throughout reproductive life has been lacking. STUDY DESIGN, SIZE, DURATION: A retrospective study was conducted with 12 188 sperm samples, obtained from individuals who attended the McGill University Health Centre reproductive clinic between 2009 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: One sample from each individual who attended the clinic during the study period was analysed by using computer-assisted sperm analysis (CASA). The analysed parameters were human-verified and included sperm concentration, motility, progressive motility, total count, morphology and semen volume. Based on this analysis, the entire dataset (n = 12 188) was further divided into two groups of samples: samples that surpassed the WHO 2010 lower reference limits ('above reference limits' group, ARL; n = 6305), and samples that did not ('below reference limit' group, BRL; n = 5883). Regression quantiles were fitted as a function of age to generate age-dependent nomograms, and these quantiles were divided into 5th, 25th, 50th, 75th and 95th percentiles. MAIN RESULTS AND THE ROLE OF CHANCE: In the entire dataset, age had a significant influence (P < 0.001) on all parameters (except morphology) which demonstrated a biphasic trend peaking in the fourth decade of life. In the ARL group, age had a significant influence (P < 0.01) on all semen parameters except sperm concentration and morphology. However, unlike in the entire dataset, only semen volume demonstrated a biphasic trend in the ARL group (peaking in the fourth decade of life), whereas other parameters either remained unchanged (concentration and morphology) or consistently declined with age (sperm motility, progressive motility and total sperm count). Percentile-based nomograms were generated for individuals between the ages of 20 and 60 years in the entire dataset and in the ARL group. LIMITATIONS, REASONS FOR CAUTION: First, the semen samples were obtained from individuals who were referred to a fertility clinic, such that the entire dataset does not necessarily represent the general population. Second, the cross-sectional sampling design increases variance, and the nomograms are less accurate in the 5th and 95th percentiles and at the extremes of the age distributions. Third, the observed age-dependent changes in semen parameters do not necessarily indicate changes in fertility, as not all factors that affect male fertility were analysed. Fourth, some of our semen analyses employed CASA, which can have variability issues. Finally, our models did not incorporate possible secular trends. WIDER IMPLICATIONS OF THE FINDINGS: We provide the first nomogram that correlates age with semen quality parameters in different population percentiles, thus complementing the current reference limits set by the WHO in 2010. Most examined semen parameters in our study changed non-linearly with age; therefore, age should be regularly employed as a factor in the clinical analysis of semen samples. STUDY FUNDING/COMPETING INTEREST(S): The authors have not received any funding to support this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Influence of stage and grade of breast cancer on fertility preservation outcome in reproductive-aged women.

RESEARCH QUESTION: Does breast cancer spread and aggressiveness affect fertility-preservation results? DESIGN: Retrospective cohort study of women with breast cancer undergoing fertility-preservation treatment. INCLUSION CRITERIA: age 18-38 years and use of gonadotrophin releasing hormone antagonist protocol; exclusion criteria: recurrent cancer, previous oncological treatment, previous ovarian surgery and known ovarian pathology. Stimulation cycle outcomes of women with low-stage breast cancer were compared with those with high-stage disease. Patients with low-grade (G1-2) were compared with those with high-grade (G3) malignancies. PRIMARY OUTCOME: total number of mature oocytes; secondary outcomes: oestradiol level and number of follicles wider than 14 mm on the day of trigger, number of retrieved oocytes and cryopreserved embryos. RESULTS: The final analysis included 155 patients. Patients with high-grade tumours (n = 80; age 32 years [28-35]) had significantly lower number of mature oocytes compared with patients with low-grade cancer (n = 75; age 32 years [28-35]; seven mature oocytes [4-10] versus 13 mature oocytes [7-17]; P = 0.0002). The number of cryopreserved embryos was also lower in the high-grade group (three [2-5] versus five [3-9]; P = 0.02). Stage-based analysis revealed a similar number of mature oocytes in high-stage (n = 73; age 32 years [28-35]) compared with low-stage group (n = 82; age 33 years [28-35]; eight mature oocytes [4-13] versus nine mature oocytes [7-15]; P = 0.06). CONCLUSIONS: High-grade breast cancer has a negative effect on total number of mature oocytes and cryopreserved embryos.

A comparison of IVF outcomes transferring a single ideal blastocyst in women with polycystic ovary syndrome and normal ovulatory controls.

PURPOSE: To assess the effects PCOS on live birth rates when transferring a single fresh ideal blastocyst. METHODS: A retrospective cohort study performed at the university-affiliated reproductive center. Women with PCOS and a control group of normal ovulatory women who underwent their first fresh embryo transfer with single ideal grade blastocyst were included in the study. Demographic, stimulation information and pregnancy outcomes were collected and analysed. The primary outcome was live birth rates, and secondary outcomes included pregnancy and clinical pregnancy rates. RESULTS: 71 Women with PCOS and 272 normal ovulatory controls underwent their first embryo transfer and met the inclusion and exclusion criteria. PCOS patient were younger (31.0 ± 3.7 vs. 33.1 ± 3.2, p = 0.0001), with higher AFC (40.0 ± 9.3 vs. 13.3 ± 4.6, p = 0.0001), required lower dose of gonadotropins to stimulate (1198 ± 786 vs. 1891 ± 1224, p = 0.0001), and had higher serum testosterone levels (2.3 ± 0.7 vs. 1.1 ± 0.3, p = 0.0001). No significant difference was found between the two groups regarding the number of previous pregnancies, the number of previous full-term pregnancies, the level of basal serum FSH, estradiol level at triggering and the BMI. When compared by Chi squared testing pregnancy rates, clinical pregnancy rates and live birth rates did not differ. However, when controlling (with multivariate stepwise logistic regression) for confounders, live birth rates were lower among the women with PCOS (p = 0.035, CI: 0.18-0.92). CONCLUSION: After controlling for confounders, when transferring a fresh single ideal blastocyst, live birth rates were lower among the women with PCOS than normal ovulatory controls.

Effects of cancer stage and grade on fertility preservation outcome and ovarian stimulation response.

STUDY QUESTION: Do the stage and grade of malignancy affect the fertility preservation outcome in females? SUMMARY ANSWER: Patients with high-grade cancer have a decreased number of retrieved mature oocytes and cryopreserved embryos. WHAT IS KNOWN ALREADY: Cancer has local and systemic effects on the host. The effects of cancer spread and aggressiveness on the ovarian function and stimulation response remain unclear. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study evaluating data of all fertility preservation treatment cycles among women with cancer at the reproductive unit of the McGill University Health Centre in the period from 2008 to 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study inclusion criteria were age 18-38 years, first stimulation cycle, GnRH-antagonist protocol and early follicular phase stimulation start. Only one stimulation cycle per patient was included. Patients with ovarian pathology, previous ovarian surgery and previous chemo- or radiotherapy were excluded. The outcomes of women with low-stage cancer (local tumor Stage I-II, no lymph node involvement, no metastases) were compared with those with high-stage disease (local tumor Stage III-IV, lymph node involvement or metastases). Similarly we compared those with low-grade (G1-2) and high-grade (G3-4) malignancies. The primary outcome measure was the number of mature oocytes retrieved. The secondary outcomes included the total number of retrieved oocytes, the number of vitrified oocytes, and the number of frozen embryos. We used Student's t-test for normally distributed data and Wilcoxon test for skewed data. To determine factors associated with good fertility preservation outcome defined as over 10 retrieved mature oocytes, we used multivariate logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 147 patients were included in the final analysis. Age, body mass index, ovarian reserve parameters of the study groups in stage- and grade-based analyses were similar. Compared to women with low-stage cancer (n = 83), those with high-stage cancer (n = 64) required a higher dose of gonadotropin (P = 0.02). The number of retrieved mature oocytes (9 (7-13) versus 8 (5-12); P = 0.37) and vitrified oocytes (10 (7-15) versus 10 (7-13); P = 0.53) were similar between the two groups. However, in cycles where fertilization of all retrieved oocytes was performed, the fertilization rate (82.7% versus 71.5%; P = 0.03) and the number of vitrified embryos (6.2 ± 3.2 versus 4.3 ± 2.1; P = 0.01) were higher in the low-stage group. Compared to patients with low-grade cancer (n = 62), those with high-grade disease (n = 85) had significantly lower number of retrieved mature oocytes (11 (7-15) versus 8 (5-11); P = 0.002) and vitrified oocytes (12 (8-15) versus 10 (7-11); P = 0.005). The number of vitrified embryos was lower in high-grade group (6.5 ± 3.5 versus 4.6 ± 2.3; P = 0.03) in cycles where the fertilization was performed. In multivariate logistical analysis, the low-grade cancer was significantly associated with retrieval of over 10 mature oocytes (OR = 4.26; 95% CI 1.82-9.98; P = 0.0009). LIMITATIONS, REASONS FOR CAUTION: The main limitations of the study include its retrospective design and the relatively small sample size in the embryological outcome analysis. The results of our study should be viewed with caution as different malignancy types were included in the study groups, although their distribution between the study groups was similar. WIDER IMPLICATIONS OF THE FINDINGS: Cancer grade seems to have a negative impact on the fertility preservation outcome and the ovarian stimulation response. STUDY FUNDING/COMPETING INTEREST(S): Authors have not received any funding to support this study. There are no conflicts of interest to declare.

Fresh transfer of Day 5 slow-growing embryos versus deferred transfer of vitrified, fully expanded Day 6 blastocysts: which is the optimal approach?

STUDY QUESTION: In IVF cycles in which the entire embryo cohort is slow growing, is it optimal to perform fresh transfer in Day 5 or to extend the culture and transfer in subsequent vitrified-warmed cycles? SUMMARY ANSWER: The outcomes depend on the degree of embryo development on Day 5. WHAT IS KNOWN ALREADY: Slow-growing blastocysts have lower implantation potential when transferred in fresh cycles. It has been suggested that embryo-endometrial asynchrony could explain this finding. However, studies that compared Days 5 and 6 embryos in frozen embryo transfer (FET) cycles showed contradictory results. There is still a lack of evidence regarding the best approach, performing fresh transfer or deferring transfer and continuing culture until fully developed blastocysts are achieved, when the entire cohort of embryos is slow growing. STUDY DESIGN SIZE, DURATION: This was a retrospective study that included 477 women aged <40 years who underwent fresh Day 5 single embryo transfer of slow-growing embryos and subsequent FET cycles of fully expanded blastocysts (FEB) originating from the same IVF cycle between 2012 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included cycles in which the embryos either began blastulation by Day 5 of culture but did not reach the fully expanded stage (Gardner Stage III) or had delayed blastulation with only morula embryos present by Day 5 of culture. All of the subjects in the study underwent elective, single embryo transfer (slow or delayed blastocysts) on Day 5 and had at least one embryo that developed into a FEB on extended culture Day 6 that was suitable for vitrification. All subjects, regardless of the outcome of the fresh transfer, returned for at least one subsequent FET cycle of Day 6 embryos. MAIN RESULTS AND ROLE OF CHANCE: A total of 1070 embryo transfer cycles (fresh + FET) were included. Of them, 365 women had elective, fresh, single transfer of slow-growing blastocysts (Group I) and 112 had elective, fresh, single morula transfer (Group II). Groups I and II underwent a subsequent 457 and 136 FET cycles, respectively. The mean age of Group I was 33.8 ± 2.9 years, the proportion of Day 5 embryos that developed to FEB by Day 6 was 92%, and the number of blastocysts vitrified was 627 (average of 1.71 blastocysts per cycle). The outcomes of fresh and FET cycles were comparable regarding clinical pregnancy rate (CPR) (31.0 vs. 30.4%, P = 0.86) and live birth rate (LBR) (23.3 vs. 20.3%, P = 0.15). In Group II, the mean age was 35.8 ± 3.4 years and the proportion of morula embryos that developed to FEB by Day 6 was 72%. The number of blastocysts vitrified on Day 6 was 155 (1.38 per cycle). The transfer of fresh embryos in Group II resulted in significantly lower clinical pregnancy (5.3 vs. 30.1%, P < 0.001) and LBRs (1.8 vs. 20.5%, P < 0.001). The results did not change after controlling for possible confounding factors. LIMITATIONS AND REASONS FOR CAUTION: The retrospective design of the study is a major limitation. Although we compared the outcomes of embryos that originated from the same cohort, the FET cycles could have been overrepresented by older patients and those with poorer prognoses. Furthermore, the study included only cycles in which there were blastocysts available for cryopreservation on Day 6; therefore, the results were not be applicable for those who had mandatory Day 5 transfer with no embryos available for vitrification. WIDER IMPLICATIONS OF THE FINDINGS: Fresh transfer of embryos that begin blastulation on Day 5 results in similar outcomes to the transfer of FEB originating from the same cohort. However, in cases where only morula/compacting embryos are available by Day 5, extending culture until FEB are achieved and then performing subsequent FET will result in significantly higher LBRs. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

A comparison of two months pretreatment with GnRH agonists with or without an aromatase inhibitor in women with ultrasound-diagnosed ovarian endometriomas undergoing IVF.

RESEARCH QUESTION: Does the addition of an aromatase inhibitor improve IVF outcomes in women with endometriomas when pretreating them with gonadotrophin-releasing hormone agonists? DESIGN: Retrospective two-centre cohort study involving 126 women aged 21-39 years who failed a previous IVF cycle and all subsequent embryo transfers and had sonographic evidence of endometriomas. Women were non-randomly assigned to either 3.75 mg intramuscular depo-leuprolide treatment alone or in combination with 5 mg of oral letrozole daily for 60 days prior to undergoing a fresh IVF cycle. Main outcome measures included clinical pregnancy rate and ongoing pregnancy rate after 24 weeks' gestation. RESULTS: Prior to treatment, antral follicle count (AFC), basal serum FSH and endometrioma diameter did not differ between groups. After treatment, AFC differed between letrozole and non-letrozole-treated groups (10.3 ± 2.0 versus 6.4 ± 2.5; P = 0.0001), as did mean endometrioma maximum diameter (1.8 ± 0.4 cm versus 3.2 ± 0.8 cm; P = 0.0001). At IVF, the gonadotrophin dose used was significantly lower in letrozole-treated subjects (2079 ± 1119 versus 3716 ± 1314; P = 0.0001), the number of mature oocytes collected was greater (9.1 ± 2.4 versus 4.0 ± 1.7; P = 0.0001), as were the number of two-pronuclear embryos and number of blastocysts. The clinical pregnancy rate was significantly higher in the letrozole-treated group (50% versus 22%, P = 0.003), as was the live birth rate (40% versus 17%, P = 0.008). CONCLUSIONS: The combination of depo-leuprolide acetate monthly for 60 days combined with daily letrozole has better clinical outcomes at IVF in women with endometriomas than depo-leuprolide acetate treatment alone.

Use of cabergoline and post-collection GnRH antagonist administration for prevention of ovarian hyperstimulation syndrome.

RESEARCH QUESTION: Does the addition of a gonadotrophin-releasing hormone (GnRH) antagonist to cabergoline treatment during the luteal phase in fresh IVF cycles triggered with a GnRH agonist, and planned for freeze-all, reduce the rate of mild and moderate ovarian hyperstimulation syndrome (OHSS)? DESIGN: Retrospective cohort study of 480 IVF patients at risk for OHSS with GnRH agonist trigger from 2011 to 2018, stratified into three groups based on treatment received: GnRH agonist trigger alone (Group 1, n = 208), GnRH agonist trigger + cabergoline (Group 2, n = 167) or GnRH agonist trigger + cabergoline + GnRH antagonist (Group 3, n = 105). Data on patient demographics, incidence, severity and symptomatology of OHSS and laboratory findings were collected. RESULTS: Group 1 had more free peritoneal fluid than Group 2 (28% versus 19%, P = 0.04) or Group 3 (28% versus 5%, P = 0.001). Group 1 reported abdominal discomfort and bloating more than Group 2 (33% versus 21%, P = 0.01) or Group 3 (33% versus 18%, P = 0.006). Group 1 had more electrolyte abnormalities than Group 2, who had more than Group 3. No patients developed severe OHSS. Mild and moderate OHSS rate was higher in Group 1 (38%) than Group 2 (29%, P = 0.048) or Group 3 (18%, P = 0.006) and in Group 2 than Group 3 (P = 0.046). CONCLUSION: Addition of cabergoline to GnRH agonist triggering in high-risk OHSS patients, and subsequent addition of GnRH antagonist for 5 days in the luteal phase, sequentially reduces the risk of mild and moderate OHSS and improves patient comfort compared with GnRH agonist trigger alone.

Revisiting serum ß-hCG cut-off levels and pregnancy outcomes using single embryo transfer.

PURPOSE: The objective of this study is to identify the pregnancy outcomes based on day-16 ß-hCG level assessed with modern assays, in fresh single embryo transfers. METHODS: A retrospective cohort study at a single academic center between 2013 and 2017. A total of 1076 pregnancies were included. RESULTS: Pregnancies were divided into 10% groupings of 107-108 patients each. The 10 groups did not differ for baseline characteristics. There was no difference on outcomes based on cleavage or blastocyst transfer. At a serum ß-hCG level of 103 ± 13 (range 74-135), 50% had a biochemical loss. Biochemical pregnancy losses remained 21% at serum ß-hCG range (136-197). It was only once serum ß-hCG level reached 199-252 that the probability of a biochemical pregnancy loss was 12%. Interestingly, if a clinical pregnancy is present even at low day-16 serum ß-hCG levels, the likelihood of live birth is approximately 50%. This maximizes to 75% when the serum ß-hCG level was at least 253 IU/L. The relationship between serum day-16 ß-hCG levels and clinical pregnancy or live birth is quite strong with correlation coefficients above 0.8 which accounted for more than 75% of the variability in outcomes in both cases. Receiver operator curves determined that the cut-off for a clinical pregnancy was 190 and for live birth, it was 213 IU/L. CONCLUSION: An increase in the serum ß-hCG levels at which to expect a reassuring outcome is required based on modern assays, as compared with the old cut-off levels.

When to do intracytoplasmic sperm injection: a prospective comparison.

PURPOSE: The purpose of the study was to assess the fertilization rate and embryo development in sibling human oocytes after split insemination in patients with and without isolated teratozoospermia. METHODS: A prospective cohort study at a university affiliated reproduction center was performed. Hundred and three patients during the time periods 01-2013 to 12-2015 had split insemination ordered for their first IVF cycle. The primary outcome measured was fertilization rate. Secondary outcomes were the number and quality of embryos. RESULTS: Mature oocytes at the time of collection were assigned as follows: 558 to IVF and 556 to ICSI. An additional 48 immature oocytes matured while awaiting spontaneous fertilization with IVF for a total of 606 in that group. The study group of normal strict sperm morphology ≤ 4 included 61 patients, and the control group included 42 patients with normal strict sperm morphology > 4. ICSI was statistically favored over IVF only in cases with normal strict sperm morphology ≤ 4%. There was a higher fertilization rate in ICSI compared to IVF (74.4% vs. 38%, p < 0.0001), a higher number of day 2 (4 ± 3.4 vs. 2.4 ± 2.7, p < 0.0001), day 3 (4 ± 3.4 vs. 2.2 ± 2.7, p < 0.0001) and day 5 embryos (2.2 ± 2.6 vs. 1.2 ± 2, p = 0.001), and they were of better quality; however, it did not reach significance (p = 0.062). A similar advantage for ICSI was seen in a subgroup of unexplained infertility with normal strict sperm morphology > 4%. CONCLUSIONS: In conclusion, in couples with normal strict sperm morphology ≤ 4%, there is an advantage of ICSI over IVF in terms of fertilization rate, quantity and quality of cleavage stage embryos and blastocysts. Based on the results, ICSI seems reasonable as a first-line treatment in patients with normal strict sperm morphology ≤ 4%, as well as in patients with unexplained infertility.

Poor ovarian response as a predictor for live birth in older women undergoing IVF.

Women of advanced age present a major challenge for fertility treatments. This study was designed to assess whether poor ovarian response (POR) according to the Bologna criteria is a significant predictor for live birth in women over 40. The outcomes of subsequent IVF cycles were also studied. The results of 1870 fresh IVF cycles in 1212 women were retrospectively analysed. The live birth per cycle was 3.3 times higher (11.61% versus 3.54%, P < 0.001) in good responders with more than three oocytes collected compared with women with less. Ovarian response defined by oocytes collected, but not by the number of follicles, was independently associated with live birth (odds ratio, 2.0; 95% confidence interval, 1.18 to 3.54; P = 0.009). The occurrence of POR in subsequent IVF cycles was only 55%. No differences in live births were found in persistent POR compared with women with at least one good response. A single episode of POR in a first IVF cycle in older women has a limited predictive value for the outcomes of subsequent cycles. POR in women aged 40-43 years, defined by the number of oocytes retrieved, is a predictor for live birth in IVF.

The Effect of Intramural Myomas Without an Intracavity Component on In Vitro Fertilization Outcomes in Single Fresh Blastocyst Transfer Cycles.

STUDY OBJECTIVE: To assess clinical pregnancy rate (CPR) and live birth rate (LBR) in the presence of non-cavity-deforming intramural myomas in single fresh blastocyst transfer cycles. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Academic fertility center. PATIENTS: A total of 929 fresh single blastocyst transfer cycles were included, 94 with only non-cavity-distorting intramural myomas and 764 without myomas. Cleavage embryo transfers were excluded to reduce bias based on embryo quality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: CPR and LBR were assessed. There were no differences noted in gravidity, parity, or body mass index between patients with myomas and those without myomas. Women with myomas required higher doses of gonadotropins (mean, 2653 ± 404 IU vs 2350 ± 1368 IU; p = .04) than women without myomas. However, the total number of mature oocytes collected and the total number of blastocysts created were similar. CPR (47% vs 32%; p = .005) and LBR (37.8% vs 25.5%; p = .02) were lower in patients who had intramural myomas compared with those without myomas. CPR and LBR were significantly reduced in the presence of even 1 myoma (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33-0.83 and OR, 0.56; 95% CI, 0.35-0.92, respectively). In patients with myomas >1.5 cm, LBR was also significantly reduced, even after adjusting for age, smoking, quality of embryo transferred, antral follicle count, and dose of gonadotropins (OR, 0.53; 95% CI, 0.29-0.97). This LBR finding was not significant if all myomas were included (including those <1.5 cm in diameter), but CPR was still significantly reduced. CONCLUSION: Relatively small (>1.5 cm) non-cavity-distorting intramural myomas negatively affect CPR and LBR in in vitro fertilization cycles, even in the presence of only 1 myoma.

Thirteen years' experience in fertility preservation for cancer patients after in vitro fertilization and in vitro maturation treatments.

PURPOSE: This study aims to describe the experience and outcomes of in vitro maturation without ovarian stimulation (IVM-FP) and conventional in vitro fertilization after ovarian stimulation (IVF-FP) in a fertility preservation (FP) program for women with cancer. METHODS: Retrospective cohort study from 2003 to 2015 was conducted. The study population consisted of 353 women with cancer who underwent 394 FP cycles (187 IVF-FP cycles and 207 IVM-FP) for oocytes and/or embryos cryopreservation. RESULT(S): Comparatively with IVM-FP, IVF-FP had a higher median [25th-75th percentile] number of oocytes collected-12 [8-18] vs 7 [5-13]; oocytes cryopreserved-10 [6-15] vs 5 [2-8]; and, where applicable, embryos cryopreserved-5 [3-7] vs 3 [2-5] (p < 0.000001). Following FP treatment, 32 patients (9.0%) died, 18 patients (5.6%) conceived spontaneously, and 23 patients (6.5%) returned to attempt pregnancy with a median lapse of returning of 4.6 [3.1-6.1] years. Of these, cryopreserved oocytes or embryos were used in 33 cycles (19 after IVF-FP and 14 after IVM-FP). Overall, the cumulative pregnancy rate (CPR) was 47.6% (10/21) and the live birth rate (LBR) was 38.1% (8/21). Per cycle, CPR and LBR were 37 and 31% following IVF-FP and 14 and 7% following IVM-FP, although these differences did not reach statistical significance. We report the fourth live birth after IVM-FP in cancer, and the first one after IVM embryo warming resulting from in vivo oocyte retrieval and IVM procedure. CONCLUSION(S): Both IVF-FP and IVM-FP are possible options for FP women with cancer. Due to minimal data regarding ultimate outcomes, further follow-up is needed.

The influence of body mass index on pregnancy outcome following single-embryo transfer.

PURPOSE: The association between obesity and reproductive outcome is controversial. The aim of this study is to evaluate the effects of obesity on clinical pregnancy rates following transfer of a single fresh embryo. METHODS: A retrospective cohort study was conducted at a single tertiary medical center, including all first, fresh, single-embryo transfers using non-donor oocytes, during 2008-2013. We compared clinical pregnancy rate and pregnancy outcomes of singleton live births resulting from the transfer of a single fresh embryo in normal weight, overweight, and obese women, defined as body mass index (BMI) < 25 kg/m2, ≥ 25 BMI <30 kg/m2, and BMI ≥ 30 kg/m2, respectively. RESULTS: Overall, 1345 cases met the inclusion criteria with 864 single-embryo transfers (SETs) in normal weight women, 292 in overweight women, and 189 SETs in obese women, resulting in 538 clinical pregnancies and 354 singleton births. The clinical pregnancy rate per transfer was similar among the three groups (41.3, 37.6, 37.5%, respectively, p = 0.416). Similarly, there were no significant differences in live births or ongoing pregnancies. On multivariate logistic regression analysis, BMI did not impact the likelihood for clinical pregnancy (OR 0.98, 95% CI 0.96-1.008, p = 0.216). CONCLUSIONS: Our study demonstrated that obesity has no detrimental effect on the clinical pregnancy rate resulting from the transfer of a single fresh embryo.

Decreased pregnancy and live birth rates after vitrification of in vitro matured oocytes.

PURPOSE: To assess effects on fertilization rate, embryo quality, pregnancy, and live birth rates of vitrification and warming of oocytes that matured in vitro (vIVM) compared to fresh in vitro maturation (fIVM) cycles. METHODS: A retrospective cohort study conducted at a university hospital-affiliated IVF unit. Fifty-six cycles of vIVM cycles and 263 fIVM in women diagnosed with polycystic ovarian syndrome (PCOS) ovaries were included in the analysis. The study group included PCOS patients who failed ovulation induction with intrauterine insemination and were offered IVM cycle followed by oocyte vitrification and warming. The embryological aspects and clinical outcomes were compared to those of controls undergoing fresh IVM cycles during the same period. The main outcome measure was live birth rate. RESULTS: One thousand seventy oocytes were collected from 56 patients and underwent vitrification and warming. In the control group, 4781 oocytes were collected from 219 patients who had undergone a fresh IVM cycle. Oocyte maturation rates were similar between the groups (mean ± SD: 0.7 ± 0.2 vs. 0.6 ± 0.2, for vIVM and fIVM, respectively). Survival rate after warming was 59.8%. Fertilization and embryo cleavage rates per oocyte were significantly lower in the vIVM group. Clinical pregnancy (10.7 vs. 36.1%) and live birth rates (8.9 vs. 25.9%) per cycle were significantly lower in the vIVM group than those in the fIVM group (P = 0.005 and P < 0.001, respectively). Five healthy babies were born in the vIVM group. CONCLUSIONS: The reproductive potential of vitrified IVM oocytes is impaired. This injury likely occurs through vitrification and warming.