Quantifying the association of sperm DNA fragmentation with assisted reproductive technology outcomes: An umbrella review.

BACKGROUND: Systematic reviews and meta-analyses are instrumental in shaping clinical practice. However, their findings can sometimes be marred by discrepancies and potential biases, thereby diluting the strength of the evidence presented. Umbrella reviews serve to comprehensively assess and synthesise these reviews, offering a clearer insight into the quality of the evidence presented. In the context of the relationship between sperm DNA fragmentation (SDF) and assisted conception outcomes, there is a divergence in the literature. Some reviews suggest a clear cause-and-effect linkage, whereas others present conflicting or inconclusive results. OBJECTIVES: In this umbrella review we aimed to synthesise the evidence collated in systematic reviews and meta-analyses summarising the association of SDF with assisted reproductive technology (ART) outcomes. SEARCH STRATEGY: After preregistration (https://doi.org/10.17605/OSF.IO/6JHDP), we performed a comprehensive search of the PubMed, Scopus, Cochrane Library, Web of Science and Embase databases. We conducted a search for systematic reviews on the association between SDF and ART without any restrictions on language or publication date. SELECTION CRITERIA: Systematic reviews and meta-analyses assessing the association between SDF and ART outcomes were eligible. DATA COLLECTION AND ANALYSIS: We assessed the quality of the included reviews using AMSTAR 2 and ROBIS, and determined the degree of overlap of primary studies between reviews estimating the corrected covered area (CCA), adjusted for structural missingness. We evaluated the most recent reviews assessing the association of SDF with live birth, pregnancy, miscarriage, implantation, blastulation and fertilisation. The synthesis of evidence was harmonised across all included quantitative syntheses, re-estimating the odds ratio (eOR) in random-effects meta-analyses with 95% confidence intervals (95% CIs) and 95% prediction intervals (95% PIs). We categorised the evidence strength into convincing, highly suggestive, suggestive, weak or nonsignificant, according to the meta-analysis re-estimated P-value, total sample size, I2 statistic for heterogeneity, small study effect, excess significance bias and the largest study significance. MAIN RESULTS: We initially captured and screened 49 332 records. After excluding duplicate and ineligible articles, 22 systematic reviews, 15 of which were meta-analyses, were selected. The 22 reviews showed a moderate degree of overlap (adjusted CCA 9.2%) in their included studies (overall n = 428, with 180 unique studies). The 15 meta-analyses exhibited a high degree of overlap (adjusted CCA = 13.6%) in their included studies (overall n = 274, with 118 unique studies). AMSTAR 2 categorised the quality of evidence in 18 reviews as critically low and the quality of evidence in four reviews as low. ROBIS categorised all the reviews as having a high risk of bias. The re-estimated results showed that the association of SDF with live birth was weak in one and nonsignificant in four meta-analyses. Similarly, the association of SDF with pregnancy, miscarriage, implantation, blastulation and fertilisation was also weak or nonsignificant. The association of high SDF with different ART outcomes was also weak or nonsignificant for different interventions (IVF, ICSI and IUI) and tests. CONCLUSIONS: This umbrella review did not find convincing or suggestive evidence linking SDF with ART outcomes. Caution should be exercised in making any claims, policies or recommendations concerning SDF.

Autophagy-related gene and protein expressions during blastocyst development.

PURPOSE: This study aims to examine the expression of autophagic genes and proteins during blastocyst development and differentiation. METHODS: This is a prospective cohort study. Between March 2018 and November 2019, 30 females aged 30.13 ± 4.83 years underwent an intracytoplasmic sperm injection (ICSI) cycle at Madina Fertility Center. ICSI was used to develop and incubate 82 leftover embryos to day 5. Then, the embryos were divided into two groups based on their developmental structure: group D (n = 49) included embryos that developed into blastocysts, whereas group A (n = 33) included arrested embryos. These embryos were used to investigate the autophagic gene and protein expressions. The current study was approved by the Clinical Trial Ethical Committee of the Faculty of Medicine, Alexandria University, following the ethical standards of scientific research (Registration no. 0303721). RESULTS: Embryos that developed into blastocysts on day 5 (group D) had significantly higher relative expression of the LC3 gene (1.11 ± 0.52) and beclin-1 gene (1.43 ± 0.34) and beclin-1 protein expression (3.8 ± 0.028) than those that did not develop into blastocysts on day 5 (group A) [0.72 ± 0.18 (P = 0.03), 0.35 ± 0.12 (P = 0.0001), and 3.14 ± 0.05, (P = 0.0001), respectively]. In contrast, mTOR and PIK3C3 protein expression was significantly higher in group A (arrested embryos) than those in group D (developed embryos) (P = 0.007 and P = 0.0001, respectively). Furthermore, the expression of the eIF4E gene was significantly lower in group D embryos (0.32 ± 0.07) than that in group A embryos (4.38 ± 1.16) (P = 0.0001). CONCLUSIONS: This work identifies  autophagy as a well regulated process required to maintain cell allocation and differentiation during late preimplantation embryo developmental stages.

Consecutive versus concomitant follicle-stimulating hormone and highly purified human menopausal gonadotropin: A milder response but better quality.

OBJECTIVE: This study investigated the impact of two stimulation protocols using highly purified human menopausal gonadotropin (HP-hMG) on the endocrine profile, follicular fluid soluble Fas levels, and outcomes of intracytoplasmic sperm injection (ICSI) cycles. METHODS: This prospective clinical trial included 100 normal-responder women undergoing ovarian stimulation for ICSI; 55 patients received concomitant follicle-stimulating hormone (FSH) plus HP-hMG from the start of stimulation, while 45 patients received FSH followed by HP-hMG during mid/late follicular stimulation. The primary outcome was the number of top-quality embryos. The secondary outcomes were the number and percentage of metaphase II (MII) oocytes and the clinical pregnancy rate. RESULTS: The number of MII oocytes was significantly higher in the concomitant protocol (median, 13.0; interquartile range [IQR], 8.5-18.0 vs. 9.0 [8.0-13.0] in the consecutive protocol; p=0.009); however, the percentage of MII oocytes and the fertilization rate were significantly higher in the consecutive protocol (median, 90.91; IQR, 80.0-100.0 vs. 83.33 [75.0-93.8]; p=0.034 and median, 86.67; IQR, 76.9-100.0 vs. 77.78 [66.7-89.9]; p=0.028, respectively). No significant between-group differences were found in top-quality embryos (p=0.693) or the clinical pregnancy rate (65.9% vs. 61.8% in the consecutive vs. concomitant protocol, respectively). The median follicular fluid soluble Fas antigen level was significantly higher in the concomitant protocol (9,731.0 pg/mL; IQR, 6,004.5-10,807.6 vs. 6,350.2 pg/mL; IQR, 4,382.4-9,418.4; p=0.021). CONCLUSION: Personalized controlled ovarian stimulation using HP-hMG during the late follicular phase led to a significantly lower response, but did not affect the quality of ICSI.

Early onset of cabergoline therapy for prophylaxis from ovarian hyperstimulation syndrome (OHSS): A potentially safer and more effective protocol.

Vascular endothelial growth factor (VEGF) is the most important angiogenic mediator in ovarian hyperstimulation syndrome OHSS. Studies proved that cabergoline administration blocks the increase in vascular permeability via dephosphorylation of VEGF receptors and hence can be used as prophylactic agent against OHSS. This study aimed at evaluating the effectiveness of early administration of cabergoline in the prevention of OHSS in high risk cases prepared for ICSI. This case series study was conducted on 126 high risk patients prepared for ICSI using the fixed antagonist protocol. High risk patients were defined as having more than 20 follicles >12 mm in diameter, and/or E2 more than 3000 pg/ml when the size of the leading follicle is more than 15 mm. When the size of the leading follicle reached 15 mm, cabergoline was administered (0.5 mg/day) for 8 days. Patients were followed up clinically, ultrasonographically and hematologically. The final E2 was 6099.5 ±â€¯2730 and the mean number of retrieved oocytes was 19.7 ±â€¯7.8. The clinical pregnancy rate was 62/126 (49.2%). There were no significant changes (p > 0.05) comparing hematological parameters, renal function tests and liver function tests between the day of HCG and the day of blastocyst transfer. The incidence of severe OHSS in this group was 1/126 (0.9%), while moderate OHSS was 12 (9.5%) and there were no cases of critical OHSS. We concluded that early administration of cabergoline is a safe and potentially more effective approach for prophylaxis against OHSS in high risk cases.

Combining several interventions to reduce the incidence of OHSS: A prospective cohort study.

OBJECTIVE: To assess the outcome of using low-dose aspirin, dopamine agonist and triggering ovulation by low dose of HCG in combination with GnRH agonist in fixed GnRH antagonist protocol in patients at risk of OHSS. STUDY DESIGN: This prospective cohort study was conducted on 50 infertile women who were at high risk of OHSS. They received low dose aspirin from first day of stimulation, cabergoline 0.5mg daily from the day of HCG for 8days and low dose of HCG (2500 IU) in combination with GnRH agonist for final oocyte maturation in fixed GnRH antagonist protocol. RESULTS: The study was conducted on 50 cases and all of them completed the study protocol. The clinical pregnancy rate was 40% (20 cases of 50) and no cases developed severe or critical OHSS. Only 8% (4 cases) developed moderate OHSS. CONCLUSION: Combining aspirin, cabergoline, and triggering with low dose of HCG in combination with GnRH agonist produced excellent clinical pregnancy rate, and decreased hospital admissions with severe or critical OHSS.

Stimulation day-six serum estradiol: a predictive indicator for the probability of embryo cryopreservation in IVF/ICSI cycles.

OBJECTIVE: To evaluate the predictive value of stimulation day six serum estradiol (E2) for the probability of embryo cryopreservation after fresh embryo transfer in intracytoplasmic sperm injection (ICSI) cycles. SUBJECTS AND METHODS: The study included 282 ICSI cycles for different causes of infertility, provided that the age of the female partner was <40 years and her basal follicle stimulating hormone <10 IU/L. SETTING: Alexandria IVF/ICSI center. MAIN OUTCOME MEASURES: Primary outcome measures are stimulation day-six serum E2, and rate of embryo cryopreservation, after transfer of three good-quality embryos. Secondary outcome measures are pregnancy rate per fresh embryo transfer, and other intermediate variables of the ICSI cycle. RESULTS: Patients were stratified into three groups according to day-six serum E2 levels: Group I with values <400 pg/mL; Group II, between 400 and 900; and Group III with values >900. The mean number of oocytes retrieved was 6.3, 8.9, and 12.4; the mean number of obtained embryos was 3.3, 4.8, and 6.7; and pregnancy rates were 18.1, 36.2, and 44.7% in the three groups, respectively. Rate of embryo cryopreservation, after transfer of three good-quality embryos was 70.7% in Group III, and 26.5% in Group I. (P = 0.01). The negative predictive value of day-six E2 <400 pg/mL for freezing was 83% while day-six serum E2 >900 pg/mL has a sensitivity of 55%, specificity of 72% and positive predictive value of 50% for embryo freezing. CONCLUSION: Higher stimulation day-six estradiol was associated with a higher probability of cryopreservation, and a higher pregnancy rate.