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.

Epididymal contribution to male infertility: An overlooked problem.

The diagnosis and treatment of male infertility, excluding assisted conception, are limited because of, but not limited to, poor understanding of sperm post-testicular development and storage. Many may think that sperm dysfunction is only self-contained in the sperm cell itself as a result of defective spermatogenesis. However, it can also be a consequence of inadequate epididymal maturation following disorders of the epididymis. Improper epididymal functions can disturb semen parameters and sperm DNA integrity, result in high leucocyte concentrations and high numbers of immature germ cells and debris or even cause idiopathic infertility. To date, the data are limited regarding critical markers of sperm maturation and studies that can identify such markers for diagnosis and managing epididymal dysfunction are scarce. Therefore, this article aims to draw attention to recognise a disturbed epididymal environment as a potential cause of male infertility.

Dizygotic twin from conjoined oocytes: a case report.

PURPOSE: Binovular follicles including a pair of conjoined oocytes within a common zona pellucida or their fusion in the zonal region gained some attentions due to its possible role in dizygotic twins. Although some cases in the literature been reported in which two conjoined oocytes arising from binovular follicles were mature, and injected with two separated sperm, no available evidence reported for dizygotic twin pregnancies. METHODS: A case report of a 37-year-old female patient underwent embryo transfer cycle whereby a pair of conjoined blastocysts after ICSI of a pair of conjoined oocytes was transferred. RESULTS: The ß-hCG level was positive 15 days after embryo transfer. The subsequent pregnancy scan revealed a dizygotic pregnancy. The woman gave birth to two healthy boys in the mid of 38 weeks of gestation by cesarean section. CONCLUSIONS: Given the insufficient evidence on how to handle conjoined oocytes, this report acknowledges the first occurrence of dizygotic twin delivery resulted from transfer of a pair of conjoined blastocysts after ICSI of a pair of conjoined oocytes. This also confirms that we should be extremely conservative in discarding any mature oocyte without sufficient data about its useless future to result in a healthy baby.

Effect of embryo selection based morphokinetics on IVF/ICSI outcomes: evidence from a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Debate exists for the optimal tool to select embryos for transfer in assisted reproductive technology (ART). Time-lapse monitoring (TLM) is a noninvasive tool suggested where each embryo can be captured every 5-20 min. Given the inconsistency in the existing studies, we conducted this meta-analysis of RCTs to summarize the evidence available concerning the predictive ability of morphokinetics compared with the routine assessment of embryo development in ART. METHODS: The primary databases MEDLINE, EMBASE, Cochrane, NHS, WHO, and Other Non-Indexed Citations were consulted for RCTs that have been published until November 2018, with no language restriction. RESULTS AND CONCLUSION: Our review includes 6 RCTs (n = 2057 patients). The data showed an improvement (~ 9%) in live birth TLM (OR 1.43; 95% CI 1.10-1.85; P = 0.007), with low-quality evidence. There was no evidence of a significant difference between both groups concerning ongoing pregnancy, clinical pregnancy and implantation rates. The data further showed that morphokinetics is associated with decreased early pregnancy loss rate. These estimates must be interpreted with caution owing to the statistical and clinical heterogeneities and the consequent difficulty in drawing any meaningful conclusion.

Artificial shrinkage of blastocoel using a laser pulse prior to vitrification improves clinical outcome.

PURPOSE: Blastocysts contain a large amount of fluid in the blastocoel, which may pose a risk for ice crystal formation during vitrification. This study aimed to evaluate the effectiveness of laser-induced artificial shrinkage of blastocoel before vitrification on clinical outcome. METHODS: Patients were divided into two groups: a control group with untreated, expanded blastocysts (n = 115) and a study group with blastocoel artificially eliminated by a laser pulse prior to vitrification (n = 309). Blastocyst survival, clinical pregnancy, and implantation rates were compared. RESULT(S): The survival rate was significantly higher in the study group compared with the control group (97.3 and 74.9 %, respectively; p > 0.01). The clinical pregnancy and implantation rates of the study group were significantly higher (p < 0.01) than that of the control group (clinical pregnancy, 67.2 vs. 41.1 %; implantation, 39.1 vs. 24.5 %. CONCLUSION(S): This study demonstrated that the removal of blastocoel fluid before vitrification by laser pulse of in vitro-produced human blastocysts significantly improves blastocyst survival, clinical pregnancy, and implantation rates.

A preliminary report of successful cleavage after calcium ionophore activation at ICSI in cases with previous arrest at the pronuclear stage.

Artificial oocyte activation (AOA) has been previously suggested as a means to overcome the problem of total fertilization failure, which affects about 1-3% of the intracytoplasmic sperm injection (ICSI) cycles. A preliminary study on the application of chemical AOA was conducted using A23187 Ca(2+) ionophore to improve embryonic development in four women with a history of complete fertilization arrest and inability to transit to cleavage stage during previous ICSI trials. Data indicated that activated oocytes resulted in better fertilization, embryonic development and clinical pregnancy in one of the four couples. Therefore, ICSI combined with AOA using Ca(2+) ionophore may be useful in selected patients with cleavage failure, and may help the zygotes to reach more advanced developmental stages.

Integrating insulin into single-step culture medium regulates human embryo development in vitro.

OBJECTIVE: To evaluate the effect of supplementing single-step embryo culture medium with insulin on human embryo development. DESIGN: Comparative study. SETTING: Two private centers. PATIENT(S): The study involved a sibling oocyte split of 5,142 retrieved oocytes from 360 patients. INTERVENTION(S): Sibling oocytes split after intracytoplasmic sperm injection for culture from day 0 through day 5 or 6 in insulin-supplemented or control medium. Women were split to receive their embryos from insulin-supplemented or control medium. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate. RESULT(S): There were significantly higher rates of clinical, ongoing, and twin pregnancies in the insulin-supplemented arm than in the control arm. On day 3, embryo quality and compaction were higher in insulin-supplemented medium. On day 5, insulin supplementation showed higher rates of blastocyst formation, quality, and cryopreservation. CONCLUSION(S): Insulin supplementation of single-step embryo culture medium from day 0 through day 5 or 6 improved clinical pregnancy rate and human embryo development. However, these findings need further confirmation through a multicenter randomized controlled trial that may include other patient populations and different culture media.

Revisiting the management of recurrent implantation failure through freeze-all policy.

OBJECTIVE: To determine whether a freeze-all policy for in vitro human blastocysts improves the ongoing pregnancy rate in patients with recurrent implantation failure (RIF). DESIGN: Prospective cohort study. SETTING: Single private center. PATIENT(S): A total of 171 women with RIF divided into two groups: freeze-all policy group (n = 81) and fresh embryo transfer (ET) group (n = 90). INTERVENTION(S): Freeze-all policy. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate. RESULT(S): The clinical pregnancy rate (52% vs. 28%; odds ratio [OR] 1.86; 95% confidence interval [CI], 1.29-2.68) and ongoing pregnancy rate (44% vs. 20%; OR 2.2; 95% CI, 1.04-3.45) were statistically significantly higher in the freeze-all group than the fresh ET group, respectively. The implantation rate was also statistically significant (freeze-all group 44.2% vs. fresh ET group 15.8%; OR 2.80; 95% CI, 2.00-3.92). CONCLUSION(S): The freeze-all policy statistically significantly improved the ongoing pregnancy and implantation rates. Thus, a freeze-all policy is likely to be the new key to helping open the black box of RIF. These findings also are useful for further investigating the adverse effect of controlled ovarian stimulation on in vitro fertilization outcomes.