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OBJECTIVE: Elevated sperm DNA fragmentation has potential implications for semen quality and fertility. The commonly used sperm chromatin dispersion test offers an indirect estimation but has limitations in terms of bias and variability. This study aimed to assess the reliability of the sperm chromatin dispersion assay for predicting assisted reproductive technology outcomes. MATERIALS AND METHODS: This systematic review included studies published until December 2023 that adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed/MEDLINE, Scopus, and Google Scholar databases were searched. Various assisted reproductive technology outcomes in patients with high (≥ 30%) versus low (< 30%) sperm DNA fragmentation were compared using a sperm chromatin dispersion assay and including a sub-analysis of intracytoplasmic sperm injection versus in vitro fertilization. A comprehensive meta-analysis software facilitated quantitative analysis with statistical comparisons between cases and controls. Interstudy heterogeneity was assessed, and sensitivity and publication bias tests were performed. RESULTS: Of the 199 abstracts assessed, 64 full-text articles were screened, and 44 articles were qualitatively synthesized. Fourteen articles representing 5346 participants were quantitatively analyzed. Using the sperm chromatin dispersion assay, elevated sperm DNA fragmentation was associated with lower fertilization and embryo cleavage rates. Notably, high sperm DNA fragmentation levels did not affect the clinical pregnancy, implantation, miscarriage, or live birth outcomes. Sub-analysis revealed lower fertilization, embryo cleavage, clinical pregnancy, live birth rates, and higher miscarriage rates in the intracytoplasmic sperm injection subgroup only. CONCLUSIONS: The sperm chromatin dispersion assay did not show significant differences in pregnancy or live birth rates between the high- and low-sperm DNA fragmentation groups. Noteworthy, high sperm DNA fragmentation was associated with worse assisted reproductive technology outcomes in the intracytoplasmic sperm injection group. Given the current quality of the evidence, affected by the experimental design and the absence of correction for female factors of infertility, clinicians should be wary of the assay's limited predictive power for pregnancy and live birth outcomes.
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OBJECTIVES: The limited data regarding obstetrical outcomes in multiple pregnancies following both fresh embryo transfer and frozen-thawed embryo transfer (FET), along with the association between multiple pregnancies and increased pregnancy complications compared to singleton pregnancies, highlight the need for research on this topic. Therefore, this study aimed to compare obstetrical and neonatal outcomes of twin pregnancies after fresh embryo transfer versus FET. DESIGN: This was a retrospective single-center study. PARTICIPANTS: There were in vitro fertilization (IVF) dichorionic twin pregnancies ≥23 weeks of gestation during 2010-2022. SETTING: This retrospective study was based on data recorded at Galilee Medical Center, a tertiary-care university-affiliated hospital, Israel. METHODS: We conducted a comparative analysis of obstetrical and neonatal outcomes between IVF dichorionic twin pregnancies after fresh embryo transfer and those after FET. This analysis included variables such as gestational age at delivery, birthweight, preterm birth rates, low birthweight rates, neonatal intensive care unit admissions, and complications related to prematurity. RESULTS: The study included 389 IVF twin pregnancies: 253 after fresh embryo transfer and 136 after FET. Following fresh embryo transfer compared to FET, the mean gestational age at delivery was earlier (34 + 6 vs. 35 + 5 weeks, p = 0.001) and the rate of preterm birth (<37 weeks) was higher (70.4% vs. 53.7%, p = 0.001). This difference in gestational age at delivery remained significant after adjustment for maternal age, parity, and BMI (OR = 2.11, 95% CI: 2.11-3.27, p = 0.001). Similarly, the difference in preterm birth rates remained significant after adjustment of the same variables (p = 0.001). For the fresh embryo transfer compared to the FET group, the mean birthweight was lower (2,179.72 vs. 2,353.35 g, p = 0.003); and low birthweight and very low birthweight rates were higher (71.2% vs. 56.3%, p < 0.001 and 13.5% vs. 6.7%, p = 0.004, respectively). For the fresh embryo transfer compared to the FET group, the proportions were higher of neonates admitted to the neonatal intensive care unit (23.3% vs. 16.0%, p = 0.019), of neonates with respiratory distress syndrome (10.5% vs. 5.9%, p = 0.045) and those needing phototherapy (23.3% vs. 16.0%, p = 0.019). LIMITATIONS: Limitations of the study include its retrospective nature. Furthermore, we were unable to adjust for some confounders, such as the number of eggs retrieved, the number of embryos transferred, and methods for ovarian stimulation or preparation of the endometrium for embryo transfer. CONCLUSIONS: Obstetrical and neonatal outcomes of twin pregnancies were worse after fresh embryo transfer than after FET. The findings support favorable fetal outcomes after FET and support the current trend of shifting from fresh embryo transfer to FET. Prospective studies are needed to support our results.
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BACKGROUND: Coronavirus disease 2019 (COVID-19) and dengue fever are difficult to distinguish given shared clinical and laboratory features. Failing to consider COVID-19 due to false-positive dengue serology can have serious implications. We aimed to assess this possible cross-reactivity. METHODS: We analyzed clinical data and serum samples from 55 individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To assess dengue serology status, we used dengue-specific antibodies by means of lateral-flow rapid test, as well as enzyme-linked immunosorbent assay (ELISA). Additionally, we tested SARS-CoV-2 serology status in patients with dengue and performed in-silico protein structural analysis to identify epitope similarities. RESULTS: Using the dengue lateral-flow rapid test we detected 12 positive cases out of the 55 (21.8%) COVID-19 patients versus zero positive cases in a control group of 70 healthy individuals (P = 2.5E-5). This includes 9 cases of positive immunoglobulin M (IgM), 2 cases of positive immunoglobulin G (IgG), and 1 case of positive IgM as well as IgG antibodies. ELISA testing for dengue was positive in 2 additional subjects using envelope protein directed antibodies. Out of 95 samples obtained from patients diagnosed with dengue before September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%) (16 IgA, 5 IgG) versus 4 positives/equivocal in 102 controls (4%) (P = 1.6E-4). Subsequent in-silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2 domain of the spike protein and the dengue envelope protein. CONCLUSIONS: Our findings support possible cross-reactivity between dengue virus and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa. This can have serious consequences for both patient care and public health.
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COVID-19 , Virus del Dengue , Anticuerpos Antivirales , Reacciones Cruzadas , Humanos , SARS-CoV-2RESUMEN
PURPOSE: To compare morphokinetic parameters and quality of embryos derived from GnRH antagonist ICSI cycles triggered either with GnRH agonist or standard hCG between matched groups of patients. METHODS: Morphokinetic parameters of embryos derived from matched first GnRH antagonist ICSI cycles triggered by GnRH agonist or standard hCG between 2013 and 2016 were compared. Matching was performed for maternal age, peak estradiol levels, and number of oocytes retrieved. Outcome measures were: time to pronucleus fading (tPNf), cleavage timings (t2-t8), synchrony of the second and third cycles (S2 and S3), duration of the second and third cycle (CC2 and CC3), optimal cell cycle division parameters, and known implantation data (KID) scoring for embryo quality. Multivariate linear and logistic regression analyses were performed for confounding factors. RESULTS: We analyzed 824 embryos from 84 GnRH agonist trigger cycles and 746 embryos from 84 matched hCG trigger cycles. Embryos derived from the cycles triggered with hCG triggering cleaved faster than those deriving from GnRH agonist trigger. The differences were significant throughout most stages of embryo development (t3-t6), and a shorter second cell cycle duration of the hCG trigger embryos was observed. There was no difference in synchrony of the second and third cell cycles and the optimal cell cycle division parameters between the two groups, but there was a higher percentage of embryos without multinucleation in the hCG trigger group (27.8% vs. 21.6%, p < 0.001). CONCLUSION: The type of trigger in matched antagonist ICSI cycles was found to affect early embryo cleavage times but not embryo quality.
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Gonadotropina Coriónica/genética , Desarrollo Embrionario/efectos de los fármacos , Fertilización In Vitro , Hormona Liberadora de Gonadotropina/genética , Adulto , Gonadotropina Coriónica/agonistas , Implantación del Embrión/efectos de los fármacos , Implantación del Embrión/genética , Transferencia de Embrión/métodos , Desarrollo Embrionario/genética , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Oocitos/efectos de los fármacos , Oocitos/crecimiento & desarrollo , Síndrome de Hiperestimulación Ovárica/genética , Síndrome de Hiperestimulación Ovárica/patología , Inducción de la Ovulación/métodos , Embarazo , Índice de Embarazo , Puntaje de Propensión , Inyecciones de Esperma Intracitoplasmáticas/métodosRESUMEN
RESEARCH QUESTION: What is the association of the entire range of trigger-day endometrial thickness (EMT) with live birth rate (LBR) after IVF and fresh embryo transfer? Although EMT is amenable to convenient non-invasive routine measurement, studies of the association between pre-trigger EMT and assisted reproductive technology outcome have yielded equivocal results. DESIGN: A cohort of IVF fresh day-3 embryo transfers in patients aged 42 years and younger in a single centre between 2009 and 2017. The LBR was calculated for all trigger-day EMT values, stratified into five groups overall and within subgroups of patient age and ovarian response. Univariate analysis and multivariate logistic regression models were used to compare the LBRs at different EMT measurements adjusting for various independent variables. RESULTS: A total of 5133 cycles were included. The LBRs were as follows: 11.22% (35/312) in cycles with EMT 6 mm or less, 17.98% (380/2114) in cycles with EMT 7-9 mm, 23.44% (476/2031) in cycles with EMT 10-12 mm, 25.62% (144/562) in cycles with EMT 13-15 mm and 34.21% (39/114) in cycles with EMT 16 mm or more (P < 0.001). Similar findings were observed by patient age and ovarian response. The observation was confirmed by multivariate logistic regression analysis in which the EMT was found to be a significant independent predictor of LBR even after controlling for various confounders (OR 0.935, 95% CI 0.908 to 0.962; P < 0.001). CONCLUSIONS: Pre-trigger EMT is in significant independent correlation with LBR, even after adjusting for age and ovarian response. Maximal endometrial proliferation is beneficial, and fresh embryo transfer can be carried out at high EMT values without endangering the outcome of the cycle.
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Tasa de Natalidad , Endometrio/diagnóstico por imagen , Fertilización In Vitro/métodos , Nacimiento Vivo , Adulto , Transferencia de Embrión/métodos , Femenino , Humanos , Embarazo , Índice de Embarazo , Estudios RetrospectivosRESUMEN
BACKGROUND: First trimester (FTM) and term human umbilical cord-derived perivascular cells (HUCPVCs), which are rich sources of mesenchymal stem cells (MSCs), can give rise to Sertoli cell (SC)-like as well as haploid germ cell (GC)-like cells in vitro using culture conditions that recapitulate the testicular niche. Gamete-like cells have been produced ex vivo using pluripotent stem cells as well as MSCs. However, the production of functional gametes from human stem cells has yet to be achieved. METHODS: Three independent lines of FTM and term HUCPVCs were cultured using a novel 5-week step-wise in vitro differentiation protocol recapitulating key physiological signals involved in testicular development. SC- and GC-associated phenotypical properties were assessed by real-time polymerase chain reaction (RT-PCR), quantitative PCR immunocytochemistry, flow cytometry, and fluorescence in-situ hybridization (FISH). Functional spermatogonial stem cell-like properties were assessed using a xenotranplantation assay. RESULTS: Within 3 weeks of differentiation, two morphologically distinct cell types emerged including large adherent cells and semi-attached round cells. Both early GC-associated markers (VASA, DAZL, GPR125, GFR1α) and SC-associated markers (FSHR, SOX9, AMH) were upregulated, and 5.7 ± 1.2% of these cells engrafted near the inner basal membrane in a xenograft assay. After 5 weeks in culture, 10-30% of the cells were haploid, had adopted a spermatid-like morphology, and expressed PRM1, Acrosin, and ODF2. Undifferentiated HUCPVCs secreted key factors known to regulate spermatogenesis (LIF, GDNF, BMP4, bFGF) and 10-20% of HUCPVCs co-expressed SSEA4, CD9, CD90, and CD49f. We hypothesize that the paracrine properties and cellular heterogeneity of HUCPVCs may explain their dual capacity to differentiate to both SC- and GC-like cells. CONCLUSIONS: HUCPVCs recapitulate elements of the testicular niche including their ability to differentiate into cells with Sertoli-like and haploid spermatid-like properties in vitro. Our study supports the importance of generating a niche-like environment under ex vivo conditions aiming at creating mature GC, and highlights the plasticity of HUCPVCs. This could have future applications for the treatment of some cases of male infertility.
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Células Madre Mesenquimatosas/citología , Comunicación Paracrina/genética , Células de Sertoli/citología , Espermátides/citología , Espermatogénesis/genética , Animales , Biomarcadores/metabolismo , Diferenciación Celular , Sangre Fetal/citología , Sangre Fetal/metabolismo , Expresión Génica , Perfilación de la Expresión Génica , Xenoinjertos , Humanos , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones SCID , Cultivo Primario de Células , Células de Sertoli/metabolismo , Espermátides/metabolismoRESUMEN
The expansion of functional testicular biopsy-derived human spermatogonial stem cells (hSSC) ex-vivo may enable the restoration of fertility in pre-pubertal males having undergone gonadotoxic therapies or men with severe male factor infertility. Various somatic cells are known to regulate SSC homeostasis and spermatogenesis in the developing and adult testis. Prior attempts to recapitulate this niche demonstrated the requirement of feeder cells, such as endogenous testicular somatic cells, for germ cell expansion ex-vivo. However, this strategy has limitations for the expansion of hSSCs from tissue biopsies where spermatogenesis is absent or defective. Our aim was to evaluate first trimester human umbilical cord perivascular cells (FTM HUCPVCs), a novel source of mesenchymal stromal-like cells (MSCs), as potential human feeder cells for standardized hSSC expansion ex-vivo. Targeted RNA sequencing analysis demonstrated that CD90+ve FTM HUCPVCs expanded in vitro under germ cell culture conditions express a profile of targeted testicular-associated transcripts that is similar to cultured human CD90+ve testicular adherent cells (hTACs) and secrete LIF, FGF2 and BMP4, key growth factors known to regulate spermatogenesis. We also demonstrated that mitotically-inactivated FTM HUCPVCs support the expansion of mouse germ cells and putative SSCs ex-vivo, and that FTM HUCPVC transplantation promotes in vivo germ cell regeneration following mono-2- ethylhexyl phthalate (MEHP)-induced seminiferous tubule damage in a murine model, including a partial reconstitution of tubular cellular architecture and reestablishment of DAZL and acrosin+ve germ cell layers. Together, these data suggest that FTM HUCPVCs have phenotypical and functional properties that may support repair of the human testicular niche.
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Ovarian follicular responsiveness to controlled ovarian hyperstimulation (COH) with gonadotropins is extremely variable between individual patients, and even from cycle to cycle for the same patient. High responder patients are characterized by an exaggerated response to gonadotropin administration, accompanied by a higher risk for ovarian hyperstimulation syndrome (OHSS). In spite of its importance, the literature regarding high responders is characterized by heterogeneous classification methodologies. A clear separation should be drawn between risk factors for a high ovarian response and the actual response exhibited by a patient to stimulation. Similarly, it is important to distinguish between high ovarian response and development of clinically significant OHSS. In this article we: (1) review recent publications pertaining to the identification and clinical management of high responders, (2) propose an integrated clinical model to differentiate sub-groups within this population based on this review, and (3) suggest specific protocols for each sub-group. The model is based on a chronological patient assessment in an effort to target treatment based on the specific clinical circumstances. It is our hope that the algorithm we have developed will assist clinicians to supply targeted and precise treatments in order to achieve a favorable reproductive outcome with minimum complications for each patient.
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Síndrome de Hiperestimulación Ovárica/prevención & control , Inducción de la Ovulación/efectos adversos , Femenino , Humanos , Síndrome de Hiperestimulación Ovárica/inducido químicamente , Síndrome de Hiperestimulación Ovárica/clasificaciónRESUMEN
We examined whether treatment with minimum-dose stimulation (MS) protocol enhances clinical pregnancy rates compared to high-dose stimulation (HS) protocol. A retrospective cohort study was performed comparing IVF and pregnancy outcomes between MS and HS gonadotropin-antagonist protocol for patients with poor ovarian reserve (POR). Inclusion criteria included patients with an anti-Müllerian hormone (AMH) ≤8 pmol/L and/or antral follicle count (AFC) ≤5 on days 2-3 of the cycle. Patients from 2008 exclusively had a HS protocol treatment, while patients in 2010 had treatment with a MS protocol exclusively. The MS protocol involved letrozole at 2.5 mg over 5 days, starting from day 2, overlapping with gonadotropins, starting from the third day of letrozole at 150 units daily. GnRH antagonist was introduced once one or more follicles reached 14 mm or larger. The HS group received gonadotropins (≥300 IU/day) throughout their antagonist cycle. Clinical pregnancy rate was significantly higher in the MS protocol compared to the HS protocol (P = 0.007). Furthermore, the live birth rate was significantly higher in the MS group compare to the HS group (P = 0.034). In conclusion, the MS IVF protocol is less expensive (lower gonadotropin dosage) and resulted in a higher clinical pregnancy rate and live birth rate than a HS protocol for poor responders.
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Human umbilical cord-derived perivascular cells (PVCs) are a recently characterized source of mesenchymal stromal cells that has gained much interest in the field of cellular therapeutics. However, very little is known about the changes in fate potential and restrictions that these cells undergo during gestational development. This study is the first to examine the phenotypic, molecular, and functional properties of first trimester (FTM)-derived PVCs, outlining properties that are unique to this population when compared to term (TERM) counterparts. FTM- and TERM-PVCs displayed analogous mesenchymal, perivascular, and immunological immunophenotypes. Both PVCs could be maintained in culture without alteration to these phenotypes or mesenchymal lineage differentiation potential. Some unique features of FTM-PVCs were uncovered in this study: (1) while the gene signatures of FTM- and TERM-PVCs were similar, key differences were observed, namely, that the Oct4A and Sox17 proteins were detected in FTM-PVCs, but not in TERM counterparts; (2) FTM-PVCs exhibited a greater proliferative potential; and (3) FTM-PVCs were more efficient in their in vitro differentiation toward selective mesenchymal cell types, including the chondrogenic and adipogenic lineages, as well as toward neuronal- and hepatocyte-like lineages, when compared to TERM-PVCs. Both PVCs were able to generate osteocytes and cardiomyocyte-like cells with similar efficiencies in vitro. Overall, FTM-PVCs show more plasticity than TERM-PVCs with regard to fate acquisition, suggesting that a restriction in multipotentiality is imposed on PVCs as gestation progresses. Taken together, our findings support the idea that PVCs from earlier in gestation may be better than later sources of multipotent stromal cells (MSCs) for some regenerative medicine applications.