F&S reviews最新文献

One key variable in the success of in vitro fertilization (IVF) cycles is the maturation of oocytes for fertilization. Current practices of both conventional IVF and intracytoplasmic sperm injection do not evaluate the maturity of eggs immediately at the time of oocyte retrieval. In conventional IVF, all retrieved eggs are inseminated with sperm without further evaluation of their maturity. With conventional IVF, immature oocytes are not identified and are inseminated with resulting poor outcomes. In intracytoplasmic sperm injection, retrieved eggs are denuded of cumulus cells (CCs) for evaluation of maturity before insemination. Immature oocytes are identified after denudation and may not reach their full maturation potential because of the loss of surrounding CCs. Both approaches can benefit from an early noninvasive evaluation of oocyte maturity. Cumulus cells are physically and biochemically connected to oocytes and could serve as a window to look into oocyte maturity. This study reviews current literature on processes essential in oocyte maturation involving CCs as well as messenger RNA (mRNA), microRNA (miRNA), and protein biomarkers of metaphase II (MII) stage oocytes identified in CCs. We use this information as a starting point to propose a path forward in the molecular analysis of CCs as a tool of MII oocyte selection. With future studies proposed in this review, we envision a clinically useful approach of selected mRNA, miRNA, and protein marker analysis and eventually a transition to mRNA–miRNA–protein expression correlation analysis and pathway analysis of CC markers to identify MII oocytes at the time of retrieval and enable metaphase I and germinal vesicle oocytes to be further matured in vitro with intact supporting CCs.

Objective

Assisted reproductive technology (ART) treatments are commonly used to aid conception in subfertile couples. This study aimed to evaluate the risks of adverse maternal and offspring outcomes in singleton pregnancy conceived with different ART treatments and techniques.

Evidence Review

We searched MEDLINE, Embase, CENTRAL, and HTA until December 2020 for all systematic reviews evaluating adverse outcomes in pregnancies conceived with various ART techniques, autologous or donor gametes, and embryo development stages. We assessed review quality using the AMSTAR 2 tool risk ratio (RR) or odds ratio (OR) with 95% confidence intervals (CIs) from the top quality reviews for each of the outcomes of interest across the identified ART treatments and population subgroups.

Results

We included 24 systematic reviews, which mostly reported on observational studies. Compared with spontaneous conception, ART pregnancies had a higher risk of placenta previa (RR, 3.71; 95% CI, 2.67–5.16), antepartum hemorrhage (RR, 2.11; 95% CI, 1.86–2.38), preterm birth (PTB) (RR, 1.71; 95% CI, 1.59–1.83), very preterm birth (RR, 2.12; 95% CI, 1.73–2.59), small for gestational age (SGA) (RR, 1.35; 95% CI, 1.20–1.52), low birth weight (LBW) (RR, 1.61; 95% CI, 1.49–1.75), and very low birth weight (VLBW) (RR, 2.12; 95% CI, 1.84–2.43).

Frozen vs. fresh embryo transfer was associated with a lower risk of PTB (RR, 0.90; 95% CI, 0.84–0.97), SGA (RR, 0.61; 95% CI, 0.56–0.67), LBW (RR, 0.72; 95% CI, 0.67–0.77), and VLBW (RR, 0.76; 95% CI, 0.69–0.82). Embryo transfer at blastocyst vs. cleavage showed a higher risk of PTB (RR, 1.10; 95% CI, 1.01–1.20) and large for gestational age (RR, 1.12; 95% CI, 1.03–1.21) with a lower risk of SGA (RR, 0.84; 95% CI, 0.76–0.92).

Using donor vs. autologous oocytes increased the odds of PTB (OR, 1.57; 95% CI, 1.33–1.86), LBW (OR, 1.94; 95% CI, 1.10–3.41), and VLBW (OR, 1.37; 95% CI, 1.22–1.54) as well as maternal complications, including postpartum hemorrhage (OR, 1.96; 95% CI, 1.20–3.20), gestational diabetes (OR, 1.27; 95% CI, 1.03–1.56), hypertensive disorders of pregnancy (OR, 2.63; 95% CI, 2.17–3.18), and cesarean section (OR, 2.28; 95% CI, 2.14–2.42).

Conclusions

Assisted reproductive technology treatments are associated with increased risks of adverse maternal and offspring outcomes, especially with donor oocytes. The characteristics of ART treatment should be incorporated into prenatal care planning to mitigate those risks.

PROSPERO Registration

CRD42020182612, registered March 9, 2020.

Oophoritis, or inflammation of the ovaries, occurs as a result of certain viral infections and may impair ovarian function. Oophoritis has been attributed to cytomegalovirus, mumps virus, Zika virus, hepatitis B virus, and hepatitis C virus due to isolation of these viruses from the ovaries, histologic evidence of ovarian inflammation, and/or signs of ovarian dysfunction in infected people or animal models. These viruses cause inflammation of the ovaries by hematogenous spread, ascending infection of the female reproductive tract, or vascular changes in the ovary, including virus-induced vasculitis. Viral oophoritis has been studied as a potential cause of irregular menstruation, premature menopause, infertility, and ovarian cancer, although evidence of these associations remains limited and inconclusive. Risk factors for developing oophoritis with resultant ovarian dysfunction have additionally been investigated and may include sexual transmission, infection during pregnancy, and peripubertal infection depending on the virus. Despite the potential adverse effects of viral oophoritis, relatively little research has been performed on this condition, perhaps because of its rarity and underdiagnosis. This review summarizes the current literature regarding the most common histologic features of viral oophoritis, its pathogenesis, and its reported or suspected consequences on reproductive function. Furthermore, it highlights gaps in knowledge and areas requiring deeper investigation to inform future research.

For decades, assisted reproductive technology (ART) procedures have been performed manually thanks to the meticulous work of skilled embryologists. Recently, new technologies have been developed with three main scopes: improving embryo culture conditions; making diagnostic evaluations more consistent and reliable; and allowing ART procedures to become progressively less subjective and operator-dependent. This review aimed to answer the following questions: is automation likely to be successfully incorporated into the in vitro fertilization laboratory and clinical ART in the future? If so, would such automation result in improved outcomes in ART?

An electronic search of PubMed was performed to identify articles in English language that addressed automation in ART. Studies were classified in decreasing categories: randomized controlled trials; prospective controlled trials; prospective noncontrolled trials; retrospective studies; and experimental studies. Research and development data from investigators were included.

There are a number of separate platforms that have been developed until now to address different parts of the ART process: gradual change of embryo culture medium; noninvasive embryo monitoring with time-lapse or metabolome analysis; and automated vitrification. It is conceivable that future automation enhancements in the in vitro fertilization laboratory may improve consistency and throughput and reduce the risk of human error associated with the performance of repetitive tasks. Nevertheless, a need remains for a platform able to integrate all separate technologies, capable of successfully interconnecting them in a way that assures continued chain of custody for the gametes and embryos. Moreover, controlled trials will be fundamental to demonstrate the usefulness of automation in ART.

Objective

While immune cells were originally thought to only play a role in maternal tolerance of the semiallogenic fetus, an active role in pregnancy establishment is becoming increasingly apparent. Uterine natural killer (uNK) cells are of specific interest because of their cyclic increase in number during the window of implantation. As a distinct entity from their peripheral blood counterparts, understanding the biology and function of uNK cells will provide the framework for understanding their role in early pregnancy establishment and adverse pregnancy outcomes.

Evidence Review

This review discusses unique uNK cell characteristics and presents clinical implications resulting from their dysfunction. We also systematically present existing knowledge about uNK cell function in three processes critical for successful human embryo implantation and placentation: stromal cell decidualization, spiral artery remodeling, and extravillous trophoblast invasion. Finally, we review the features of uNK cells that could help guide future investigations.

Results

It is clear the uNK cells are intimately involved in multiple facets of early pregnancy. This is accomplished directly, through the secretion of factors that regulate stromal cells and trophoblast function; and indirectly ,via interaction with other maternal cell types present at the maternal-fetal interface. Current work also suggests that uNK cells are a heterogenous population, with subsets that potentially accomplish different functions.

Conclusion

Establishment of pregnancy through successful embryo implantation and placentation requires crosstalk between multiple maternal cell types and invading fetal trophoblast cells. Defects in this process have been associated with multiple adverse perinatal outcomes including hypertensive disorders of pregnancy, placenta accreta, and recurrent miscarriage though the mechanism underlying development of these defects remain unclear. Abnormalities in NK cell number and function which would disrupt physiological maternal-fetal crosstalk, could play a critical role in abnormal implantation and placentation. It is therefore imperative to dissect the unique physiological role of uNK cells in pregnancy and use this knowledge to inform clinical practice by determining how uNK cell dysfunction could lead to reproductive failure.

Objective

To evaluate whether gonadotropin-releasing hormone agonist (GnRHa) triggering improves oocyte maturation, pregnancy outcomes, and safety compared with human chorionic gonadotropin (hCG) triggering during controlled ovarian stimulation.

Evidence Review

A systematic review was performed using the following keywords: “GnRH agonist”; “hCG”; and “triggering.” Searches were conducted on MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov, and EudraCT for randomized controlled clinical trials between January 1, 1990, and April 15, 2020. The primary outcomes were the total number of retrieved oocytes and the number of mature oocytes. The main secondary outcomes were the number of embryos obtained, clinical pregnancy rate (CPR), early pregnancy loss rate, live birth rate, and incidence of ovarian hyperstimulation syndrome (OHSS). Two independent reviewers performed the study selection, bias assessment using the RoB2 tool, and data extraction according to the Cochrane methods. Random-effects meta-analysis was performed followed by prespecified sensitivity and subgroup analyses.

Result(s)

Our search yielded 1,369 published studies and 216 unpublished studies. After screening the titles and abstracts, 65 published studies and 25 unpublished abstracts were assessed for eligibility. Of these, we excluded 61 studies. A total of 29 randomized controlled trials were included. The 26 studies with the number of oocytes retrieved enrolled a total of 2,755 women, of whom 1,419 had GnRHa triggering and 1,336 had hCG alone for triggering. A total of 12 studies reported the number of mature oocytes with a total of 1,619 women (806 had GnRHa triggering and 813 had hCG alone for triggering). The mean numbers of retrieved oocytes (difference in the means [95% confidence interval], 0.99 [0.21, 1.78]; n = 26) and mature oocytes (0.68 [0.04, 1.33]; n = 12) were statistically significantly higher after GnRHa than after hCG triggering. A similar difference was observed for the number of embryos (0.94 [0.19, 1.68]; n = 10). No differences in the CPR (risk ratio, 1.01 [0.90, 1.14]; n = 23), early pregnancy loss (1.27 [0.94, 1.71]; n = 16), and live birth rate (1.00 [0.77, 1.29]; n = 6) were noted. Gonadotropin-releasing hormone agonist was associated with a lower incidence of OHSS (odds ratio, 0.25 [0.08, 0.74]; n = 20). Moreover, after dual triggering (GnRHa associated with hCG) compared with hCG alone, the meta-analysis showed a statistically significantly higher number of retrieved and mature oocytes and CPR.

Conclusion(s)

The final triggering using GnRHa allows a higher number of retrieved and mature oocytes to be obtained with comparable clinical outcomes and, after GnRHa alone, a lower OHSS risk compared with hCG triggering.

The prevalence of obesity and diabetes, two of the most prevalent metabolic disorders (MetDs) in the world, has been rising exponentially over the last two decades. In addition to other comorbidities, MetDs have a detrimental impact on reproductive features, leading to a boost of the use of assisted reproductive technologies (ARTs) to overcome fertility problems. Although ARTs help to improve MetD male reproductive outcomes, data show that the results are less successful compared with those of men without MetD. Currently, intracytoplasmic sperm injection is the election procedure to bypass infertility in men with MetD. Nevertheless, embryos obtained by intracytoplasmic sperm injection using spermatozoa of men with MetD have a lower probability to end in a live birth. This embryo development shutdown has been related to a higher rate of spermatozoa with fragmented DNA and with modifications on pathways that do not allow embryos to go further in the development process. This special detrimental feature of sperm from men with MetD indicates that advanced sperm selection techniques should be used in these patients to avoid sperm with fragmented DNA. Fortunately, sperm selection procedures are under constant development and eventually will allow physicians to select spermatozoa with higher quality and low DNA fragmentation to be used in further ART, increasing the outcome of those procedures. Future research should be performed to enlighten alterations in embryos derived from spermatozoa of men with MetD.

Human menopausal gonadotropins (hMGs) had been developed long before the advent of assisted reproductive technology (ART) for the induction of ovulation in women suffering from hypogonadotropic hypogonadism. The advent of ART offered a new application for hMGs, for inducing multiple follicular ovarian stimulation (OS) in generally normally ovulating women. The advent of follicle-stimulating hormone (FSH) preparations obtained by genetic recombination techniques in the early 1990s, recombinant FSH, was originally seen as an imminent death knell for hMG preparations obtained from menopausal urine. Yet, 25 years later, hMG preparations—now in a highly purified form—are still part of our treatment options for OS in ART.

Over the years, meta-analyses have generally shown a similar or slight advantage in terms of ART outcomes (implantation, ongoing pregnancy, and live birth rates) for hMG preparations, albeit small in magnitude. Yet, recently, mounting evidence has indicated that certain women whose endogenous luteinizing hormone (LH) levels are low, who are older, and/or who are prone to hyper-respond to OS are likely to benefit from receiving hMGs for OS. Today, hMG preparations gain their LH bioactivity from human chorionic gonadotropin obtained from a pituitary or chorionic source, with higher numbers of matured metaphase-II oocytes obtained in the latter case.

Objective

To study the association between paternal lifestyle factors in the preconception period and the risk of pregnancy loss.

Evidence Review

The Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines for systematic reviews and meta-analysis were followed. PubMed and Embase databases were searched up to August 2020. Original articles in English language addressing the relation between paternal exposure status in the preconception period and pregnancy loss were included. The paternal lifestyle factors examined were smoking, alcohol consumption, and body mass index. Studies that only examined exposure status during pregnancy (and not in the preconception period) and those that solely focused on pregnancy outcome after artificial reproductive technology were excluded. The qualitative risk of bias assessments was performed. Meta-analysis using a random-effects model was performed if sufficient data were available, with the risk of pregnancy loss as the primary outcome.

Results

The systematic search included 3,386 articles, of which 11 met the inclusion criteria. In a meta-analysis of 8 studies, paternal smoking of >10 cigarettes per day in the preconception period was found to be associated with an increased risk of pregnancy loss, after adjustment for maternal smoking status (1–10 cigarettes per day, 1.01; 95% confidence interval [CI], 0.97–1.06; 11–19 cigarettes per day, 1.12; 95% CI, 1.08–1.16; ≥20 cigarettes per day, 1.23; 95% CI, 1.17–1.29). No clear association was found between paternal alcohol consumption and pregnancy loss, based on 5 available studies. No studies were identified evaluating the association between paternal body mass index and spontaneous pregnancy loss.

Conclusion

Awareness of the association between paternal smoking in the preconception period and the risk of pregnancy loss should be raised. More well-designed studies are needed to further investigate the effects of other paternal lifestyle factors on the risk of pregnancy loss.