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Journal of Assisted Reproduction and... Mar 2023While delayed parenthood is increasing worldwide, the effect of paternal age on in vitro fertilization (IVF) outcomes remains unclear. The egg donation model appears to... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
While delayed parenthood is increasing worldwide, the effect of paternal age on in vitro fertilization (IVF) outcomes remains unclear. The egg donation model appears to be relevant to studying the independent impact of paternal age on clinical outcome, but the available studies are heterogeneous and contradictory. This systematic review and meta-analysis aimed to assess the relationship between paternal age and live birth rate (LBR) in egg donation cycles.
METHODS
A systematic search of the literature was conducted in PubMed, Embase, and the Cochrane Library from inception to June 30, 2021. All studies on egg donation cycles where LBR is reported according to male age were included. Study selection, bias assessment, and data extraction were performed by two independent reviewers according to the Cochrane methods.
RESULTS
Eleven studies involving 10,527 egg donation cycles were finally included. The meta-analysis showed a slight but significant and linear decrease in LBR with increasing paternal age (estimate - 0.0055; 95% CI (- 0.0093; - 0.0016), p = 0.006), with low heterogeneity (I = 25%). No specific threshold was identified. A similar trend toward decreased clinical pregnancy rate with advancing paternal age was found but did not reach statistical significance (p = 0.07).
CONCLUSION
This meta-analysis demonstrates that increasing paternal age is associated with a slight but significant and linear decrease in the live birth rate in egg donation cycles, with no apparent threshold effect. Although this requires further confirmation, this information is important for counseling men who are considering delayed childbearing.
Topics: Pregnancy; Female; Male; Humans; Birth Rate; Paternal Age; Pregnancy Rate; Fertilization in Vitro; Oocytes; Live Birth; Retrospective Studies; Oocyte Donation
PubMed: 36652117
DOI: 10.1007/s10815-023-02714-1 -
Human Reproduction Update 2011The first week of human embryonic development comprises a series of events that change highly specialized germ cells into undifferentiated human embryonic stem cells... (Review)
Review
BACKGROUND
The first week of human embryonic development comprises a series of events that change highly specialized germ cells into undifferentiated human embryonic stem cells (hESCs) that display an extraordinarily broad developmental potential. The understanding of these events is crucial to the improvement of the success rate of in vitro fertilization. With the emergence of new technologies such as Omics, the gene expression profiling of human oocytes, embryos and hESCs has been performed and generated a flood of data related to the molecular signature of early embryo development.
METHODS
In order to understand the complex genetic network that controls the first week of embryo development, we performed a systematic review and study of this issue. We performed a literature search using PubMed and EMBASE to identify all relevant studies published as original articles in English up to March 2010 (n = 165). We also analyzed the transcriptome of human oocytes, embryos and hESCs.
RESULTS
Distinct sets of genes were revealed by comparing the expression profiles of oocytes, embryos on Day 3 and hESCs, which are associated with totipotency, pluripotency and reprogramming properties, respectively. Known components of two signaling pathways (WNT and transforming growth factor-β) were linked to oocyte maturation and early embryonic development.
CONCLUSIONS
Omics analysis provides tools for understanding the molecular mechanisms and signaling pathways controlling early embryonic development. Furthermore, we discuss the clinical relevance of using a non-invasive molecular approach to embryo selection for the single-embryo transfer program.
Topics: Embryonic Development; Embryonic Stem Cells; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Maternal Age; Oocytes; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome
PubMed: 20716614
DOI: 10.1093/humupd/dmq036 -
International Journal of Molecular... Apr 2022Gamete membrane fusion is a critical cellular event in sexual reproduction. In addition, the generation of knockout models has provided a powerful tool for testing the... (Review)
Review
Gamete membrane fusion is a critical cellular event in sexual reproduction. In addition, the generation of knockout models has provided a powerful tool for testing the functional relevance of proteins thought to be involved in mammalian fertilization, suggesting IZUMO1 and TMEM95 (transmembrane protein 95) as essential proteins. However, the molecular mechanisms underlying the process remain largely unknown. Therefore, the aim of this study was to summarize the current knowledge about IZUMO1 and TMEM95 during mammalian fertilization. Hence, three distinct databases were consulted-PubMed, Scopus and Web of Science-using single keywords. As a result, a total of 429 articles were identified. Based on both inclusion and exclusion criteria, the final number of articles included in this study was 103. The results showed that IZUMO1 is mostly studied in rodents whereas TMEM95 is studied primarily in bovines. Despite the research, the topological localization of IZUMO1 remains controversial. IZUMO1 may be involved in organizing or stabilizing a multiprotein complex essential for the membrane fusion in which TMEM95 could act as a fusogen due to its possible interaction with IZUMO1. Overall, the expression of these two proteins is not sufficient for sperm-oocyte fusion; therefore, other molecules must be involved in the membrane fusion process.
Topics: Animals; Cattle; Fertilization; Immunoglobulins; Male; Mammals; Membrane Proteins; Sperm-Ovum Interactions; Spermatozoa
PubMed: 35409288
DOI: 10.3390/ijms23073929 -
The Journal of International Medical... Apr 2014To investigate the effect of recombinant human luteinizing hormone supplementation (rLH priming) during the early follicular phase on in vitro fertilization (IVF) and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To investigate the effect of recombinant human luteinizing hormone supplementation (rLH priming) during the early follicular phase on in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) outcomes.
METHODS
In order to evaluate available evidence regarding the efficacy of rLH priming in IVF/ICSI procedures, a systematic review and meta-analysis was preformed. Searches were conducted on MEDLINE®, EMBASE and the Cochrane Database of Clinical Trials without language limitation, but were restricted to randomized controlled trials (RCTs).
RESULTS
Three RCTs including 346 patients were included in this meta-analysis, which demonstrated that rLH priming did not increase ongoing pregnancy rate. Although less recombinant follicle-stimulating hormone (rFSH) was required and the oestradiol level was higher on the day of human chorionic gonadotropin administration in the rLH priming group, the numbers of oocytes retrieved and embryos produced were comparable between patients treated with rLH priming and those treated with rFSH alone.
CONCLUSIONS
This systematic review and meta-analysis has demonstrated that at present there is insufficient evidence that patients undergoing IVF/ICSI may benefit from rLH priming during the early follicular phase.
Topics: Chorionic Gonadotropin; Estradiol; Female; Follicle Stimulating Hormone; Follicular Phase; Humans; Luteinizing Hormone; Oocytes; Ovulation Induction; Pregnancy; Pregnancy Rate; Recombinant Proteins; Sperm Injections, Intracytoplasmic
PubMed: 24595152
DOI: 10.1177/0300060513509044 -
Journal of Assisted Reproduction and... Jan 2018This systematic review sought to evaluate the clinical outcomes of vitrification at the cleavage stage and blastocyst stage for embryo transfer in patients undergoing... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
This systematic review sought to evaluate the clinical outcomes of vitrification at the cleavage stage and blastocyst stage for embryo transfer in patients undergoing assisted reproductive technology (ART) treatment.
METHODS
We searched for related comparative studies published in the PubMed, EMBASE, and Cochrane Library databases up to July 2017. The primary outcomes were clinical pregnancy rate (CPR) and embryo implantation rate (IR). Secondary outcomes were multiple pregnancy rate (MPR), miscarriage rate (MR), live birth rate (LBR), and ongoing pregnancy rate (OPR). The Mantel-Haenszel fixed effects model and random effects model were used to analyze the summary risks ratios (RRs) with 95% confidence intervals (CIs).
RESULTS
Eight studies with more than 6590 cycles were included in our meta-analysis. Seven studies were observational retrospective comparative studies. One was a prospective study. Overall, the current study summarizes information from 6590 vitrification warming cycles (cleavage stage n = 4594; blastocysts n = 1996). There was no difference in the primary outcome clinical pregnancy rate (RR = 0.97, 95% CI = 0.90-1.04; fixed effects model; I = 21%), whereas vitrified blastocyst transfer was significantly superior to vitrified cleavage-stage embryo transfer regarding the implantation rate (RR = 0.85, 95% CI = 0.74-0.97; random effects model; I = 43). Regarding the secondary outcomes, no differences were found in the multiple pregnancy rate (RR = 1.20, 95% CI = 0.79-1.82; fixed effects model; I = 22), live birth rate (RR = 1.07, 95% CI = 0.98-1.16; fixed effects model; I = 0), and ongoing pregnancy rate (RR = 1.01, 95% CI = 0.92-1.120; fixed effects model; I = 0), whereas a higher miscarriage rate was observed with vitrified blastocyst transfer (RR = 0.65, 95% CI = 0.45-0.93; random effects model; I = 23).
CONCLUSION
In summary, this meta-analysis shows that vitrification at any stage has no detrimental effect on clinical outcome. Blastocyst transfer will still remain a favorable and promising option in ART. Due to the small sample evaluated in the pool of included studies, large-scale, prospective, and randomized controlled trials are required to determine if these small effects are clinically relevant.
Topics: Blastocyst; Cleavage Stage, Ovum; Embryo Transfer; Female; Humans; Observational Studies as Topic; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Retrospective Studies; Vitrification
PubMed: 28940130
DOI: 10.1007/s10815-017-1040-1 -
Reproductive Biomedicine Online Oct 2022Ovarian tissue cryopreservation and subsequent autotransplantation is a successful technique for fertility preservation in oncological patients. However, there are... (Review)
Review
Ovarian tissue cryopreservation and subsequent autotransplantation is a successful technique for fertility preservation in oncological patients. However, there are concerns regarding safety, as the graft may contain malignant cells that could lead to the reintroduction of cancer. To circumvent this problem several experimental strategies are being pursued. This systematic review was conducted to provide an overview of the strategies aiming to safely use cryopreserved human ovarian tissue to restore fertility after cancer. Thirty-one studies were included, covering five different experimental strategies: (i) in-vitro maturation of oocytes, (ii) constructing an artificial ovary as a scaffold for reseeding pre-antral follicles, (iii) purging strategies aimed at the eradication of contaminating malignant cells, (iv) maturation of oocytes by xenotransplantation, and (v) stem cell-based oogenesis. These strategies to circumvent the reintroduction of cancer cells through ovarian tissue autotransplantation are being developed, but so far have not reached the stage of clinical trials. Further research is required to establish their risks and effectiveness while the ethical aspects associated with these strategies also need to be discussed. Despite the fact that these experimental procedures are still under development, they might provide safe fertility restoration options for oncological patients in the future.
Topics: Cryopreservation; Female; Fertility Preservation; Humans; Neoplasms; Oocytes; Oogenesis; Ovary
PubMed: 35945106
DOI: 10.1016/j.rbmo.2022.05.020 -
The Cochrane Database of Systematic... Mar 2018In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non-invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment.
OBJECTIVES
To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (Feburary 2018). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings.
SELECTION CRITERIA
Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART.
DATA COLLECTION AND ANALYSIS
Pairs of review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.
MAIN RESULTS
We included four trials with a total of 924 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity.We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.02, 95% CI 0.77 to 1.35, I² = 0%; four RCTs; N = 924), live birth alone (OR 0.99, 95% CI 0.69 to 1.44, I² = 0%; three RCTs; N = 597), or miscarriage (OR 1.18, 95% CI 0.77 to 1.82; I² = 0%; three RCTs; N = 869). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.90, 95% CI 0.66 to 1.25, I² = 0%; two RCTs; N = 744). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics.We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.11, 95% CI 0.85 to 1.45; I²= 44%; four trials; N = 924) or multiple pregnancy (OR 1.50, 95% CI 0.70 to 3.19; I² = 0%; two RCTs, N = 180). Rates of cycle cancellation were higher in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744, low quality evidence). There was very low-quality evidence of little or no difference between groups in rates of ectopic pregnancy rates (OR 3.00, 95% CI 0.12 to 74.07; one RCT; N = 417), and foetal abnormality (no events; one RCT; N = 125). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.03, 95% CI 0.76 to 1.38; I² = 40%; two RCTs; N = 744).The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials.
AUTHORS' CONCLUSIONS
According to current trials in women undergoing ART, there is no evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy or foetal abnormalities. The existing evidence varied from very low to low-quality. Data on other adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.
Topics: Abortion, Spontaneous; Adult; Endometrium; Female; Humans; Live Birth; Metabolomics; Oocytes; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic; Reproductive Techniques, Assisted; Sensitivity and Specificity
PubMed: 29547689
DOI: 10.1002/14651858.CD011872.pub3 -
The Cochrane Database of Systematic... May 2017In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non-invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment.
OBJECTIVES
To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (November 2016). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings.
SELECTION CRITERIA
Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.
MAIN RESULTS
We included four trials with a total of 802 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity.We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.11, 95% CI 0.83 to 1.48; I² = 0%; four RCTs; N = 802), or miscarriage (OR 0.96, 95% CI 0.52 to 1.78; I² = 0%; two RCTs; N = 434). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.99, 95% CI 0.71 to 1.38; I² = 0%; two RCTs; N = 621). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics.We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.22, 95% CI 0.92 to 1.62; I²= 26%; four trials; N = 802), or multiple pregnancy (OR 1.52, 95% CI 0.71 to 3.23; I² = 0%; two RCTs, N = 181). There was very low-quality evidence of little or no difference between groups in ectopic pregnancy rates (OR 3.37, 95% CI 0.14 to 83.40; one RCT; N = 309), and foetal abnormalities (no events; one RCT; N = 125), and very low-quality evidence of higher rates of cycle cancellation in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.14, 95% CI 0.83 to 1.57; I² = 0%; two RCTs; N = 621).The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials.
AUTHORS' CONCLUSIONS
According to current trials in women undergoing ART, there is insufficient evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, or miscarriage rates. The existing evidence varied from very low to low-quality. Data on adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.
Topics: Abortion, Spontaneous; Adult; Endometrium; Female; Humans; Live Birth; Metabolomics; Oocytes; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic; Reproductive Techniques, Assisted; Sensitivity and Specificity
PubMed: 28534597
DOI: 10.1002/14651858.CD011872.pub2 -
Reproduction (Cambridge, England) Apr 2022Genetic testing is becoming increasingly required at almost every stage of failed female reproduction/infertility. Nonetheless, clinical evidence for the majority of...
Genetic testing is becoming increasingly required at almost every stage of failed female reproduction/infertility. Nonetheless, clinical evidence for the majority of identified gene-disease relationships is ill-defined, thus leading to difficult gene variant interpretation and poor translation of existing knowledge into clinics. We aimed to identify the genes that have ever been implicated in monogenic female reproductive failure in humans and to classify the identified gene-disease relationship pairs using a standardized clinical validity assessment. A PubMed search following PRISMA guidelines was conducted on 20 September 2021 aiming to identify studies pertaining to genetic causes of phenotypes of female reproductive failure. The clinical validity of identified gene-disease pairs was assessed using standardized criteria, counting whether sufficient genetic and experimental evidence has been accumulated to consider a single gene 'characterized' for a single Mendelian disease. In total, 1256 articles were selected for the data extraction; 183 unique gene-disease pairs were classified spanning the following phenotypes: hypogonadotropic hypogonadism, ovarian dysgenesis, premature ovarian failure/insufficiency, ovarian hyperstimulation syndrome, empty follicle syndrome, oocyte maturation defect, fertilization failure, early embryonic arrest, recurrent hydatidiform mole, adrenal disfunction and Mullerian aplasia. Twenty-four gene-disease pairs showed definitive evidence, 36 - strong, 19 - moderate, 81 - limited and 23 - showed no evidence. Here, we provide comprehensive, systematic and timely information on the genetic causes of female infertility. Our classification of genetic causes of female reproductive failure will facilitate the composition of up-to-date guidelines on genetic testing in female reproduction, the development of diagnostic gene panels and the advancement of reproductive decision-making.
Topics: Female; Genetic Testing; Humans; Infertility, Female; Neoplasm Recurrence, Local; Oocytes; Ovarian Hyperstimulation Syndrome; Pregnancy
PubMed: 35451369
DOI: 10.1530/REP-21-0486 -
Human Reproduction Update 2011Non-invasive selection of developmentally competent human oocytes may increase the overall efficiency of human assisted reproduction and is regarded as crucial in... (Review)
Review
BACKGROUND
Non-invasive selection of developmentally competent human oocytes may increase the overall efficiency of human assisted reproduction and is regarded as crucial in countries where legal, social or religious factors restrict the production of supernumerary embryos. The purpose of this study was to summarize the predictive value for IVF success of morphological features of the oocyte that can be obtained by light or polarized microscopic investigations.
METHODS
Studies about oocyte morphology and IVF/ICSI outcomes were identified by using a systematic literature search.
RESULTS
Fifty relevant articles were identified: 33 analysed a single feature, 9 observed multiple features and investigated the effect of these features individually, 8 summarized the effect of individual features. Investigated structures were the following: meiotic spindle (15 papers), zona pellucida (15 papers), vacuoles or refractile bodies (14 papers), polar body shape (12 papers), oocyte shape (10 papers), dark cytoplasm or diffuse granulation (12 papers), perivitelline space (11 papers), central cytoplasmic granulation (8 papers), cumulus-oocyte complex (6 papers) and cytoplasm viscosity and membrane resistance characteristics (2 papers). None of these features were unanimously evaluated to have prognostic value for further developmental competence of oocytes.
CONCLUSIONS
No clear tendency in recent publications to a general increase in predictive value of morphological features was found. These contradicting data underline the importance of more intensive and coordinated research to reach a consensus and fully exploit the predictive potential of morphological examination of human oocytes.
Topics: Cell Culture Techniques; Cryopreservation; Cumulus Cells; Fertilization in Vitro; Humans; Oocytes; Zona Pellucida
PubMed: 20639518
DOI: 10.1093/humupd/dmq029