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Human Reproduction Update Mar 2019Early reproductive failure is the most common complication of pregnancy with only 30% of conceptions reaching live birth. Establishing a successful pregnancy depends... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Early reproductive failure is the most common complication of pregnancy with only 30% of conceptions reaching live birth. Establishing a successful pregnancy depends upon implantation, a complex process involving interactions between the endometrium and the blastocyst. It is estimated that embryos account for one-third of implantation failures, while suboptimal endometrial receptivity and altered embryo-endometrial dialogue are responsible for the remaining two-thirds. Endometrial receptivity has been the focus of extensive research for over 80 years, leading to an indepth understanding of the processes associated with embryo-endometrial cross-talk and implantation. However, little progress has been achieved to translate this understanding into clinically meaningful prognostic tests and treatments for suboptimal endometrial receptivity.
OBJECTIVE AND RATIONALE
The objective of this systematic review was to examine the evidence from observational studies supporting the use of endometrial receptivity markers as prognostic factors for pregnancy outcome in women wishing to conceive, in order to aid clinicians in choosing the most useful marker in clinical practice and for informing further research.
SEARCH METHODS
The review protocol was registered with PROSPERO (CRD42017077891). MEDLINE and Embase were searched for observational studies published from inception until 26 February 2018. We included studies that measured potential markers of endometrial receptivity prior to pregnancy attempts and reported the subsequent pregnancy outcomes. We performed association and accuracy analyses using clinical pregnancy as an outcome to reflect the presence of receptive endometrium. The Newcastle-Ottawa scale for observational studies was employed to assess the quality of the included studies.
OUTCOMES
We included 163 studies (88 834 women) of moderate overall quality in the narrative synthesis, out of which 96 were included in the meta-analyses. Studies reported on various endometrial receptivity markers evaluated by ultrasound, endometrial biopsy, endometrial fluid aspirate and hysteroscopy in the context of natural conception, IUI and IVF. Associations were identified between clinical pregnancy and various endometrial receptivity markers (endometrial thickness, endometrial pattern, Doppler indices, endometrial wave-like activity and various molecules); however, their poor ability to predict clinical pregnancy prevents them from being used in clinical practice. Results from several modern molecular tests are promising and further data are awaited.
WIDER IMPLICATIONS
The post-test probabilities from our analyses may be used in clinical practice to manage couples' expectations during fertility treatments (IUI and IVF). Conventionally, endometrial receptivity is seen as a dichotomous outcome (present or absent), but we propose that various levels of endometrial receptivity exist within the window of implantation. For instance, different transcriptomic signatures could represent varying levels of endometrial receptivity, which can be linked to different pregnancy outcomes. Many studies reported the means of a particular biomarker in those who achieved a pregnancy compared with those who did not. However, extreme values of a biomarker (as opposite to the means) may have significant prognostic and diagnostic implications that are not captured in the means. Therefore, we suggest reporting the outcomes by categories of biomarker levels rather than reporting means of biomarker levels within clinical outcome groups.
Topics: Biomarkers; Embryo Implantation; Endometrium; Female; Fertility; Fertilization in Vitro; Humans; Hysteroscopy; Live Birth; Observational Studies as Topic; Pregnancy; Pregnancy, Multiple
PubMed: 30624659
DOI: 10.1093/humupd/dmy044 -
Human Reproduction Update Mar 2017Successful cryopreservation of oocytes and embryos is essential not only to maximize the safety and efficacy of ovarian stimulation cycles in an IVF treatment, but also... (Meta-Analysis)
Meta-Analysis Review
Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance.
BACKGROUND
Successful cryopreservation of oocytes and embryos is essential not only to maximize the safety and efficacy of ovarian stimulation cycles in an IVF treatment, but also to enable fertility preservation. Two cryopreservation methods are routinely used: slow-freezing or vitrification. Slow-freezing allows for freezing to occur at a sufficiently slow rate to permit adequate cellular dehydration while minimizing intracellular ice formation. Vitrification allows the solidification of the cell(s) and of the extracellular milieu into a glass-like state without the formation of ice.
OBJECTIVE AND RATIONALE
The objective of our study was to provide a systematic review and meta-analysis of clinical outcomes following slow-freezing/thawing versus vitrification/warming of oocytes and embryos and to inform the development of World Health Organization guidance on the most effective cryopreservation method.
SEARCH METHODS
A Medline search was performed from 1966 to 1 August 2016 using the following search terms: (Oocyte(s) [tiab] OR (Pronuclear[tiab] OR Embryo[tiab] OR Blastocyst[tiab]) AND (vitrification[tiab] OR freezing[tiab] OR freeze[tiab]) AND (pregnancy[tiab] OR birth[tiab] OR clinical[tiab]). Queries were limited to those involving humans. RCTs and cohort studies that were published in full-length were considered eligible. Each reference was reviewed for relevance and only primary evidence and relevant articles from the bibliographies of included articles were considered. References were included if they reported cryosurvival rate, clinical pregnancy rate (CPR), live-birth rate (LBR) or delivery rate for slow-frozen or vitrified human oocytes or embryos. A meta-analysis was performed using a random effects model to calculate relative risk ratios (RR) and 95% CI.
OUTCOMES
One RCT study comparing slow-freezing versus vitrification of oocytes was included. Vitrification was associated with increased ongoing CPR per cycle (RR = 2.81, 95% CI: 1.05-7.51; P = 0.039; 48 and 30 cycles, respectively, per transfer (RR = 1.81, 95% CI 0.71-4.67; P = 0.214; 47 and 19 transfers) and per warmed/thawed oocyte (RR = 1.14, 95% CI: 1.02-1.28; P = 0.018; 260 and 238 oocytes). One RCT comparing vitrification versus fresh oocytes was analysed. In vitrification and fresh cycles, respectively, no evidence for a difference in ongoing CPR per randomized woman (RR = 1.03, 95% CI: 0.87-1.21; P = 0.744, 300 women in each group), per cycle (RR = 1.01, 95% CI: 0.86-1.18; P = 0.934; 267 versus 259 cycles) and per oocyte utilized (RR = 1.02, 95% CI: 0.82-1.26; P = 0.873; 3286 versus 3185 oocytes) was reported. Findings were consistent with relevant cohort studies. Of the seven RCTs on embryo cryopreservation identified, three met the inclusion criteria (638 warming/thawing cycles at cleavage and blastocyst stage), none of which involved pronuclear-stage embryos. A higher CPR per cycle was noted with embryo vitrification compared with slow-freezing, though this was of borderline statistical significance (RR = 1.89, 95% CI: 1.00-3.59; P = 0.051; three RCTs; I2 = 71.9%). LBR per cycle was reported by one RCT performed with cleavage-stage embryos and was higher for vitrification (RR = 2.28; 95% CI: 1.17-4.44; P = 0.016; 216 cycles; one RCT). A secondary analysis was performed focusing on embryo cryosurvival rate. Pooled data from seven RCTs (3615 embryos) revealed a significant improvement in embryo cryosurvival following vitrification as compared with slow-freezing (RR = 1.59, 95% CI: 1.30-1.93; P < 0.001; I2 = 93%).
WIDER IMPLICATIONS
Data from available RCTs suggest that vitrification/warming is superior to slow-freezing/thawing with regard to clinical outcomes (low quality of the evidence) and cryosurvival rates (moderate quality of the evidence) for oocytes, cleavage-stage embryos and blastocysts. The results were confirmed by cohort studies. The improvements obtained with the introduction of vitrification have several important clinical implications in ART. Based on this evidence, in particular regarding cryosurvival rates, laboratories that continue to use slow-freezing should consider transitioning to the use of vitrification for cryopreservation.
Topics: Birth Rate; Blastocyst; Cohort Studies; Cryopreservation; Embryo Culture Techniques; Embryo Transfer; Female; Humans; Odds Ratio; Oocytes; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic
PubMed: 27827818
DOI: 10.1093/humupd/dmw038 -
Journal of Assisted Reproduction and... Aug 2021Wide controversy is still ongoing regarding efficiency of preimplantation genetic testing for aneuploidy (PGT-A). This systematic review and meta-analysis, aims to... (Meta-Analysis)
Meta-Analysis
PURPOSE
Wide controversy is still ongoing regarding efficiency of preimplantation genetic testing for aneuploidy (PGT-A). This systematic review and meta-analysis, aims to identify the patient age group that benefits from PGT-A and the best day to biopsy.
METHODS
A systematic search of the literature was performed on MEDLINE/PubMed, Embase and Cochrane Central Library up to May 2020. Eleven randomized controlled trials employing PGT-A with comprehensive chromosomal screening (CCS) on Day-3 or Day-5 were eligible.
RESULTS
PGT-A did not improve live-birth rates (LBR) per patient in the general population (RR:1.11; 95%CI:0.87-1.42; n=1513; I=75%). However, PGT-A lowered miscarriage rate in the general population (RR:0.45; 95%CI:0.25-0.80; n=912; I=49%). Interestingly, the cumulative LBR per patient was improved by PGT-A (RR:1.36; 95%CI:1.13-1.64; n=580; I=12%). When performing an age-subgroup analysis PGT-A improved LBR in women over the age of 35 (RR:1.29; 95%CI:1.05-1.60; n=692; I=0%), whereas it appeared to be ineffective in younger women (RR:0.92; 95%CI:0.62-1.39; n=666; I=75%). Regarding optimal timing, only day-5 biopsy practice presented with improved LBR per ET (RR: 1.37; 95% CI: 1.03-1.82; I=72%).
CONCLUSION
PGT-A did not improve clinical outcomes for the general population, however PGT-A improved live-birth rates strictly when performed on blastocyst stage embryos of women over the 35-year-old mark.
Topics: Adult; Aneuploidy; Female; Fertilization in Vitro; Genetic Testing; Humans; Network Meta-Analysis; Pregnancy; Preimplantation Diagnosis; Randomized Controlled Trials as Topic
PubMed: 34036455
DOI: 10.1007/s10815-021-02227-9 -
Scientific Reports Jan 2021The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF)... (Meta-Analysis)
Meta-Analysis
The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF) on a subsequent IVF cycle outcome. Twenty-two RCTs and nineteen observational studies were included. Pooling of results showed a beneficial effect of intrauterine PBMC infusion on both CPR (RR 2.18; 95% CI 1.58-3.00; p < 0.00001; OR 2.03; 95% CI 1.22-3.36; p = 0.006) and LBR (RR 2.41; 95% CI 1.40-4.16; p = 0.002; OR 3.73; 95% CI 1.13-12.29; p = 0.03), of subcutaneous G-CSF administration on CPR (RR 2.29; 95% CI 1.58-3.31; p < 0.0001) and of intrauterine PRP infusion on CPR (RR 2.45; 95% CI 1.55-3.86; p = 0.0001). Observational studies also demonstrated a positive effect of IVIG and intrauterine hCG infusion on both CPR and LBR and of atosiban on CPR. Studies investigating intrauterine G-CSF infusion, LMWH, intravenous intralipid, hysteroscopy, blastocyst-stage ET, ZIFT, PGT-A and AH failed to observe an impact on IVF outcome. The quality of the evidence that emerged from RCTs focused on intrauterine PBMC infusion and subcutaneous G-CSF administration was moderate. For all other therapies/interventions it varied from low to very low. In conclusion, intrauterine PBMC infusion and subcutaneous G-CSF administration are the most promising therapeutic options for RIF. However, further well conducted RCTs are necessary before their introduction into clinical practice.
Topics: Abortion, Spontaneous; Birth Rate; Embryo Implantation; Female; Fertilization in Vitro; Humans; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 33462292
DOI: 10.1038/s41598-021-81439-6 -
Human Reproduction Update Sep 2023A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50-60%. This gap of knowledge on the causes of euploid blastocysts' reproductive failure is known as 'the black box of implantation'.
OBJECTIVE AND RATIONALE
Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with reproductive success or implantation failure of euploid blastocysts.
SEARCH METHODS
A systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords were '(blastocyst OR day5 embryo OR day6 embryo OR day7 embryo) AND (euploid OR chromosomally normal OR preimplantation genetic testing) AND (implantation OR implantation failure OR miscarriage OR abortion OR live birth OR biochemical pregnancy OR recurrent implantation failure)'. Overall, 1608 items were identified and screened. We included all prospective or retrospective clinical studies and randomized-controlled-trials (RCTs) that assessed any feature associated with live-birth rates (LBR) and/or miscarriage rates (MR) among non-mosaic euploid blastocyst transfer after TE biopsy and PGT-A. In total, 41 reviews and 372 papers were selected, clustered according to a common focus, and thoroughly reviewed. The PRISMA guideline was followed, the PICO model was adopted, and ROBINS-I and ROB 2.0 scoring were used to assess putative bias. Bias across studies regarding the LBR was also assessed using visual inspection of funnel plots and the trim and fill method. Categorical data were combined with a pooled-OR. The random-effect model was used to conduct the meta-analysis. Between-study heterogeneity was addressed using I2. Whenever not suitable for the meta-analysis, the included studies were simply described for their results. The study protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329).
OUTCOMES
We included 372 original papers (335 retrospective studies, 30 prospective studies and 7 RCTs) and 41 reviews. However, most of the studies were retrospective, or characterized by small sample sizes, thus prone to bias, which reduces the quality of the evidence to low or very low. Reduced inner cell mass (7 studies, OR: 0.37, 95% CI: 0.27-0.52, I2 = 53%), or TE quality (9 studies, OR: 0.53, 95% CI: 0.43-0.67, I2 = 70%), overall blastocyst quality worse than Gardner's BB-grade (8 studies, OR: 0.40, 95% CI: 0.24-0.67, I2 = 83%), developmental delay (18 studies, OR: 0.56, 95% CI: 0.49-0.63, I2 = 47%), and (by qualitative analysis) some morphodynamic abnormalities pinpointed through time-lapse microscopy (abnormal cleavage patterns, spontaneous blastocyst collapse, longer time of morula formation I, time of blastulation (tB), and duration of blastulation) were all associated with poorer reproductive outcomes. Slightly lower LBR, even in the context of PGT-A, was reported among women ≥38 years (7 studies, OR: 0.87, 95% CI: 0.75-1.00, I2 = 31%), while obesity was associated with both lower LBR (2 studies, OR: 0.66, 95% CI: 0.55-0.79, I2 = 0%) and higher MR (2 studies, OR: 1.8, 95% CI: 1.08-2.99, I2 = 52%). The experience of previous repeated implantation failures (RIF) was also associated with lower LBR (3 studies, OR: 0.72, 95% CI: 0.55-0.93, I2 = 0%). By qualitative analysis, among hormonal assessments, only abnormal progesterone levels prior to transfer were associated with LBR and MR after PGT-A. Among the clinical protocols used, vitrified-warmed embryo transfer was more effective than fresh transfer (2 studies, OR: 1.56, 95% CI: 1.05-2.33, I2 = 23%) after PGT-A. Lastly, multiple vitrification-warming cycles (2 studies, OR: 0.41, 95% CI: 0.22-0.77, I2 = 50%) or (by qualitative analysis) a high number of cells biopsied may slightly reduce the LBR, while simultaneous zona-pellucida opening and TE biopsy allowed better results than the Day 3 hatching-based protocol (3 studies, OR: 1.41, 95% CI: 1.18-1.69, I2 = 0%).
WIDER IMPLICATIONS
Embryo selection aims at shortening the time-to-pregnancy, while minimizing the reproductive risks. Knowing which features are associated with the reproductive competence of euploid blastocysts is therefore critical to define, implement, and validate safer and more efficient clinical workflows. Future research should be directed towards: (i) systematic investigations of the mechanisms involved in reproductive aging beyond de novo chromosomal abnormalities, and how lifestyle and nutrition may accelerate or exacerbate their consequences; (ii) improved evaluation of the uterine and blastocyst-endometrial dialogue, both of which represent black boxes themselves; (iii) standardization/automation of embryo assessment and IVF protocols; (iv) additional invasive or preferably non-invasive tools for embryo selection. Only by filling these gaps we may finally crack the riddle behind 'the black box of implantation'.
Topics: Pregnancy; Female; Humans; Abortion, Spontaneous; Embryo Implantation; Blastocyst; Embryo Transfer; Genetic Testing; Retrospective Studies; Aneuploidy; Pregnancy Rate; Preimplantation Diagnosis
PubMed: 37192834
DOI: 10.1093/humupd/dmad010 -
The Cochrane Database of Systematic... May 2022Advances in embryo culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage-stage embryo transfer to blastocyst-stage embryo transfer.... (Review)
Review
BACKGROUND
Advances in embryo culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage-stage embryo transfer to blastocyst-stage embryo transfer. The rationale for blastocyst-stage transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates.
OBJECTIVES
To determine whether blastocyst-stage (day 5 to 6) embryo transfer improves the live birth rate (LBR) per fresh transfer, and other associated outcomes, compared with cleavage-stage (day 2 to 3) embryo transfer.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL, from inception to October 2021. We also searched registers of ongoing trials and the reference lists of studies retrieved.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) which compared the effectiveness of IVF with blastocyst-stage embryo transfer versus IVF with cleavage-stage embryo transfer.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. Our primary outcomes were LBR per fresh transfer and cumulative clinical pregnancy rates (cCPR). Secondary outcomes were clinical pregnancy rate (CPR), multiple pregnancy, high-order multiple pregnancy, miscarriage (all following first embryo transfer), failure to transfer embryos, and whether supernumerary embryos were frozen for transfer at a later date (frozen-thawed embryo transfer). We assessed the overall quality of the evidence for the main comparisons using GRADE methods.
MAIN RESULTS
We included 32 RCTs (5821 couples or women). The live birth rate following fresh transfer was higher in the blastocyst-stage transfer group (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06 to 1.51; I = 53%; 15 studies, 2219 women; low-quality evidence). This suggests that if 31% of women achieve live birth after fresh cleavage-stage transfer, between 32% and 41% would do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR. A post hoc analysis showed that vitrification could increase the cCPR. This is an interesting finding that warrants further investigation when more studies using vitrification are published. The CPR was also higher in the blastocyst-stage transfer group, following fresh transfer (OR 1.25, 95% CI 1.12 to 1.39; I = 51%; 32 studies, 5821 women; moderate-quality evidence). This suggests that if 39% of women achieve a clinical pregnancy after fresh cleavage-stage transfer, between 42% and 47% will probably do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer increases multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; I = 30%; 19 studies, 3019 women; low-quality evidence) or miscarriage rates (OR 1.12, 95% CI 0.90 to 1.38; I = 24%; 22 studies, 4208 women; low-quality evidence). This suggests that if 9% of women have a multiple pregnancy after fresh cleavage-stage transfer, between 8% and 12% would do so after fresh blastocyst-stage transfer. However, a sensitivity analysis restricted only to studies with low or 'some concerns' for risk of bias, in the subgroup of equal number of embryos transferred, showed that blastocyst transfer probably increases the multiple pregnancy rate. Embryo freezing rates (when there are frozen supernumerary embryos for transfer at a later date) were lower in the blastocyst-stage transfer group (OR 0.48, 95% CI 0.40 to 0.57; I = 84%; 14 studies, 2292 women; low-quality evidence). This suggests that if 60% of women have embryos frozen after cleavage-stage transfer, between 37% and 46% would do so after blastocyst-stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; I = 36%; 17 studies, 2577 women; moderate-quality evidence). This suggests that if 1% of women have no embryos transferred in planned fresh cleavage-stage transfer, between 2% and 4% probably have no embryos transferred in planned fresh blastocyst-stage transfer. The evidence was of low quality for most outcomes. The main limitations were serious imprecision and serious risk of bias, associated with failure to describe acceptable methods of randomisation.
AUTHORS' CONCLUSIONS
There is low-quality evidence for live birth and moderate-quality evidence for clinical pregnancy that fresh blastocyst-stage transfer is associated with higher rates of both than fresh cleavage-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR derived from fresh and frozen-thawed cycles following a single oocyte retrieval. Although there is a benefit favouring blastocyst-stage transfer in fresh cycles, more evidence is needed to know whether the stage of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage. They should also evaluate women with a poor prognosis to enable those undergoing assisted reproductive technology (ART) and service providers to make well-informed decisions on the best treatment option available.
Topics: Abortion, Spontaneous; Blastocyst; Embryo Transfer; Female; Humans; Live Birth; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted
PubMed: 35588094
DOI: 10.1002/14651858.CD002118.pub6 -
Fertility and Sterility Dec 2021To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes.
DESIGN
Systematic review and meta-analysis.
SETTING
Not applicable.
PATIENT(S)
Women undergoing FET.
INTERVENTION(S)
We conducted electronic searches of MEDLINE, PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and grey literature (not widely available) from inception to March 2021 to identify cohort studies in which the serum luteal progesterone level was measured around the time of FET.
MAIN OUTCOME MEASURE(S)
Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate.
RESULT(S)
Among the studies analyzing serum progesterone level thresholds <10 ng/mL, a higher serum progesterone level was associated with increased rates of ongoing pregnancy or live birth (relative risk [RR] 1.47, 95% confidence interval [CI] 1.28 to 1.70), higher chance of clinical pregnancy (RR 1.31, 95% CI 1.16 to 1.49), and lower risk of miscarriage (RR 0.62, 95% CI 0.50 to 0.77) in cycles using exclusively vaginal progesterone and blastocyst embryos. There was uncertainty about whether progesterone thresholds ≥10 ng/mL were associated with FET outcomes in sensitivity analyses including all studies, owing to high interstudy heterogeneity and wide CIs.
CONCLUSION(S)
Our findings indicate that there may be a minimum clinically important luteal serum concentration of progesterone required to ensure an optimal endocrine milieu during embryo implantation and early pregnancy after FET treatment. Future clinical trials are required to assess whether administering higher-dose luteal phase support improves outcomes in women with a low serum progesterone level at the time of FET.
PROSPERO NUMBER
CRD42019157071.
Topics: Cryopreservation; Embryo Transfer; Female; Humans; Live Birth; Luteal Phase; Pregnancy; Pregnancy Rate; Progesterone; Prospective Studies; Reproductive Techniques, Assisted; Retrospective Studies
PubMed: 34384594
DOI: 10.1016/j.fertnstert.2021.07.002 -
Fertility and Sterility Aug 2023Maternal age-related embryo aneuploidy is considered the most significant limiting factor for a favorable outcome after assisted reproduction technology (ART)... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Maternal age-related embryo aneuploidy is considered the most significant limiting factor for a favorable outcome after assisted reproduction technology (ART) procedures. Thus, preimplantation genetic testing for aneuploidies has been proposed as a strategy to genetically evaluate embryos before transfer to the uterus. However, whether embryo ploidy justifies all the aspects of age-related fertility decline remains controversial.
OBJECTIVE
To investigate the effect of different maternal ages on ART success rates after transfer of euploid embryos.
DATA SOURCES
ScienceDirect, PubMed, Scopus, Embase, the Cochrane library, Clinicaltrials.gov, EU Clinical Trials Register, and World Health Organization International Clinical Trials Registry were searched from inception until November 2021 using combinations of relevant keywords.
STUDY SELECTION AND SYNTHESIS
Observational and randomized controlled studies were included if they investigated the impact of maternal age on ART outcomes after the transfer of euploid embryos and reported frequencies of women achieving ongoing pregnancy or live birth.
MAIN OUTCOMES
The ongoing pregnancy rate or live birth rate (OPR/LBR) after euploid embryo transfer comparing women <35 vs. women ≥35 years old was the primary outcome. Secondary outcomes included implantation rate and miscarriage rate. Subgroup and sensitivity analyses were also planned to explore the sources of inconsistency among studies. The quality of studies was assessed using a modified version of the Newcastle-Ottawa Scale, and body of evidence was evaluated using the Grading of Recommendations Assessment Development and Evaluation working group methodology.
RESULTS
A total of 7 studies were included (n = 11,335 ART embryo transfers of euploid embryos). A higher OPR/LBR (odds ratio, 1.29; 95% confidence interval [CI], 1.07-1.54; I = 40%) in women aged <35 years than in women ≥35 with a risk difference equal to 0.06 (95% CI, 0.02-0.09) was found. In line, implantation rate was higher in the youngest group (odds ratio, 1.22; 95% CI, 1.12-1.32; I = 0%). A statistically significant higher OPR/LBR was also found comparing women aged <35 to women 35-37, 38-40, or 41-42. A gradient relationship between age and OPR/LBR could be observed in proportion meta-analysis, especially if restricted to studies with low risk of bias.
CONCLUSION AND RELEVANCE
Increasing maternal age is associated with a decline in ART success rates independent of embryo ploidy. This message contributes to an appropriate patient's counseling before starting preimplantation genetic testing for aneuploidies procedures.
PROSPERO REGISTRATION NUMBER
CRD42021289760.
Topics: Pregnancy; Female; Humans; Adult; Maternal Age; Embryo Transfer; Reproductive Techniques, Assisted; Pregnancy Rate; Embryo Implantation; Live Birth; Aneuploidy; Blastocyst
PubMed: 36878347
DOI: 10.1016/j.fertnstert.2023.02.036 -
International Journal of Molecular... May 2023Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of the blastocyst. ESCs have two distinctive properties: ability to proliferate indefinitely, a... (Review)
Review
Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of the blastocyst. ESCs have two distinctive properties: ability to proliferate indefinitely, a feature referred as "self-renewal", and to differentiate into different cell types, a peculiar characteristic known as "pluripotency". Self-renewal and pluripotency of ESCs are finely orchestrated by precise external and internal networks including epigenetic modifications, transcription factors, signaling pathways, and histone modifications. In this systematic review, we examine the main molecular mechanisms that sustain self-renewal and pluripotency in both murine and human ESCs. Moreover, we discuss the latest literature on human naïve pluripotency.
Topics: Humans; Animals; Mice; Embryonic Stem Cells; Human Embryonic Stem Cells; Blastocyst; Signal Transduction; Transcription Factors; Cell Differentiation
PubMed: 37176093
DOI: 10.3390/ijms24098386 -
Morphological and morphokinetic associations with aneuploidy: a systematic review and meta-analysis.Human Reproduction Update Aug 2022A time lapse system (TLS) is utilized in some fertility clinics with the aim of predicting embryo viability and chance of live birth during IVF. It has been hypothesized... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A time lapse system (TLS) is utilized in some fertility clinics with the aim of predicting embryo viability and chance of live birth during IVF. It has been hypothesized that aneuploid embryos display altered morphokinetics as a consequence of their abnormal chromosome complement. Since aneuploidy is one of the fundamental reasons for IVF failure and miscarriage, attention has focused on utilizing morphokinetics to develop models to non-invasively risk stratify embryos for ploidy status. This could avoid or reduce the costs associated with pre-implantation genetic testing for aneuploidy (PGT-A). Furthermore, TLS have provided an understanding of the true prevalence of other dysmorphisms. Hypothetically, the incorporation of morphological features into a model could act synergistically, improving a model's discriminative ability to predict ploidy status.
OBJECTIVE AND RATIONALE
The aim of this systematic review and meta-analysis was to investigate associations between ploidy status and morphokinetic or morphological features commonly denoted on a TLS. This will determine the feasibility of a prediction model for euploidy and summarize the most useful prognostic markers to be included in model development.
SEARCH METHODS
Five separate searches were conducted in Medline, Embase, PubMed and Cinahl from inception to 1 July 2021. Search terms and word variants included, among others, PGT-A, ploidy, morphokinetics and time lapse, and the latter were successively substituted for the following morphological parameters: fragmentation, multinucleation, abnormal cleavage and contraction. Studies were limited to human studies.
OUTCOMES
Overall, 58 studies were included incorporating over 40 000 embryos. All except one study had a moderate risk of bias in at least one domain when assessed by the quality in prognostic studies tool. Ten morphokinetic variables were significantly delayed in aneuploid embryos. When excluding studies using less reliable genetic technologies, the most notable variables were: time to eight cells (t8, 1.13 h, 95% CI: 0.21-2.05; three studies; n = 742; I2 = 0%), t9 (2.27 h, 95% CI: 0.5-4.03; two studies; n = 671; I2 = 33%), time to formation of a full blastocyst (tB, 1.99 h, 95% CI 0.15-3.81; four studies; n = 1640; I2 = 76%) and time to expanded blastocyst (tEB, 2.35 h, 95% CI: 0.06-4.63; four studies; n = 1640; I2 = 83%). There is potentially some prognostic potential in the degree of fragmentation, multinucleation persisting to the four-cell stage and frequency of embryo contractions. Reverse cleavage was associated with euploidy in this meta-analysis; however, this article argues that these are likely spurious results requiring further investigation. There was no association with direct unequal cleavage in an embryo that progressed to a blastocyst, or with multinucleation assessed on Day 2 or at the two-cell stage. However, owing to heterogeneous results and poor-quality evidence, associations between these morphological components needs to be investigated further before conclusions can be reliably drawn.
WIDER IMPLICATIONS
This first systematic review and meta-analysis of morphological and morphokinetic associations with ploidy status demonstrates the most useful morphokinetic variables, namely t8, t9 and tEB to be included in future model development. There is considerable variability within aneuploid and euploid embryos making definitively classifying them impossible; however, it is feasible that embryos could be prioritized for biopsy. Furthermore, these results support the mechanism by which algorithms for live birth may have predictive ability, suggesting aneuploidy causes delayed cytokinesis. We highlight significant heterogeneity in our results secondary to local conditions and diverse patient populations, therefore calling for future models to be robustly developed and tested in-house. If successful, such a model would constitute a meaningful breakthrough when accessing PGT-A is unsuitable for couples.
Topics: Aneuploidy; Blastocyst; Embryo Culture Techniques; Embryo Implantation; Female; Humans; Live Birth; Pregnancy; Retrospective Studies
PubMed: 35613016
DOI: 10.1093/humupd/dmac022