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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 -
Seizure Mar 2024Wolf-Hirschhorn syndrome (WHS) is araredisorderwithan estimated prevalence being around 1 in 50,000 births. The syndrome is caused by the deletion of a critical region... (Review)
Review
Wolf-Hirschhorn syndrome (WHS) is araredisorderwithan estimated prevalence being around 1 in 50,000 births. The syndrome is caused by the deletion of a critical region (Wolf-Hirschhorn Syndrome Critical region- WHSCR) on chromosome 4p16.3. WHS is clinically characterized by pre-and postnatal growth restriction, hypotonia, intellectual disability, craniofacial dysmorphismand congenital fusion anomalies. The clinical aspects are variable due to the deletion size.Consistently, epilepsy is one of the major concerns for parents and professionals caring for children with WHS. Seizures tend to occur in over 90% of patients, with onset within the first 3 years of life, and a peak incidence at around 6-12 months of age. Approximately 20% of patients had the first seizure onset within the first 6 months of age, almost 50% at 6 to 12 months of age and about 25% later than 12 months of age. The main types of epileptic seizures occurring in patients with WHS were generalized tonic-clonic seizures (around 70%). These were followed by tonic spasms (20%); focal seizures with impaired awareness (12%) and clonicseizures in 7% of patients.Seizures are often triggered by fever, followed by infections of various systems. Particularly, half of WHS patients experience status epilepticus in the first years of life, which can be fatal. Due to limited number of reports on the topic of EEG abnormalities in epilepsy among WHS patients, it is difficult to determine whether there are any characteristic deviations for WHS. Although more than 300 persons with WHS have been reported in the literature, there is sparse knowledge about epilepsy and methods of its anti-seizure medication (ASM) management with an assessment of their effectiveness. The purpose of this systematic review is to briefly summarize achievements and advances in the field of epilepsy in Wolf-Hirschhorn syndrome.
Topics: Child; Humans; Infant; Wolf-Hirschhorn Syndrome; Epilepsy; Intellectual Disability; Status Epilepticus; Craniofacial Abnormalities; Chromosome Deletion; Phenotype
PubMed: 36526544
DOI: 10.1016/j.seizure.2022.12.001 -
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 -
Frontiers in Endocrinology 2023Preimplantation genetic testing for aneuploidy (PGT-A) is an emerging technology that aims to identify euploid embryos for transfer, reducing the risk of embryonic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Preimplantation genetic testing for aneuploidy (PGT-A) is an emerging technology that aims to identify euploid embryos for transfer, reducing the risk of embryonic chromosomal abnormalities. However, the clinical benefits of PGT-A in recurrent pregnancy failure (RPF) patients, particularly in young RPF patients, remains uncertain.
OBJECTIVE AND RATIONALE
This meta-analysis aimed to determine whether RPF patients undergoing PGT-A had better clinical outcomes compared to those not undergoing PGT-A, thus assessing the value of PGT-A in clinical practice.
SEARCH METHODS
We systematically searched PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database for Chinese Technical Periodicals (VIP) from 2002 to 2022. Thirteen published studies involving 930 RPF patients screened using PGT-A and over 1,434 RPF patients screened without PGT-A were included in this meta-analysis. Clinical outcomes were evaluated based on embryo transfers after PGT-A (n=1,015) and without PGT-A (n=1,799).
CLINICAL OUTCOMES
The PGT-A group demonstrated superior clinical outcomes compared to the fertilization (IVF)/intracytoplasmic sperm injection (ICSI) group. The PGT-A group had a significantly higher implantation rate (IR) (RR=2.01, 95% CI: [1.73; 2.34]), clinical pregnancy rate (CPR) (RR=1.53, 95% CI: [1.36; 1.71]), ongoing pregnancy rate (OPR) (RR=1.76, 95% CI: [1.35; 2.29]), live birth rate (LBR) (RR=1.75, 95% CI: [1.51; 2.03]), and significantly lower clinical miscarriage rate (CMR) (RR=0.74, 95% CI: [0.54; 0.99]). Subgroup analysis based on patient age (under 35 years and 35 years or older) showed that both PGT-A subgroups had significantly better CPR (P<0.01) and LBR (P<0.05) values compared to the IVF/ICSI groups.
SUMMARY
This meta-analysis demonstrates that PGT-A in RPF patients, is associated with improved clinical outcomes, including higher IR, CPR, OPR, and LBR values, and lower CMR compared to the IVF/ICSI group. These findings support the positive clinical application of PGT-A in RPF patients.
SYSTEMATIC REVIEW REGISTRATION
http://INPLASY.com, identifier INPLASY 202320118.
Topics: Pregnancy; Female; Humans; Male; Adult; Preimplantation Diagnosis; Semen; Genetic Testing; Fertilization in Vitro; Abortion, Spontaneous; Aneuploidy
PubMed: 37850092
DOI: 10.3389/fendo.2023.1178294 -
Fertility and Sterility Jan 2024To investigate whether Azoospermia Factor c (AZFc) microdeletions affect Assisted Reproductive Technology (ART) outcomes. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To investigate whether Azoospermia Factor c (AZFc) microdeletions affect Assisted Reproductive Technology (ART) outcomes.
DESIGN
Systematic review and meta-analysis.
SETTING
Not applicable.
PATIENTS
Infertile men with and without AZFc microdeletions.
INTERVENTION(S)
Electronic databases were searched for case-control studies reporting sperm retrieval rates and outcomes of ART in infertile men with and without AZFc microdeletions from inception to April 2023. Study quality was assessed using the Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for both categories of infertile men.
MAIN OUTCOME MEASURES
The primary outcome was successful sperm retrieval and the secondary outcomes were outcomes of ART.
RESULTS
Case-control studies reporting sperm retrieval rates and ART outcomes in men with AZFa and AZFb deletions were unavailable. On the basis of the data from 3,807 men, sperm retrieval rates were found to be higher in men with AZFc microdeletions compared to their non-deleted counterparts [OR = 1.82, 95% CI 0.97, 3.41], but the difference was not statistically significant. A significantly lower fertilization rate (OR = 0.61, 95% CI [0.50, 0.74]), clinical pregnancy rate (OR = 0.61, 95% CI [0.42, 0.89]), and live birth rate (OR = 0.54, 95% CI [0.40, 0.72]) were observed in men with AZFc deletions compared with men without deletions. There was no statistically significant difference in rates of embryo cleavage, blastocyst formation, good-quality embryos, implantation, and miscarriage between the two groups. On correcting for female factors, the fertilization rate (OR = 0.76, 95% CI [0.71, 0.82]), cleavage rate (OR = 0.54, 95% CI [0.41, 0.72]), clinical pregnancy rate (OR = 0.39, 95% CI [0.30, 0.52]), and live birth rate (OR = 0.48, 95% CI [0.35, 0.65]) were significantly lower in men with AZFc deletions compared with controls.
CONCLUSIONS
Presence of AZFc microdeletions adversely affects outcomes of ART in infertile men. Further in-depth studies delineating the role of the AZF genes in embryonic development are necessary to understand the full-impact of this finding.
CLINICAL TRIAL REGISTRATION NUMBER
CRD42022311738.
Topics: Pregnancy; Humans; Male; Female; Azoospermia; Oligospermia; Retrospective Studies; Chromosome Deletion; Chromosomes, Human, Y; Semen; Infertility, Male; Sertoli Cell-Only Syndrome
PubMed: 37923163
DOI: 10.1016/j.fertnstert.2023.10.029 -
Journal of Assisted Reproduction and... Oct 2023To establish if preimplantation genetic testing for aneuploidy (PGT-A) at the blastocyst stage improves the composite outcome of live birth rate and ongoing pregnancy... (Meta-Analysis)
Meta-Analysis
PURPOSE
To establish if preimplantation genetic testing for aneuploidy (PGT-A) at the blastocyst stage improves the composite outcome of live birth rate and ongoing pregnancy rate per embryo transfer compared to conventional morphological assessment.
METHODS
A systematic literature search was conducted using PubMed, EMBASE and Cochrane database from 1st March 2000 until 1st March 2022. Studies comparing reproductive outcomes following in vitro fertilisation using comprehensive chromosome screening (CCS) at the blastocyst stage with traditional morphological methods were evaluated.
RESULTS
Of the 1307 citations identified, six randomised control trials (RCTs) and ten cohort studies fulfilled the inclusion criteria. The pooled data identified a benefit between PGT-A and control groups in the composite outcome of live birth rate and ongoing pregnancy per embryo transfer in both the RCT (RR 1.09, 95% CI 1.02-1.16) and cohort studies (RR 1.50, 95% CI 1.28-1.76). Euploid embryos identified by CCS were more likely to be successfully implanted amongst the RCT (RR 1.20, 95% CI 1.10-1.31) and cohort (RR 1.69, 95% CI 1.29-2.21) studies. The rate of miscarriage per clinical pregnancy is also significantly lower when CCS is implemented (RCT: RR 0.73, 95% CI 0.56-0.96 and cohort: RR 0.48, 95% CI 0.32-0.72).
CONCLUSIONS
CCS-based PGT-A at the blastocyst biopsy stage increases the composite outcome of live births and ongoing pregnancies per embryo transfer and reduces the rate of miscarriage compared to morphological assessment alone. In view of the limited number of studies included and the variation in methodology between studies, future reviews and analyses are required to confirm these findings.
Topics: Female; Humans; Pregnancy; Abortion, Spontaneous; Aneuploidy; Birth Rate; Blastocyst; Genetic Testing
PubMed: 37479946
DOI: 10.1007/s10815-023-02866-0 -
Prenatal Diagnosis Aug 2023Unexplained stillbirth is defined as a stillbirth with no known cause after the exclusion of common causes, including obstetric complications, infections, placental... (Review)
Review
Unexplained stillbirth is defined as a stillbirth with no known cause after the exclusion of common causes, including obstetric complications, infections, placental insufficiency or abruption, umbilical cord complications, and congenital abnormalities with or without known genetic cause. More than 60% of stillbirth cases remain unexplained. The aim of this systematic review was to investigate the known genetic causes of unexplained stillbirth cases and to evaluate the current position and future directions for the use of genetic and genomic testing in expanding the knowledge in this field. A systematic search through several databases was performed using the keywords genetics and stillbirths in humans. Different methods to detect various types of causal genetic aberrations have been used in the past decades, from standard karyotyping to novel methods such as chromosomal microarray analysis and next generation sequencing technologies. Apart from common chromosomal aneuploidies, a promising hypothesis about genetic causes included genes related to cardiomyopathies and channelopathies. However, these were tested in the research settings, since molecular karyotyping is currently the standard approach in the routine evaluation of genetic causes of stillbirth. Hereby, we provide evidence that expanding knowledge using novel genetic and genomic testing might uncover new genetic causes of unexplained stillbirth.
Topics: Humans; Female; Pregnancy; Stillbirth; Placenta; Aneuploidy; Databases, Factual; Genetic Profile
PubMed: 37072878
DOI: 10.1002/pd.6354 -
Journal of Assisted Reproduction and... Oct 2023Evaluate which factors are involved in the increased rate of mosaicism in embryos. (Meta-Analysis)
Meta-Analysis
PURPOSE
Evaluate which factors are involved in the increased rate of mosaicism in embryos.
METHODS
A systematic review and meta-analysis was performed. After an exhaustive search of the literature, a total of seven papers were included in the analysis. In addition, data collected from IVF cycles performed in our fertility clinic were also analysed. Day of biopsy, embryo quality, maternal and paternal age and seminal quality were the chosen factors to be studied.
RESULTS
The results of the meta-analysis show that neither embryo quality nor seminal quality were related to mosaic embryo rate (OR: 1.09; 95% CI: 0.94-1.28 and OR: 1.10; 95% CI: 0.87-1.37, respectively). A positive association was observed for the variable "biopsy day" with embryos biopsied at day 6 or 7 having the highest rate of mosaicism (OR: 1.06; 95% CI: 1.01-1.11). In opposite to what happens with aneuploidy rate, which increases with maternal age, embryo mosaicism is higher in younger women (<34 years) rather than in older ones (≥34 years) (OR: 0.95; 95% CI: 0.92-0.98). However, for the "paternal age" factor, no association with mosaicism was found (OR: 1.04; 95% CI: 0.90-1.21).
CONCLUSIONS
With the present study, we can conclude that the factors related to the presence of mosaicism in embryos are the embryo biopsy day and maternal age. The rest of the studied factors showed no significant relationship with mosaicism. These results are of great importance as knowing the possible causes leading to mosaicism helps to improve the clinical results of reproductive treatments.
Topics: Female; Humans; Aged; Adult; Mosaicism; Aneuploidy; Age Factors; Biopsy; Embryo, Mammalian
PubMed: 37592098
DOI: 10.1007/s10815-023-02914-9 -
Fertility and Sterility Aug 2023Noninvasive and minimally invasive preimplantation genetic testing for aneuploidy (PGT-A) is a tool that may one day become the gold standard for embryonic chromosomal...
Noninvasive and minimally invasive preimplantation genetic testing for aneuploidy (PGT-A) is a tool that may one day become the gold standard for embryonic chromosomal screening. Investigations on this topic have ranged from studying the culture media of embryos to the fluid inside the blastocoel, all in an attempt to find a reliable source of DNA without the need to biopsy the embryo. There is great interest across the board, both from those for and against biopsy, in a reliable test process that would give the patient and provider the same information possible from a biopsy without the risk. We aim to explore the current available research to better understand the utility and accuracy of PGT-A with these new sampling techniques. General concordance rates in comparison with biopsy-based PGT-A are promising, but it is clear that additional research and understanding are needed before adopting noninvasive and minimally invasive PGT-A as a widely used tool with strong clinical utility.
Topics: Pregnancy; Female; Humans; Preimplantation Diagnosis; Genetic Testing; Aneuploidy; Blastocyst; Culture Media; Fertilization in Vitro
PubMed: 37356468
DOI: 10.1016/j.fertnstert.2023.06.013 -
Journal of Magnetic Resonance Imaging :... Nov 2023As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in... (Review)
Review
As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in patients with glioma. The purpose of this study is to systematically review the literature concerning the magnetic resonance imaging (MRI) with artificial intelligence (AI) methods for predicting 1p/19q co-deletion status in glioma. PubMed, Scopus, Embase, and IEEE Xplore were searched in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses guidelines. Methodological quality of studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2. Finally, 28 studies were included in the quantitative analysis. Diagnostic test accuracy reached an area under the ROC curve of 0.71-0.98 were reported in 24 studies. The remaining four studies with no available AUC provided an accuracy of 0.75-0. 89. The included studies varied widely in terms of imaging sequences, input features, and modeling methods. The current review highlighted that integrating MRI with AI technology is a potential tool for determination 1p/19q status pre-operatively and noninvasively, which can possibly help clinical decision-making. However, the reliability and feasibility of this approach still need to be further validated and improved in a real clinical setting. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: 2.
Topics: Humans; Artificial Intelligence; Brain Neoplasms; Reproducibility of Results; Chromosome Deletion; Glioma; Isocitrate Dehydrogenase; Oligodendroglioma; Mutation
PubMed: 37083159
DOI: 10.1002/jmri.28737