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The Cochrane Database of Systematic... Oct 2014Human chorionic gonadotropin (HCG) is routinely used for final oocyte maturation triggering in in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Human chorionic gonadotropin (HCG) is routinely used for final oocyte maturation triggering in in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles, but the use of HCG for this purpose may have drawbacks. Gonadotropin-releasing hormone (GnRH) agonists present an alternative to HCG in controlled ovarian hyperstimulation (COH) treatment regimens in which the cycle has been down-regulated with a GnRH antagonist. This is an update of a review first published in 2010.
OBJECTIVES
To evaluate the effectiveness and safety of GnRH agonists in comparison with HCG for triggering final oocyte maturation in IVF and ICSI for women undergoing COH in a GnRH antagonist protocol.
SEARCH METHODS
We searched databases including the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and trial registers for published and unpublished articles (in any language) on randomised controlled trials (RCTs) of gonadotropin-releasing hormone agonists versus HCG for oocyte triggering in GnRH antagonist IVF/ICSI treatment cycles. The search is current to 8 September 2014.
SELECTION CRITERIA
RCTs that compared the clinical outcomes of GnRH agonist triggers versus HCG for final oocyte maturation triggering in women undergoing GnRH antagonist IVF/ICSI treatment cycles were included.
DATA COLLECTION AND ANALYSIS
Two or more review authors independently selected studies, extracted data and assessed study risk of bias. Treatment effects were summarised using a fixed-effect model, and subgroup analyses were conducted to explore potential sources of heterogeneity. Treatment effects were expressed as mean differences (MDs) for continuous outcomes and as odds ratios (ORs) for dichotomous outcomes, together with 95% confidence intervals (CIs). Primary outcomes were live birth and rate of ovarian hyperstimulation syndrome (OHSS) per women randomised. Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods were used to assess the quality of the evidence for each comparison.
MAIN RESULTS
We included 17 RCTs (n = 1847), of which 13 studies assessed fresh autologous cycles and four studies assessed donor-recipient cycles. In fresh autologous cycles, GnRH agonists were associated with a lower live birth rate than was seen with HCG (OR 0.47, 95% CI 0.31 to 0.70; five RCTs, 532 women, I(2) = 56%, moderate-quality evidence). This suggests that for a woman with a 31% chance of achieving live birth with the use of HCG, the chance of a live birth with the use of an GnRH agonist would be between 12% and 24%.In women undergoing fresh autologous cycles, GnRH agonists were associated with a lower incidence of mild, moderate or severe OHSS than was HCG (OR 0.15, 95% CI 0.05 to 0.47; eight RCTs, 989 women, I² = 42%, moderate-quality evidence). This suggests that for a woman with a 5% risk of mild, moderate or severe OHSS with the use of HCG, the risk of OHSS with the use of a GnRH agonist would be between nil and 2%.In women undergoing fresh autologous cycles, GnRH agonists were associated with a lower ongoing pregnancy rate than was seen with HCG (OR 0.70, 95% CI 0.54 to 0.91; 11 studies, 1198 women, I(2) = 59%, low-quality evidence) and a higher early miscarriage rate (OR 1.74, 95% CI 1.10 to 2.75; 11 RCTs, 1198 women, I² = 1%, moderate-quality evidence). However, the effect was dependent on the type of luteal phase support provided (with or without luteinising hormone (LH) activity); the higher rate of pregnancies in the HCG group applied only to the group that received luteal phase support without LH activity (OR 0.36, 95% CI 0.21 to 0.62; I(2) = 73%, five RCTs, 370 women). No evidence was found of a difference between groups in risk of multiple pregnancy (OR 3.00, 95% CI 0.30 to 30.47; two RCTs, 62 women, I(2) = 0%, low-quality evidence).In women with donor-recipient cycles, no evidence suggested a difference between groups in live birth rate (OR 0.92, 95% CI 0.53 to 1.61; one RCT, 212 women) or ongoing pregnancy rate (OR 0.88, 95% CI 0.58 to 1.32; three RCTs, 372 women, I² = 0%). We found evidence of a lower incidence of OHSS in the GnRH agonist group than in the HCG group (OR 0.05, 95% CI 0.01 to 0.28; three RCTs, 374 women, I² = 0%).The main limitation in the quality of the evidence was risk of bias associated with poor reporting of methods in the included studies.
AUTHORS' CONCLUSIONS
Final oocyte maturation triggering with GnRH agonist instead of HCG in fresh autologous GnRH antagonist IVF/ICSI treatment cycles prevents OHSS to the detriment of the live birth rate. In donor-recipient cycles, use of GnRH agonists instead of HCG resulted in a lower incidence of OHSS, with no evidence of a difference in live birth rate.Evidence suggests that GnRH agonist as a final oocyte maturation trigger in fresh autologous cycles is associated with a lower live birth rate, a lower ongoing pregnancy rate (pregnancy beyond 12 weeks) and a higher rate of early miscarriage (less than 12 weeks). GnRH agonist as an oocyte maturation trigger could be useful for women who choose to avoid fresh transfers (for whatever reason), women who donate oocytes to recipients or women who wish to freeze their eggs for later use in the context of fertility preservation.
Topics: Chorionic Gonadotropin; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Oocyte Donation; Oocytes; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic; Sperm Injections, Intracytoplasmic
PubMed: 25358904
DOI: 10.1002/14651858.CD008046.pub4 -
Fertility and Sterility Jun 2015To systematically review the reporting of MII (MII) oocyte development after xenotransplantation of human ovarian tissue. (Review)
Review
Xenotransplantation of cryopreserved human ovarian tissue--a systematic review of MII oocyte maturation and discussion of it as a realistic option for restoring fertility after cancer treatment.
OBJECTIVE
To systematically review the reporting of MII (MII) oocyte development after xenotransplantation of human ovarian tissue.
DESIGN
Systematic review in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).
SETTING
Not applicable.
PATIENT(S)
Not applicable.
INTERVENTION(S)
Formation of MII oocytes after xenotransplantation of human ovarian tissue.
MAIN OUTCOME MEASURE(S)
Any outcome reported in Pubmed.
RESULT(S)
Six publications were identified that report on formation of MII oocytes after xenotransplantation of human ovarian tissue.
CONCLUSION(S)
Xenografting of human ovarian tissue has proved to be a useful model for examining ovarian function and follicle development in vivo. With human follicles that have matured through xenografting, the possibility of cancer transmission and relapse can also be eliminated, because cancer cells are not able to penetrate the zona pellucida. The reported studies have demonstrated that xenografted ovarian tissue from a range of species, including humans, can produce antral follicles that contain mature (MII) oocytes, and it has been shown that mice oocytes have the potential to give rise to live young. Although some ethical questions remain unresolved, xenotransplantation may be a promising method for restoring fertility. This review furthermore describes the value of xenotransplantation as a tool in reproductive biology and discusses the ethical and potential safety issues regarding ovarian tissue xenotransplantation as a means of recovering fertility.
Topics: Animals; Cell Survival; Cells, Cultured; Cryopreservation; Female; Fertility Preservation; Humans; Mice; Mice, SCID; Neoplasms; Oocyte Retrieval; Oocytes; Oogenesis; Transplantation, Heterologous
PubMed: 25881879
DOI: 10.1016/j.fertnstert.2015.03.001 -
Journal of Assisted Reproduction and... Oct 2016The purpose of this study was to undertake a review of the available evidence comparing the use of a single medium versus sequential media for embryo culture to the... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The purpose of this study was to undertake a review of the available evidence comparing the use of a single medium versus sequential media for embryo culture to the blastocyst stage in clinical IVF.
METHODS
We searched the Cochrane Central, PubMed, Scopus, ClinicalTrials.gov, Current Controlled Trials and WHO International Clinical Trials Registry Platform to identify randomized controlled trials comparing single versus sequential media for blastocyst culture and ongoing pregnancy rate. Included studies randomized either oocytes/zygotes or women. Eligible oocyte/zygote studies were analyzed to assess the risk difference (RD) and 95 % confidence intervals (CI) between the two media systems; eligible woman-based studies were analyzed to assess the risk ratio (RR) and 95 % CI for clinical pregnancy rate.
RESULTS
No differences were observed between single and sequential media for either ongoing pregnancy per randomized woman (relative risk (RR) = 0.9, 95 % CI = 0.7 to 1.3, two studies including 246 women, I = 0 %) or clinical pregnancy per randomized woman (RR = 1.0, 95 % CI = 0.7 to 1.4, one study including 100 women); or miscarriage per clinical pregnancy: RR = 1.3, 95 % CI = 0.4 to 4.3, two studies including 246 participants, I = 0 %). Single media use was associated with an increase blastocyst formation per randomized oocyte/zygote (relative distribution (RD) = +0.06, 95 % CI = +0.01 to +0.12, ten studies including 7455 oocytes/zygotes, I = 83 %) but not top/high blastocyst formation (RD = +0.05, 95 % CI = -0.01 to +0.11, five studies including 3879 oocytes/zygotes, I = 93 %). The overall quality of the evidence was very low for all these four outcomes.
CONCLUSIONS
Although using a single medium for extended culture has some practical advantages and blastocyst formation rates appear to be higher, there is insufficient evidence to recommend either sequential or single-step media as being superior for the culture of embryos to days 5/6. Future studies comparing these two media systems in well-designed trials should be performed.
Topics: Adult; Blastocyst; Cleavage Stage, Ovum; Embryo Culture Techniques; Embryo Transfer; Embryonic Development; Female; Fertilization in Vitro; Humans; Live Birth; Oocytes; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic
PubMed: 27491772
DOI: 10.1007/s10815-016-0774-5 -
Fertility and Sterility Jul 2008To examine the literature systematically in order to identify prospective comparative trials answering the following question: Is vitrification of human embryos... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To examine the literature systematically in order to identify prospective comparative trials answering the following question: Is vitrification of human embryos associated with a higher postthawing survival rate as compared with slow freezing?
DESIGN
Systematic review and meta-analysis.
SETTING
University-based hospital.
PATIENT(S)
Not applicable.
INTERVENTION(S)
Vitrification versus slow freezing for cryopreservation of human embryos.
MAIN OUTCOME MEASURE(S)
Postthawing survival rate.
RESULT(S)
Four eligible studies were identified, three of which were randomized controlled trials. Overall, the current review summarizes information from 8,824 cryopreserved human cleavage stage embryos/blastocysts (vitrification: n = 7,482; slow freezing: n = 1,342). Survival rate of cleavage stage embryos was significantly higher after vitrification as compared with slow freezing (odds ratio 15.57, 95% confidence interval 3.68-65.82; random effects model). Postthawing survival rate of vitrified blastocysts was significantly higher compared with that observed with slow freezing (odds ratio 2.20, 95% confidence interval 1.53-3.16; fixed effects model).
CONCLUSION(S)
Vitrification appears to be associated with a significantly higher postthawing survival rate than slow freezing. Further prospective trials are necessary to confirm the above results and, in addition, allow the evaluation of the two cryopreservation methods in terms of pregnancy achievement.
Topics: Blastocyst; Cell Survival; Cleavage Stage, Ovum; Cryopreservation; Cryoprotective Agents; Embryo Implantation; Embryo Transfer; Embryo, Mammalian; Evidence-Based Medicine; Female; Fertilization in Vitro; Freezing; Humans; Live Birth; Odds Ratio; Pregnancy; Pregnancy Rate; Risk Assessment; Time Factors
PubMed: 17980870
DOI: 10.1016/j.fertnstert.2007.06.010 -
Journal of Assisted Reproduction and... Jan 2022Does existing scientific literature suggest an impact of oocyte dysmorphisms on biological or clinical outcomes of assisted reproduction treatments?
PURPOSE
Does existing scientific literature suggest an impact of oocyte dysmorphisms on biological or clinical outcomes of assisted reproduction treatments?
METHODS
Studies of interest were selected from an initial cohort of 6651 potentially relevant records retrieved. PubMed was systematically searched for peer-reviewed original papers and reviews identified by keywords and medical subject heading (MeSH) terms. The most relevant publications were critically evaluated to identify criteria for oocyte morphological evaluation and IVF outcomes. For each morphological abnormality, we generated an oocyte literature score (OLS) through the following procedure: (a) papers showing a negative, absence of, or positive correlation between a given abnormality and IVF outcome were scored 1, 0, and - 1, respectively; (b) the sum of these scores was expressed as a fraction of all analyzed papers; (c) the obtained fraction was multiplied by 10 and converted into decimal number.
RESULT
We identified eleven different dysmorphisms, of which six were extracytoplasmic (COC, zona pellucida, perivitelline space, polar body 1, shape, giant size) and five intracytoplasmic (vacuoles, refractile bodies, SER clusters, granularity, color). Among the extracytoplasmic dysmorphisms, abnormal morphology of the COC generated an OLS of 8.33, indicating a large prevalence (5/6) of studies associated with a negative outcome. Three intracytoplasmic dysmorphisms (vacuoles, SER clusters, and granularity) produced OLS of 7.14, 7.78, and 6.25, respectively, suggestive of a majority of studies reporting a negative outcome.
CONCLUSION
COC morphology, vacuoles, SER clusters, and granularity produced OLS suggestive of a prevalence of studies reporting a negative outcome.
Topics: Humans; Oocytes; Oogenesis; Zona Pellucida
PubMed: 34993709
DOI: 10.1007/s10815-021-02370-3 -
Frontiers in Endocrinology 2024The leading indicator for successful outcomes in fertilization (IVF) is the quality of gametes in oocytes and sperm. Thus, advanced research aims to highlight the... (Review)
Review
Unravelling the role of HAS2, GREM1, and PTGS2 gene expression in cumulus cells: implications for human oocyte development competency - a systematic review and integrated bioinformatic analysis.
The leading indicator for successful outcomes in fertilization (IVF) is the quality of gametes in oocytes and sperm. Thus, advanced research aims to highlight the parameter in assessing these qualities - DNA fragmentation in sperm and oocyte development capacity (ODC) via evaluation of microenvironments involving its maturation process. Regarding oocytes, most evidence reveals the role of cumulus cells as non-invasive methods in assessing their development competency, mainly via gene expression evaluation. Our review aims to consolidate the evidence of GDF-9 derivatives, the HAS2, GREM1, and PTGS2 gene expression in cumulus cells used as ODC markers in relevant publications and tailored to current IVF outcomes. In addition to that, we also added the bioinformatic analysis in our review to strengthen the evidence aiming for a better understanding of the pathways and cluster of the genes of interest - HAS2, GREM1, and PTGS2 in cumulus cell level. Otherwise, the current non-invasive method can be used in exploring various causes of infertility that may affect these gene expressions at the cumulus cell level. Nevertheless, this method can also be used in assessing the ODC in various cohorts of women or as an improvement of markers following targeted tools or procedures by evaluating the advancement of these gene expressions following the targeted intervention.
Topics: Humans; Male; Female; Cyclooxygenase 2; Cumulus Cells; Semen; Oocytes; Gene Expression; Intercellular Signaling Peptides and Proteins; Hyaluronan Synthases
PubMed: 38524634
DOI: 10.3389/fendo.2024.1274376 -
Women's Health (London, England) 2022Review the safety of fertility preservation through ovarian stimulation with oocyte or embryo cryopreservation, including cycle and medication options.
OBJECTIVE
Review the safety of fertility preservation through ovarian stimulation with oocyte or embryo cryopreservation, including cycle and medication options.
EVIDENCE REVIEW
A systematic review of peer-reviewed sources revealed 2 applicable randomized control trials and 60 cohort studies as well as 20 additional expert opinions or reviews.
RESULTS
The capacity for future family building is important for the majority of reproductive age people, despite life-altering medical or oncologic diagnosis. Modern fertility preservation generates a high rate of oocyte yield while utilizing protocols that can be started at multiple points in the menstrual cycle and suppressing supra-physiologic levels of estrogen. Finally, more than one quarter of fertility preservation patients will return to later utilize fertility services.
CONCLUSION
For most patients, fertility preservation can safely be pursued and completed within 2 weeks without affecting disease severity or long-term survival.
Topics: Cohort Studies; Cryopreservation; Female; Fertility Preservation; Humans; Neoplasms; Oocytes; Ovulation Induction
PubMed: 35130799
DOI: 10.1177/17455065221074886 -
The Linacre Quarterly Nov 2018The purpose of this review was to determine whether there is evidence that ovulation can occur in women using hormonal contraceptives and whether these drugs might...
UNLABELLED
The purpose of this review was to determine whether there is evidence that ovulation can occur in women using hormonal contraceptives and whether these drugs might inhibit implantation. We performed a systematic review of the published English-language literature from 1990 to the present which included studies on the hormonal milieu following egg release in women using any hormonal contraceptive method. High circulating estrogens and progestins in the follicular phase appear to induce dysfunctional ovulation, where follicular rupture occurs but is followed by low or absent corpus luteum production of progesterone. Hoogland scoring of ovulatory activity may inadvertently obscure the reality of ovum release by limiting the term "ovulation" to those instances where follicular rupture is followed by production of a threshold level of luteal progesterone, sufficient to sustain fertilization, implantation, and the end point of a positive β-human chorionic gonadotropin. However, follicular ruptures and egg release with subsequent low progesterone output have been documented in women using hormonal contraception. In the absence of specific ovulation and fertilization markers, follicular rupture should be considered the best marker for egg release and potential fertilization. Women using hormonal contraceptives may produce more eggs than previously described by established criteria; moreover, suboptimal luteal progesterone production may be more likely than previously acknowledged, which may contribute to embryo loss. This information should be included in informed consent for women who are considering the use of hormonal contraception.
SUMMARY
For this study, the authors looked at English-language research articles that focused on how hormonal birth control, such as the birth control pill, may affect very early human embryos. The authors found that abnormal ovulation, or release of an egg followed by abnormal hormone levels, may often occur in women using hormonal birth control. This may increase the number of very early human embryos who are lost before a pregnancy test becomes positive. For women who are thinking about using hormonal birth control, this is important information to consider.
PubMed: 32431378
DOI: 10.1177/0024363918815611 -
Human Reproduction (Oxford, England) Jan 2023What are the associations between a history of cancer and outcomes after ART? (Meta-Analysis)
Meta-Analysis
STUDY QUESTION
What are the associations between a history of cancer and outcomes after ART?
SUMMARY ANSWER
Compared to women without cancer, on average, women with cancer had a lower return for embryo transfer and a lower likelihood of clinical pregnancy and live birth after ART.
WHAT IS KNOWN ALREADY
Small, single-institution studies have suggested that cancer and its treatment may negatively affect ART outcomes.
STUDY DESIGN, SIZE, DURATION
We conducted a systematic review with meta-analysis of studies comparing ART outcomes between women with and without cancer. PubMed, Embase and Scopus were searched for original, English-language studies published up to June 2021.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Inclusion criteria required reporting of ART outcomes after controlled ovarian stimulation (COS) among women with a history of cancer compared to women without cancer who used ART for any indication. Outcomes of interest ranged from duration of COS to likelihood of live birth after embryo transfer. Random-effects meta-analysis was used to calculate mean differences and odds ratios (ORs) with 95% CIs and 95% prediction intervals (PIs). We assessed heterogeneity by age-adjustment, referent group indication for ART, study location and among women with breast cancer and women who initiated ART before cancer treatment. We used visual inspection, Egger's test and the trim-and-fill method to assess funnel plot asymmetry.
MAIN RESULTS AND THE ROLE OF CHANCE
Of 6094 unique records identified, 42 studies met inclusion criteria, representing a median per study of 58 women with cancer (interquartile range (IQR) = 159) and 114 women without cancer (IQR = 348). Compared to women without cancer, on average, women with cancer had a lower return for embryo transfer (OR: 0.22; 95% CI: 0.07, 0.74; 95% PI: 0.00, 64.98); lower likelihood of clinical pregnancy (OR: 0.51; 95% CI: 0.35, 0.73; 95% PI: 0.19, 1.35); and lower likelihood of live birth (OR: 0.56; 95% CI: 0.38, 0.83; 95% PI: 0.19, 1.69). Substantial among-study heterogeneity was observed for COS duration, gonadotropin dose, cycle cancellation, total oocytes and mature oocytes. Fertilization percentage showed less heterogeneity, but study-specific estimates were imprecise. Similarly, number of embryos showed less heterogeneity, and most studies estimated minimal differences by cancer history. Funnel plot asymmetry was observed for estradiol peak and oocyte maturation percentage.
LIMITATIONS, REASONS FOR CAUTION
Appreciable confounding is possible in 11 studies that lacked adequate control for group differences in age, and among-study heterogeneity was observed for most outcomes. Lack of data limited our ability to assess how cancer clinical factors (e.g. cancers other than breast, cancer stage and treatment) and ART cycle characteristics (e.g. fresh versus frozen embryo transfers and use of gestational carriers) may affect outcomes.
WIDER IMPLICATIONS OF THE FINDINGS
Women with cancer may be less likely to achieve pregnancy and live birth after embryo transfer. Further examination of reproductive outcomes and sources of heterogeneity among studies is warranted to improve evidence of the expected success of ART after a cancer diagnosis.
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported in part by R01 CA211093 and P30 ES010126. C.M. was supported by the University of North Carolina Lineberger Cancer Control Education Program (T32 CA057726) and the National Cancer Institute (F31 CA260787). J.A.R.-H. was supported by the National Cancer Institute (K08 CA234333, P30 CA016672). J.A.R.-H. reports receiving consulting fees from Schlesinger Group and Guidepoint. The remaining authors declare no competing interests.
REGISTRATION NUMBER
N/A.
Topics: Pregnancy; Female; Humans; Reproductive Techniques, Assisted; Embryo Transfer; Live Birth; Neoplasms; Oocytes; Fertilization in Vitro; Pregnancy Rate; Retrospective Studies; Birth Rate
PubMed: 36342891
DOI: 10.1093/humrep/deac235 -
Reproductive Biology and Endocrinology... Dec 2018The objective of this study was to carry out a systematic review and meta-analysis of embryologic and clinical outcomes following open versus closed vitrification of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The objective of this study was to carry out a systematic review and meta-analysis of embryologic and clinical outcomes following open versus closed vitrification of human oocytes and embryos.
METHODS
An electronic literature search was conducted in main electronic databases up to June 30, 2018 using the following key terms: 'oocyte', 'embryo', 'blastocyst', 'vitrification', 'cryopreservation', 'device', 'survival rate', 'pregnancy rate', etc. A meta-analysis was performed using a random effect model to estimate the value of risk ratios (RRs) and 95% confidence interval (CI). Subgroup analyses and sensitivity analyses were carried out to further confirm the results.
RESULTS
Twelve (Eight prospective and four retrospective) studies comparing open versus closed vitrification of human oocytes or embryos were included. For prospective studies on oocytes, no evidence for a significant difference in cryosurvival rate (RR = 0.91, 95% CI: 0.80-1.03, P = 0.14; n = 2048) or clinical pregnancy rate (RR = 1.29, 95% CI: 0.80-2.06, P = 0.30; n = 150) was observed. Additionally, there were no significant differences between the two methods concerning secondary endpoints included positive βHCG rate, implantation rate, miscarriage rate, ongoing pregnancy rate, live birth rate, cancellation rate, babies born per transferred blastocysts, or multiple birth rate (P > 0.05). The results of the retrospective studies were similar as the prospective studies.
CONCLUSIONS
It is still impossible to conclude that closed vitrification system could be a substitution for open system in human oocyte and embryo cryopreservation based on current evidence. Therefore, more well-designed prospective studies addressing these issues are still warranted.
Topics: Cryopreservation; Embryo Implantation; Embryo Transfer; Female; Humans; Oocytes; Pregnancy; Pregnancy Rate; Vitrification
PubMed: 30522492
DOI: 10.1186/s12958-018-0440-0