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1.  The long path to pregnancy: early experience with dual anonymous gamete donation in a European in vitro fertilisation referral centre 
Reproductive Health  2010;7:20.
Background
This investigation describes features of patients undergoing in vitro fertilisation (IVF) and embryo transfer (ET) where both gametes were obtained from anonymous donors.
Methods
Gamete unsuitability or loss was confirmed in both members of seven otherwise healthy couples presenting for reproductive endocrinology consultation over a 12-month interval in Ireland. IVF was undertaken with fresh oocytes provided by anonymous donors in Ukraine; frozen sperm (anonymous donor) was obtained from a licensed tissue establishment. For recipients, saline-enhanced sonography was used to assess intrauterine contour with endometrial preparation via transdermal estrogen.
Results
Among commissioning couples, mean±SD female and male age was 41.9 ± 3.7 and 44.6 ± 3.5 yrs, respectively. During this period, female age for non dual anonymous gamete donation IVF patients was 37.9 ± 3 yrs (p < 0.001). Infertility duration was ≥3 yrs for couples enrolling in dual gamete donation, and each had ≥2 prior failed fertility treatments using native oocytes. All seven recipient couples proceeded to embryo transfer, although one patient had two transfers. Clinical pregnancy was achieved for 5/7 (71.4%) patients. Non-transferred cryopreserved embryos were available for all seven couples.
Conclusions
Mean age of females undergoing dual anonymous donor gamete donation with IVF is significantly higher than the background IVF patient population. Even when neither partner is able to contribute any gametes for IVF, the clinical pregnancy rate per transfer can be satisfactory if both anonymous egg and sperm donation are used concurrently. Our report emphasises the role of pre-treatment counselling in dual anonymous gamete donation, and presents a coordinated screening and treatment approach in IVF where this option may be contemplated.
doi:10.1186/1742-4755-7-20
PMCID: PMC2925351  PMID: 20701806
2.  Predicting Live Birth, Preterm Delivery, and Low Birth Weight in Infants Born from In Vitro Fertilisation: A Prospective Study of 144,018 Treatment Cycles 
PLoS Medicine  2011;8(1):e1000386.
Using the HFEA database of all 144,018 live births in all IVF cycles in the UK between 2003 and 2007, Scott Nelson and Debbie Lawlor show that couple- and treatment-specific factors can be used to help predict successful outcome following IVF.
Background
The extent to which baseline couple characteristics affect the probability of live birth and adverse perinatal outcomes after assisted conception is unknown.
Methods and Findings
We utilised the Human Fertilisation and Embryology Authority database to examine the predictors of live birth in all in vitro fertilisation (IVF) cycles undertaken in the UK between 2003 and 2007 (n = 144,018). We examined the potential clinical utility of a validated model that pre-dated the introduction of intracytoplasmic sperm injection (ICSI) as compared to a novel model. For those treatment cycles that resulted in a live singleton birth (n = 24,226), we determined the associates of potential risk factors with preterm birth, low birth weight, and macrosomia. The overall rate of at least one live birth was 23.4 per 100 cycles (95% confidence interval [CI] 23.2–23.7). In multivariable models the odds of at least one live birth decreased with increasing maternal age, increasing duration of infertility, a greater number of previously unsuccessful IVF treatments, use of own oocytes, necessity for a second or third treatment cycle, or if it was not unexplained infertility. The association of own versus donor oocyte with reduced odds of live birth strengthened with increasing age of the mother. A previous IVF live birth increased the odds of future success (OR 1.58, 95% CI 1.46–1.71) more than that of a previous spontaneous live birth (OR 1.19, 95% CI 0.99–1.24); p-value for difference in estimate <0.001. Use of ICSI increased the odds of live birth, and male causes of infertility were associated with reduced odds of live birth only in couples who had not received ICSI. Prediction of live birth was feasible with moderate discrimination and excellent calibration; calibration was markedly improved in the novel compared to the established model. Preterm birth and low birth weight were increased if oocyte donation was required and ICSI was not used. Risk of macrosomia increased with advancing maternal age and a history of previous live births. Infertility due to cervical problems was associated with increased odds of all three outcomes—preterm birth, low birth weight, and macrosomia.
Conclusions
Pending external validation, our results show that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have low or high risk of a successful outcome following IVF.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 10% of couples are infertile. Sometimes there is no obvious reason for a couple's inability to have children but, for many couples, problems with their eggs or sperm prevent “fertilization”—the union of an egg and a sperm that leads, eventually, to the birth of a baby. Until recently, little could be done to help infertile couples. Then, on the 25 July 1978, the world's first “test-tube baby” was born. Since then, 4 million babies have been born through in vitro fertilization (IVF). In IVF, mature eggs are collected from the woman (or from an egg donor if the woman cannot make her own eggs) after a course of special hormones, and they are mixed in a dish with her partner's sperm. If her partner has a low sperm count or abnormal sperm, a single sperm can be injected directly into the egg in a procedure called intracytoplasmic sperm injection (ICSI), which became widely available in the mid 1990s, or sperm from a donor can be used. Finally, a number (depending on the country) of embryos (eggs that have begun to divide and develop) are put back into the woman where, hopefully, they will establish a successful pregnancy.
Why Was This Study Done?
Not every attempt at IVF is successful. In the US and the UK, IVF is successful in about a third of women under 35 years old but in only 5%–10% of women over the age of 40. It would be useful to have a way to predict the likelihood of a live birth after IVF for individual couples. Such a “prediction model” would facilitate patient counseling, clinical decision making, and the allocation of IVF resources. In this study, the researchers use information on IVF cycles collected by the Human Fertilisation and Embryology Authority (HFEA), which regulates IVF in the UK, to assess the extent to which the characteristics of infertile couples and the treatment they receive can be used to predict live birth after IVF. They also use these data to identify which factors are associated with preterm delivery, low birthweight, and macrosomia (the birth of an unusually large baby), three undesirable birth characteristics.
What Did the Researchers Do and Find?
Between 2003 and 2007, 163,425 IVF cycles were completed in the UK, 23.4% of which resulted in at least one live birth. The researchers used the data collected by the HFEA on 144,018 of these cycles (the other cycles had missing data) to develop a multivariable logistic regression prediction model (a type of statistical model) for the outcome of IVF. According to this model, a decreased chance of at least one live birth was associated with several factors including increasing maternal age, increasing duration of infertility, and the use of the woman's own oocytes. By contrast, a previous IVF live birth and the use of ICSI were associated with increased chances of success. Importantly, compared with an established multivariable prediction model, which was developed before the introduction of ICSI, the researchers' new prediction model predicted the chance of a live birth following IVF with greater accuracy. Finally, the researchers report that the chances of preterm and low birthweight after IVF were increased if donor eggs were required and ICSI was not used, that an increased risk of macrosomia was associated with increasing maternal age and with a history of previous live births, and that all three undesirable birth characteristics were associated with infertility due to cervical problems.
What Do These Findings Mean?
These findings indicate that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have a low or high chance of a successful outcome following IVF. The prediction model developed here provides a more accurate assessment of likely outcomes after IVF than a previously established model. Furthermore, because the new model considers the effect of ICSI on outcomes, it should be more useful in contemporary populations than the established model, which does not consider ICSI. However, before this new prediction model is used to guide clinical decisions and to counsel patients, it needs to be validated using independent IVF data. To facilitate the external validation of their model, the researchers are currently generating a free web-based prediction tool and iPhone application (IVFpredict).
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000386.
The Human Fertilisation and Embryology Authority provides information on IVF and IVF statistics for the UK
The UK National Health Service Choices website provides information for patients on infertility and on IVF
The American Pregnancy Association has information for patients on infertility and on IVF
MedlinePlus has links to further resources on infertility and IVF (in English and Spanish)
The history of the development of IVF is described on the Nobel Prize website
The prediction tool that was used in this study is at http://www.IVFpredict.com
doi:10.1371/journal.pmed.1000386
PMCID: PMC3014925  PMID: 21245905
3.  In Vitro Fertilization and Multiple Pregnancies 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.
Clinical Need: Target Population and Condition
Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.
The Technology Being Reviewed
IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman’s egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility.
An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%.
An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost.
Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.
Ontario Health Insurance Plan Coverage
Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS.
Diffusion of Technology
According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually.
Literature Review
Royal Commission Report on Reproductive Technologies
The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not.
Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990’s as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF.
Studies After the Royal Commission Report: Review Strategy
Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.
Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.
Cost effectiveness of IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewed
Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.
OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies.
Summary of Findings
Comparative Clinical Effectiveness of IVF
Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...).
Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings:
A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.
A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.
In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility.
Cost-Effectiveness of IVF
Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option.
Clinical Outcomes After Single Versus Double Embryo Transfer Strategies of IVF
Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs.
All of these studies reached similar conclusions:
Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).
SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT).
Most trials on SET included women younger than 36 years old with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to older women.
Estimate of the Target Population
Based on results of the literature review and consultations with experts, four categories of infertile patients who may benefit from increased access to IVF/ICSI were identified:
Patients with severe male factor infertility, where IVF should be offered in conjunction with ICSI;
Infertile women with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET;
Infertile patients who want to avoid the risk of multiple pregnancy and thus opt for IVF-SET; and
Patients who failed treatment with IUI and wish to try IVF.
Since, however, the latter indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered in this analysis.
Economic Analysis
Economic Review: Cost–Effectiveness of SET Versus DET
Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent. While some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies, other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.
Ontario-Based Economic Analysis
An Ontario-based economic analysis compared cost per birth using three treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed three cycles for each treatment option. Two separate models were considered; the first included only fresh cycles of IVF, while the second had a combination of fresh and frozen cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancies (only short-term complications), IVF-SET was still associated with a highest cost per birth. The approximate budget impact to cover the first three indications for IVF listed above (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of only first two indications, namely, ICSI in patients with severe male factor infertility and infertile women with serious medical contraindications to multiple pregnancy, is estimated at $3.8 to $5.5 million Cdn.
Other Considerations
International data shows that both IVF utilization and the average number of embryos transferred in IVF cycles are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by governments.
Surveys of patients with infertility demonstrated that a significant proportion (~40%) of patients not only do not mind having multiple babies, but consider twins being an ideal outcome of infertility treatment.
A women’s age may impose some restrictions on the implementation of a SET strategy.
Conclusions and Recommendations
A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancies after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.
Thus, 2 indications where additional IVF access should be considered include:
IVF/ICSI for patients with severe male factor infertility
IVF-SET in infertile women with serious medical contraindications to multiple pregnancy
PMCID: PMC3379537  PMID: 23074488
4.  IVF for premature ovarian failure: first reported births using oocytes donated from a twin sister 
Background
Premature ovarian failure (POF) remains a clinically challenging entity because in vitro fertilisation (IVF) with donor oocytes is currently the only treatment known to be effective.
Methods
A 33 year-old nulligravid patient with a normal karyotype was diagnosed with POF; she had a history of failed fertility treatments and had an elevated serum FSH (42 mIU/ml). Oocytes donated by her dizygotic twin sister were used for IVF. The donor had already completed a successful pregnancy herself and subsequently produced a total of 10 oocytes after a combined FSH/LH superovulation regime. These eggs were fertilised with sperm from the recipient's husband via intracytoplasmic injection and two fresh embryos were transferred to the recipient on day three.
Results
A healthy twin pregnancy resulted from IVF; two boys were delivered by caesarean section at 39 weeks' gestation. Additionally, four embryos were cryopreserved for the recipient's future use. The sister-donor achieved another natural pregnancy six months after oocyte retrieval, resulting in a healthy singleton delivery.
Conclusion
POF is believed to affect approximately 1% of reproductive age females, and POF patients with a sister who can be an oocyte donor for IVF are rare. Most such IVF patients will conceive from treatment using oocytes from an anonymous oocyte donor. This is the first report of births following sister-donor oocyte IVF in Ireland. Indeed, while sister-donor IVF has been successfully undertaken by IVF units elsewhere, this is the only known case where oocyte donation involved twin sisters. As with all types of donor gamete therapy, pre-treatment counselling is important in the circumstance of sister oocyte donation.
doi:10.1186/1477-7827-8-31
PMCID: PMC2861671  PMID: 20334702
5.  Determining parental origin of embryo aneuploidy: analysis of genetic error observed in 305 embryos derived from anonymous donor oocyte IVF cycles 
Molecular Cytogenetics  2014;7(1):68.
Background
Since oocyte donors are typically young and believed to be a source of highly competent gametes, donor oocyte IVF is considered to be an effective treatment for diminished ovarian reserve. However, the aneuploidy rate for embryos originating from anonymously donated oocytes remains incompletely characterized. Here, comprehensive chromosomal screening results were reviewed from embryos obtained from anonymous donor-egg IVF cycles to determine both the aneuploidy rate and parental source of the genetic error. To measure this, preimplantation genetic screening (PGS) data on embryos were retrospectively collated with parental DNA obtained before IVF for chromosome-specific assessments. This approach permitted mitotic and meiotic copy errors to be differentiated for each chromosome among all embryos tested, thus providing information on the parental source of embryo aneuploidy (i.e., from the anonymous egg donor vs. sperm source).
Results
305 embryos generated for 24 patients who began IVF treatment in 2013. For oocyte donors (n = 24), mean (±SD) age was 24.0 ± 2.7 years (range = 20-29). For embryos with full chromosomal reporting (n = 284), euploidy was present in only 133 (46.8%). Considering all embryo chromosomes, the average error rate was 18%. 133 of 151 observed embryo aneuploidies (88.1%) were attributable to an oocyte donor source. Among all aneuploid embryos (n = 151), chromosomal errors from both genetic parents (i.e., oocyte donor and sperm source) were present in 57%. The average correlation coefficient across all pairs of chromosomal abnormalities (r = 0.60) suggests that chromosomes tend to have multiple and simultaneous errors (complex aneuploidy) even when oocytes from young donors are used.
Conclusion
These data show that even when young donors provide oocytes for IVF, the probability of embryo aneuploidy remains high. The oocyte donor appears to make an important contribution to embryo aneuploidy even when her age is <30 yrs. If these findings are confirmed with larger, prospective studies, the routine integration of PGS with donor oocyte IVF cycles to identify single euploid embryos for transfer should be considered.
doi:10.1186/s13039-014-0068-5
PMCID: PMC4212126  PMID: 25356087
6.  IVF outcomes in obese donor oocyte recipients: a systematic review and meta-analysis 
Human Reproduction (Oxford, England)  2013;28(10):2720-2727.
STUDY QUESTION
Does obesity influence the chance of pregnancy after IVF in donor oocyte recipients?
SUMMARY ANSWER
The chance of pregnancy after IVF is no different in obese donor oocyte recipients versus those in the normal BMI range.
WHAT IS KNOWN ALREADY
Obesity is associated with decreased chances of pregnancy in women undergoing IVF with autologous oocytes. Prior studies have investigated the impact of obesity on IVF outcomes in donor oocyte recipients, with disparate results. This is the first systematic review and meta-analysis to address this topic.
STUDY DESIGN, SIZE, DURATION
A systematic review and meta-analysis of published literature identified in Medline, EMBASE and Scopus through December of 2011 were performed to address the association between BMI and outcomes for donor oocyte recipients. The primary outcome of this study was implantation.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Two authors conducted the searches independently, selected the studies and abstracted the data. Studies in English of first donor oocyte cycles with reported recipient BMI were included. Primary data collected from the IVF program at Washington University were also included as one study (n = 123 donor oocyte recipients). Studies limited to frozen embryo transfer were excluded. Data were synthesized using DerSimonian–Laird random effects models for implantation, clinical pregnancy, miscarriage and live birth.
MAIN RESULTS AND THE ROLE OF CHANCE
Of 475 screened articles, 7 were reviewed and 5 were included together with primary data from Washington University, giving a total of 4758 women who were included for the assessment of the primary outcome. No associations between obesity (BMI ≥ 30 kg/m2) and chance of pregnancy after IVF were noted in women using donor oocytes [risk ratio (RR): 0.98, 95% confidence intervals (CI): 0.83–1.15, I2: 61.6%]. Additional analyses assessing associations between recipient obesity and embryo implantation (RR: 0.93, 95% CI: 0.80–1.07, I2: 0%), miscarriage (RR: 1.12, 95% CI: 0.83–1.50, I2: 0%) and live birth (RR: 0.91, 95% CI: 0.65–1.27, I2 47.9%) also failed to show a negative effect.
LIMITATIONS, REASONS FOR CAUTION
Included studies were small and they were performed in a variety of locations and practice settings where stimulation and laboratory protocols may differ, and extremes of BMI may also differ. Furthermore, included studies had different inclusion and exclusion criteria. These factors could not be controlled for in this meta-analysis and statistical heterogeneity was noted for some outcomes.
WIDER IMPLICATIONS OF THE FINDINGS
These data suggest obesity does not affect IVF outcomes in women using donor oocytes. Oocyte quality rather than endometrial receptivity may be the overriding factor influencing IVF outcomes in obese women using autologous oocytes.
STUDY FUNDING/COMPETING INTEREST(S)
E.S.J. and M.G.T receive support from the Women's Reproductive Health Research Program sponsored by the National Institutes of Health (K12 HD063086). The authors do not have any competing interests.
TRIAL REGISTRATION NUMBER
N/A.
doi:10.1093/humrep/det292
PMCID: PMC3777569  PMID: 23847110
BMI; female infertility; gamete donation; donor oocyte recipients
7.  Oocyte quality in polycystic ovaries revisited: Identification of a particular subgroup of women 
Purpose: Our purpose was to assess the endocrine status of women with polycystic ovaries (PCO) undergoing IVF, and to compare oocyte quality with endocrine markers of the syndrome, in an attempt to define a subpopulation with poor quality oocytes.
Methods: This was a retrospective study. Patients were first endocrinologically analyzed: serum levels of androgens (T, androstenedione, DHEAS), FSH, and LH as well as glucose and insulin after an oral glucose tolerance test (OGTT) were recorded and are expressed as absolute values and area under the curve (AUC). Subsequently, they were followed over a 2-year period in which patients underwent several attempts of IVF as well as serving as oocyte donors. Patients were divided into three groups: group I (n=4) was women who displayed embryos unable to implant in 15 IVF cycles and 10 ovum donation cycles in which they served as donors; group II (n=16) was PCO patients in whom IVF (n=38) and/or oocyte donation cycles (n=42) resulted in pregnancies; and group III (n=13) was IVF patients with normal appearance of the ovaries by ultrasound. The endocrine status was compared with the IVF results.
Results: There was no difference among groups in the endocrinological parameters tested, except for the OGTT which identified women in group I as having higher serum glucose and insulin levels than patients in groups II and III. Similarly, the OGTT showed higher serum glucose values in group II compared to group III. Women in group I were also obese. Patients in group III were older than PCO patients and needed more gonadotropins to reach an ovarian response which resulted in a reduced number of oocytes retrieved. Fertilization was also impaired in group I, in which no pregnancy was recorded.
Conclusions: This study shows that there is a particular subgroup of PCO patients with lower fertilization rates and embryos unable to implant. These patients are obese and nonhyperandrogenic and show derangements of insulin secretion.
doi:10.1007/BF02765826
PMCID: PMC3454720  PMID: 9147238
polycystic ovary; oocyte quality; insulin resistance; in vitro fertilization; insulin; glucose
8.  Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF 
Human Reproduction (Oxford, England)  2012;27(12):3583-3592.
STUDY QUESTION
In women undergoing IVF, are urinary bisphenol A (BPA) concentrations associated with ovarian response and early reproductive outcomes, including oocyte maturation and fertilization, Day 3 embryo quality and blastocyst formation?
SUMMARY ANSWER
Higher urinary BPA concentrations were found to be associated with decreased ovarian response, number of fertilized oocytes and decreased blastocyst formation.
WHAT IS KNOWN ALREADY
Experimental animal and in vitro studies have reported associations between BPA exposure and adverse reproductive outcomes. We previously reported an association between urinary BPA and decreased ovarian response [peak serum estradiol (E2) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limited human data on reproductive health outcomes, such as fertilization and embryo development.
STUDY DESIGN, SIZE AND DURATION
Prospective preconception cohort study. One hundred and seventy-four women aged 18–45 years and undergoing 237 IVF cycles were recruited at the Massachusetts General Hospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010. These women were followed until they either had a live birth or discontinued treatment. Cryothaw and donor egg cycles were not included in the analysis.
PARTICIPANTS/MATERIALS, SETTINGAND METHODS
Urinary BPA concentrations were measured by online solid-phase extraction-high-performance liquid chromatography-isotope dilution-tandem mass spectrometry. Mixed effect models, poisson regression and multivariate logistic regression models were used wherever appropriate to evaluate the association between cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation (metaphase II), fertilization, embryo quality and cleavage rate. We accounted for correlation among multiple IVF cycles in the same woman using generalized estimating equations.
MAIN RESULTS AND THE ROLE OF CHANCE
The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) µg/l. After adjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was a significant linear dose–response association between increased urinary BPA concentrations and decreased number of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreased E2 levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, when compared with the lowest quartile, respectively; P-value for trend = 0.001). The mean number of oocytes and normally fertilized oocytes decreased by 24 and 27%, respectively, for the highest versus the lowest quartile of urinary BPA (trend test P < 0.001 and 0.002, respectively). Women with urinary BPA above the lowest quartile had decreased blastocyst formation (trend test P-value = 0.08).
LIMITATIONS AND REASONS FOR CAUTION
Potential limitations include exposure misclassification due to the very short half-life of BPA and its high variability over time; uncertainty about the generalizability of the results to the general population of women conceiving naturally and limited sample.
WIDER IMPLICATIONS OF THE FINDINGS
The results from this extended study, using IVF as a model to study early reproductive health outcomes in humans, indicate a negative dose–response association between urinary BPA concentrations and serum peak E2 and oocyte yield, confirming our previous findings. In addition, we found significantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and a suggestive association between BPA urinary concentrations and decreased blastocyst formation, thus indicating that BPA may alter reproductive function in susceptible women undergoing IVF.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and grant OH008578 from the National Institute for Occupational Safety and Health. None of the authors has actual or potential competing financial interests. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
doi:10.1093/humrep/des328
PMCID: PMC3501244  PMID: 23014629
bisphenol A; oocyte; fertility; human; women; reproduction
9.  The clinical ramifications of polycystic ovarian morphology in oocyte donors 
Objective
To determine the relationship between Polycystic Ovary (PCO) morphology and In Vitro Fertilization (IVF) outcome in oocyte donation cycles.
Design
Cross sectional study
Setting
Private IVF clinic
Patients
164 consecutive ovum donors and their recipients were reviewed, 149 were included in the study where 113 patients had normal ovarian morphology and 36 patients had PCO morphology.
Interventions
All donors underwent ovarian stimulation in conjunction with GnRH agonist or antagonist in standard fashion.
Main Outcome Measures
Baseline donor characteristics were recorded, as well as details of IVF stimulation and embryo data. Recipient data on pregnancy and miscarriage were also collected.
Results
Patients with PCO ovaries had significantly higher peak estradiol levels and required less gonadotropins during IVF stimulation. In addition, the baseline characteristics between donor groups did not differ except for ovarian morphology. The number of oocytes retrieved and indicators of embryo quality did not differ between the two groups, and there was no significant difference between pregnancy and miscarriage rates in the recipients.
Conclusions
Oocyte donors with PCO morphology have equivalent pregnancy rates and do not need to be excluded as potential donors.
doi:10.1007/s10815-012-9924-6
PMCID: PMC3585686  PMID: 23292354
Polycystic ovary morphology; Polycystic ovary syndrome; Oocyte donation
10.  Current status of assisted reproductive technology in Korea, 2009 
Obstetrics & Gynecology Science  2013;56(6):353-361.
Great advances have been made in the field of assisted reproductive technology (ART) since the first in vitro fertilization (IVF) baby was born in Korea in the year of 1985. However, it deserve to say that the invaluable data from fertility centers may serve as a useful source to find out which factors affect successful IVF outcome and to offer applicable information to infertile patients and fertility clinics. This article intended to report the status of ART in 2009 Korean Society of Obstetrics and Gynecology surveyed. The current survey was performed to assess the status and success rate of ART performed in Korea, between January 1 and December 31, 2009. Reporting forms had been sent out to IVF centers via e-mail, and collected by e-mail as well in 2012. With International Committee Monitoring Assisted Reproductive Technologies recommendation, intracytoplasmic sperm injection (ICSI) and non-ICSI cases have been categorized and also IVF-ET cases involving frozen embryo replacement have been surveyed separately. Seventy-four centers have reported the treatment cycles initiated in the year of 2009, and had performed a total of 27,947 cycles of ART treatments. Among a total of 27,947 treatment cycles, IVF and ICSI cases added up to 22,049 (78.9%), with 45.3% IVF without ICSI and 54.7% IVF with ICSI, respectively. Among the IVF and ICSI patients, patients confirmed to have achieved clinical pregnancy was 28.8% per cycle with oocyte retrieval, and 30.9% per cycle with embryo transfer. The most common number of embryos transferred in 2009 is three embryos (40.4%), followed by 2 embryos (28.4%) and a single embryo transferred (13.6%). Among IVF and ICSI cycles that resulted in multiple live births, twin pregnancy rate was 45.3% and triple pregnancy rate was 1.1%. A total of 191 cases of oocyte donation had been performed to result in 25.0% of live birth rate. Meanwhile, a total of 5,619 cases of frozen embryo replacement had been performed with 33.7% of clinical pregnancy rate per cycle with embryo transfer. When comparing with international registry data, clinical pregnancy rate per transfer from fresh IVF cycles including ICSI (34.1%,) was comparable to clinical pregnancy rate per transfer in European Society for Human Reproduction and Embryology report was 32.5% though lower than 45.0% for USA data. There was no remarkable difference in status of assisted reproductive technology in Korea between the current report and the data reported in 2008. The age of women trying to get pregnant was reconfirmed to be the most important factor that may have impact on success of ART treatment.
doi:10.5468/ogs.2013.56.6.353
PMCID: PMC3859020  PMID: 24396813
International Committee for Monitoring Assisted Reproductive Technologies; Korea; Reproductive techniques; Survey
11.  Attitudes towards disclosure and relationship to donor offspring among a national cohort of identity-release oocyte and sperm donors 
Human Reproduction (Oxford, England)  2014;29(9):1978-1986.
STUDY QUESTION
What are oocyte donors and sperm donors' attitudes towards disclosure and relationship to donor offspring?
SUMMARY ANSWER
Oocyte and sperm donors in an identity-release donor programme support disclosure to donor offspring and have overall positive or neutral attitudes towards future contact with offspring.
WHAT IS KNOWN ALREADY
There is a global trend towards open-identity gamete donation with an increasing number of countries introducing legislation allowing only identifiable donors. While women and men who enrol in identity-release donor programmes accept that they may be contacted by donor offspring, there is limited knowledge of their attitudes towards disclosure to donor offspring and how they perceive their relationship to potential donor offspring.
STUDY DESIGN, SIZE AND DURATION
The present study is part of the ‘Swedish study on gamete donation’, a prospective cohort study including donors at all fertility clinics performing donation treatment in Sweden. During a 3-year period (2005–2008), donors were recruited consecutively and a total of 157 oocyte donors and 113 sperm donors (who did not donate to a specific ‘known’ couple) were included prior to donation. Participants in the present study include 125 female (80%) and 80 male donors (71%) that completed two follow-up assessments.
PARTICIPANTS/MATERIALS, SETTINGS AND METHODS
Participants completed two postal questionnaires 2 months after donation and 14 months after donation. Attitudes towards disclosure to donor offspring were assessed with an established instrument. Perceptions of involvement with donor offspring and need for counselling was assessed with study-specific instruments. Statistical analyses were performed with non-parametric tests.
MAIN RESULTS AND THE ROLE OF CHANCE
A majority of oocyte and sperm donors supported disclosure to donor offspring (71–91%) and had positive or neutral attitudes towards future contact with offspring (80–87%). Sperm donors reported a higher level of involvement with potential donor offspring compared with oocyte donors (P = 0.005). Few donors reported a need for more counselling regarding the consequences of their donation.
LIMITATIONS, REASONS FOR CAUTION
While the multicentre study design strengthens external validity, attrition induced a risk of selection bias. In addition, the use of study-specific instruments that have not been psychometrically tested is a limitation.
WIDER IMPLICATIONS OF THE FINDINGS
The positive attitudes towards disclosure to offspring of female and male identity-release donors are in line with previous reports of anonymous and known donors. While our results on donors' general positive or neutral attitudes towards future contact with potential donor offspring are reassuring, a subset of donors with negative attitudes towards such contact warrants concern and suggests a need for counselling on long-term consequences of donating gametes.
STUDY FUNDING
The ‘Swedish study on gamete donation’ was funded by the Swedish Research Council, the Swedish Council for Health, Working Life and Welfare, and the Regional Research Council in Uppsala-Örebro. There are no conflicts of interest to declare.
doi:10.1093/humrep/deu152
PMCID: PMC4131739  PMID: 25030191
oocyte donation; insemination; artificial; heterologous; disclosure; psychology
12.  Can anti-ovarian antibody testing be useful in an IVF-ET clinic? 
Objective
To establish importance of anti-ovarian antibodies (AOA) testing in infertile women.
Design
A clinical reproductive outcome comparative study between two groups of women undergoing IVF-ET. Group 1 consists of women tested positive for AOA, put on corticosteroid therapy, reverted to AOA negative and then taken up for IVF-ET. Group 2 were seronegative for AOA.
Setting
Major urban infertility reference centre and National research institute.
Patient(s)
Five hundred seventy infertile women enrolled for IVF-ET.
Intervention(s)
AOA testing, corticosteroid therapy and IVF-ET/ICSI.
Main outcome measure(s)
Comparable clinical outcome and significance of AOA testing established.
Results
AOA positive serum samples were sent periodically to re-investigate presence of AOA after corticosteroid therapy and women turned AOA negative were taken up for IVF-ET. Of the 70/138 women in group 1 who were treated with corticosteroids and turned seronegative for AOA, 22/70 were poor responders and needed donor oocyte-recipient cycles. Results demonstrated that fertilization and clinical pregnancy rates between both groups are comparable. Nevertheless, it is also observed that there is poor response to stimulation protocol, smaller number of oocytes retrieved and more spontaneous abortions in group 1 women. Hence not all outcomes following the treatment are comparable between the two groups. Usefulness of the test was established in two case studies.
Conclusions
AOA testing could be included in the battery of tests investigating and treating infertility.
doi:10.1007/s10815-010-9488-2
PMCID: PMC3045491  PMID: 20938805
AOA, Infertility in women; IVF-ET success; IVF-ET treatment; Ovarian autoimmunity
13.  Utilizing FMR1 Gene Mutations as Predictors of Treatment Success in Human In Vitro Fertilization 
PLoS ONE  2014;9(7):e102274.
Context
Mutations of the fragile X mental retardation 1 (FMR1) gene are associated with distinct ovarian aging patterns.
Objective
To confirm in human in vitro fertilization (IVF) that FMR1 affects outcomes, and to determine whether this reflects differences in ovarian aging between FMR1 mutations, egg/embryo quality or an effect on implantation.
Design, Setting, Patients
IVF outcomes were investigated in a private infertility center in reference to patients' FMR1 mutations based on a normal range of CGGn = 26–34 and sub-genotypes high (CGGn>34) and low (CGG<26). The study included 3 distinct sections and study populations: (i) A generalized mixed-effects model of morphology (777 embryos, 168 IVF cycles, 125 infertile women at all ages) investigated whether embryo quality is associated with FMR1; (ii) 1041 embryos in 149 IVF cycles in presumed fertile women assessed whether the FMR1 gene is associated with aneuploidy; (iii) 352 infertile patients (< age 38; in 1st IVF cycles) and 179 donor-recipient cycles, assessed whether the FMR1 gene affects IVF pregnancy chances via oocyte/embryo quality or non-oocyte maternal factors.
Interventions
Standardized IVF protocols.
Main Outcome Measures
Morphologic embryo quality, ploidy and pregnancy rates.
Results
(i) Embryo morphology was reduced in presence of a low FMR1 allele (P = 0.032). In absence of a low allele, the odds ratio (OR) of chance of good (vs. fair/poor) embryos was 1.637. (ii) FMR1 was not associated with aneuploidy, though aneuploidy increased with female age. (iii) Recipient pregnancy rates were neither associated with donor age or donor FMR1. In absence of a low FMR1 allele, OR of clinical pregnancy (vs. chemical or no pregnancy) was 2.244 in middle-aged infertility patients.
Conclusions
A low FMR1 allele (CGG<26) is associated with significantly poorer morphologic embryo quality and pregnancy chance. As women age, low FMR1 alleles affect IVF pregnancy chances by reducing egg/embryo quality by mechanisms other than embryo aneuploidy.
doi:10.1371/journal.pone.0102274
PMCID: PMC4096763  PMID: 25019151
14.  Maternal death after oocyte donation at high maternal age: case report 
Reproductive Health  2008;5:12.
Background
The percentage of women giving birth after the age of 35 increased in many western countries. The number of women remaining childless also increased, mostly due to aging oocytes. The method of oocyte donation offers the possibility for infertile older women to become pregnant. Gestation after oocyte-donation-IVF, however, is not without risks for the mother, especially at advanced age.
Case presentation
An infertile woman went abroad for oocyte-donation-IVF, since this treatment is not offered in The Netherlands after the age of 45. The first oocyte donation treatment resulted in multiple gestation, but was ended by induced abortion: the woman could not cope with the idea of being pregnant with twins. During the second pregnancy after oocyte donation, at the age of 50, she was mentally more stable. The pregnancy, again a multiple gestation, was uneventful until delivery. Immediately after delivery the woman had hypertension with nausea and vomiting. A few hours later she had an eclamptic fit. HELLP-syndrome was diagnosed. She died due to cerebral haemorrhage.
Conclusion
In The Netherlands, the age limit for women receiving donor oocytes is 45 years and commercial oocyte donation is forbidden by law. In other countries there is no age limit, the reason why some women are going abroad to receive the treatment of their choice.
Advanced age, IVF and twin pregnancy are all risk factors for pre-eclampsia, the leading cause of maternal death in The Netherlands.
Patient autonomy is an important ethical principle, but doctors are also bound to the principle of 'not doing harm', and do have the right to refuse medical treatment such as IVF-treatment. The discussion whether women above 50 should have children is still not closed. If the decision is made to offer this treatment to a woman at advanced age, the doctor should counsel her intensively about the risks before treatment is started.
doi:10.1186/1742-4755-5-12
PMCID: PMC2615743  PMID: 19116003
15.  Attitudes towards embryo donation in Swedish women and men of reproductive age 
Upsala Journal of Medical Sciences  2013;118(3):187-195.
Background
When performing in-vitro fertilization (IVF), more embryos than needed are often derived. These embryos are usually frozen and stored, but as ruled by Swedish law they have to be discarded after 5 years. In other countries it is legal to donate the excess embryos to other infertile couples who for different reasons cannot undergo the procedure of IVF. The aim of the present study was to investigate public opinion in Sweden regarding different aspects of embryo donation.
Methods
A questionnaire regarding attitudes towards aspects of embryo donation was sent to a randomized sample of 1,000 Swedish women and men of reproductive age.
Results
A total of 34% responded to the questionnaires. A majority of the respondents (73%) were positive towards embryo donation. Seventy-five per cent agreed that it should be possible to donate embryos to infertile couples. Approximately half of the participants (49%) supported embryo donation to single women. A majority of the participants emphasized that demands should be imposed on the recipient's age (63%), alcohol addiction (79%), drug addiction (85%), and criminal record (67%). Forty-seven per cent of the respondents agreed that the recipient should be anonymous to the donor, and 38% thought that the donor should remain anonymous to the child.
Conclusions
The results of the present study indicate support for embryo donation among a subset of the Swedish population of reproductive age. If embryo donation were to be allowed in Sweden, strategies for treatment and counselling need to be developed.
doi:10.3109/03009734.2013.808294
PMCID: PMC3713384  PMID: 23786323
Attitudes; disclosure; embryo donation; gender; Swedish population
16.  Assisted reproductive technology in Europe, 2007: results generated from European registers by ESHRE 
BACKGROUND
This 11th European IVF-monitoring report presents the results of assisted reproductive technology (ART) treatments initiated in Europe during 2007.
METHODS
From 33 countries, 1029 clinics reported 493 184 treatment cycles: IVF (120 761), ICSI (256 642), frozen embryo replacement (91 145), egg donation (15 731), preimplantation genetic diagnosis/preimplantation genetic screening (4638), in vitro maturation (660) and frozen oocytes replacements (3607). Overall, this represents a 7.6% increase since 2006, mostly related to an increase in all registers. IUI using husband/partner's (IUI-H) and donor (IUI-D) semen was reported from 23 countries: 142 609 IUI-H (+6.2%) and 26 088 IUI-D (+7.2%).
RESULTS
In 18 countries where all clinics reported, 376 971 ART cycles were performed in a population of 425.6million (886 cycles per million). The clinical pregnancy rates per aspiration and per transfer were 29.1 and 32.8% for IVF, and 28.6 and 33.0% for ICSI. Delivery rate after IUI-H was 10.2% in women aged < 40 years. In IVF/ICSI cycles, 1, 2, 3 and ≥4 embryos were transferred in 21.4, 53.4, 22.7 and 2.5% of cycles, with no decline in the number of embryos per transfer since 2006. The proportion of multiple deliveries (22.3: 21.3% twin and 1.0% triplet), did not decrease compared with 2006 (20.8%) and 2005 (21.8%). In women < 40 years undergoing IUI-H, twin deliveries occurred in 11.7% and triplets in 0.5%.
CONCLUSIONS
In comparison with previous years, the reported number of ART cycles in Europe increased in 2007; pregnancy rates increased marginally, but the earlier decline in the number of embryos transferred and multiple births did not continue.
doi:10.1093/humrep/des023
PMCID: PMC3303494  PMID: 22343707
European Society of Human Reproduction and Embryology; assisted reproduction technology; intrauterine insemination; register data
17.  Comparison of mild ovarian stimulation with conventional ovarian stimulation in poor responders 
Objective
To compare the IVF outcomes of mild ovarian stimulation with conventional ovarian stimulation in poor responders.
Methods
From 2004 to 2009, 389 IVF cycles in 285 women showed poor responses (defined as either a basal FSH level ≥12 mIU/mL, or the number of retrieved oocytes ≤3, or serum E2 level on hCG day <500 pg/mL) were analyzed, retrospectively. In total, 119 cycles with mild ovarian stimulation (m-IVF) and 270 cycles with conventional ovarian stimulation (c-IVF) were included. Both groups were divided based on their age, into groups over and under 37 years old.
Results
The m-IVF group was lower than the c-IVF group in the duration of stimulation, total doses of gonadotropins used, serum E2 level on hCG day, the number of retrieved oocytes, and the number of mature oocytes. However, there was no significant difference in the number of good embryos, the number of transferred embryos, the cancellation rate, or the clinical pregnancy rate. In the m-IVF group over 37 years old, the clinical pregnancy rate and live birth rate were higher when compared with the c-IVF group, but this result was not statistically significant.
Conclusion
In poor responder groups, mild ovarian stimulation is more cost effective and patient friendly than conventional IVF. Therefore, we suggest that mild ovarian stimulation could be considered for poor responders over 37 years old.
doi:10.5653/cerm.2011.38.3.159
PMCID: PMC3283064  PMID: 22384436
Mild Ovarian Stimulation; Poor Response; In Vitro Fertilization; Human
18.  Donor Oocyte Cytoplasmic Transfer Did Not Enhance Implantation of Embryos of Women with Poor Ovarian Reserve 
Purpose: To determine whether donor oocyte cytoplasm transferred into the oocytes of women ≥40 years or with diminished ovarian reserve would enhance embryo quality, implantation, or pregnancy rates.
Methods: Study subjects included women ≥40 years (15) or with abnormal FSH levels (3). Healthy volunteers (18) produced oocytes for cryopreservation. Donor oocytes were thawed and cytoplasm from surviving oocytes was injected with a single sperm into the cytoplasm of recipient oocytes. Outcome measures included embryo quality scores, implantation, and pregnancy rates.
Results: Eighteen donors produced 213 oocytes for cryopreservation and 39/171 (22.8%) survived thawing. Eighteen recipients initiated 25 IVF cycles with embryo transfer in 20 cycles after cytoplasmic transfer (CT). Four cycles resulted in three biochemical losses and one aneuploid clinical loss. Embryo quality did not improve with CT compared to pre-CT IVF cycles in six recipients.
Conclusions: CT with cryopreserved donor oocyte cytoplasm did not enhance success in women with advanced reproductive age or low ovarian reserve.
doi:10.1023/A:1014728603309
PMCID: PMC3468255  PMID: 12005304
Age factors; cryopreservation; cytoplasmic transfer; in vitro fertilization; ovarian reserve
19.  In vitro fertilisation (IVF) with donor eggs in post-menopausal women: are there differences in pregnancy outcomes in women with premature ovarian failure (POF) compared with women with physiological age-related menopause? 
Purpose
This study assessed pregnancy rates and obstetric outcomes in women with premature ovarian failure (Group A) with post-menopausal women ≥40 years (Group B) who had IVF ± ICSI using donor eggs.
Methods
This was a retrospective analysis of 54 recipients with either premature ovarian failure or physiological menopause undergoing oocyte donation between 2000 and 2007 at Monash IVF.
Results
The average number of stimulated cycles required for a woman in group A and B to deliver a baby was 1.75 and 1.4 respectively. Both groups had high cumulative pregnancy rates; however, there was a statistically significant difference with regards to rates of complications.
Conclusion
Oocyte donation in both premature ovarian failure and physiological menopause is highly successful and cumulative pregnancy rate is an important statistic which can be used to inform women seeking this technique. High rates of complications, in conjunction with individual risk-factor analysis needs to be considered when counselling post-menopausal women about oocyte donation.
doi:10.1007/s10815-009-9351-5
PMCID: PMC2788687  PMID: 19847640
Cumulative pregnancy rate; Oocyte donation; Outcomes; Post-menopausal; Premature ovarian failure
20.  Does the Number of Oocytes Retrieved Influence Pregnancy after Fresh Embryo Transfer? 
PLoS ONE  2013;8(2):e56189.
Background
The nature of the association between the number of oocytes retrieved and in vitro fertilization (IVF) outcomes after fresh embryo transfer remains unclear because of conflicting results reported in the studies on this subject. In addition, the influence of the quality of the embryos transferred is usually neglected. The objective of this study is to assess the relationships of the number of oocytes retrieved, the number and quality of embryos transferred, and the prospects of pregnancy after fresh embryo transfer.
Methods
The data on 3131 infertile women undergoing their first IVF treatment cycle between January 2009 and December 2010 were collected retrospectively. Restricted cubic splines and stratified analyses were used to explore the relationships between the number of oocytes retrieved, the number and quality of embryos transferred, and the IVF outcomes.
Results
When stratified by the number and quality of transferred embryos, no significant differences in the chances for clinical pregnancy and live birth were found in three groups of oocytes yielded (≤6, 7–14, or ≥15). The relationship between the number of oocytes retrieved and pregnancy is nearly a reflection of the pattern of the relationship between the number of oocytes retrieved and the probability of having two good-quality embryos transferred. The patients with the “optimal” number of oocytes were not only younger but also had the highest probability of having two good-quality embryos replaced.
Conclusions
Similarly aged patients have similar pregnancy prospects after fresh embryo transfer when the same number and quality of embryos are replaced, irrespective of their number of oocytes. Selecting the desired number of good-quality embryos for transfer is the key to IVF success. Thus, aiming at retrieving an optimal number of oocytes to maximize IVF outcomes in a fresh cycle could place undue stress on the patients and may not be the best medical decision.
doi:10.1371/journal.pone.0056189
PMCID: PMC3574022  PMID: 23457525
21.  Single thawed euploid embryo transfer improves IVF pregnancy, miscarriage, and multiple gestation outcomes and has similar implantation rates as egg donation 
Purpose
The objective of our study was to determine if trophectoderm biopsy, vitrification, array-comparative genomic hybridization and single thawed euploid embryo transfer (STEET) can reduce multiple gestations and yield high pregnancy and low miscarriage rates.
Methods
We performed a retrospective observational study comparing single thawed euploid embryo to routine age matched in vitro fertilization (IVF) patients that underwent blastocyst transfer from 2008 to 2011 and to our best prognosis group donor oocyte recipients (Donor). Our main outcome measures were implantation rate, clinical pregnancy rate, spontaneous abortion rate and multiple gestation rate.
Results
The STEET group had a significantly higher implantation rate (58 %, 53/91) than the routine IVF group (39 %, 237/613) while the Donor group (57 %, 387/684) had a similar implantation rate. The clinical pregnancy rates were not statistically different between the STEET and IVF groups. However, the multiple gestation rate was significantly lower in the STEET group (STEET 2 % versus IVF 34 %, Donor 47 %).
Conclusions
STEET results in a high pregnancy rate, low multiple gestation rate and miscarriage rates. Despite the older age of STEET patients and transfer of twice as many embryos, the implantation rate for STEET was indistinguishable from that for egg donation. STEET offers an improvement to IVF, lowering risks without compromising pregnancy rate.
doi:10.1007/s10815-012-9929-1
PMCID: PMC3585677  PMID: 23307447
Trophectoderm biopsy; Single embryo transfer; Array-comparative genomic hybridization; Aneuploidy; Embryo biopsy; Donor egg; IVF; Embryo transfer
22.  The effect of transcutaneous electrical acupoint stimulation on pregnancy rates in women undergoing in vitro fertilization: a study protocol for a randomized controlled trial 
Trials  2014;15:162.
Background
The latest meta-analysis demonstrated that acupuncture improves pregnancy rates among women undergoing in vitro fertilization-embryo transfer (IVF-ET), and surface acupoint stimulation, such as transcutaneous electrical acupoint stimulation (TEAS), may have the same or better potential.
Methods/Design
To explore the effect of TEAS on the clinical pregnancy rate (CPR) and live birth rate (LBR) compared with real acupuncture and controls in women undergoing IVF, a multicenter, randomized controlled trial will be conducted. The inclusion criteria are the following: infertile women <40 years of age undergoing a fresh IVF or intracytoplasmic sperm injection cycle, and the study will be restricted to women with the potential for a lower success rate as defined by two or more previous unsuccessful ETs (fresh or frozen). Those who have severe illnesses possibly precluding IVF or pregnancy, have FSH levels greater than 20 IU/L, received donor eggs, had been previously randomized for this study or had undergone acupuncture (in any modality) as infertility treatment will be excluded. The subjects will be randomly assigned to the TEAS group (IVF + TEAS), the electro-acupuncture (EA) group (IVF + EA), or the control group (only IVF). A total sample size of 2,220 women is required to detect differences in CPR among the three groups. TEAS or EA treatments will start once every two or three days from day 3 of menstruation in the ovarian stimulation cycle until the day of ET. The parameters of TEAS or EA will be the following: a frequency of 2/100 Hz, a moderate electrical current of 3 to 5 mA for TEAS and 0.8 to 1.0 mA for EA. The primary outcome is CPR. Secondary outcomes are LBR, the number of oocytes aspirated and the total gonadotropin dose used in the stimulation cycle.
Discussion
This study will provide significant evidence for using a new method (TEAS) in IVF.
Trial registration
ClinicalTrials.govID: NCT01608048 (05/24/2012).
doi:10.1186/1745-6215-15-162
PMCID: PMC4020380  PMID: 24886647
acupuncture; transcutaneous electrical acupoint stimulation; TEAS
23.  The clinical significance of calcium-signalling pathways mediating human sperm hyperactivation 
STUDY QUESTION
What is the prevalence of defects in the Ca2+-signalling pathways mediating hyperactivation (calcium influx and store mobilization) among donors and sub-fertile patients and are they functionally significant, i.e. related to fertilization success at IVF?
SUMMARY ANSWER
This study identifies, for the first time, the prevalence of Ca2+ store defects in sperm from research donors, IVF and ICSI patients. It highlights the biological role and importance of Ca2+ signalling (Ca2+ store mobilization) for fertilization at IVF.
WHAT IS KNOWN ALREADY
Sperm motility and hyperactivation (HA) are important for fertility, mice with sperm incapable of HA are sterile. Recently, there has been significant progress in our knowledge of the factors controlling these events, in particular the generation and regulation of calcium signals. Both pH-regulated membrane Ca2+ channels (CatSper) and Ca2+ stores (potentially activating store-operated Ca2+ channels) have been implicated in controlling HA.
STUDY DESIGN, SIZE, AND DURATION
This was a prospective study examining a panel of 68 donors and 181 sub-fertile patients attending the Assisted Conception Unit, Ninewells Hospital Dundee for IVF and ICSI. Twenty-five of the donors gave a second sample (∼4 weeks later) to confirm consistency/reliability of the recorded responses. Ca2+ signalling was manipulated using three agonists, NH4Cl (activates CatSper via pH), progesterone (direct activation of CatSper channels, potentially enhancing mobilization of stored Ca2+ by CICR) and 4-aminopyridine (4-AP) (effect on pH equivalent to NH4Cl and mobilizes stored Ca2+). The broad-spectrum phosphodiesterase inhibitor 3-isobutyl-1-methyxanthine (IBMX), a potent activator of HA was also used for comparison. For patient samples, an aliquot surplus to requirements for IVF/ICSI treatment was examined, allowing direct comparison of Ca2+ signalling and motility data with functional competence of the sperm.
MATERIALS, SETTING, METHODS
The donors and sub-fertile patients were screened for HA (using CASA) and changes in intracellular Ca2+ were assessed by loading with Fura-2 and measuring fluorescence using a plate reader (FluoStar).
MAIN RESULTS AND THE ROLE OF CHANCE
The relative efficacy of the stimuli in inducing HA was 4-AP >> IBMX > progesterone. NH4Cl increased [Ca2+]i similarly to 4-AP and progesterone but did not induce a significant increase in HA. Failure of samples to generate HA (no significant increase in response to stimulation with 4-AP) was seen in just 2% of research donors but occurred in 10% of IVF patients (P = 0.025). All donor samples generated a significant [Ca2+]i increase when stimulated with 4-AP but 3.3% of IVF and 28.6% of ICSI patients failed to respond. Amplitudes of HA and [Ca2+]i responses to 4-AP were correlated with fertilization rate at IVF (P= 0.029; P = 0.031, respectively). Progesterone reliably induced [Ca2+]i responses (97% of donors, 100% of IVF patients) but was significantly less effective than 4-AP in inducing HA. Twenty seven per cent of ICSI patients failed to generate a [Ca2+]i response to progesterone (P= 0.035). Progesterone-induced [Ca2+]i responses were correlated with fertilization rate at IVF (P= 0.037) but induction of HA was not. In donor samples examined on more than one occasion consistent responses for 4-AP-induced [Ca2+]i (R2 = 0.97) and HA (R2 = 0.579) were obtained. In summary, the data indicate that defects in Ca2+ signalling leading to poor HA do occur and that ability to undergo Ca2+ -induced HA affects IVF fertilizing capacity. The data also confirm that release of stored Ca2+ is the crucial component of Ca2+ signals leading to HA and that Ca2+ store defects may therefore underlie HA failure.
LIMITATIONS, REASONS FOR CAUTION
This is an in vitro study of sperm function. While the repeatability of the [Ca2+]i and HA responses in samples from the same donor were confirmed, data for patients were from 1 assessment and thus the robustness of the failed responses in patients’ needs to be established. The focus of this study was on using 4AP, which mobilizes stored Ca2+ and is a potent inducer of HA. The n values for other agonists, especially calcium assessments, are smaller.
WIDER IMPLICATIONS OF THE FINDINGS
Previous studies have shown a significant relationship between basal levels of HA, calcium responses to progesterone and IVF fertilization rates. Here, we have systematically investigated the ability/failure of human sperm to generate Ca2+ signals and HA in response to targeted pharmacological challenge and, related defects in these responses to IVF success. [Ca2+]i signalling is fundamental for sperm motility and data from this study will lead to assessment of the nature of these defects using techniques such as single-cell imaging and patch clamping.
STUDY FUNDING/COMPETING INTEREST(S)
Resources from a Wellcome Trust Project Grant (#086470, Publicover and Barratt PI) primarily funded the study. The authors have no competing interests.
doi:10.1093/humrep/des467
PMCID: PMC3600839  PMID: 23406974
calcium signalling; sperm; male fertility; hyperactivation; sperm motility; IVF.
24.  The clinical significance of calcium signalling pathways mediating human sperm hyperactivation 
Study question
To determine the incidence of defects in Ca2+ signalling pathways mediating hyperactivation (calcium influx and store mobilisation) among donors and sub fertile patients and to ascertain if these are functionally significant i.e. related to fertilisation success at IVF.
Summary answer
This study identifies, for the first time, the incidence of Ca2+store defects among research donors, IVF and ICSI patients and highlights the biological role and importance of Ca2+-signalling (Ca2+ store mobilisation) for fertilisation at IVF.
What is known already
Sperm motility and hyperactivation (HA) are important for fertility, mice with sperm incapable of HA are sterile. Recently there has been significant progress in our knowledge of the factors controlling these events, in particular the generation and regulation of calcium signals. Both pH-regulated membrane Ca2+channels (CatSper) and Ca2+ stores (potentially activating store-operated Ca2+ channels) have been implicated in controlling HA.
Study design, size, and duration
This was a prospective study examining a panel of 68 donors and 181 sub fertile patients attending the Assisted Conception Unit, Ninewells Hospital Dundee for IVF and ICSI. 21 of the donors gave a second sample (~4 weeks later) to confirm consistency/reliability of the recorded responses. Ca2+ signaling was manipulated using three agonists, NH4Cl (activates CatSper via pH), progesterone (direct activation of CatSper channels, potentially enhancing mobilisation of stored Ca2+ by CICR) and 4-AP (effect on pH equivalent to NH4Cl and mobilises stored Ca2+). IBMX, a potent activator of HA was also used for comparison. For patient samples, an aliquot surplus to requirements for IVF/ICSI treatment was examined, allowing direct comparison of Ca2+-signalling and motility data with functional competence of the sperm.
Materials, setting, methods
The donors and sub fertile patients were screened for HA (using CASA) and changes in intracellular Ca2+ were assessed by loading with fura and measuring fluorescence using a plate reader (FluoStar).
Main results and the role of chance
Relative efficacy of the stimuli in inducing HA was 4-AP>>IBMX>progesterone. NH4Cl increased [Ca2+]i similarly to 4-AP and progesterone but did not induce a significant increase in HA. Failure of samples to generate HA (no significant increase in response to stimulation with 4-AP) was seen in just 2% of research donors but occurred in 10% of IVF patients (P= 0.025). All donor samples generated a significant [Ca2+]i increase when stimulated with 4-AP but 3.3% of IVF and 25% of ICSI patients failed to respond. Amplitudes of HA and [Ca2+]i responses to 4-AP were correlated with fertilisation rate at IVF (P= 0.029; P=0.031 respectively). Progesterone reliably induced [Ca2+]i responses (97% of donors, 100% of IVF patients) but was significantly less effective than 4-AP in inducing HA. 25% of ICSI patients failed to generate a [Ca2+]i response to progesterone (P=0.035). Progesterone-induced [Ca2+]i responses were correlated with fertilisation rate at IVF (P= 0.037) but induction of HA was not. In donor samples examined on more than one occasion consistent responses for 4-AP-induced [Ca2+]i (R2 = 0.97) and HA (R2=0.579) were obtained.
In summary, the data indicate that defects in Ca2+ leading to poor HA do occur and that ability to undergo Ca2+ -induced HA affects IVF fertilising capacity. The data also confirm that release of stored Ca2+ is the crucial component of Ca2+signals leading to HA and that Ca2+ store defects may therefore underlie HA failure.
Limitations, reasons for caution
This is an in vitro study of sperm function. Whilst the repeatability of the [Ca2+]i and HA responses in samples from the same donor were confirmed, data for patients were from 1 assessment and thus the robustness of the failed responses in patients’ needs to be established. The focus of this study was on using 4AP, which mobilizes stored Ca2+ and is a potent inducer of HA. The n values for other agonists, especially calcium assessments, are smaller.
Wider implications of the findings
Previous studies have shown a significant relationship between basal levels of HA, calcium responses to progesterone and IVF fertilisation rates. Here we have systematically investigated the ability/failure of human sperm to generate Ca2+ signals and HA in response to targeted pharmacological challenge and, related defects in these responses to IVF success. [Ca2+]i signalling is fundamental for sperm motility and data from this study will lead to assessment of the nature of these defects using techniques such as single cell imaging and patch clamping.
Study funding/competing interest(s)
Resources from a Welcome Trust Project Grant (# 086470, Publicover and Barratt PI) primarily funded the study. The authors have no competing interests.
doi:10.1093/humrep/des467
PMCID: PMC3600839  PMID: 23406974
calcium signalling; sperm; male fertility; hyperactivation; sperm motility; IVF
25.  Treatment variables in relation to oocyte maturation: Lessons from a clinical micromanipulation-assisted in vitro fertilization program 
Objective: In an effort to understand the mechanism underlying the improved pregnancy rate observed in IVF cycles when gonadotropin-releasing hormone analogues (GnRH-a) are applied, we investigated a possible relationship between treatment variables and oocyte-nuclear maturity.
Design: Nuclear maturity was retrospectively assessed in cumulus-free, denuded oocytes, obtained from women undergoing micromanipulation-assisted IVF treatment following controlled ovarian hyperstimulation with GnRH-a and menotropins.
Setting: The setting was the infertility and IVF unit of a tertiary academic medical center.
Participants: Two hundred twenty-one patients underwent 435 treatment cycles.
Main Outcome Measure: This was the proportion of germinal vesicle-intact immature (GVII) oocytes.
Results: One hundred fifty-four of the 3520 oocytes studied (4.4%) were in the GVII stage. These oocytes were found in 66 of the treatment cycles (15.2%) and in 54 of the patients (24.4%). Cycles in which GVII oocytes were detected did not differ from those in which all the aspirated oocytes were mature in the following respects: patient age, type and duration of infertility, controlled ovarian hyperstimulation protocol and time of ovum pickup. However, the GVII group was characterized by a significantly higher peak estradiol level, as well as a higher number of mature follicles visualized sonographically (diameter, >14 mm) and oocytes retrieved.
Conclusions: Comparing the present findings with previously published data, it appears that the inclusion of GnRH-a in the stimulation regimen is associated with a lower proportion of immature oocytes. A higher occurrence of oocyte-nuclear immaturity is apparently associated with a significantly better ovarian response to stimulation. The high incidence of immature oocytes observed in patients with normospermic partners and low fertilization rates in previous cycles may suggest that the fertilization failure in some of these cases is due to oocyte, rather than sperm, dysfunction.
doi:10.1007/BF02765838
PMCID: PMC3454788  PMID: 9226513
in vitro fertilization; gonadotropin releasing hormone analogues; oocyte maturation

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