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1.  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
2.  Monozygotic multiple gestation following in vitro fertilization: analysis of seven cases from Japan 
We present a series of monozygous multiple gestations achieved following in vitro fertilization (IVF): one case of monochorionic triplet pregnancy and six cases of dizygotic triplet pregnancy. From September 2000 to December 2006, all patients achieving clinical pregnancy by ART were reviewed (n = 2433). A 37 year-old woman who delivered a healthy singleton after IVF returned two years later for FET, and a single blastocyst was transferred. This also resulted in pregnancy, but TV-USG revealed a single gestational sac with three distinct amniotic sacs, each containing a distinct fetal pole with cardiac activity. This pregnancy was electively terminated at nine weeks' gestation. An additional six cases of dizygotic triplets established after fresh embryo transfer (no ICSI or assisted hatching) are also described. Of these, one resulted in a miscarriage at eight weeks' gestation and five patients have an ongoing pregnancy. This case series suggests the incidence of dizygotic/monochorionic triplets following IVF is approximately 10 times higher than the expected rate in unassisted conceptions, and underscores the importance of a conservative approach to lower the number of embryos at transfer. The role of embryo transfer technique and in vitro culture media in the twinning process requires further study.
doi:10.1186/1743-1050-4-4
PMCID: PMC2034589  PMID: 17888172
3.  Dichorionic twins and monochorionic triplets after the transfer of two blastocysts 
Purpose
To describe a unique case of MZ dichorionic twins and MZ monochorionic triplets in a quintuplet gestation after intracytoplasmatic sperm injection (ICSI) and blastocyst transfer.
Methods
Case report. A 24-year-old woman underwent ICSI and received two blastocysts transferred. A quintuplet gestation was established .Transvaginal ultrasonography was performed sequentially during early pregnancy.
Results
Three intrauterine gestational sacs were revealed at about 5th week. At the 7th week, five gestational sacs presenting heart beats were detected and a quintuplet pregnancy consisting of two monozygotic (MZ) dichorionic twins and three MZ monochorionic triplets was determined. At the 10th week, a single gestational sac with heart beats was detected. The prenatal course was uneventful. A healthy baby was born at 36th week.
Conclusion
Few other reports have described the occurrence of a quintuplet gestation after the transfer of two blastocysts generated by ICSI. Our case is unique in that the two blastocysts underwent two different splitting processes, which occurred possibly at a similar time giving rise to MZ dichorionic twins and MZ monochorionic triplets.
doi:10.1007/s10815-010-9446-z
PMCID: PMC2965338  PMID: 20665238
Quintuplets; Monozygosity; ICSI; Blastocysts
4.  Monozygotic Triplets and Dizygotic Twins following Transfer of Three Poor-Quality Cleavage Stage Embryos 
Background. Assisted reproductive technology has been linked to the increased incidence of monozygotic twinning. It is of clinical importance due to the increased risk of complications in multiple pregnancies in general and in monozygotic twins in particular. Case. A 29-year-old female, nulligravida underwent her first IVF cycle. Three poor-quality cleavage stage embryos were transferred resulting in monochorionic triamniotic triplets and dichorionic diamniotic twins. Selective embryo reduction was performed at 12 weeks leaving dichorionic twins. The patient underwent emergency cesarean section due to preterm labor and nonreassuring fetal heart tracing at 30 weeks of gestation. Conclusion. Our case emphasizes that even embryos with significant morphological abnormalities should be considered viable and the possibility of simultaneous spontaneous embryo splitting must be factored into determining number of embryos to transfer.
doi:10.1155/2012/763057
PMCID: PMC3540689  PMID: 23320217
5.  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
6.  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
7.  Maternal and neonatal outcomes in dichorionic twin pregnancies following IVF treatment: a hospital-based comparative study 
Aim: To compare maternal, and neonatal outcomes in IVF/ICSI and spontaneously conceived dichorionic twin pregnancy. Method: We collected data regarding dichorionic twin pregnancies following in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI, n=162) with the transfer of fresh embryos as well as data regarding spontaneously conceived pregnancies (n=213) delivered after 28 weeks of gestation at the Department of Obstetrics and Gynecology, Renmin Hospital in Wuhan in the years of 2010-2013. We then compared maternal and neonatal outcomes between IVF/ICSI and spontaneous dichorionic twin pregnancies, with a subgroup analysis separating traditional IVF from ICSI pregnancies. Odds ratios (OR) for associations between IVF/ICSI and pregnancy outcomes were adjusted for maternal factors. Results: The mean maternal age and the percentage of primiparous women were significantly higher in the IVF/ICSI group. Multivariate analysis revealed that maternal outcomes were comparable in both groups with/without adjustment for maternal age and parity. However, IVF/ICSI twins were less likely to have birth weight discordance than those spontaneously conceived (unadjusted OR=0.526, 95% CI 0.297-0.932; adjusted OR=0.486, 95% CI 0.255-0.856). In subgroup analyses, these associations were confirmed in the IVF (adjusted OR=0.496, 95% CI 0.265-0.926), but not in the ICSI group (adjusted OR=0.500, 95% CI 0.139-1.807). Conclusion: IVF/ICSI treatment was not a risk factor for adverse maternal neonatal outcomes, but the risk for birth weight discordance is lower among IVF/ICSI twins.
PMCID: PMC3796243  PMID: 24133599
In vitro fertilization/intracytoplasmic sperm injection; dichorionic twin pregnancy; maternal outcome; neonatal outcome
8.  Monochorionic triamniotic triplet pregnancy with a co-triplet fetus discordant for congenital cystic adenomatoid malformation of the lung 
Background
Spontaneous monochorionic triamniotic pregnancy is rare and is at increased risk for pregnancy complications. The presence of an anomalous fetus further complicates the management.
Case presentation
We present a case of monochorionic triamniotic triplet pregnancy diagnosed at 15 weeks of gestation with one fetus having developed a multicystic lung lesion, suggestive of congenital cystic adenomatoid malformation (CCAM). At 24 weeks, the largest cyst measured 10 mm in diameter. We managed the pregnancy conservatively and delivered three live male fetuses with birth weights 1560 g, 1580 g and 1590 g at 35 weeks of gestation. Two newborns were admitted to the neonatal intensive care unit with respiratory distress, the third one died due to sepsis 7 days postpartum. One of the newborns was discharged healthy at 24 days postpartum. The newborn with CCAM developed a pneumothorax on the right side, recovered after treatment, and was discharged after one month. Computerized tomography (CT) of the infant at 3 months demonstrated two cystic lesions in the middle lobe of the right lung measuring 25 mm and 15 mm. A repeat CT of the infant at 6 months showed a 30 mm solitary cystic mass.
Conclusion
Monochorionic triamniotic triplet pregnancy with a co-triplet fetus discordant for CCAM, present rarely and can be managed conservatively. These findings may help in decision making and counselling of parents.
doi:10.1186/1742-4755-2-2
PMCID: PMC1082912  PMID: 15819977
9.  CLINICAL ASSISTED REPRODUCTION: IVF-Patients With Nonmale Factor “To ICSI” or “Not to ICSI” That is the Question? 
Purpose: Intracytoplasmic sperm injection (ICSI) guarantees high fertilization rates and could theoretically lead to higher implantation rates as well. Furthermore injection into oocyte creates a hole in the zona pellucida similar to the procedure of assisted hatching. We were therefore interested to assess such a potential benefit for infertile IVF patients without male factor.
Materials and Methods: Open randomized prospective study according to the rules “Good Clinical Practice” with informed consent of the patients and institutional review board approval. Ninety-one consecutively seen patients with tubal infertility or hostile cervical mucus were randomized to undergo either ICSI (44 patients) or IVF (45 patients). In two patients fertilization of oocytes failed and so a repeated ICSI had to be performed. All these patients were stimulated with the same protocol, using the gonadotropin releasing hormone-agonist (GnRH-a) buserelin acetate in an ultrashort flair-up protocol together with pure follicle stimulating hormone (rFSH). The two study groups did not differ in terms of age, BMI, and all baseline hormone levels.
Results: The total pregnancy rate was 42% in the normal IVF group with 33% ongoing pregnancies. The ICSI group had a total pregnancy rate of 39% with 23% ongoing pregnancies. The implantation rate per transferred embryo was higher for normal IVF but not significant (18% versus 11%). The variables, fertilization rate, age, body mass index, baseline hormone levels, endometrial thickness, embryo score, and the highest grade embryo per transfer were very similar in both groups.
Conclusion: ICSI should be applied only when conventional IVF fails, that is, for male factor patients and for patients with unexplained infertility.
doi:10.1023/A:1009403928600
PMCID: PMC3455365
ICSI; IVF; nonmalefactor; tubal infertility capsule
10.  Short Communication: Successful Outcome of Intrathoracic Injection of Autologous Amniotic Fluid in Fetal Reduction: Report of Two Cases 
Potassium chloride is reported to kill both monochorionic twins after injection into only one. In this study, two women undergoing in vitro fertilization and embryo transfer were pregnant with triplets containing monochorionic twinning, which were detected by ultrasound with the presence of a “twin-peak” sign. Instead of potassium chloride, intrathoracic injection of amniotic fluid was employed to sacrifice one of the monochorionic fetuses in dichorionic triplets. Our aim was to sacrifice one of the monochorionic twins in order to prevent adverse perinatal outcomes and to avoid the harmful effect of potassium chloride on monochorionic cotwins. One twin pregnancy was terminated with preterm premature rupture of membranes at 25 weeks of gestation. In the second one, two healthy babies were delivered by cesarean section at 36 weeks of gestation. The female baby weighed 2100 gm and the male baby 2600 gm, respectively. Intrathoracic injection of amniotic fluid to create a tamponade is an alternative management for fetal reduction.
doi:10.1023/B:JARG.0000045475.90846.89
PMCID: PMC3468266  PMID: 15587149
Amniotic fluid; fetal reduction; monochorionic twin; tamponade
11.  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
12.  Comparison of semen quality and outcome of assisted reproductive techniques in Chinese men with and without hepatitis B 
Asian Journal of Andrology  2011;13(3):465-469.
In this study, we aimed to determine the effects of hepatitis B virus (HBV) infection on sperm quality and the outcome of assisted reproductive technology (ART). A total of 916 men (457 HBV-positive and 459 HBV-negative) seeking fertility assistance from January 2008 to December 2009 at the Women's Hospital in the School of Medicine at Zhejiang University were analysed for semen parameters. Couples in which the men were hepatitis B surface antigen (HBsAg)-seropositive were categorized as HBV-positive and included 587 in vitro fertilisation (IVF) and 325 intracytoplasmic sperm injection (ICSI) cycles from January 2004 to December 2009; negative controls were matched for female age, date of ova retrieval, ART approach used (IVF or ICSI) and randomized in a ratio of 1:1 according to the ART treatment cycles (587 for IVF and 325 for ICSI). HBV-infected men exhibited lower semen volume, lower total sperm count as well as poor sperm motility and morphology (P<0.05) when compared to control individuals. Rates of two-pronuclear (2PN) fertilisation, high-grade embryo acquisition, implantation and clinical pregnancy were also lower among HBV-positive patients compared to those of HBV-negative patients after ICSI and embryo transfer (P<0.05); IVF outcomes were similar between the two groups (P>0.05). Logistic regression analysis showed that HBV infection independently contributed to increased rates of asthenozoospermia and oligozoospermia/azoospermia (P<0.05) as well as decreased rates of implantation and clinical pregnancy in ICSI cycles (P<0.05). Our results suggest that HBV infection in men is associated with poor sperm quality and worse ICSI and embryo transfer outcomes but does not affect the outcome of IVF and embryo transfer.
doi:10.1038/aja.2010.164
PMCID: PMC3739335  PMID: 21399651
hepatitis B virus; infection; infertility; intracytoplasmic sperm injection; in vitro fertilisation; male infertility; sperm; sperm motility
13.  Should few retrieved oocytes be as an indication for intracytoplasmic sperm injection? 
Objective: To reevaluate whether relatively few oocytes obtained in one cycle are an indication for intracytoplasmic sperm injection (ICSI). Methods: A total of 406 cycles with three or fewer retrieved oocytes performed in 396 non-male infertile couples were retrospectively reviewed. Cycles were classified into three groups by different fertilization techniques: the in vitro fertilization (IVF) group, insemination with conventional IVF; the ICSI group, insemination with ICSI though semen parameters were normal; and the rescue ICSI group, re-insemination with ICSI after conventional IVF failure. Results: The ICSI group resulted in higher normal fertilization compared with the conventional IVF group. Correspondingly, the cycle cancellation rate was decreased in the ICSI group, though it was not statistically significant. The clinical pregnancy rate and implantation rate were lower in the ICSI group compared with the conventional IVF group. Rescue ICSI was a method to avert total fertilization failure in conventional IVF, increasing fertilization and ensuring embryo availability for transfer, but the normal fertilization was the lowest due to delayed insemination and the chance of pregnancy was very little. Conclusions: Obtaining only few oocytes in one cycle is not considered as an indication for ICSI when the sperm sample is apparently normal. Rescue ICSI is either not recommended if conventional insemination fails. Such patients should not be subjected to the unnecessary costs and potential risks of ICSI.
doi:10.1631/jzus.B1100370
PMCID: PMC3437369  PMID: 22949362
Fertilization rate; Intracytoplasmic sperm injection (ICSI); Indication; Oocyte number; Patient age
14.  Clinical outcome of frozen blastocyst transfer; single vs. double transfer 
Purpose
Frozen embryo transfer has been established as an indispensable ART procedure for both the effective use of surplus embryos and the prevention of ovarian hyperstimulation syndrome. The frequency of frozen embryo transfer is increasing in our clinic, and we report that frozen embryo transfer is effective for patients with repeat failures. We present our clinical outcome of frozen blastocyst transfer (FBT).
Methods
In 2006, 470 patients received FBT (562 cycles (IVF: 354 cycles; ICSI: 208 cycles)). One frozen blastocyst was transferred in 412 cycles (335 patients) and two blastocysts were transferred in 150 cycles (135 patients). Assisted hatching was performed in all cases.
Results
In 412 cycles (average age: 34.6 years) who received a single FBT, the rate of clinical pregnancy per cycle was 40.7%, the live birth rate was 29.1%, the abortion rate was 21.6%, the ectopic pregnancy rate was 1.2%, the frequency of monochorionic twins was 2.3%, and the cesarean section rate was 38.3%. In 150 cycles (average patient age 34.8 years) who received two FBTs, the clinical pregnancy rate was 46%, the live birth rate was 35.3%, the abortion rate was 16.3%, the ectopic pregnancy rate was 4.4%, the frequency of twins was 15.9% and the cesarean section rate was 39.6%. A significant difference in the ectopic pregnancy rate and the twinning rate was found between single transfers and double transfers (P < 0.05). When IVF and ICSI were compared, there was no statistically significant difference in the abortion rate, the ectopic pregnancy rate, and the cesarean section rate.
Conclusions
The clinical pregnancy rate was similar for the transfer of one and two blastocysts. Single FBT decreases obstetrical risk without reducing the pregnancy rate.
doi:10.1007/s10815-008-9275-5
PMCID: PMC2593763  PMID: 18989770
Blastocyst; Vitrification; In vitro fertilization; Pregnancy
15.  Obstetric and perinatal outcomes in IVF versus ICSI-conceived pregnancies at a tertiary care center - a pilot study 
Background
Although most pregnancies after IVF result in normal healthy outcomes, an increased risk for a number of obstetric and neonatal complications, compared to naturally conceived pregnancies, has been reported. While there are many studies that compare pregnancies after assisted reproductive techniques with spontaneously conceived pregnancies, fewer data are available that evaluate the differences between IVF and ICSI-conceived pregnancies. The aim of our present study was, therefore, to compare obstetric and perinatal outcomes in pregnancies conceived after in vitro fertilization (IVF) versus intracytoplasmatic sperm injection (ICSI).
Methods
Three-hundred thirty four women who had become pregnant after an IVF or ICSI procedure resulted in a total of 530 children referred between 2003 und 2009 to the Department of Obstetrics and Gynecology of the Medical University of Vienna, a tertiary care center, and were included in this retrospective cohort study. We assessed maternal and fetal parameters in both groups (IVF and ICSI). The main study outcomes were preterm delivery, the need for neonatal intensive care, and congenital malformations. Moreover, we compared the course of pregnancy between both groups and the occurrence of complications that led to maternal hospitalization during pregnancy.
Results
There were 80 children conceived via ICSI and 450 children conceived via IVF.
Mean gestational age was significantly lower in the ICSI group (p = 0.001). After ICSI, the birth weight (p = 0.008) and the mean APGAR values after 1 minute and after 10 minutes were lower compared to that of the IVF group (p = 0.016 and p = 0.047, respectively). Moreover, ICSI-conceived children had to be hospitalized more often at a neonatal intensive care unit (p = 0.004). There was no difference in pH of the umbilical artery or in major congenital malformations between the two groups. Pregnancy complications (i.e., premature rupture of membranes, cervical insufficiency, and premature uterine contractions) and the need for maternal hospitalization during pregnancy were found significantly more often after IVF (p = 0.0016 and p = 0.0095, respectively), compared to the ICSI group.
Conclusions
When comparing IVF versus ICSI-conceived pregnancies at a tertiary care center, we found the course of pregnancy to be more complicated after IVF, whereas the primary fetal outcome seemed to be better in this group than after ICSI treatment.
doi:10.1186/1477-7827-11-84
PMCID: PMC3844416  PMID: 24004836
IVF; ICSI; Pregnancy course; Obstetric outcome; Perinatal outcome
16.  Transfer of spontaneously hatching or hatched blastocyst yields better pregnancy rates than expanded blastocyst transfer 
CONTEXT:
Blastocyst stage embryo transfer (ET) has become routine practice in recent years. However, probably due to limitations of assisted hatching techniques, expanded blastocyst transfer (EBT) is still the preferred mode. Inexplicably, not much consideration has been given to spontaneously hatching/hatched blastocyst transfer (SHBT).
AIM:
This study aimed to investigate developmental potential of spontaneously hatching/hatched blastocyst against EBT in in vitro fertilization (IVF) cycles.
SETTINGS AND DESIGN:
Prospective study of 146 women undergoing their first IVF- ET cycle.
SUBJECTS AND METHODS:
On the basis of blastocyst status, women were classified into SHBT and EBT groups. Intracytoplasmic sperm injection cycles were excluded to remove male factor bias. Implantation rate (IR), clinical pregnancy rate, and live birth rate were the main outcome measures.
STATISTICAL ANALYSIS:
Graph-pad Prism 5 statistical package.
RESULTS:
SHBT group showed significantly higher blastocyst formation rate (53.3 ± 17.5 vs. 43.1 ± 14.5%, P = 0.0098), top-quality blastocysts (71.8 vs. 53.7%, P = 0.0436), IR (43.6 vs. 27.9%, P = 0.0408), pregnancy rate (59.4 vs. 45.1%, P = 0.0173), and live birth rate (36.8 vs. 22.8%, P = 0.003) compared to EBT group. Multiple pregnancy rates remained comparable between the two groups. Implantation correlated strongly with top-quality blastocysts (Pearson, r = 0.4441) in SHBT group, while the correlation was nonsignificant in EBT group.
CONCLUSION:
Extending culture of expanded blastocysts by a few hours to allow transfer of spontaneously hatching/hatched blastocysts gives higher implantation and pregnancy rates with no added risk of multiple gestations. Spontaneously hatching/hatched blastocysts have a better potential to implant and develop into a positive pregnancy.
doi:10.4103/0974-1208.121420
PMCID: PMC3853874  PMID: 24347932
Blastocyst transfer; expanded blastocyst; extended culture; implantation; in vitro fertilization; pregnancy outcome; spontaneously hatching/hatched blastocyst
17.  Perinatal Outcomes by Mode of Assisted Conception and Sub-Fertility in an Australian Data Linkage Cohort 
PLoS ONE  2014;9(1):e80398.
Background
Fertility treatment is associated with increased risk of major birth defects, which varies between in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), and is significantly reduced by embryo freezing. We therefore examined a range of additional perinatal outcomes for these exposures.
Methods
All patients in South Australia receiving assisted conception between Jan 1986–Dec 2002 were linked to the state-wide perinatal collection (all births/stillbirths ≥20 weeks gestation or 400 g birth weight, n = 306 995). We examined stillbirth, mean birth weight, low birth weight (<2500 g, <1500 g), small size for gestational age (<10th percentile, <3rd percentile), large size for gestational age (>90th percentile), preterm birth (32–<37 weeks, <32 weeks gestation), postterm birth (≥41 weeks gestation), Apgar <7 at 5 minutes and neonatal death.
Results
Relative to spontaneous conceptions, singletons from assisted conception were more likely to be stillborn (OR = 1.82, 95% Confidence Interval (CI) 1.34–2.48), while survivors as a group were comprehensively disadvantaged at birth, including lower birth weight (−109 g, CI −129–−89), very low birth weight (OR = 2.74, CI 2.19–3.43), very preterm birth (OR = 2.30, CI 1.82–2.90) and neonatal death (OR = 2.04, CI 1.27–3.26). Outcomes varied by type of assisted conception. Very low and low birth weight, very preterm and preterm birth, and neonatal death were markedly more common in singleton births from IVF and to a lesser degree, in births from ICSI. Using frozen-embryos eliminated all significant adverse outcomes associated with ICSI but not with IVF. However, frozen-embryo cycles were also associated with increased risk of macrosomia for IVF and ICSI singletons (OR = 1.36, CI 1.02–1.82; OR = 1.55, CI 1.05–2.28). Infertility status without treatment was also associated with adverse outcomes.
Conclusions
Births after assisted conception show an extensive range of compromised outcomes that vary by treatment modality, that are substantially reduced after embryo freezing, but which co-occur with an increased risk of macrosomia.
doi:10.1371/journal.pone.0080398
PMCID: PMC3885393  PMID: 24416127
18.  Late Fertilization of Unfertilized Human Oocytes in In Vitro Fertilization and Intracytoplasmic Sperm Injection Cycles: Conventional Insemination versus ICSI 
Purpose: The aim of this study was to evaluate the efficacyof intracytoplasmic sperm injection (ICSI) in comparisonwith conventional reinsemination using fertilization failedoocytes by conventional in vitro fertilization (IVF).
Methods: Oocytes were collected from patients of IVF orICSI cycles. Patients were grouped by fertilizationtechniques: group 1: conventional IVF; group 2: reinseminationafter conventional IVF failure; group 3: regular ICSI; group4: 1-day-old ICSI after conventional IVF failure; group 5:2-day-old ICSI after conventional IVF failure; group 6:re-ICSI after regular ICSI failure.
Results: In different insemination groups, normalfertilization rate was higher (P < 0.001) in 1-day-old ICSI (47.1%)and 2-day-old ICSI groups (40.0%) than in reinsemination(14.7%). Abnormal fertilization rate was higher (P < 0.05)in re-ICSI group (21.7%) than any other groups (range:0–8%). Cleavage rate was higher in 1-day-old (36.7%)and 2-day-old ICSI groups (36.0%) than in reinsemination(5.3%, P < 0.001) or re-ICSI groups (17.4%, P < 0.05).Pregnancy rate was 27.6% and 20.0% in conventional IVFand regular ICSI groups, respectively. However, 1-day-oldICSI (group 4) and 2-day-old ICSI (group 5) were attemptedonce embryo transfer (ET) but failed pregnancy occurredin each group.
Conclusions: In fertilization failure cycles, late ICSIincreases the rate of fertilization and embryonic developmentand may rescue the completely failed attempt of pregnancy.
doi:10.1023/A:1009409100941
PMCID: PMC3455574  PMID: 11062851
Conventional IVF; reinsemination; 1-day-old ICSI; 2-day-old ICSI; re-ICSI
19.  Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials 
Objective To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers.
Design One stage meta-analysis of individual patient data.
Data sources A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer.
Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded.
Results Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18).
Conclusions Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.
doi:10.1136/bmj.c6945
PMCID: PMC3006495  PMID: 21177530
20.  Assisted hatching in assisted reproduction: a state of the art 
The World Health Organization estimates that one in six couples experience some delay in conception and an increasing number require treatment by the assisted conception (AC) procedures of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).The implantation rate of embryos resulting from in vitro fertilization cycles is generally less than 20%. The exposure of oocytes and embryos to the artificial conditions of in vitro culture may have negative effects on the embryo’s ability to undergo normal hatching, resulting in low rates of implantation following IVF and embryo transfer. Human embryos resulting from superovulation develop more slowly in vitro compared to embryos in vivo, manifest a relatively high degree of cytogenetic abnormalities and undergo cellular fragmentation. Artificially disrupting the zona pellucida is known as assisted hatching (AH) and there is some evidence that embryos that have undergone zona manipulation for assisted hatching tend to implant one day earlier than unhatched embryos. A variety of techniques have since been employed to assist embryo hatching, including partial mechanical zona dissection, zona drilling and zona thinning, making use of acid tyrodes, proteinases, piezon vibrator manipulators and lasers. This review will consider the impact of IVF conditions on zona pellucida physiology, zona hardening, different techniques of assisted hatching, who may benefit from assisted hatching and potential hazards.
doi:10.1007/s10815-010-9495-3
PMCID: PMC3059528  PMID: 21042844
Assisted hatching; Zona pellucida; Implantation; LASER; Zona drilling; Tyrode’s solution
21.  Efficacy of dehydroepiandrosterone to overcome the effect of ovarian ageing (DITTO): a proof of principle randomised controlled trial protocol 
BMJ Open  2014;4(10):e005767.
Introduction
Dehydroepiandrosterone (DHEA) has been proposed to improve pregnancy rates in women with diminished ovarian reserve undergoing in vitro fertilisation (IVF) treatment. However, evidence regarding its efficacy is supported by a limited number of randomised controlled trials (RCTs). This double-blinded RCT aims to measure the effect of DHEA supplementation prior to and during controlled ovarian hyperstimulation on ovarian response prior to IVF treatment in women predicted to have poor ovarian reserve.
Methods and analysis
Sixty women with ovarian antral follicle count ≤10 and serum anti-Mullerian hormone ≤5 pmol/L undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment at the Nurture fertility clinic, Nottingham will be recruited. They will be randomised to either receive DHEA capsule 75 mg/day or placebo for at least 12 weeks before egg collection. All participants will undergo standard long down regulation protocol using human menopausal gonadotropin 300 IU/day. Serum samples and follicular fluids at the time of egg collection will be collected for hormonal immunoassays. For ICSI participants, cumulus cells stripped from oocyte will be collected for cumulus gene expression analyses regarding oocyte competence. Microdrops of oocyte culture media before the time of ICSI will be assessed for glucose, pyruvate and lactate utilisation. Embryo transfer will be performed on day 2, 3 or 5 based on the number and quality of the embryos available. Pregnancy will be defined as urine pregnancy test positive (biochemical pregnancy) and 6–8 weeks ultrasound scan with fetal heart beat (clinical pregnancy) and live birth. It is planned to perform the molecular and nutritional fingerprint analyses in batches after finishing the clinical phase of the study.
Ethics and dissemination
The approval of the study was granted by the NHS Research Ethics Committee (Ref number NRES 12/EM/0002), the Medicines and Healthcare products Regulatory Agency (MHRA), and the Nottingham University Hospitals Trust Research and Development department. All participants shall provide written informed consent before being randomised into allocated treatment groups.
Trial registration number
Protocol V.2.0; EudraCT number: 2011-002425-21; http://www.clinicaltrials.gov; NCT01572025; CTA reference: 03057/0053/001-0002
doi:10.1136/bmjopen-2014-005767
PMCID: PMC4194749  PMID: 25296654
GYNAECOLOGY
22.  The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial 
BMC Women's Health  2012;12:22.
Background
In in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment a large drop is present between embryo transfer and occurrence of pregnancy. The implantation rate per embryo transferred is only 30%. Studies have shown that minor intrauterine abnormalities can be found in 11–45% of infertile women with a normal transvaginal sonography or hysterosalpingography. Two randomised controlled trials have indicated that detection and treatment of these abnormalities by office hysteroscopy after two failed IVF cycles leads to a 9–13% increase in pregnancy rate. Therefore, screening of all infertile women for intracavitary pathology prior to the start of IVF/ICSI is increasingly advocated. In absence of a scientific basis for such a policy, this study will assess the effects and costs of screening for and treatment of unsuspected intrauterine abnormalities by routine office hysteroscopy, with or without saline infusion sonography (SIS), prior to a first IVF/ICSI cycle.
Methods/design
Multicenter randomised controlled trial in asymptomatic subfertile women, indicated for a first IVF/ICSI treatment cycle, with normal findings at transvaginal sonography. Women with recurrent miscarriages, prior hysteroscopy treatment and intermenstrual blood loss will not be included. Participants will be randomised for a routine fertility work-up with additional (SIS and) hysteroscopy with on-the-spot-treatment of predefined intrauterine abnormalities versus the regular fertility work-up without additional diagnostic tests. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months of IVF/ICSI treatment after randomisation. Secondary study outcome parameters are the cumulative implantation rate; cumulative miscarriage rate; patient preference and patient tolerance of a SIS and hysteroscopy procedure. All data will be analysed according to the intention-to-treat principle, using univariate and multivariate logistic regression and cox regression. Cost-effectiveness analysis will be performed to evaluate the costs of the additional tests as routine procedure. In total 700 patients will be included in this study.
Discussion
The results of this study will help to clarify the significance of hysteroscopy prior to IVF treatment.
Trial registration
NCT01242852
doi:10.1186/1472-6874-12-22
PMCID: PMC3434069  PMID: 22873367
Hysteroscopy; Subfertility; IVF
23.  Embryo developmental stage at transfer influences outcome of treatment with intracytoplasmic sperm injection 
Purpose: Our purpose was to determine if embryo cell stage at the time of intrauterine transfer correlates with pregnancy rate in patients treated with intracytoplasmic sperm injection (ICSI).
Methods: We conducted a retrospective analysis of 455 embryo transfer cycles following ICSI and 304 conventional in vitro fertilization (IVF) and embryo transfer cycles in women aged 40 years or less. Abstracted information included grading of the embryo cell stage and quality at the time of transfer.
Results: The overall ICSI pregnancy rate was 30.8%, while that of conventional IVF was 29.3%. However, the ICSI pregnancy rate fell to 9.3% for embryo transfers taking place at the two-cell stage but increased to 35.8% when at least one embryo had more than two cells, and this difference was statistically significant (P≤0.0001). The pregnancy rate following conventional IVF was 22.0% when only two-cell embryos were transferred and 32.0% when at least one of the embryos had more than two cells, but this difference in pregnancy rates was not significant (P>0.05).
Conclusions: The stage of embryo development at transfer appears to exert a powerful influence on the successful establishment of pregnancy after ICSI.
doi:10.1007/BF02765824
PMCID: PMC3454723  PMID: 9147236
embryo stage; embryo quality; intracytoplasmic sperm injection; in vitro fertilization; pregnancy rate
24.  The Outcome of Cryopreserved Human Embryos After Intracytoplasmic Sperm Injection and Traditional IVF 
Objective:Our objective was to analyze the outcome of cryopreserved embryos obtained after intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) in terms of survival rate, implantation rate (IR), total and clinical pregnancy rate (PR) in a retrospective, comparative study.
Methods:Three hundred seventy-five IVF and 463 ICSI surnumerary cleaved embryos, frozen on Day 2 with 1,2-propanediol, were thawed.
Results:Thirty-two percent of the thawed IVF embryos survived and 11 pregnancies (8 clinical) were obtained from 68 transfers (16.1%). Fourty-seven percent of the ICSI embryos survived, with 19 pregnancies (18 clinical) from 116 transfers (16.4%). The IR was 8.5% (8/94) in IVF cycles and 10.8% (20/185) in ICSI cycles.
Conclusions:A significantly better survival rate of ICSI embryos was observed but with no difference in PR, preclinical, and clinical abortion rate, or IR.
doi:10.1023/A:1020561307110
PMCID: PMC3455487  PMID: 10478318
in vitro fertilization; intracytoplasmic sperm injection; cryopreservation; survival rate; pregnancy rate; implantation rate
25.  The IMSI procedure improves poor embryo development in the same infertile couples with poor semen quality: A comparative prospective randomized study 
Background
Sperm of poor quality can negatively affect embryo development to the blastocyst stage. The aim of this comparative prospective randomized study was to evaluate the role of an intracytoplasmic morphologically selected sperm injection (IMSI) in the same infertile couples included in the programme of intracytoplasmic sperm injection (ICSI) due to their indications of male infertility which had resulted in all arrested embryos following a prolonged 5-day culture in previous ICSI cycles.
Methods
Couples exhibiting poor semen quality and with all arrested embryos following a prolonged 5-day culture in previous ICSI cycles were divided into two groups: Group 1: IMSI group (n = 20) with IMSI performed in a current attempt and Group 2: ICSI group (n = 37) with a conventional ICSI procedure performed in a current attempt of in vitro fertilization. Fertilization rate, embryo development, implantation, pregnancy and abortion rates were compared between current IMSI and conventional ICSI procedures, and with previous ICSI attempts.
Results
The IMSI group was characterized by a higher number of blastocysts per cycle than the ICSI group (0.80 vs. 0.65) after a prolonged 5-day embryo culture. There was a significantly lower number of cycles with all arrested embryos and cycles with no embryo transfer in the IMSI group versus the ICSI group (0% vs. 27.0%, p = 0.048). After the transfer of embryos at the blastocyst or morula stage (on luteal day 5) a tendency toward higher implantation and pregnancy rates per cycle was achieved in the IMSI group compared to the ICSI group (17.1% vs. 6.8%; 25.0% vs. 8.1%, respectively), although not statistically significant. After IMSI, all pregnancies achieved by the blastocyst transfer were normally on-going, whereas after ICSI, two of three pregnancies ended in spontaneous abortion. After IMSI, two pregnancies were also achieved by the morula stage embryos, whereas after the conventional ICSI procedure, embryos at the morula stage did not implant.
Conclusions
The IMSI procedure improved embryo development and the laboratory and clinical outcomes of sperm microinjection in the same infertile couples with male infertility and poor embryo development over the previous ICSI attempts.
doi:10.1186/1477-7827-9-123
PMCID: PMC3170257  PMID: 21875440

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