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1.  Female infertility 
Clinical Evidence  2010;2010:0819.
Introduction
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count. In developed countries, 80% to 90% of couples attempting to conceive are successful after 1 year and 95% after 2 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for infertility caused by ovulation disorders? What are the effects of treatments for tubal infertility? What are the effects of treatments for infertility associated with endometriosis? What are the effects of treatments for unexplained infertility? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 55 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: clomifene; drug-induced ovarian suppression; gonadotrophin priming of oocytes before in vitro maturation; gonadotrophins; gonadotrophin-releasing hormone agonists plus gonadotrophins; gonadotrophin-releasing hormone antagonists; in vitro fertilisation; intrauterine insemination alone, or combined with gonadotrophins or clomifene; laparoscopic ablation of endometrial deposits; laparoscopic ovarian drilling; laparoscopic removal; metformin; ovarian wedge biopsy; pulsatile gonadotrophin-releasing hormone; selective salpingography plus tubal catheterisation; tamoxifen; tubal flushing; and tubal surgery before in vitro fertilisation.
Key Points
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count.
In women with ovulatory disorders, clomifene and metformin increase ovulation and pregnancy rates. There is some evidence that tamoxifen may have similar efficacy to clomifene, but we found no RCTs of sufficient quality comparing tamoxifen with placebo, and it is rarely used nowadays. Gonadotrophins may increase pregnancy rates but may increase ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. Laparoscopic ovarian drilling may be as effective as gonadotrophins. We don't know whether pulsed gonadotrophin-releasing hormone (GnRH), or gonadotrophin priming of oocytes before in vitro maturation increase pregnancy rates.Consensus suggests that in vitro fertilisation may lead to pregnancy, but increases the risks of multiple pregnancy unless single embryo replacement is practised.We don't know whether GnRH agonists plus gonadotrophins increase pregnancy rates compared with gonadotrophins alone but the combination treatment may be associated with an increased risk of OHSS. We don't know how effective GnRH antagonists are because we found few trials.We don't know whether intrauterine insemination alone, or combined with gonadotrophins or clomifene is effective for infertility caused by ovulation disorders.
In women with tubal infertility, tubal flushing may increase pregnancy rates, with oil soluble media possibly more effective than water soluble media; however, we found few trials solely in women with tubal infertility. Tubal surgery before in vitro fertilisation may increase pregnancy rates compared with no treatment in women with hydrosalpinges, but we don't know whether selective salpingography plus tubal catheterisation is beneficial.Consensus suggests that in vitro fertilisation is beneficial.
In women with endometriosis, adding gonadotrophins to intrauterine insemination increases live birth rates compared with no treatment and increases pregnancy rates compared with intrauterine insemination alone. Laparoscopic ablation of endometrial deposits may increase live birth rates compared with diagnostic laparoscopy.Drugs to induce ovarian suppression may not increase pregnancy rates.Consensus suggests that in vitro fertilisation may be beneficial.Tubal flushing with oil-based media may increase live birth rates and pregnancy rates in women with minimal or mild endometriosis.
In women with unexplained infertility, clomifene does not increase live birth rates. It is not better than expectant management. Intrauterine insemination without ovarian stimulation does not result in a significant increase in live birth rates. Intrauterine insemination plus controlled ovarian stimulation may increase pregnancy rates but may increase OHSS and multiple pregnancy. In vitro fertilisation may be beneficial, however, evidence is insufficient to make any conclusions.
PMCID: PMC3217752  PMID: 21406133
2.  Female infertility 
Clinical Evidence  2005;2005:0819.
Introduction
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count. In resource-rich countries, 80-90% of couples attempting to conceive are successful after 1 year and 95% after 2 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for infertility caused by ovulation disorders? What are the effects of treatments for tubal infertility? What are the effects of treatments for infertility associated with endometriosis? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2004 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 56 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: clomifene; cyclofenil; drug-induced ovarian suppression; gonadotrophin priming of oocytes before in vitro maturation; gonadotrophins; gonadotrophin-releasing hormone agonists plus gonadotrophins; gonadotrophin-releasing hormone antagonists; in vitro fertilisation; intrauterine insemination plus controlled ovarian stimulation; intrauterine insemination plus gonadotrophins; laparoscopic ablation of endometrial deposits; laparoscopic ovarian drilling; metformin; ovarian wedge biopsy; pulsatile gonadotrophin-releasing hormone; selective salpingography plus tubal catheterisation; tamoxifen; tubal flushing with oil-soluble media or with water-soluble media; tubal surgery before in vitro fertilisation.
Key Points
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis or a low sperm count.
In women with infertility, in vitro fertilisation may be as likely to lead to pregnancy as intracytoplasmic sperm injection, but increases the risks of multiple pregnancy. Gonadotrophin releasing hormone agonists also increase pregnancy rates, but gonadotrophin releasing hormone antagonists may be less effective. Intrauterine insemination plus controlled ovarian stimulation is considered to be beneficial in women with unexplained infertility or cervical hostility.
In women with ovulatory disorders, clomifene and tamoxifen increase ovulation and pregnancy rates, and metformin increases ovulation rates. Gonadotrophins may increase pregnancy rates but may increase the risk of ovarian cancer, ovarian hyperstimulation syndrome and multiple pregnancy. Laparoscopic ovarian drilling may be as effective as gonadotrophins.We don't know whether cyclofenil, pulsed gonadotrophin releasing hormone, gonadotrophin priming of oocytes before in vitro maturation, or ovarian wedge biopsy increase pregnancy rates compared with no treatment.
In women with tubal infertility, tubal flushing increases pregnancy rates, with oil soluble media possibly more effective than water soluble media. Tubal surgery before in vitro fertilisation may increase pregnancy rates compared with no treatment in women with hydrosalpinges, but we don't know whether selective salpingography plus tubal catheterisation is beneficial.
In women with endometriosis, adding gonadotrophins to intrauterine insemination increases live birth rates compared with intrauterine insemination alone. Laparoscopic ablation of endometrial deposits may increase live birth rates compared with diagnostic laparoscopy.Drugs to induce ovarian suppression may not increase pregnancy rates.
PMCID: PMC2907557
3.  Intrauterine insemination versus fallopian tube sperm perfusion in non-tubal infertility 
Background
Controlled ovarian hyperstimulation (COH) combined with intrauterine insemination (IUI), using a volume of 0.5 ml of inseminate is commonly offered to couples with non-tubal sub fertility. Another method is Fallopian tube sperm perfusion (FSP) which is based on a pressure injection of 4 ml of sperm suspension while attempting to seal the cervix to prevent semen reflux. This technique ensures the presence of higher sperm density in the fallopian tubes at the time of ovulation than standard IUI. The aim of this study was to compare the efficiency of standard intrauterine insemination (IUI) and Fallopian tube sperm perfusion (FSP) in the treatment of non-tubal infertility.
Methods
200 consecutive patients with infertility in 404 stimulated cycles were included in the study. Those randomized to standard IUI included 100 patients in 184 cycles [158 clomiphene citrate/human menopausal gonadotrophin cycles and 26 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group A). Patients subjected to FSP included 100 patients in 220 cycles (193 clomiphene citrate/human menopausal gonadotrophin cycles and 27 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group B). Swim up semen preparation technique was used in all cases. Insemination was performed in both groups 34–37 h after hCG administration. Standard IUI was performed using 0.5 ml of inseminate. In FSP 4 ml inseminate was used.
Results
In group A (184 IUI cycles in 100 patients), 22 clinical pregnancies (presence of gestational sac with fetal cardiac activity) occurred (11.95% per cycle over four cycles). In group B, (220 cycles of FSP in 100 patients), 48 clinical pregnancies occurred (21.81% per cycle over four cycles) and this difference was statistically significant (p < 0.05).
Conclusions
For non-tubal sub fertility, the results indicate clear benefit for FSP (Fallopian tube sperm perfusion) over IUI (Intrauterine insemination).
doi:10.1016/j.mjafi.2012.02.013
PMCID: PMC3862360  PMID: 24532873
Intrauterine insemination; Fallopian tube sperm perfusion; Non-tubal infertility
4.  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
5.  Letrozole versus Clomiphene Citrate for Induction of Ovulation in Patients with Polycystic Ovarian Syndrome Undergoing Intrauterine Insemination 
Background
Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women in the reproductive age group, and is one of the most common causes of hyperandrogenic anovulatory infertility. The aromatase inhibitor, letrozole, has been used for induction of ovulation. The purpose of this study was to compare the effects of letrozole and clomiphene citrate in induction of ovulation among patients with PCOS undergoing intrauterine insemination.
Methods
In a double-blind randomized study, 60 infertile patients with PCOS received standard doses of either clomiphene citrate or letrozole as an induction protocol prior to intrauterine insemination. A hormonal profile, pelvic ultrasound, hysterosalpingogram, and/ or laparoscopy were done for all patients. The patients were monitored for ovulation by translational ultrasonographic folliculometry, with measurement of number and size of the follicles, as well as endometrial thickness. Human chorionic gonadotrophin (HCG) was injected intramuscularly when at least one mature follicle ≥18 mm diameter was detected, and intrauterine insemination was performed 32–36 hours later. Transvaginal ultrasound and β-HCG measurement were performed for confirmation of pregnancy.
Results
Letrozole and clomiphene citrate achieved follicle maturation within a mean ± standard deviation (SD) of 13.2 ± 1.53 and 14.1 ± 1.35 days, respectively, showing no significant difference (P > 0.05). The mean number of follicles reaching ≥18 mm on the day of HCG administration was significantly higher in patients who received clomiphene citrate (2.9 ± 1.77) than in those receiving letrozole (1.2 ± 0.9). Letrozole had a significantly greater effect than clomiphene citrate on endometrial thickness (9.16 ± 1.36 versus 4.46 ± 1.71). The number of pregnancies achieved in the letrozole group was significantly (P < 0.05) greater than in the clomiphene group.
Conclusion
Letrozole in patients with PCOS is as effective as clomiphene citrate in inducing ovulation, and although the number of follicles produced by induction with letrozole were less than those produced by clomiphene, letrozole had a significantly greater effect on endometrial thickness than clomiphene citrate, and the incidence of pregnancy after intrauterine insemination was significantly higher, with a lower incidence of multiple pregnancy.
doi:10.4137/CMRH.S6598
PMCID: PMC3888072  PMID: 24453507
polycystic ovary syndrome; letrozole; clomiphene citrate; intrauterine insemination
6.  Polycystic ovaries and infertility: Our experience 
BACKGROUND:
Polycystic ovary syndrome (PCOS) is one of the most common (15–20%) endocrine disorders in women of childbearing age. Although it is a major cause of infertility, its etiology remains unknown and its treatment difficult.
AIM:
To evaluate the incidence, treatment and outcome of patients with PCOS.
DESIGN:
Retrospective analysis.
MATERIALS AND METHODS:
PCOS patients (914 of the 1057) attending the outpatient department (OPD) from June 2003 to February 2008 were evaluated for this study. Of the 914 patients investigated, 814 came for treatment and these patients were studied for hormonal disturbances and their response to various modalities of treatment.
RESULTS:
Of the 2270 infertility patients, 46.50% (1057) had PCOS, out of these, 86.47% (914) were investigated and 77% (814) came for treatment. Our overall pregnancy rate was 48.40% (394/814). The pregnancy rate per cycle with timed intercourse (TI) was 44.77% (47/105), 17.09% (286/1673) with intrauterine insemination (IUI), 29.82% (51/171) with in vitro fertilization (IVF) and 22.22% (10/45) with frozen embryo transfer (FET). The maximum number of pregnancies (85.29%, 284/333) were achieved in the first three treatment cycles. The abortion rate was 19.01% (73/384) and the incidence of ectopic pregnancy was 5.47% (21/384). Complications seen were in the form of ovarian hyperstimulation (OHSS), retention cyst on day two and multiple pregnancies in 11.71% (228/1946) of the total treatment cycles.
CONCLUSION:
Most PCOS symptoms could be adequately controlled or eliminated with proper diagnosis and treatment. Thus, ovulation induction (OI) protocols and treatment modalities must be balanced for optimal results.
PMCID: PMC2700664  PMID: 19562048
Infertility; intrauterine insemination (IUI); in vitro fertilization (IVF); ovulation induction (OI); polycystic ovary syndrome (PCOS); pregnancy rate (PR); timed intercourse (TI); ultrasonography (USG)
7.  Andrology: Effect of Inseminated Volume on Intrauterine Insemination 
Purpose: Intrauterine insemination (IUI) is a method for the treatment of marital infertility involving the intrauterine or fallopian deposition of washed spermatozoa, depending on the amount of inseminated semen. In view of the divergent opinions about the inseminated volume, the objective of this study was to compare the two techniques (3.0 mL or 0.5 mL) in two groups of patients.
Methods: We performed 164 cycles of ovulation induction followed by IUI. The patients were divided into two groups according to the technique used. Group low volume – 50 cycles and 0.5 mL of inseminated semen; Group high volume – 114 cycles and 3.0 mL of inseminated semen. The cycle was monitored on the basis of endometrial thickness and follicular development measured by transvaginal ultrasound. Human chorionic gonadotrophin (hCG) was administered in the presence of a follicle measuring 18 mm in mean diameter. The procedure was performed after sperm washing using a discontinuous PureSperm® gradient, 40 h later.
Results: We obtained a similar clinical pregnancy rate for the two groups (14.0% for Group low volume and 15.7% for Group high volume). There was one abortion in each group. We detected no interference by any etiology of infertility or by the total motile recovered sperm with pregnancy rate.
Conclusions: The results did not demonstrate superiority of one method over the other, with both therapeutic alternatives being satisfactory for the treatment of infertile couples.
doi:10.1023/A:1016678519490
PMCID: PMC3455511  PMID: 11599460
fallopian perfusion; infertility; intrauterine insemination; ovulation induction
8.  An open multicenter study to compare the efficacy of intraperitoneal insemination and intrauterine insemination following multiple follicular development as treatment for unexplained infertility 
Purpose: This multicenter study was carried out to compare the efficacy of intrauterine insemination (IUI) and intraperitoneal insemination (IPI) associated with multiple follicular development as treatment for unexplained infertility.
Method: A total of 205 couples completed the trial. Sixty-seven couples underwent treatment with IPI (group A) and 138 couples underwent treatment with IUI (group B).
Results: Clinical pregnancy was obtained in 23 couples in group A (pregnancy rate: 34.3%) and in 36 couples in group B (pregnancy rate: 26.1%). No significant difference was observed between group A and group B. As for the evolution of pregnancies and the incidence of twin pregnancies, no significant difference was observed between the two groups.
Conclusions: Because IUI and IPI allow us to obtain same results and IPI is more invasive than IUI, the latter technique can be considered the method of choice and IPI should be used when IUI is difficult to perform, as in the presence of a tight cervical canal.
doi:10.1007/BF02765745
PMCID: PMC3454718  PMID: 9013304
intraperitoneal insemination; intrauterine insemination; multicenter study; multiple follicular development; unexplained infertility
9.  The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility 
BMC Women's Health  2009;9:35.
Background
Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART.
Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate.
This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples.
Methods/Design
We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months.
Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded.
Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total).
Discussion
Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment.
Trial registration
Current Controlled Trials ISRCTN 52843371
doi:10.1186/1472-6874-9-35
PMCID: PMC2804565  PMID: 20021654
10.  Successful Pregnancies in Patients with Estrogenic Anovulation After Low-Dose Human Chorionic Gonadotropin Therapy Alone Following hMG for Controlled Ovarian Hyperstimulation 
Objective: To demonstrate that folliculogenesis can be sustained with 200 IU human chorionic gonadotropins (hCG) after FSH-priming and result in pregnancy in women with estrogenic ovulatory dysfunction and risk factors for severe ovarian hyperstimulation syndrome (OHSS).
Design:Case report: Three women with infertility associated with estrogenic ovulatory dysfunction and hyperinsulinemia who appeared to be at high risk for severe OHSS during gonadotropin therapy.
Interventions: After 10 days of receiving either 150 IU hMG or recombinant FSH, patients were switched to 200 IU hCG/day alone for 2–3 days. 5,000 IU of hCG was then administered followed by either home intercourse, intrauterine insemination or transvaginal oocyte retrieval-embryo transfer.
Main Outcome Measures: Endovaginal ultrasound measurement of follicle number and size, serum estradiol levels, symptoms of ovarian hyperstimulation, pregnancy test, and evaluation of pregnancy by transvaginal ultrasound.
Results: After discontinuation of hMG or recombinant FSH, serum estradiol concentrations continued to rise, and follicles > 14 mm continued to grow during low-dose hCG administration. All women conceived without developing symptoms of OHSS. Pregnancy outcomes achieved include a term singleton delivery, a term twin delivery, and triplets delivered at 31 weeks gestation.
Conclusion: The use of low-dose hCG alone is sufficient for supporting the late stages of folliculogenesis in women with estrogenic ovulatory dysfunction. This ovulation induction regimen appears to support the follicular growth of larger follicles while decreasing the number of smaller preovulatory follicles, thereby reducing a known risk factor for OHSS. We report on the positive pregnancy outcomes in 3 women with estrogenic ovulatory dysfunction and clinically appeared to be at high risk for developing severe OHSS who safely underwent this protocol.
doi:10.1007/s10815-005-0819-7
PMCID: PMC3455389  PMID: 15807221
Gonadotropin therapy; infertility; ovarian hyperstimulation syndrome; polycystic ovarian syndrome; pregnancy
11.  Parental infertility and cerebral palsy in children 
Human Reproduction (Oxford, England)  2010;25(12):3142-3145.
BACKGROUND
Children born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have been reported to have a higher risk of cerebral palsy (CP), perhaps due to the higher frequency of preterm birth, multiple births or vanishing embryo in the pregnancies. However, it has been suggested that the underlying infertility may be part of the pathway. In this study, we examined whether untreated subfecundity (measured by time to pregnancy) or infertility treatment was associated with an increased risk of CP in the offspring.
METHODS
Using the Danish National Birth Cohort (1997–2003), we compared children born after 0–2 months of waiting time to pregnancy (n = 35 848) with those born after a time to pregnancy of 3–5 months (n = 15 361), 6–12 months (n = 11 528) and >12 months (n = 7387), as well as those born after IVF/ICSI (n = 3617), ovulation induction with or without intrauterine insemination (n = 3000), and unplanned pregnancies (n = 13 462). CP cases were identified through the Danish CP Register.
RESULTS
In total, 165 (0.18%) children were diagnosed with CP in the entire cohort. We found no significant association between time to pregnancy and the risk of CP in children conceived spontaneously. Children born after IVF/ICSI had an increased risk of CP, even after adjustment for preterm birth and multiplicity (hazard ratio 2.30, 95% confidence interval 1.12–4.73).
CONCLUSIONS
Subfecundity per se did not appear to be associated with the risk of CP in children, whereas being born after IVF/ICSI conferred an increased risk.
doi:10.1093/humrep/deq206
PMCID: PMC2989872  PMID: 21045245
cerebral palsy; infertility; infertility treatment; time to pregnancy; Danish National Birth Cohort
12.  In Vitro Fertilization and Intracytoplasmic Sperm Injection for Couples with Unexplained Infertility After Failed Direct Intraperitoneal Insemination 
Purpose: The objective was to determine the optimal insemination technique in patients undergoing in vitro fertilization (IVF) after failed direct intraperitoneal insemination (DIPI) and the outcome of intracytoplasmic sperm injection (ICSI) in such cases.
Methods: In case–control studies, 53 couples with unexplained infertility who underwent IVF after four failed DIPI cycles were compared with 75 couples with tubal or endometriosis infertility as controls. Thirty couples with unexplained infertility after failing to conceive with DIPI and conventional IVF who underwent ICSI and 58 couples with male-factor infertility as controls also were compared. Fertilization cleavage, embryo quality, implantation, and pregnancy were compared after IVF and after ICSI.
Results: There was a significant difference in fertilization rates after IVF between cases of unexplained infertility after failing to conceive with DIPI (40.4%) and patients with tubal or endometriosis infertility (67.9%). There also was a significant difference in total fertilization failure rates between the two groups (30.4% and 3.9%, respectively). There was a slight but significant difference in numbers of fertilized oocytes after ICSI between patients with low fertilization rate undergoing IVF after failing to conceive DIPI (85.8%) and patients with male factor (90.4%). Total fertilization failure was not observed in these cases.
Conclusions: Couples with unexplained infertility after failing to conceive with DIPI show a failed fertilization or a low fertilization rate after IVF. However, they demonstrated a good chance of becoming pregnant after subsequent ICSI, even with statistically significant difference in fertilization rate as compared with male-factor cases.
doi:10.1023/A:1009445909023
PMCID: PMC3455262  PMID: 11155325
intracytoplasmic sperm injection; unexplained infertility; in vitro fertilization; direct intraperitoneal insemination; failed fertilization
13.  Role of laparohysteroscopy in women with normal pelvic imaging and failed ovulation stimulation with intrauterine insemination 
CONTEXT:
Women with primary infertility and no obvious pelvic pathology on clinical evaluation and imaging are either treated empirically or further investigated by laparoscopy.
AIMS:
The role of diagnostic laparoscopy in women who fail to conceive after empirical treatment with ovulation induction and intrauterine insemination was evaluated.
SETTINGS AND DESIGN:
Retrospective study at a private infertility center.
MATERIALS AND METHODS:
A study of patients who underwent diagnostic laparoscopy between 1st January 2001 and 31st December 2008 was performed. Those patients who had no detectable pathology based on history, physical examination, and ultrasound and had treatment for three or more cycles in the form of ovulation induction and IUI were included in the study. Moderate and severe male factor infertility and history of any previous surgery were exclusion criteria.
STATISTICAL ANALYSIS USED:
Data were statistically analyzed using Statistics Package for Social Sciences (ver. 16.0; SPSS Inc., Chicago).
RESULTS:
Of the 127 women who underwent diagnostic laparoscopy and hysteroscopy, 87.4% (n = 111) of patients had positive findings. Significant pelvic pathology (moderate endometriosis, pelvic inflammatory disease, and tubal pathology) was seen in 26.8% of cases.
CONCLUSION:
One in four women had significant pelvic pathology where treatment could possibly improve future fertility. Diagnostic laparoscopy has a role in infertile women with no obvious abnormality before they proceed to more aggressive treatments.
doi:10.4103/0974-1208.63117
PMCID: PMC2890905  PMID: 20607004
Female infertility; intrauterine insemination; laparoscopy
14.  The impact of thyroid function on intrauterine insemination outcome - a retrospective analysis 
Background
Hashimoto’s thyroiditis is the most common endocrinopathy in premenopausal women, and is associated with various gynecological problems, including recurrent miscarriage and unexplained infertility. A possible influence of Hashimoto’s thyroiditis on the success of intrauterine insemination seems likely, but has not been evaluated as yet. Therefore, the aim of our study was to retrospectively analyze the impact on intrauterine insemination outcome of thyroid function and markers suggestive for Hashimoto’s thyroiditis.
Methods
Retrospective cohort study in a tertiary care center of 540 women who underwent Intrauterine Insemination. The clinical pregnancy rate was the main outcome parameters. The following possible influencing factors were tested: thyroid-stimulating hormone (TSH); thyroid autoantibodies; age; body mass index; type of sterility (primary/secondary); parity; male factor; presence of PCO syndrome; ovulation induction; ovarian stimulation; and current thyroid medication.
Results
The overall clinical pregnancy rate was 6.9% (37/540). Age, thyroid hormone supplementation for thyroid-stimulating hormone (TSH) levels > 2.5 micro-IU/ml, and ovulation induction with HCG were significantly predictive in the multivariate analysis (p < 0.05) as influencing factors for the pregnancy rate after intrauterine insemination.
Conclusions
Women undergoing intrauterine insemination seem to benefit from a strict thyroid hormone supplementation regimen in order to achieve lower TSH levels.
doi:10.1186/1477-7827-12-28
PMCID: PMC3978130  PMID: 24708845
Intrauterine insemination; Hypothyroidism; Autoimmune thyroiditis; TSH; Target value
15.  Balloon Fluoroscopy as Treatment for Intrauterine Adhesions: a Novel Approach 
Fertility and sterility  2008;90(5):2005.e15-2005.e17.
Objective
To report a unique fluoroscopically guided approach to treat severe intrauterine adhesions and cervical stenosis using balloon hysteroplasty.
Design
Case report.
Setting
Military-based fertility center.
Patient
A 33-year-old woman undergoing assisted reproductive technologies whose uterus could not be cannulated because of the development of intrauterine synechiae and cervical stenosis following a post-intrauterine insemination infection that was further complicated by a prominent lower uterine segment filling defect in the location of a prior cesarean delivery scar.
Intervention
Fluoroscopic cannulation and balloon uterine dilation.
Main Outcome Measure
Resolution of synechiae by hysterosalpingogram and successful uterine cannulation.
Results
A post-procedure hysterosalpingogram demonstrated a normalized uterine cavity with the exception of a persistent prominent lower uterine segment filling defect from a prior cesarean delivery. A frozen embryo transfer cycle was performed successfully.
Conclusions
Hysteroplasty, using standard interventional radiographic techniques, may provide an alternative treatment modality for patients with intrauterine adhesions and lower uterine defects from prior cesarean deliveries, in select cases. While treating intrauterine adhesions improves pregnancy outcome, the effect of lower uterine segment filling defects from cesarean deliveries on pregnancy outcome in assisted reproductive technology cycles warrants further investigation.
doi:10.1016/j.fertnstert.2008.07.1752
PMCID: PMC2602802  PMID: 18793771
Asherman’s syndrome; synechiae; intrauterine adhesions; balloon dilation; cesarean section scar
16.  Intrauterine insemination experience in a government teaching hospital setup 
Objectives
Intrauterine insemination with or without controlled ovarian hyperstimulation is a viable treatment option for male factor, cervical factor and unexplained infertility.We enumerate our 10 year experience in performing intrauterine insemination at a government teaching hospital setup.
Study Design
Retrospective observational study.
Results
Nine hundred eighty nine couples were observed for 3104 treatment cycles.Male factor and anovulation were the two common causes of infertility in this cohort. Out of the 232 pregnancies that occurred during the study, 34.05% resulted in live birth. Highest cycle fecundity was seen in cases of idiopathic infertility (16%) followed by male factor infertility (15%). 91.8% conceptions occurred in the 1st cycles of intrauterine insemination.
Conclusion
In the resource deprived Indian scenario controlled ovarian hyperstimulation with intrauterine insemination is an effective, less invasive, feasible & financially acceptable modality for the treatment of sub-fertility.
doi:10.1007/s13224-010-0043-y
PMCID: PMC3394531
intrauterine insemination; male factor; idiopathic infertility; ovarian; hyperstimulation
17.  Sperm Motility Is a Major Determinant of Pregnancy Outcome Following Intrauterine Insemination 
Purpose:Our purpose was to assess whether one or more sperm parameters have predictive value for the outcome of intrauterine insemination treatment.
Methods:Infertile couples whose normoovulatory and normomechanical female partners underwent superovulation and intrauterine insemination were investigated. The semen profile of the male partner was discounted. In 160 couples, 544 cycles were obtained, resulting in 59 ongoing pregnancies (10.84%/cycle, 36.87%/patient).
Results:The only parameter found to be significantly correlated with a positive outcome was the degree of sperm motility following preparation for intrauterine insemination. Close to half (47.5%) of the couples with a very good or an excellent degree of sperm motility conceived, whereas only 8.3% of those patients who had poor or fair sperm motility conceived. None of the semen characteristics, such as volume, count, percentage motility, or percentage normal morphology, were found to correlate with cycle outcome. Although there was a progressive increase in the pregnancy rate with an increase in the total number of motile sperm inseminated, it did not reach significance. Seventy percent of the pregnancies were achieved within a maximum of three treatment cycles. The spermatogram is not accurate enough as a prognostic factor for treatment outcome.
Conclusions:The degree of sperm motility, after appropriate preparation for intrauterine insemination, is the only parameter to be correlated with treatment outcome. For couples with a normal female partner, we suggest a maximum of three treatment cycles of induction of ovulation and intrauterine insemination, whenever good progressive motile sperm is obtained after suitable preparation. For cases with poor sperm progression, we suggest appropriate couple counseling and that an alternative assisted reproduction procedure be taken into consideration.
doi:10.1023/A:1022585000740
PMCID: PMC3455014  PMID: 9673883
conception; intrauterine insemination; sperm motility; pregnancy
18.  Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation 
Objectives To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child.
Design Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial.
Setting 17 centres in the Netherlands.
Participants Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility.
Interventions Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation.
Main outcome measures The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality
Results 602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation).
Conclusions In vitro fertilisation with single embryo transfer and in vitro fertilisation in a modified natural cycle were non-inferior to intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child and showed comparable, low multiple pregnancy rates.
Trial registration Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.
doi:10.1136/bmj.g7771
PMCID: PMC4288434  PMID: 25576320
19.  Successful IVF pregnancy after radical trachelectomy using transabdominal cervico isthmic cerclage 
BMJ Case Reports  2009;2009:bcr10.2008.1069.
A 34-year-old woman was referred to the in vitro fertilisation (IVF) clinic following failure to conceive after ovulation induction with antioestrogens and intrauterine insemination. She had a long history of hypothalamic amenorrhoea secondary to weight loss and stress and received hormone replacement to maintain her bone density. She also underwent radical trachelectomy and bilateral laparoscopic pelvic node dissection as fertility sparing surgery for cancer of the cervix stage 1B. She remained under our care for 4 years during which she had two successful IVF pregnancies with elective single embryo transfers on both occasions. She delivered preterm by caesarean section at 31 weeks and 35 weeks, respectively, for premature rupture of membranes with good outcomes. There was no evidence of local or distant recurrence of her early cervical cancer at 10-year follow-up at the combined gynaecology oncology clinic and she was discharged to primary care for follow-up.
doi:10.1136/bcr.10.2008.1069
PMCID: PMC3029031  PMID: 21686471
20.  Low Multiple Pregnancy Rates and Reduced Frequency of Cancellation After Ovulation Induction with Gonadotropins, If Eventual Supernumerary Follicles Are Aspirated to Prevent Polyovulation 
Purpose:Our purpose was to demonstrate the feasibility of the routine aspiration of supernumerary follicles in infertile patients with imminent polyovulation after ovulation induction with gonadotropins and to examine its effect on the frequency of cycle cancellation and on the (multiple) pregnancy rate.
Methods:The data on 796 treatment cycles, performed between 1989 and 1996 on 410 infertile couples, were analyzed retrospectively. From October 1992, whenever necessary, supernumerary ovarian follicles were selectively aspirated transvaginally under ultrasound guidance to prevent the ovulation of more than three follicles. Thereafter, intrauterine insemination was performed.
Results:After the adoption of transvaginal ultrasound-guided aspiration of supernumerary follicles into the treatment protocol in October 1992, the number of canceled cycles (P < 0.0001) and the multiple pregnancy rate (P < 0.01) were significantly reduced compared to those previously. The overall pregnancy rate remained stable. No ovarian hyperstimulation syndrome requiring hospitalization was noted, and no complications resulting from the follicle aspiration were registered.
Conclusions:Transvaginal ultrasound-guided aspiration of supernumerary ovarian follicles increases both the efficacy and the safety of ovulation induction with gonadotropins. Because of the limited equipment required, this method represents an alternative for conversion of overstimulated cycles to more costly alternatives such as in vitro fertilization.
doi:10.1023/A:1023000719569
PMCID: PMC3454980  PMID: 9547686
intrauterine insemination; ovulation induction; ultrasound-guided follicle puncture; ovarian stimulation; multiple pregnancy
21.  Evaluation of Pregnancy Rates After Intrauterine Insemination According to Indication, Age, and Sperm Parameters 
Purpose:Our purpose was to evaluate intrauterine insemination results obtained in our clinic and identify prognostic factors for the chance of pregnancy.
Methods:A retrospective study of data from 1989 to 1996 was undertaken. Only first attempts were included in this study, except for the part on the cumulative pregnancy rates. Couples with either one-sided tubapathology, hormonal dysfunction, idiopathic infertility, or andrological indication were selected. All women were stimulated with clomiphene citrate. Five hundred sixty-six couples who underwent 1763 cycles were included in the study.
Results:The overall pregnancy rate for first pregnancies was 6.9% per cycle and 21.4% per patient. For first intrauterine insemination attempts this was 8.8% per cycle/patient, varying between 5.0% for andrological indication and 10.6% for tubapathology, 10.0% for idiopatic indication, and 10.3% for hormonal indication. These differences were not significant. Age did not have a significant effect either, although there were no pregnancies observed in women 40 years or older. The number of inseminated spermatozoa significantly affected the pregnancy rate: <2 million, 4.6%; ≥2 to <10 million, 3.9%; and ≥10 million, 11.3%.
Conclusions:Unless semen characteristics are insufficient, intrauterine insemination is a useful treatment for infertile couples.
doi:10.1023/A:1022576831691
PMCID: PMC3455020  PMID: 9673879
age; indication; intrauterine insemination; pregnancy rate; sperm characteristics
22.  Estimating Rates of Multiple Gestation Pregnancies: Sample Size Calculation from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) Trial 
Contemporary clinical trials  2011;32(6):902-908.
Infertility afflicts fifteen percent of couples who wish to conceive. Despite intensive evaluation of both male and female partners, the etiology may remain unknown leading to a diagnosis of unexplained infertility. For such couples, treatment often entails ovulation induction (OI) with fertility medications coupled with intrauterine insemination. Complications of this therapy include ovarian hyperstimulation syndrome and creation of multiple gestation pregnancies, which can be complicated by preterm labor and delivery, and the associated neonatal morbidity and expense of care for preterm infants. The Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) study is designed to assess whether OI in couples with unexplained infertility with an aromatase inhibitor produces mono-follicular development in most cycles, thereby reducing multiple gestations while maintaining a comparable pregnancy success rate to that achieved by OI with either gonadotropins or clomiphene citrate. These results will provide future guidance of therapy for couples with unexplained infertility, and if comparable pregnancy rates are achieved with a substantial reduction in multiple gestations, the public health benefit will be considerable.
doi:10.1016/j.cct.2011.07.009
PMCID: PMC3708642  PMID: 21787883
Multiple gestation; ovulation induction; gonadotropins; aromatase inhibitor; unexplained infertility
23.  Expression of antiapoptosis gene survivin in luteinized ovarian granulosa cells of women undergoing IVF or ICSI and embryo transfer: clinical correlations 
Background
The purpose of the study was to determine the incidence of survivin gene expression in human granulosa cells during ovarian stimulation in Greek women with normal FSH levels, undergoing IVF or ICSI and to discover any correlation between levels of gene expression and clinical parameters, efficacy of ovulation or outcomes of assisted reproduction.
Methods
Twenty nine women underwent ovulation induction for IVF or ICSI and ET with standard GnRH analogue-recombinant FSH protocol. Infertility causes were male and tubal factor. Cumulus–mature oocyte complexes were denuded and the granulosa cells were analyzed for each patient separately using quantitative reverse transcription polymerase chain reaction analysis for survivin gene expression with internal standard the ABL gene.
Results
The ABL and survivin mRNA were detected in granulosa cells in 93.1%. The expression levels of survivin were significantly lower in normal women (male infertility factor) compared to women with tubal infertility factor (p = 0.007). There was no additional statistically significant correlation between levels of survivin expression and estradiol levels or dosage of FSH for ovulation induction or number of dominant follicles aspirated or number of retrieved oocytes or embryo grade or clinical pregnancy rates respectively.
Conclusions
High levels of survivin mRNA expression in luteinized granulosa cells in cases with tubal infertility seem to protect ovaries from follicular apoptosis. A subpopulation of patients with low levels of survivin mRNA in granulosa cells might benefit with ICSI treatment to bypass possible natural barriers of sperm-oocyte interactions.
doi:10.1186/1477-7827-10-74
PMCID: PMC3489854  PMID: 22958786
Granulosa cells; Infertile patients; Survivin; IVF; ICSI
24.  Population study of causes, treatment, and outcome of infertility. 
Specialist infertility practice was studied in a group of 708 couples within a population of residents of a single health district in England. They represented an annual incidence of 1.2 couples for every 1000 of the population. At least one in six couples needed specialist help at some time in their lives because of an average of infertility of 21/2 years, 71% of whom were trying for their first baby. Those attending gynaecology clinics made up 10% of new and 22% of all attendances. Failure of ovulation (amenorrhoea or oligomenorrhoea) occurred in 21% of cases and was successfully treated (two year conception rates of 96% and 78%). Tubal damage (14%) had a poor outlook (19%) despite surgery. Endometriosis accounted for infertility in 6%, although seldom because of tubal damage, cervical mucus defects or dysfunction in 3%, and coital failure in up to 6%. Sperm defects or dysfunction were the commonest defined cause of infertility (24%) and led to a poor chance of pregnancy (0-27%) without donor insemination. Obstructive azoospermia or primary spermatogenic failure was uncommon (2%) and hormonal causes of male infertility rare. Infertility was unexplained in 28% and the chance of pregnancy (overall 72%) was mainly determined by duration of infertility. In vitro fertilisation could benefit 80% of cases of tubal damage and 25% of unexplained infertility--that is, 18% of all cases, representing up to 216 new cases each year per million of the total population.
PMCID: PMC1418755  PMID: 3935248
25.  Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial  
Objective To compare the effectiveness of clomifene citrate and unstimulated intrauterine insemination with expectant management for the treatment of unexplained infertility.
Design Three arm parallel group, pragmatic randomised controlled trial.
Setting Four teaching hospitals and a district general hospital in Scotland.
Participants Couples with infertility for over two years, confirmed ovulation, patent fallopian tubes, and motile sperm.
Intervention Expectant management, oral clomifene citrate, and unstimulated intrauterine insemination.
Main outcome measures The primary outcome was live birth. Secondary outcome measures included clinical pregnancy, multiple pregnancy, miscarriage, and acceptability.
Results 580 women were randomised to expectant management (n=193), oral clomifene citrate (n=194), or unstimulated intrauterine insemination (n=193) for six months. The three randomised groups were comparable in terms of age, body mass index, duration of infertility, sperm concentration, and motility. Live birth rates were 32/193 (17%), 26/192 (14%), and 43/191 (23%), respectively. Compared with expectant management, the odds ratio for a live birth was 0.79 (95% confidence interval 0.45 to 1.38) after clomifene citrate and 1.46 (0.88 to 2.43) after unstimulated intrauterine insemination. More women randomised to clomifene citrate (159/170, 94%) and unstimulated intrauterine insemination (155/162, 96%) found the process of treatment acceptable than those randomised to expectant management (123/153, 80%) (P=0.001 and P<0.001, respectively).
Conclusion In couples with unexplained infertility existing treatments such as empirical clomifene and unstimulated intrauterine insemination are unlikely to offer superior live birth rates compared with expectant management.
Trial registration ISRCT No: 71762042
doi:10.1136/bmj.a716
PMCID: PMC2505091  PMID: 18687718

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