Replacing IUI with IVF for initial treatment of unexplained infertility: why this NICE recommendation is cause for concern.

The latest guidelines from the National Institute for Health and Care Excellence (NICE) for assisted conception recommend that people experiencing unexplained infertility should no longer be offered stimulated intra-uterine insemination (IUI) as a first-line treatment, but rather be directed towards IVF or alternatively be left to expectant management. NICE has acknowledged that the cited evidence leading to this decision was not sufficiently robust. As such, we are concerned that accordance with these new NICE guidelines may result in people with no identifiable cause of their infertility being prematurely referred for IVF treatment. Since IVF constitutes a more invasive and expensive treatment process, which also represents an additional and unnecessary cost pressure to the National Health Service, there is a longstanding need for a robust clinical trial to resolve the uncertainty as to whether one treatment is more appropriate than another. Until such data is available, we suggest that provision of stimulated IUI, in centres achieving a satisfactory live birth rate, represents a significant cost-saving to those commissioning fertility services, with lower risks to people treated.

Long term outcome in subfertile couples with isolated cervical factor.

OBJECTIVE: A previous randomized clinical trial (RCT) compared immediate treatment with intrauterine insemination (IUI) to expectant management for six months in subfertile couples with an isolated cervical factor. That study showed higher ongoing pregnancy rates in couples receiving intrauterine insemination. The current study compared the long-term effectiveness and costs of this intervention. STUDY DESIGN: We followed all couples (N=99) who were previously included in the RCT for three years after randomization and registered pregnancies and treatments. After the initial trial period, couples in both groups were offered further treatment according to local protocol. The primary outcome was an ongoing pregnancy after three years. RESULTS: After three years, there were 36 ongoing pregnancies in the immediate IUI group (N=51 couples) and 38 ongoing pregnancies in the expectant management group (N=48 couples). The ongoing pregnancy rates were 71% and 79% respectively (RR 0.89 (95% confidence interval (CI) 0.7-1.1)). CONCLUSIONS: In couples with an isolated cervical factor, a treatment strategy including immediate treatment with IUI does not result in higher ongoing pregnancy rates on the long term. Initial expectant management is therefore justified in these couples and identifying a cervical factor by a post-coital test is unnecessary.

Low cost, simple, intrauterine insemination procedure with unwashed centrifuged husband's sperm for developing countries.

There is an increased need for low cost procedures in treating infertility particularly in developing countries. Intrauterine insemination was used long before the advent of in vitro fertilization. During the last 30 years however, intrauterine insemination has evolved with the introduction of ovulation stimulating protocols and sperm preparation methods taken from assisted reproduction techniques. Costs have risen, but the success rate has not risen to the same extent. We have therefore developed a quite simple intrauterine insemination technique which may be performed in developing countries, without the need of sophisticated equipment, costly materials, media, or disposable insemination catheters; it is quite inexpensive and may be performed by trained staff, such as nurses or midwives. 20 to 27% (depending on the aetiology of their reproduction problem) of the couples remained clinically pregnant after an average of 3.5 to 3.8 intrauterine inseminations procedures.

Long-term outcome in couples with unexplained subfertility and an intermediate prognosis initially randomized between expectant management and immediate treatment.

BACKGROUND: We recently reported that treatment with intrauterine insemination and controlled ovarian stimulation (IUI-COS) did not increase ongoing pregnancy rates compared with expectant management (EM) in couples with unexplained subfertility and intermediate prognosis of natural conception. Long-term cost-effectiveness of a policy of initial EM is unknown. We investigated whether the recommendation not to treat during the first 6 months is valid, regarding the long-term effectiveness and cumulative costs. METHODS: Couples with unexplained subfertility and intermediate prognosis of natural conception (n=253, at 26 public clinics, the Netherlands) were randomly allocated to 6 months EM or immediate start with IUI-COS. The couples were then treated according to local protocol, usually IUI-COS followed by IVF. We followed couples until 3 years after randomization and registered pregnancies and resources used. Primary outcome was time to ongoing pregnancy. Secondary outcome was treatment costs. Analysis was by intention-to-treat. Economic evaluation was performed from the perspective of the health care institution. RESULTS: Time to ongoing pregnancy did not differ between groups (log-rank test P=0.98). Cumulative ongoing pregnancy rates were 72-73% for EM and IUI-COS groups, respectively [relative risk 0.99 (95% confidence interval (CI) 0.85-1.1)]. Estimated mean costs per couple were € 3424 (95% CI € 880-€ 5968) in the EM group and € 6040 (95% CI € 4055-€ 8125) in the IUI-COS group resulting in an estimated saving of € 2616 per couple (95% CI € 385-€ 4847) in favour of EM. CONCLUSIONS: In couples with unexplained subfertility and an intermediate prognosis of natural conception, initial EM for 6 months results in a considerable cost-saving with no delay in achieving pregnancy or jeopardizing the chance of pregnancy. Further comparisons between aggressive and milder forms of ovarian stimulation should be performed.

Periconception pre-exposure prophylaxis to prevent HIV transmission: benefits, risks, and challenges to implementation.

HIV-serodiscordant couples face complicated choices between fulfilling reproductive desire and risking HIV transmission to their partners and children. Sexual HIV transmission can be dramatically reduced through artificial insemination and sperm washing; however, most couples cannot access these resources. We propose that periconception pre-exposure prophylaxis (PrEP) could offer an important, complementary therapy to harm reduction counseling programs that aim to decrease HIV transmission for couples who choose to conceive. In this paper, we describe the potential benefits of periconception PrEP and define critical points of clarification prior to implementation of PrEP as part of a reproductive health program. We consider sexual transmission risk, current risk reduction options, PrEP efficacy, cost, adherence, resistance, fetal toxicity, and impact of PrEP counseling on entry into health services. We address PrEP in the context of other periconception HIV-prevention strategies, including antiretroviral treatment of the HIV-infected partner. We conclude that, should PrEP prove safe and efficacious in ongoing trials, periconception PrEP may offer a useful approach to minimize risk of HIV transmission for individuals of reproductive age in HIV-endemic countries.

Should luteal phase support be introduced in ovarian stimulation/IUI programmes? An evidence-based review.

World-wide, intrauterine insemination (IUI) is still one of the most applied techniques to enhance the probability of conception in couples with longstanding subfertility. The outcome of this treatment option depends on many confounding factors. One of the confounding factors receiving little attention is the quality of the luteal phase. From IVF studies, it is known that ovarian stimulation causes luteal phase deficiency. Based on the best available evidence, this short review summarizes the indications for mild ovarian stimulation combined with IUI and the optimal stimulation programme. While it has been established that stimulated IVF/intracytoplasmic sperm injection cycles have deficient luteal phases, the question remains whether the quality of the luteal phase when only two or three corpora lutea are present (as is the case in stimulated IUI cycles) is impaired as well. There are too few large non-IVF trials studying luteal phase quality to answer this question. Recently a randomized trial has been published that investigated luteal phase support in an IUI programme. This study is discussed in detail. It is recommended to apply luteal phase support in stimulated IUI cycles only when proven costeffective. Further trials are mandatory to investigate both endometrial and hormonal profile changes in the luteal phase after mild ovarian stimulation, and the cost-effectiveness of luteal support in IUI programmes.

Stimulated intrauterine insemination: efficient, cost-effective, safe?

A retrospective report of pregnancy and birth rates achieved in 1010 cycles of stimulated intrauterine insemination (SIUI). Over the years there has been an increasing emphasis on safety, particularly towards reducing the number of high order multiple pregnancies. SIUI is a complex form of assisted conception and requires a high level of clinical judgement to maintain an optimal balance between maximising pregnancy and birth rates and minimising complications, of which the most serious is multiple pregnancy. Extrapolating from these results, it is concluded that a well managed SIUI programme that selects patients appropriately, monitors them intensively and has in place effective strategies to manage over-responders safely, should be able to deliver at least a 15% live birth rate per cycle started with only a 5% cycle cancellation rate. Although SIUI birth rates are lower than IVF rates, the much lower cost of SIUI means that this treatment can be more cost-effective than IVF. However SIUI remains more risky than IVF and, despite careful management, high order multiple pregnancy rates will occasionally occur. It is estimated that the rate of unavoidable high order multiple pregnancies (triplets and above) is 4 per 1000 cycles started.

The cost-effectiveness of treatment for varicocele related infertility.

PURPOSE: We compared the cost-effectiveness of 4 treatment strategies for varicocele related infertility from the perspective of the health care payor and patient. MATERIALS AND METHODS: Cost-effectiveness analysis was performed by studying 4 treatment strategies, namely observation, surgical varicocelectomy followed by in vitro fertilization (IVF) if unsuccessful, gonadotropin stimulated intrauterine insemination (IUI) followed by IVF if unsuccessful, and immediate IVF. The main outcome measure was incremental cost per live delivery of any number of newborns. RESULTS: Immediate IVF cost more per live delivery and was less effective than varicocelectomy/IVF or IUI/IVF. When electing the latter 2 procedures, the preferred approach depended on the choice of perspective. From the health care payor viewpoint each additional birth that resulted from choosing varicocelectomy/IVF over observation cost $52,152, while each additional birth that occurred by electing IUI/IVF over varicocelectomy/IVF cost $561,423. From the patient perspective, while varicocelectomy/IVF resulted in improved outcomes over observation, a rational decision maker would always be willing to pay the slightly higher cost of IUI/IVF (incremental cost per live birth versus observation $27,371) for the added benefit in effectiveness if they were initially willing to invest in varicocelectomy/IVF (incremental cost per live birth versus observation $27,618). CONCLUSIONS: The optimal choice of treatment for varicocele related infertility depends strongly on the decision maker perspective. Regardless of perspective the most technologically advanced treatment, that is immediate IVF, is never favored. The findings of this study should be used to counsel infertile patients with varicocele that immediate IVF is not cost-effective.

Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vitro fertilization.

OBJECTIVE: To determine prognostic factors for achieving a pregnancy with intrauterine insemination (IUI) and IVF. To compare the effectiveness and cost-effectiveness of IUI and IVF based on semen analysis results. DESIGN: Retrospective cohort study. SETTING: Academic university hospital-based infertility center. PATIENT(S): One thousand thirty-nine infertile couples undergoing 3,479 IUI cycles. Four hundred twenty-four infertile couples undergoing 551 IVF cycles. INTERVENTION(S): IUI and IVF treatment. MAIN OUTCOME MEASURE(S): Multiple logistic regression analysis was used to assess the significance of prognostic factors including a woman's age, gravidity, duration of infertility, diagnoses, use of ovulation induction, and sperm parameters for predicting the outcomes of clinical pregnancy and live birth rate after the first cycle of IUI and IVF. The relative effectiveness and cost-effectiveness of these treatments were then determined based on sperm count results. RESULT(S): Female age, gravidity, and use of ovulation induction were all independent factors in predicting pregnancy after IUI. The average total motile sperm count in the ejaculate was also an important factor, with a threshold value of 10 million. For IVF, only female age was an important predictor for both clinical and ongoing pregnancy. When the average total motile sperm count was under 10 million, IVF with ICSI was more cost-effective than IUI in our clinic. CONCLUSION(S): An average total motile sperm count of 10 million may be a useful threshold value for decisions about treating a couple with IUI or IVF.

Clinical andrology: from evidence-base to ethics. The 'E' quintet in clinical andrology.

The management of the infertile man should be founded on consensus-based medicine, i.e. the consensual opinion of experts considering evidence-based as well as empirical or experience-based medicine, the effective cumulative rate of successful deliveries, ethical and economic considerations. The apparent contradictions between conclusions from experience-based medicine and evidence-based medicine regarding the efficacy of varicocele treatment and tamoxifen treatment can be explained by scientific reasons. It is argued that the suggestion not to implement these treatments is ill founded because of flawed meta-analyses. The effective cumulative rate of successful deliveries and time to pregnancy as observed in cohort studies should be considered the ultimate touchstone of treatment efficacy. Based on the data of effective cumulative delivery rate, cost per successful delivery, and the known prevalence of aetiological diagnoses in infertile men, it is possible to estimate the number of deliveries that can be attained thanks to an investment of, e.g. 1 million Euro. This number is approximately 70-80 if IVF (including intracytoplasmic sperm injection) is chosen as first line treatment, and four times higher if conventional treatment (including intrauterine insemination) is applied. It is concluded that the well thought out approach recommended by the World Health Organization should generally be implemented for the management of couples in whom infertility is (mainly) due to a male factor.

Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles.

OBJECTIVE: To investigate the effectiveness of double IUI and to determine the optimal timing of IUI in relation to hCG administration. DESIGN: Prospective randomized study. SETTING: Infertility Center, Department of Obstetrics and Gynecology, University of Milan. PATIENT(S): Patients with male factor and unexplained infertility undergoing controlled ovarian hyperstimulation (COH) and IUI. INTERVENTION(S): After COH with clomiphene citrate and gonadotropins, patients were randomly assigned to one of the following groups: group A received a single IUI 34 hours after hCG administration, group B received a double IUI 12 hours and 34 hours after hCG administration, and group C received a double IUI 34 hours and 60 hours after hCG administration. MAIN OUTCOME MEASURE(S): Number of follicles > 15 mm in diameter on the day of hCG administration, number of motile spermatozoa inseminated, clinical pregnancy rate. RESULT(S): Two hundred seventy-three patients underwent 449 treatment cycles: 90 patients were treated for 156 cycles in group A, 92 patients for 144 cycles in group B, and 91 patients for 149 cycles in group C. The overall pregnancies rates for groups A, B, and C were 13 (14.4% per patient and 8.3% per cycle), 28 (30.4% per patient and 19.4% per cycle), and 10 (10.9% per patient and 6.7% per cycle), respectively. There was a statistically significant difference between group B and groups A and C. CONCLUSION(S): Our data indicate that two IUIs performed 12 hours and 34 hours after hCG administration is the most cost-effective regimen for women undergoing COH cycles with clomiphene citrate and gonadotropins. Although the second insemination adds up to a slightly higher cost, it significantly increases the chance of pregnancy.

Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome.

A total of 811 intrauterine insemination (IUI) cycles in which clomiphene citrate/human menopausal gonadotrophin (HMG) was used for ovarian stimulation were analysed retrospectively to identify prognostic factors regarding treatment outcome. The overall pregnancy rate was 12.6% per cycle, the multiple pregnancy rate 13.7%, and the miscarriage rate 23.5%. Logistic regression analysis revealed five predictive variables as regards pregnancy: number of the treatment cycle (P = 0.009), duration of infertility (P = 0.017), age (P = 0.028), number of follicles (P = 0.031) and infertility aetiology (P = 0.045). The odds ratios for age < 40 years, unexplained infertility aetiology (versus endometriosis) and duration of infertility < or = 6 years were 3.24, 2.79 and 2.33, respectively. A multifollicular ovarian response to clomiphene citrate/HMG resulted in better treatment success than a monofollicular response, and 97% of the pregnancies were obtained in the first four treatment cycles. The results indicate that clomiphene citrate/HMG/IUI is a useful and cost-effective treatment option in women < 40 years of age with infertility duration < or = 6 years, who do not suffer from endometriosis.

Cost-effectiveness of infertility treatments: a cohort study.

OBJECTIVE: To determine the cost-effectiveness of infertility treatments. DESIGN: Retrospective cohort study. SETTING: Academic medical center infertility practice. PATIENT(S): All patients treated for infertility in a 1-year time span. INTERVENTION(S): Intrauterine inseminations, clomiphene citrate and IUI (CC-IUI), hMG and IUI (hMG-IUI), assisted reproductive techniques (ART), and neosalpingostomy by laparotomy. MAIN OUTCOME MEASURE(S): All medical charges and pregnancy outcomes associated with the treatments were obtained. Cost-effectiveness ratios defined as cost per delivery were determined for each procedure. The effects of a woman's age and the number of spermatozoa inseminated on cost-effectiveness of the procedures was also determined. RESULT(S): Intrauterine inseminations, CC-IUI, and hMG-IUI have a similar cost per delivery of between $7,800 and $10,300. All of these were more cost-effective than ART, which had a cost per delivery of $37,000. Assisted reproductive techniques in women with blocked fallopian tubes was more cost-effective than tubal surgery performed by laparotomy, which had a cost per delivery of $76,000. Increasing age in women and lower numbers of spermatozoa inseminated were factors leading to higher costs per delivery for IUI, CC-IUI, hMG-IUI, and ART. Use of donor oocytes reduced the cost per delivery of older women to the range seen in younger women with ART. CONCLUSION(S): Our analysis supports, in general, the use of IUI, CC-IUI, and hMG-IUI before ART in women with open fallopian tubes. For women with blocked fallopian tubes, IVF-ET appears to be the best treatment from a cost-effectiveness standpoint.

Cost-effectiveness of intracytoplasmic sperm injection in comparison with donor insemination.

BACKGROUND: Due to the need for cost containment in the national health services in many countries, there is a demand for analysis of both medical and cost benefits of new technologies. Intracytoplasmic sperm injection has in recent years been proved to be the method of choice for treating severe infertility. It also needs to be shown that intracytoplasmic sperm injection is a cost-effective treatment. AIM AND METHODS: The aim of this study was to evaluate the cost-effectiveness of intracytoplasmic sperm injection over a two-year period and to compare it with the cost-effectiveness of donor insemination. The mean direct and indirect costs of the two modes of treatment were compared with the outcome of the subsequent pregnancies and the cost per delivery in the two groups were calculated. RESULTS AND CONCLUSIONS: The cost analysis showed a direct and indirect cost per delivery after intracytoplasmic sperm injection of 264.300 SEK in 1993, decreasing to 174.900 SEK in 1994. The corresponding cost of donor insemination was 88.900 SEK during the two-year period. The cost analysis showed a 34% increase in cost-effectiveness of intracytoplasmic sperm injection from the first to the second year, an increase that will most probably continue. In the near future intracytoplasmic sperm injection will be a cost-effective treatment and, in addition, intracytoplasmic sperm injection will have the advantage of resulting in genetic children in a majority of the treated couples suffering from severe male subfertility.

Pregnancy following use of the cervical cup for home artificial insemination utilizing homologous semen.

Sixty-one couples with infertility from 1 to 11 years were instructed in the use of the cervical cup for artificial insemination using homologous semen in the privacy of their own homes. There have been 36 reported pregnancies in 32 of these couples. Among women with primary infertility, the pregnancy rate was 43%; it was 67% for those with secondary infertility and 53% overall. Sperm counts and percent motility, as well as postcoital test results, however, failed to be indicative of eventual ability to conceive. Regardless, among couples with documented infertility, this method provided over half of the couples with at least one pregnancy. Additionally, the technique is simple, inexpensive, without significant risk or discomfort, and can be carried out by a couple at their convenience and in privacy.

PIP: 61 couples with infertility from 1-11 years duration were instructed in the use of the cervical cup for artificial insemination using homologous semen in the privacy of their own homes. There have been 36 reported pregnancies in 32 of these couples. Among women with primary infertility, the pregnancy rate was 43%; it was 67% for those with secondary infertility and 53% overall. Sperm counts and percent motility, as well as postcoital test results, however, failed to indicate the eventual ability to conceive. Regardless, among couples with documented infertility, this method provided over 1/2 of the couples with at least 1 pregnancy. Additionally, the technique is simple, inexpensive, without significant risk or discomfort, and can be carried out by the couple at their convenience and in privacy.