COMMENTARY

Fast-Track Infertility Treatment

Peter Kovacs, MD, PhD

Disclosures

September 09, 2010

A Randomized Clinical Trial to Evaluate Optimal Treatment for Unexplained Infertility: The Fast Track and Standard Treatment (FASTT) Trial

Reindollar RH, Regan MM, Neuman PJ, et al
Fertil Steril. 2010;94:888-899

Background

Infertility, defined as the inability to achieve a successful pregnancy after 1 year of trying to conceive, affects approximately 10% to 15% of couples. Couples who fail to conceive undergo an evaluation, and treatment is offered on the basis of the results. The initial evaluation assesses ovarian function, sperm parameters, and anatomic structures. Further tests may be needed, depending on the results of the initial evaluation and the clinical picture.

In approximately 20% of couples, the initial tests will not identify any problems, and these couples are diagnosed with so-called unexplained infertility. Unexplained infertility could be related to an unidentified problem (eg, problem with egg, sperm, or embryo transport; fertilization; implantation) or to a low-efficacy reproductive process, in which case it will take longer for the couple to conceive. Some couples who are diagnosed with unexplained infertility will achieve a pregnancy without any treatment if they continue trying beyond the first year. Others will seek fertility treatment.

Typical first-line treatment involves controlled ovarian stimulation in combination with intrauterine insemination (IUI). Stimulation increases pregnancy rates compared with no stimulation, and IUI is more effective than intravaginal or intracervical insemination.[1]Most centers offer 3 to 6 cycles of IUI, and if this does not produce results, they proceed with in vitro fertilization (IVF) as the next step. In most cases, the first choice of drug for stimulation is clomiphene citrate, and gonadotropins are introduced only if success is not achieved during the first few attempts. The ideal medication and number of IUI cycles that should be offered are not known. This study evaluated whether accelerating this approach was associated with shorter time to pregnancy and reduced overall costs.

Study Summary

This randomized controlled trial recruited 503 couples who were diagnosed with unexplained infertility, in which the age of the female partner was younger than 40 years. Couples were randomly assigned to 3 cycles of clomiphene citrate plus IUI, followed by 3 cycles of gonadotropin plus IUI and up to 6 cycles of IVF if needed (standard treatment, n = 247), or to 3 cycles of clomiphene citrate plus IUI followed by 6 cycles of IVF if needed (accelerated approach, n = 256). Baseline demographic characteristics were well matched.

Overall, 64% of the couples delivered at least 1 child during the study period. The time to pregnancy was shorter in the accelerated group (8 vs 11 months; hazard ratio: 1.25; 95%; confidence interval: 1 - 1.56). Cumulative pregnancy rates at 6, 9, and 12 months (standard vs accelerated protocol) are shown in the Table.

Table. Cumulative Pregnancy Rates

Study Group Cumulative Pregnancy Rate
6 months 9 months 12 months
Standard 31.9% 43.8% 55.4%
Accelerated 43.2% 54.7% 65.4%


Pregnancy rates per cycle were 7.6% in the clomiphene citrate plus IUI cycles, 9.8% in the gonadotropin plus IUI cycles, and 30.7% in the IVF cycles. The incidence of multiple births was similar in the 2 main groups. The total cost per delivery was $9800 lower in the accelerated protocol group (95% confidence interval, $25,100 lower - $3900 higher).

Viewpoint

In this study, Reindollar and colleagues did not find an additional benefit of using gonadotropin plus IUI treatment after 3 failed cycles of clomiphene citrate plus IUI, suggesting that the best approach is to proceed with IVF after failed clomiphene citrate plus IUI treatments. Fertility treatment should be cause-specific (eg, intracytoplasmic sperm injection for severe male factor infertility), simple, inexpensive, and effective. The various treatment options follow each other in a stepwise fashion. IUI is considered a good first-line option (when indicated by the evaluation) because it requires minimal medication use, involves limited monitoring, necessitates no invasive steps, is associated with low costs, and is effective when compared with no treatment. The problem with IUI is that the rate of multiple pregnancies is unpredictable, and controlled ovarian hyperstimulation (COH) and COH plus IUI are now the main causes of high-order multiple gestations.[2] Furthermore, success rates of these methods are low when compared with IVF. The per-cycle pregnancy rate is in the range of 5% to 20%, and the cumulative pregnancy rate is approximately 40%.[1,3,4]This cumulative rate is similar to the rate that can be achieved with a single cycle of IVF. Therefore, IUI should be limited to a reasonable, minimal number of attempts. Except for special cases (donor sperm use, anovulatory cycles), the limit is 3 to 4 attempts of IUI, and IUI should be avoided completely in women older than 40 years.[1,5]

With gonadotropin stimulation, higher pregnancy and multiple pregnancy rates have been reported, but these results were not supported by the findings of Reindollar and colleagues. In this study, however, gonadotropins were used only after 3 failed cycles of clomiphene citrate. By the third cycle, a good proportion of women who will achieve a pregnancy have already done so; therefore, starting gonadotropin after 3 cycles negatively influences its efficacy. It would have been advantageous to include a third group in this study, in which clomiphene citrate treatment was skipped and patients started receiving gonadotropin plus IUI. This approach would probably have led to an even shorter time to pregnancy but would have resulted in more multiple gestations, thereby increasing overall healthcare costs.

Insurance availability is an important factor in treatment decisions. The goal of insurance companies is to maximize success at the lowest possible expense. IVF is associated with the highest success rates and is the most expensive treatment. Clomiphene citrate plus IUI is the least effective but is the most economical treatment. Gonadotropin plus IUI is more effective than clomiphene citrate plus IUI but is associated with more multiple gestations and therefore higher overall costs. In countries that have mandatory insurance coverage for infertility treatment, the insurance companies may influence the treatment protocols. In countries where insurance coverage for infertility treatment is not available, recommendations can still be made. IUI appears to be a good first-line treatment but should be limited to 3 to 4 cycles if IVF is available. It is yet to be determined whether gonadotropins should be offered for IUI treatment. This study suggests that their use adds no further benefit, but this study is unable to answer this question adequately because gonadotropin stimulation was offered only after 3 failed cycles of clomiphene citrate.

Abstract

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