SO with IUI has become the mainstay of treatment for unexplained and mild male factor infertility. Historically, therapy was initiated with clomiphene and IUI, and when not pregnant, couples moved in a step wise fashion through gonadotropin and IUI treatments to IVF. This progression seemed logical as an initial literature-wide review (primarily observational studies) reported success rates of 1.3% to 4% for no treatment, 8.3% for CC/IUI, 17.1% for hMG/IUI, and 20.7% for IVF (6
The National Collaborative Reproductive Medicine Network designed and performed a randomized clinical trial to determine the effectiveness of gonadotropin/IUI treatments, given the significant risks of twins, high order multiple births, and OHSS (7
). Nine hundred and thirty-two couples were randomized to one of four arms: intracervical insemination (ICI), IUI, FSH/ICI, and FSH/IUI. They concluded that “treatment with induction of superovulation and intrauterine insemination is three times as likely to result in pregnancy as is intracervical insemination and twice as likely to result in pregnancy as is treatment with either superovulation and intracervical insemination or intrauterine insemination alone.” As such, they felt that FSH/IUI was an effective treatment for couples with unexplained infertility. Further examination of that study, however, revealed that the per cycle pregnancy rate for FSH/IUI was only 9%/cycle, a figure not that different from reported studies for CC/IUI, but with a far higher multiple (especially high order multiple) birth rate than had been consistently found for CC/IUI. For couples treated with gonadotropins in that study, the 186 pregnancies included three sets of quadruplets, four sets of triplets, and seventeen sets of twins. In addition, six women developed OHSS requiring hospitalization.
The Fast Track and Standard Treatment Trial (FASTT) was designed to evaluate the role of FSH/IUI in a standard treatment paradigm for couples with unexplained infertility, when the female partner was younger than 40 years of age (8
). 503 treatment naïve couples were randomized to either a conventional treatment arm or an arm that eliminated FSH/IUI from treatment. All couples in both arms initiated treatment with up to three cycles of CC/IUI. In the conventional arm, couples who were not pregnant then proceeded through a maximum of three cycles of FSH/IUI and, if not pregnant, to a maximum of six cycles of IVF. Couples in the accelerated arm proceeded directly from CC/IUI to IVF. CC/IUI was included in the accelerated arm (rather than have patients initiate treatment with immediate IVF) because a pretrial computer simulation demonstrated that an immediate IVF arm would not be cost-effective. The reason for this unexpected finding was the fact that, although IVF was much more successful than CC/IUI, its high twin pregnancy rate compared to the low twin rate of CC/IUI added sufficient cost to negate any savings.
An analysis of the FASTT data demonstrated that for couples with unexplained infertility (including some with mild male factor), and a female partner under age 40 years, moving directly from CC/IUI to IVF resulted in a 40% shorter time to pregnancy that was statistically significant(8
). There was an estimated savings of $10,000 per delivery when compared to couples whose treatment included FSH/IUI.
Computer simulations using the FASTT data demonstrated that an IVF cycle would have to cost $17,749 in order for the conventional arm to have a lower cost per delivery. The per cycle pregnancy rates for CC/IUI and FSH/IUI cycles were not that different at 7.6% and 9.8%, respectively. In addition, 8% and 20% of pregnancies from CC/IUI and FSH/IUI, respectively, were multiple gestations. We concluded that the routine use of FSH/IUI did not add value to a contemporary infertility treatment paradigm.
For the reproductively younger women, beginning treatment with a minimum of three CC/IUI cycles using 100 mg for 5 days and timing the IUI with LH kits allows over 20% of couples to become pregnant with a therapy that, except for expectant management, costs less than most other infertility treatments. Few cycles are cancelled with this protocol in which ultrasound monitoring is used only if there is no LH surge by cycle day 16. In addition, this protocol allows the most fertile patients (i.e., those with the highest chance for multiple births) to become pregnant from a treatment with a low chance for multiple births.
Recently there has been an effort to use mild gonadotropin stimulation for SO as an alternative to conventional stimulation. In 2007, Dankert and colleagues from the Netherlands reported the outcome of a randomized clinical trial comparing the use of CC vs. low dose recombinant FSH in a SO/IUI protocol (9
). Live birth rates per couple over a maximum of four treatment cycles for CC/IUI and FSH/IUI were 28% and 27%, respectively, and per cycle were 10% for CC/IUI and 8.7% fir FSH/IUI. The Dankert study demonstrated that, for their mild protocol, FSH/IUI was no better than CC/IUI. Custers et al. reported data from a large Dutch multicenter cohort study of 15,303 cycles of IUI of which 51% included the use of CC and 19% the use of gonadotropins for SO (10
). In a logistic analysis, they determined that controlled ovarian hyperstimulation did not have a significant influence on pregnancy outcome. This was explained by the fact that in the Netherlands patients have mild stimulation for both clomiphene and gonadotropin cycles and “mono or bifollicular cycles are quite common.” In 2006, Steures et al. reported findings from a randomized controlled trial comparing 6 months of COH/IUI to observation (11
). The vast majority of SO was achieved from gonadotropins. Their mild stimulation and cancellation protocols resulted in 14% of cycles being cancelled for > 3 mature follicles and 58% having only 1 mature follicle. Thus, 72% of cycles in the SO group had essentially no treatment effect when using their mild stimulation protocol. Pregnancy rates for mono- and multifollicular cycles were 4% and 5%/ cycle, respectively. They concluded that the pregnancy rate of their mild stimulation SO/IUI protocol was no different than the pregnancy rate of six cycles of observation. The data from the FASTT trial and studies evaluating the efficacy of FSH/IUI around the world do not support its use for the younger population of infertile couples having IUI, either in conventional or mild stimulation protocols. Given the lower costs, decreased health risks, and reasonable success of CC/IUI, this treatment seems to have borne the test of time for use in women younger than 40 years of age.
Data from the FASTT trial did not address the reproductively older woman. In particular, we sought to understand the most effective treatment strategy for women with unexplained infertility who were at the end of their reproductive years and demonstrated a reasonable chance for success. As a progression from the FASTT trial and our desire to understand the most appropriate treatment paradigm for the reproductively mature woman, we designed The Forty and Over Infertility Treatment Trial (FORT-T) (12
Infertility care for women at or around age 40 years brings special considerations that are very different from the reproductively younger woman. It is well known that there is a limited window of opportunity for the reproductively mature woman to become pregnant. Data from the Hutterites have demonstrated that for women whose cultural pressure is to continue to bear children as long as possible and who don’t use contraception, the average age of the last pregnancy is just before the 41st birthday (13
). Some data have suggested that half of women attempting pregnancy at age 40 will become pregnant over one year. However, for the 50% who do not conceive, their fertility window may well have passed. Another difference for these reproductively older women has been the general belief that CC/IUI is not appropriate for them. Historically, the belief has held that, given their limited time for becoming pregnant, one should “pull out all stops” and immediately use FSH/IUI, despite the higher dosages required in this older population and thus much higher costs. Evidence in the literature has never supported this belief. On the other hand, adverse events, e.g., OHSS and high order multiple births, from treatment begin to drop.
The FORT-T trial was designed to test the hypothesis that immediate IVF is more effective than a treatment strategy that begins with either CC/IUI or FSH/IUI (12
). Couples were randomized to begin treatment in one of three arms: 1) 2 cycles of CC/IUI, 2) 2 cycles of FSH/IUI, or 3) 2 cycles of IVF. If not pregnant and continuing to demonstrate a reasonable chance for success by study criteria, couples proceeded to a maximum of four fresh and two frozen IVF cycles. The preliminary data were presented at the ASRM annual meeting in October 2011 (12
). That early analysis suggests that immediate IVF is the most effective strategy for couples with unexplained infertility in women age 38 years and older. If subsequent FORT-T data analysis is consistent with our preliminary findings, the combination of data from FASTT and FORT-T, we believe, will sound the death knell for the routine use of FSH in a standard treatment paradigm prior to IVF therapy.