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In vitro fertilization (IVF) is the most efficacious treatment modality for infertility. While it is absolutely indicated in some conditions, such as obstructed fallopian tubes and most cases of azoospermia, in others, conservative approaches are traditionally used first and IVF applied only when they fail. The rationale for this approach is that simpler, lower cost, yet effective strategies should be utilized before more complex, risky, and expensive IVF treatments are attempted.

This paradigm is being challenged by accumulating data on the actual effectiveness of traditional first line fertility treatments as compared with current IVF results. We argue in favor of IVF as a first line treatment, or first gonadotropin alternative, for several etiologies of infertility: unexplained infertility, advanced maternal age (>40 years), and subcategories of polycystic ovarian syndrome (PCOS).

Unexplained infertility is a diagnosis of exclusion, established when normal semen analysis, tubal patency and normal ovulation have been established. After a sufficient period of expectant management, ovarian stimulation with or without intrauterine insemination, is thought to increase the probability of delivery. Early studies suggested clomiphene citrate (CC) to be an effective treatment for unexplained infertility. However, forty years since its introduction, a 2010 Cochrane Review summarized pooled data from 1,159 participants in seven trials. There was no evidence that CC was more effective than no treatment or placebo for live-birth or clinical pregnancy per woman randomized, either with or without intrauterine insemination (IUI), or without IUI but using human chorionic gonadotropin (hCG). A 2013 American Society for Reproductive Medicine committee opinion discourages the use of CC with intercourse but, based on data from a single small study, suggests that in combination with IUI, CC seems to increase pregnancy rate per cycle compared to expectant management. However, actual pregnancy rates of this treatment are as low as 7.6% per cycle as reported in one recent randomized controlled trial (RCT) (1).

Gonadotropins combined with IUI for unexplained infertility yield a pregnancy rate of approximately 10% per cycle, likely because of multiple follicle growth. However, a closer look at specific studies reveals a complex clinical situation. In the largest randomized study, performed by the National Cooperative Reproductive Medicine Network, it was shown that pregnancy rates per cycle following gonadotropins+IUI were superior to IUI in non-stimulated cycles (9% and 5%, respectively) with a cumulative pregnancy rate after four cycles of 33% vs 18% respectively (2). In contrast, a multicenter Dutch study assigned 253 couples to IUI and gonadotropins or to expectant management. The pregnancy rate per cycle in the IUI group was 6.5%, and similar to that of couples who had no intervention (3). The disparity in results stems from different treatment philosophies: a higher gonadotropins starting dose of 150 IU/day in the American vs. 75 IU/day in the European study. The more aggressive American approach had a cumulative multiple pregnancy rate of 20% and an ovarian hyperstimulation syndrome (OHSS) rate of 1%, compared to 5% multiple pregnancy and no cases of OHSS with the European approach.

The message for stimulated IUI cycles appears clear: in order to achieve effective treatment over the background rate, a meaningful stimulation is necessary. However, this comes at the price of multifetal pregnancies and OHSS with their well-known risks.

We therefore suggest that women with unexplained infertility should move directly to IVF. This recommendation is further supported by the fast track and standard treatment (FASTT) trial, which demonstrated that follicle- stimulating hormone/IUI therapy in these patients is of no added value (1).

Infertile women of advanced age (>40 years) are a unique subgroup in the broader population of patients diagnosed with 'unexplained infertility'. In this subgroup the main reasons for infertility are reduced oocyte number and quality.

Retrospective studies demonstrate that pregnancy rates following CC at age 40 and older are below 5% per cycle, and are 5-10% for gonadotropins. Reported live-birth rates by SART in 2011, using fresh embryos at age 40-41, are 19.5%, declining to 9% beyond 42 years. In the single prospective randomized study focusing on this age group, patients between the ages of 38 and 42 were randomized to three treatment arms of first line intervention (4). The clinical pregnancy rates per cycle were 6.9% in the CC/IUI arm, 7.7% in the follicle-stimulating hormone/IUI arm, and 24.7% in the IVF group.

In contrast to younger women, avoiding unnecessary delays in this subgroup is crucial, since each year of age is associated with a significantly lower chance to have a child. This population should move immediately to IVF as a first line of treatment because of the frustrating results of the conventional alternative interventions.

Clomiphene citrate is first line treatment for PCOS patients. It achieves an ovulation rate of 60% to 85%, a cumulative live-birth rate of 50% to 60% after six cycles, and is associated with 0-3% multiple pregnancy rate and only rarely with OHSS events. The traditional next step for those who do not ovulate or do not conceive within six cycles is ovarian stimulation by gonadotropins. The ovaries of PCOS patients are highly sensitive to gonadotropins.

Therefore achievement of the desired monofollicular ovulation may be difficult and standard doses may result in high multiple pregnancy rates or require cancelation. Low dose regimens are recommended for PCOS patients and may induce monofollicular response in 60-70% of women. However in two relatively large RCTs it was demonstrated that even when used prudently the incidence of multiple pregnancies and OHSS were 14% of all clinical pregnancies and 2.3% of cycles respectively (5). Analysis of the predictors of successful ovulation in low dose gonadotropin therapy demonstrated that women with amenorrhea, or a BMI >30 and high antral follicle count, are more difficult to treat as compared to patients with normal BMI and low antral follicle count. In addition, young lean PCOS patients are at considerably increased risk of OHSS.

These data support adoption of an individually tailored treatment approach for women in these subgroups of PCOS patients. Gonadotropin treatment should be abandoned and IVF should be applied as second line therapy if CC treatment fails. IVF protocols combining antagonist cycles with agonist triggering for final oocyte maturation and single embryo transfer, dramatically reduce the risk of both OHSS and multiple fetal pregnancies without compromising success rates.

We focused here on the pure clinical aspects of infertility treatments. A thorough discussion of economic implications of different infertility treatments is complex and beyond the scope of this text. The cost per live- birth, resulting from various interventions, differs from country to country and within the same country according to different healthcare models and the levels of public and private funding.

In conclusion, based on current published data and collective shared experience we propose that IVF should be employed as either first line treatment (women aged >40 years) or first gonadotropin therapy (unexplained infertility and high risk PCOS subgroups). IVF has evolved into a safer and extremely effective therapeutic umbrella. From a purely medical point of view it seems inevitable that IVF commencement should be accelerated and extended to broader segments of the infertile patient population.