A recent update of a Cochrane review on intra uterine insemination (IUI) for couples with unexplained infertility was published in 2012 [6]. One trial was included that compared IUI in a natural cycle with EM and showed no evidence of increased live births (334 women: OR 1.6, 95 % CI: 0.92–2.8). Two trials compared EM with IUI with ovarian stimulation (OS) and both concluded there was no evidence of a difference in pregnancy rate (in total 304 women: data could not be pooled) [6]. In the last comparison (IUI-OS versus EM) one large multicentre randomised controlled trial (RCT) from the Netherlands was included. This RCT randomised 253 couples with unexplained infertility and intermediate prognosis of natural conception between either 6 months of EM or immediate start with OS and IUI. Within 6 months, the ongoing pregnancy rate in the EM group was 27 % and in the OS group with IUI 24 % (RR 0.85 CI: 0.63–1.1) [7]. The couples were then treated according to the centre’s standard protocol, usually OS with IUI, followed by IVF. Three years after randomisation, the cumulative ongoing pregnancy rates were 72 and 73 % for EM and OS with IUI, respectively (RR 0.99 (95 % CI: 0.85–1.1). The time of ongoing pregnancy also did not differ between groups (log-rank test, p = 0.98) [8]. An RCT from the UK included 334 couples with unexplained infertility that were randomised to EM , oral clomiphene citrate or unstimulated IUI. After 6 months, a live birth rate of 23 % was obtained in the IUI group versus 16 % in the EM group, which was not significantly different (OR 1.60, 95 % CI 0.92) [9].

A systematic Cochrane review on in vitro fertilisation (IVF) for couples with unexplained infertility concluded that the added value of IVF in relation to EM or IUI with or without OS in couples with unexplained infertility has not been conclusively proven due to a paucity of data: only one trial with 51 women compared IVF with EM and the live birth rate per woman was significantly higher with IVF (45.8 %) compared to EM (3.7 %; OR 22, 95 % CI 2.5–189) [10].

Thus, RCTs in couples with unexplained infertility comparing EM with IUI with or without OS, OS alone with timed intercourse (TI) or IVF so far do not provide irrefutable evidence of a beneficial effect of treatment over EM.

High rates of natural conception have also been observed in several cohort studies. In one cohort study that included 652 couples with unexplained infertility, the cumulative live birth rate after 36 months was 33 % [11]. In another study, 218 couples with unexplained infertility were included and the cumulative live birth rate within 36 months was 60 % [12]. And in a third cohort study of 443 couples with unexplained infertility, EM was advised in couples with good prospects of natural conception. The chance of natural conception within 12 months was determined according the prognostic model of Hunault; and if less than 30 %, couples were counselled to continue to try on their own for up to 2 years, and if still not pregnant, they would undergo up to six cycles of IUI with controlled ovarian stimulation (COS-IUI) [13]. If no pregnancy was achieved, up to three cycles of IVF were recommended. If the chance of natural conception was greater than 30 % and the female’s age was greater than 38 years, 3–6 cycles of IUI-COS cycles were offered before IVF was started. If female age was ≥ 38 years, IVF was offered directly. Patients were followed until their first ongoing pregnancy, which caused variation in the follow-up period per couple from 2 to 8 years. After the fertility workup, 93 % (408/437) couples were eligible for EM. In total, 37 % (163/437) couples started with IUI and 15 % (64/437) couples started with IVF. Of all couples, 81.5 % (356/437) achieved an ongoing pregnancy and 73.9 % (263/356) of the pregnancies were conceived naturally. IUI and IVF were responsible for 12.6 % (45/356) and 13.5 % (48/356) of all pregnancies, respectively. Of all the pregnancies, 98.6 % were conceived within 3 years after first visit to the hospital. Predictors for overall pregnancy chance and mode of conception were duration of infertility, female age and obstetrical history [14].

The most difficult problem to overcome with recommending EM is how to identify couples that would benefit from EM over treatment; and how to convince the patient frustrated with her monthly failures of conception to continue to “do nothing” but keep on trying. Gynaecologists differ widely in estimating fertility prognoses in subfertile couples. Prognostic models may be of help here [11]. For several treatment policies, prognostic models have been developed. For eight models, the validity has been assessed in populations other than the one in which the model was developed (external validation), and only three of these showed good performance. One model predicting the chance of natural conception has reached the phase of impact analysis [11, 15]. This prognostic model is based on three prognostic models: data of these three models [12, 16, 17] were pooled and integrated in a synthesis model. This synthesis model predicts the chance of live birth, and contains the variables: female age, duration of subfertility/infertility, infertility being primary or secondary, semen motility and referral status and is available in a version with and without the post-coital test (PCT) as a predictor. The Dutch guideline for unexplained infertility recommends the use of this prognostic model and EM for 6–12 months in couples with a good prognosis (> 30 %) [18]. In agreement with this, both the European Society of Human Reproduction and Embryology (ESHRE) guidelines and the guidelines of the National Institute of Clinical Excellence (NICE) emphasize that couples should not be exposed to unnecessary risks or ineffective treatments, and encourage that each couple should receive information about the estimate of their chances of natural conception [19, 20]. Guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG, 1998) have recommended that couples should have tried EM before assisted reproductive treatment.