CHAPTER 14 Anne‐Sophie Boes1Diane De Neubourg1Karen Peeraer1Carla Tomassetti1Christel Meuleman1 and Thomas D’Hooghe2 Leuven University Fertility Centre (LUFC), UZ Leuven, Leuven, Belgium Division of Reproductive Medicine and Biology, Department of Obstetrics and Gynecology, University of Leuven, Leuven, Belgium Subfertility is defined as the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse in women less than 35 years of age, and after six months of regular intercourse without use of contraception in women 35 years and older [1]. It affects 13–15% of couples worldwide [2]. Many disorders can lead to subfertility. The most common causes of subfertility are ovulatory disorders, tubal disease and semen abnormalities, each accounting for the source of subfertility in approximately 25% of the couples. Other causes such as endometriosis, cervical factor and uterine abnormalities can explain subfertility in approximately 10% of the couples. About 15% of the couples are classified as having unexplained subfertility. The diagnosis of unexplained subfertility is made when the couple has tried to conceive for at least one year (or six months in women 35 years and older) without success despite evidence of ovulation, tubal patency and normal semen parameters [3–6]. The management of unexplained subfertility is empiric as correctable abnormalities lack. Proposed treatment regiments include expectant management, ovarian stimulation with oral or injectable medications, intrauterine insemination (IUI), and assisted reproductive technologies (ART). When starting a treatment for unexplained infertility, the effectiveness of each treatment option should be evaluated. The following clinical questions are relevant to search the literature for the evidence regarding management strategy. Furthermore, it is important to use internationally accepted terms and definitions, recently developed by the World Health Organization (WHO) [7]. Literature searches were performed in the common electronic databases such as Pubmed, MEDLINE, Embase and the Cochrane Library. We looked for systematic reviews, meta‐analyses and randomized controlled trials (RCTs). Evidence‐based clinical practice guidelines for treatment of subfertility were retrieved from the European Society of Human Reproduction and Embryology (ESHRE), Royal College of Obstetricians and Gynaecologists (RCOG), the American College of Obstetricians and Gynaecologists (ACOG), and the WHO. A combination of medical subject headings and text words were used to find articles related to unexplained subfertility. The terms used were “subfertility,” “unexplained subfertility,” “definition of subfertility,” “treatment options,” “conservative management,” “expectant management,” “Clomiphene Citrate,” “gonadotropins,” “aromatase inhibitors,” “intrauterine insemination,” “ovarian stimulation,” “assisted reproductive technology,” “in vitro fertilization,” “laparoscopy.” These terms were combined using “AND”. In a review of studies of unexplained subfertility, the average cycle fecundity over three years of follow‐up in the untreated control groups was 1.8% in 11 non‐randomized studies and 3.8% in 6 randomized studies [8]. Therefore, effective fertility treatment for unexplained subfertility must demonstrate an increase in the pregnancy rate above this baseline fecundability. With expectant management, 14–28% of couples will achieve a successful pregnancy within 12 months [9–11]. Pregnancy rates are lower when the duration of infertility exceeds three years and the female partner is more than 35 years of age. If the duration of infertility is less than two years, the prognosis is relatively good even without therapy, unless the female partner is more than 35 years. Treatment has generally been indicated if duration is more than two years or the female is more than 35 years of age [11]. In conclusion, couples should have tried expectant treatment before medically assisted reproduction is considered. The chance of such a pregnancy depends mainly on patient’s age, duration of infertility and history of any other pregnancy in the same relationship [12]. CC combined with intercourse has been evaluated in different trials. Three level‐I RCTs and one case–control study showed a significant but small effect of CC: approximately one additional pregnancy in 40 CC cycles (95% CI, 20–202) compared with untreated control cycles [15–18]. The latest RCT reported on live‐birth rates and showed that CC offered inferior live‐birth rates than expectant management: 26/192 (14%) women in the clomiphene group and 32/193 (17%) women in the control group. Compared with expectant management, the odds ratio for a live birth was 0.79 (95% CI 0.45–1.38) after CC [19]. The most reliable evidence comes from a systematic review, which showed data relating to 1159 participants from seven trials [20]. There was no evidence that CC was more effective than no treatment or placebo for live birth (odds ratio 0.79, 95% CI 0.45–1.38; P = 0.41) or for clinical pregnancy per woman randomized both with IUI (OR 2.40, 95% CI 0.70–8.19; P = 0.16), without IUI (OR 1.03, 95% CI 0.64–1.66; P = 0.91) and without IUI but using human chorionic gonadotropin (hCG) (OR 1.66, 95% CI 0.56–4.80; P = 0.35). The number of cycles in the studies ranged from four to six. The clinical heterogeneity and variable methodological quality of the studies should be noticed. In one study surgically treated endometriosis was present in 40% of the patients [21]. There was also some discrepancy in the use of hCG as an ovulation‐trigger. Despite the lack of homogeneity among the studies, it is important to counsel patients regarding the effectiveness of CC. Realistic expectations should be clearly defined prior treatment. Possible side‐effects such as transient hot flushes and visual disturbances of CC should also be discussed. Multiple pregnancies occur in 8–10% of cases and ovarian cysts in 5–10% [22]. A case‐cohort study has suggested a link with ovarian cancer when used for more than 12 months [23]. In conclusion, these data suggest no evidence that CC has an effect on pregnancy rate in women with unexplained subfertility and would therefore not recommend CC as a treatment for unexplained subfertility. Gonadotropins have an established role in women with anovulation with resistance to CC [24]. The role of gonadotropins in women with normal ovulatory function is not clear. There are no RCTs which compare gonadotropins with expectant management. Therefore the question should be rephrased: does gonadotropin therapy offer benefit over anti‐estrogen therapy such as CC in couples with unexplained subfertility? The use of gonadotropin therapy must be justifiable on the grounds of robust evidence of its effectiveness as it is linked to higher risks than CC, such as ovarian hyperstimulation syndrome (OHSS), multiple pregnancy and miscarriage. Also there are increased costs associated with gonadotropin therapy. A recent review of a Cochrane database reviewed the evidence of oral anti‐estrogens versus gonadotropins (either human menopausal gonadotropins or recombinant FSH) with intercourse or IUI in the treatment of unexplained subfertility [25]. Five RCTs, including a total of 231 identified couples with unexplained subfertility, were included [26–30]. CC was compared with human menopausal gonadotropins (hMG) in two studies. The results of the two studies as a whole were not significantly different in live‐birth rate per couple (OR 0.51, 95% CI 0.18–1.47). Clinical pregnancy rate per woman was examined in three studies, two comparing CC versus hMG and one comparing CC versus high purity urinary gonadotropins. There was a statistically significant higher pregnancy rate with the hMG group when the data from the three studies were combined (OR 0.44, 95% CI 0.19–0.99). The meta‐analysis was repeated excluding the trials with co‐intervention of an hCG trigger injection (given only in the gonadotropin group). The results were not statistically significant (OR 0.33, 95% CI 0.09–1.20). Pregnancy rate per cycle was reported in five trials. Main pregnancy rate per cycle was 8% (CC) and 25% (gonadotropins), indicating a benefit associated with gonadotropins, although the confidence intervals of all five trials crossed the line of no effect. Miscarriage rate per pregnancy (defined as a woman being clinically pregnant who does not deliver a live baby) was reported in three studies, one comparing CC versus hMG, one comparing CC versus high purity urinary gonadotropins and one comparing CC with recombinant FSH (rFSH). The results as a whole were not statistically significant (OR 0.46 95% CI 0.06–3.33). Three trials reported on multiple birth rate per pregnancy (defined as a woman who delivers two or more babies in one pregnancy), one comparing CC versus hMG, one comparing CC versus high purity urinary gonadotropins and one comparing CC with rFSH. The rate of multiple pregnancies after OS with CC was 1/11 (9%) compared to 5/22 (22.7%) after OS with gonadotropins. The results as a whole were not statistically significant (OR 0.37, 95% CI 0.06–2.43). OHSS was reported in none of the trials, neither was cancellation due to overstimulation. Important considerations should be made about the trials. They all used a different regiment with regard to the treatment that was being prescribed. Almost all trials used an hCG trigger in the gonadotropin groups, but most of the CC groups did not receive hCG. When the trials with this important co‐intervention were excluded from the meta‐analysis, no significant differences were apparent between gonadotropins and anti‐estrogens for the primary outcome. Cost of treatment is also an important factor when choosing the method of treatment. A retrospective analysis suggested that though gonadotropins were more likely to produce pregnancy, the cost per pregnancy was less in the CC group as opposed to the gonadotropin group. In their study CC was more cost‐effective [8]. Although there might be a benefit associated with gonadotropins this review showed that there was insufficient evidence to prefer either of the methods comparing pregnancy or live‐birth rates. In conclusion, further RCTs are needed to answer this question. Aromatase inhibitors have been successfully used to induce ovulation. In contrast to CC they do not deplete estrogen receptors and therefore have no adverse effect on endometrium or endocervix and they result in lower serum estrogen concentrations. They are also associated with good pregnancy rates and with a lower incidence of multiple pregnancies than CC [31]. There are no trials comparing the use of aromatase inhibitors versus placebo in unexplained subfertility. A systematic review and meta‐analysis of five RCTs compared the efficacy of aromatase inhibitors (letrozole or anastrozole) versus CC for unexplained subfertility. A total of 273 patients were included. Two of the trials compared anastrozole versus CC and three compared letrozole and CC. There was no significant difference observed for live pregnancies between the compared arms (pooled OR 0.87, 95% CI, 0.46–1.65). The methodological qualities of the trials were not highly scored and OS with FSH was also included where aromatase inhibitor and CC were used [32]. The use of aromatase inhibitors as a standard treatment for unexplained subfertility should not be recommended.
Unexplained infertility
Background
Clinical questions
General search strategy
Searching for evidence synthesis
Primary search strategy
Critical review of the literature
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