Unexplained infertility

INTRODUCTION — It is relatively simple to identify the cause of infertility in women with ovulatory disorders or tubal disease, and in men with semen abnormalities. These categories account for the source of infertility in approximately 75 to 85 percent of couples [1]. Infertility in the remaining couples is due to endometriosis (8 percent) or miscellaneous factors (eg, cervical factor, immunological factor, uterine synechiae) (2 percent) or is unexplained (15 percent) [2-4].

Management of couples with unexplained infertility will be reviewed here. Related content on the overview of infertility and evaluation of patients is presented separately:

●(See "Overview of infertility".)

●(See "Female infertility: Evaluation".)

●(See "Approach to the male with infertility".)

In this topic, when discussing study results, we will use the terms "woman/en", "man/en", or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

DEFINITION AND DIAGNOSIS — Unexplained infertility refers to the absence of a definable cause for a couple's failure to achieve pregnancy after 12 months of attempting conception despite a thorough evaluation, or after six months in women 35 and older [5,6]. Authorities vary in their concept of what constitutes a thorough evaluation, and these opinions have evolved over time. Currently, a thorough evaluation typically includes documentation of:

●Ovulation

●Tubal patency

●Normal uterine cavity

●Normal semen analysis

●Adequate ovarian oocyte reserve

A detailed description of these tests, and the role of laparoscopy in the diagnostic evaluation, can be found separately. (See "Female infertility: Evaluation".)

POSSIBLE ETIOLOGIES — Several possibilities have been proposed to explain why some couples fail to conceive in the absence of an identifiable cause. Subtle changes in follicle development, ovulation, and the luteal phase have been reported in some of these women [7,8]. In other couples, the male partner's semen analysis shows sperm concentration and motility at the lower end of the normal range [9]. Implantation failure, subtle cervical factors, or problems with sperm and egg transport or interaction are other possibilities [10]. Many cases of unexplained infertility are probably caused by the presence of multiple factors (eg, female partner over 35 years of age with diminished ovarian reserve and male partner with low normal semen parameters), each of which on their own do not significantly reduce fertility, but can reduce the pregnancy rate when combined.

Couples with unexplained infertility who are treated with in vitro fertilization (IVF) demonstrate reduced oocyte fertilization and embryo cleavage rates compared with couples in whom tubal factor is the cause of the infertility, although the rates of live birth per transfer are equivalent for both groups. This was illustrated in a study that showed that the oocyte fertilization and the embryo cleavage rate for unexplained and tubal factor infertility were 52 and 60 percent, respectively [11]. Couples with unexplained infertility also had a higher rate of complete fertilization failure when treated with IVF than couples with tubal factor infertility (6 versus 3 percent). These results suggest that couples with unexplained infertility probably have subtle functional abnormalities in oocyte and/or sperm function. In this sense, IVF is also a diagnostic procedure.

Defective endometrial receptivity is thought to prevent normal attachment, invasion, and implantation of the blastocyst, and may account for some cases of unexplained infertility and recurrent pregnancy loss [12]. No biomarkers have been validated for clinical diagnosis of these patients.

Undiagnosed/untreated celiac disease may be more prevalent in women with unexplained infertility. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

Comprehensive genetic studies are needed to better understand the etiologies of unexplained infertility. A comprehensive, 10-year evaluation is underway by the National Institutes of Health entitled "The All Of Us Research Program," which is inviting one million people to help build one of the most diverse health databases in history; the database will combine genetic histories, lifestyle, medical conditions, and whole genome application [13]. From this information, multiple breakthroughs are expected, such as recurrent pregnancy wastage and unexplained infertility. We are signing our patients up and hope others will as well.

OUR APPROACH — The management of couples with unexplained infertility should balance the efficacy, cost, safety, and risks of various treatment alternatives. A common approach is to start with treatments that consume few resources and are patient-directed (eg, lifestyle changes or timed intercourse), and then move sequentially to treatments requiring proportionately greater resources (clomiphene citrate [CC] plus intrauterine insemination [IUI]), and finally to high-resource interventions (gonadotropin injections plus IUI, in vitro fertilization [IVF]) (table 1) [11]. The approach to treatment should be individualized for each couple. In general, if a specific fertility treatment does not result in pregnancy after three cycles, alternative treatments should be considered [14]. (See 'Lifestyle changes' below and "Natural fertility and impact of lifestyle factors" and 'Low-resource interventions' below and 'High-resource interventions' below.)

Once any lifestyle issues have been addressed, we begin treatment with CC/IUI, or letrozole/IUI [15-17]. As women with unexplained infertility are ovulatory, the purpose of ovulation induction is to cause mild ovarian hyperstimulation and resultant double ovulation in normally mono-ovulatory women. CC is combined with IUI based on the hypothesis that placing a large number of sperm high in the reproductive tract enhances the likelihood of conception. (See 'Clomiphene plus IUI' below.)

For women who do not conceive with clomiphene or letrozole/IUI in three to four cycles of treatment, we proceed with IVF [17]. IVF is the intervention that results in the highest per-cycle pregnancy rate in the shortest time interval, with up to 40 percent of cycles resulting in a live birth [18]. However, IVF is also the most expensive treatment option.

In women for whom IVF is not an option because of insurance, financial, religious, or personal reasons, we offer either ovulation induction with injectable gonadotropins or laparoscopy. (See 'In vitro fertilization' below and 'Gonadotropin injections with or without IUI' below and "Female infertility: Reproductive surgery".)

●The section editor and one author (MH) perform laparoscopy on women with pelvic symptoms suggestive of disease, such as endometriosis, and proceed with injectable gonadotropins for women without pelvic symptoms. For symptomatic women, treatment following laparoscopy is determined by the intraoperative findings (eg, endometriosis, adhesions).

For asymptomatic women, ovulation induction with another oral agent or gonadotropin ovulation induction and IUI is offered because this approach is established in the treatment of unexplained infertility and has higher rates of conception compared with CC/IUI or aromatase inhibitors [16]. However, patients are counseled that gonadotropin/IUI also increases the rate of multiple gestations, including triplets and greater, compared with either CC or the aromatase inhibitor letrozole. (See 'Gonadotropin injections with or without IUI' below.)

●One author (WG) performs laparoscopy, rather than offering gonadotropin/IUI, as the next treatment step for women unable to pursue IVF. In the author's experience, a number of these women will have findings of endometriosis and/or adhesive disease at the time of laparoscopy, regardless of symptomatology, and surgical treatment of endometriosis has been associated with improved fertility [19]. After laparoscopy, another course of CC/IUI is initiated. In addition, gonadotropin/IUI is associated with a high rate of multiple gestation and increases the cost out of proportion to the modest improvement in outcome (live birth rate 32 percent for gonadotropin/IUI compared with 23 percent for CC/IUI) [16]. In the author's experience, some women who initially decline IVF and then fail other treatments will change their decision and pursue IVF rather than gonadotropin treatment because the live birth rate is higher with IVF compared with gonadotropins (45 versus 32 percent) [16] and the cost is similar. (See "Female infertility: Reproductive surgery" and 'In vitro fertilization' below.)

For women with unexplained infertility who do not conceive with CC/IUI, IVF, gonadotropin/IUI, or laparoscopy, alternate treatment options include ovulation induction with the aromatase inhibitor letrozole, donor-egg pregnancy, gestational surrogacy, adoption, and cessation of treatment. It should be noted that letrozole treatment for ovulation induction is an off-label use of this medication [20]. We believe that there is no single algorithm for women at this point in their treatment; the next steps are determined by the patient after extensive counseling by her fertility team. Additional discussions are available in related content.

●(See 'Aromatase inhibitors plus IUI' below.)

●(See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)

●(See "Gestational carrier pregnancy".)

●(See "Adoption".)

EXPECTANT MANAGEMENT — One to 3 percent of couples with unexplained infertility followed prospectively without active treatment become pregnant each month [21,22]. Therefore, effective fertility treatment for unexplained infertility must demonstrate an increase in the pregnancy rate above this baseline fecundability.

The age of the female partner influences the pregnancy rate associated with expectant management [23]. Women with unexplained infertility older than 37 years of age have a pregnancy rate of less than 1 percent per cycle with expectant management. In randomized trials, six months of expectant management for couples with a good prognosis for fertility (young age, no bilateral tubal disease, no sperm problems) or an intermediate prognosis (30 to 40 percent probability of pregnancy without treatment) was associated with an ongoing pregnancy rate comparable to that achieved with intrauterine insemination plus gonadotropin injections (see below) [24,25]. Thus, expectant management may be an option for a couple with unexplained infertility in whom the female partner is less than 32 years of age and there is no immediate concern about oocyte depletion. However, the ovarian oocyte pool declines rapidly for women over 37 years of age, inevitably causing ovarian aging and depletion to become a major component of the fertility problem. Thus, expectant management is not recommended for these women.

PATIENT-CONTROLLED APPROACHES

Lifestyle changes — Epidemiologic studies indicate cigarette smoking, abnormal body mass index, and excessive caffeine consumption reduce fertility in the female partner and possibly the male partner. (See "Natural fertility and impact of lifestyle factors".)

Couples with unexplained infertility should be informed of a possible relationship between cigarette smoking and their infertility and advised to stop smoking for this reason, as well as for benefits in overall health. (See "Overview of smoking cessation management in adults".)

The female partner should be counseled to try to achieve a body mass index between 20 and 27 kg/m², reduce caffeine intake to no more than approximately 250 mg daily (two cups of coffee), and reduce alcohol intake to no more than four standardized drinks per week [26]. These changes may be useful for enhancing both natural and assisted conception [27,28].

This is also an appropriate time to mention lifestyle changes for health promotion to the male partner for his general health benefits, and because the couple's coordinated efforts to modify their lifestyle may provide support and reinforcement for each other.

LOW-RESOURCE INTERVENTIONS — Couples of all ages often become frustrated with their inability to conceive. Active treatment is recommended for these couples when lifestyle interventions fail to result in pregnancy. The following interventions increase the number of gametes available in a given cycle and/or facilitate the ability of the gametes to interact. These interventions have less risk and cost compared with in vitro fertilization (IVF) procedures.

Intrauterine insemination (IUI) — For patients with unexplained infertility, IUI alone is not more likely to achieve pregnancy than expectant management [17]. However, when combined with ovarian stimulation (either clomiphene citrate or aromatase inhibitors) it is an effective treatment [9].

●Procedure – IUI consists of washing an ejaculated semen specimen to remove prostaglandins and semen proteins that would promote an allergic reaction if injected into the uterus, concentrating the sperm in a small volume of culture media, and injecting the sperm suspension directly into the upper uterine cavity using a small catheter threaded through the cervix. (See "Procedure for intrauterine insemination (IUI) using processed sperm".)

●Supporting data – The efficacy of IUI for couples with unexplained infertility was demonstrated in a large clinical trial sponsored by the National Institutes of Health (NIH) [9]. Over 900 infertile couples with unexplained infertility were randomly assigned to one of four treatment groups:

•Intracervical insemination of sperm (ICI)

•IUI of sperm

•FSH injections plus ICI

•FSH injections plus IUI

The purpose of the ICI was to act as a control treatment mimicking natural intercourse; the purpose of IUI was to place a large number of sperm high in the reproductive tract; and the purpose of FSH injections was to stimulate multiple follicular development and ovulation, thereby increasing the number of oocytes available for fertilization in a single cycle. Most of the women in this study had either unexplained infertility or early stage endometriosis.

The investigators observed a 2 percent per cycle pregnancy rate in the group that received the control ICI treatment; this pregnancy rate is similar to that achieved with expectant management. IUI treatment was associated with a 5 percent per cycle pregnancy rate; thus, in the randomized trial, IUI alone was effective, but only marginally for the treatment of unexplained infertility.

The pregnancy rates in the FSH-ICI and FSH-IUI groups were higher, and are described below. (See 'Gonadotropin injections with or without IUI' below.)

Clomiphene citrate — Clomiphene alone has been demonstrated to be effective in the treatment of infertility due to oligoanovulation or anovulation. For patients with unexplained infertility, treatment with clomiphene alone is not helpful but pairing it with IUI improves outcomes [17]. (See "Ovulation induction with clomiphene citrate".)

In a 2010 meta-analysis of randomized trials of unexplained subfertility treated with clomiphene versus placebo or no treatment, use of clomiphene alone (no IUI) did not increase the pregnancy rate per woman randomized (odds ratio [OR] 1.03, 95% CI 0.64-1.66; 2 trials, 458 participants) [29]. However, these results need to be interpreted with caution as there was significant heterogeneity between trials. In one trial, clomiphene citrate (CC) was associated with significantly more pregnancies over the course of four months, with a pregnancy rate of 19 percent versus no pregnancies with placebo [30]. A 1998 retrospective analysis of 45 published reports of treatment of unexplained infertility reported pregnancy rates of 5.6 percent with clomiphene alone versus rates of 1.3 to 4.1 percent with no treatment [31]. Based on these data, the American Society of Reproductive Medicine (ASRM) concluded that empiric use of CC with intercourse for unexplained infertility should be discouraged, but further studies are needed to provide better data on the effectiveness of this approach [32]. The ASRM Practice Committee placed significant weight on a study comparing clomiphene with expectant management and with IUI alone [33]. In this study, when multifollicular development was observed with clomiphene 50 mg, the cycle was cancelled and the subject was administered 25 mg of clomiphene for 5 days or 25 mg every other day, which is a marked variance to the standard use of clomiphene. Thus, it appears that CC use is best paired with IUI in patients with unexplained infertility. (See 'Clomiphene plus IUI' below.)

The main complication of clomiphene is an increase in the incidence of multiple gestation. This risk was illustrated in a study of 2369 clomiphene induced pregnancies that reported the incidence of twins, triplets, quadruplets, and quintuplets was 7, 0.5, 0.3, and 0.13 percent, respectively [34]. The risk of high-order multiple pregnancies with clomiphene treatment is low, but the high volume of clomiphene cycles makes this intervention an important contributor to the total number of high-order multiple gestations [35].

In comparative treatment trials, clomiphene was not as effective as gonadotropin injections [36]. (See 'Gonadotropin injections with or without IUI' below.)

Clomiphene plus IUI — CC/IUI is generally the first-line treatment for unexplained infertility because of its good clinical pregnancy rate, relatively low rate of multiple gestations, oral route of intake, lack of need for monitoring, and low cost [15,17,37]. The combination of CC (to increase the rate of double ovulation) plus IUI (to place a large number of motile sperm high in the female reproductive tract) may simultaneously treat mild abnormalities of ovulation, oocyte function, and sperm function. In trial of 900 women with unexplained infertility randomly assigned to treatment with CC, letrozole, or gonadotropin (all combined with IUI), the clinical pregnancy rates were 28 (CC), 22 (letrozole), and 36 (gonadotropin) percent [16]. However, the rates of multiple gestation were lowest for the women treated with CC/IUI (9 percent) compared with letrozole (13 percent) or gonadotropin (32 percent).

The optimal method for timing IUI is to use a commercial kit to determine daily urinary luteinizing hormone (LH) levels starting on day 10 of the cycle. IUI is performed when urinary LH is detected. This method is as effective, but less expensive, than timing based on ultrasound monitoring of folliculogenesis with human chorionic gonadotropin (hCG) injection upon development of an appropriately sized dominant follicle, followed by IUI. This approach was supported by a systematic review showing that women who underwent hCG administration before IUI had lower clinical pregnancy rates than women who underwent IUI based on detection of urinary LH (OR 0.74, 95% CI 0.57-0.96) [38]. No cost analysis was performed. The authors concluded that the available data did not demonstrate a consistent, clinically important benefit of hCG-induced ovulation compared with spontaneous ovulation for IUI timing. Although the question of whether two IUIs per cycle is superior to a single IUI is somewhat controversial, most clinicians perform a single IUI [39-43].

A retrospective multicenter cohort study of couples who underwent over 15,000 IUI cycles reported acceptable pregnancy rates after one to nine cycles [44]. In this series, 70 percent of the patients underwent both IUI and controlled ovarian stimulation (51 percent CC, 19 percent gonadotropins). The cumulative ongoing pregnancy rate after three, six, and nine cycles was 18, 30, and 41 percent, respectively. Thus, this study suggests that up to nine IUI cycles is an appropriate treatment course. By comparison, older literature showed that the vast majority of pregnancies occurred by the sixth treatment cycle, and relatively few occurred beyond six cycles. We typically administer three to four treatment cycles before moving on to another modality.

However, age should be taken into account; multiple treatment cycles are not beneficial in older women. One study showed that on a per patient treated basis, cumulative pregnancy rates by age were 24.2 percent under age 35, 18.5 percent ages 35 to 37, 15.1 percent ages 38 to 40, 7.4 percent ages 41 to 42, and 1.8 percent age above 42 (one pregnancy in 55 patients) [45]. In this study, there were no pregnancies beyond the fourth cycle in women age 41 and older.

Aromatase inhibitors plus IUI — Ovarian stimulation with aromatase inhibitors (AIs) plus IUI may result in pregnancy for women with unexplained infertility who do not respond to CC plus IUI and who cannot or choose not to use IVF or gonadotropin therapy. AIs have similar clinical pregnancy, multiple gestation, and live birth rates compared with CC [16,46,47], and they are easier to use (oral dosing, no monitoring required) and less expensive compared with injectable gonadotropin therapy. Although AIs are associated with a lower clinical pregnancy rate compared with gonadotropin treatment, AIs are also associated with a lower rate of multiple gestations, including a much lower rate of triplet pregnancy. Therefore, when other treatment options do not result in pregnancy, AI treatment is a reasonable option. It should be noted that AI therapy for ovulation induction is an off-label use of this medication. (See "Ovulation induction with letrozole".)

Support for this approach comes from a trial of 900 women, 18 to 40 years of age with unexplained infertility, who were randomly assigned to receive the AI letrozole, CC, or gonadotropin for ovulation induction in addition to timed IUI [16]. The overall live birth rates were 19 percent for the letrozole group, 23 percent for the CC group, and 32 percent for the gonadotropin group. While the birth rate was highest for women receiving gonadotropin, these women also had the highest rate of multiple births, including triplets. Multiple gestations occurred in 13 percent of the gonadotropin group, 1 percent of the CC group, and 3 percent of the letrozole group. For women receiving gonadotropin treatment, approximately 30 percent of the multiple pregnancies were triplet pregnancies. In contrast, the women receiving letrozole and CC who conceived multiple gestations had only twin pregnancies; no triplet pregnancies occurred.

Lastly, theoretical concerns that aromatase inhibitors may be teratogenic have not been supported in large trials [16,48] and a large retrospective study [49]. In the trial reviewed above, the number of infants born with congenital malformations was similar across the three treatment groups (4 percent for clomiphene, 4 percent for letrozole, and 3 percent for gonadotropin) and similar to the anticipated baseline risk of major congenital malformations, which is 3 to 4 percent [16]. (See "Ovulation induction with letrozole", section on 'Fetal safety'.)

HIGH-RESOURCE INTERVENTIONS

Gonadotropin injections with or without IUI — In general, due to the increased risk of multiple gestations associated with gonadotropin ovulation induction/intrauterine insemination (IUI) and the increased efficacy of in vitro fertilization (IVF) compared with ovulation induction, we favor IVF rather than gonadotropin/IUI for women in whom clomiphene citrate/IUI has failed [17,50-52]. In a meta-analysis of eight trials comparing gonadotropins versus oral agents with IUI for patients with unexplained infertility, gonadotropin use did not result in improved live birth rates [52]. To gain additional live births, high doses of gonadotropins with more relaxed cancellation protocols were required, which resulted in a higher risk of multiple gestation. While the lower gonadotropin dose was no better than the oral agents, with higher doses, 13 cycles were needed to treat to exceed the oral medications, but only 7 were needed to harm patients with multiple gestations. Thus, the data do not support the use of gonadotropins with IUI in patients with unexplained infertility.

In vitro fertilization — IVF is the intervention that results in the highest per cycle pregnancy rate in the shortest time interval. It is also the most costly intervention and has a high rate of high order multiple pregnancy, unless single embryo transfer is performed [53]. In a 2012 Cochrane review of randomized trials examining the effectiveness of IVF against other treatment options in couples with unexplained infertility, live birth rates were significantly higher with IVF than with expectant management (45.8 versus 3.7 percent; 1 trial of 51 women), but comparisons with active treatments were either not available or unable to detect moderate differences in live birth rates because the studies were small and heterogeneous [54]. In a subsequent trial that randomized 154 couples with ≥6 months of unexplained infertility and female partner aged 38 to 42 years to two cycles of clomiphene/IUI, two cycles of gonadotropin injections/IUI, or immediate IVF, live birth rates were: 8, 7, and 16 percent, respectively [55]. Overall, 84 percent of all pregnancies resulted from IVF. Thus, in this age group the best outcome is achieved with immediate IVF. However, an IVF cycle is several times more expensive than a clomiphene/IUI or a gonadotropin/IUI cycle.

The utility of a step-wise protocol was illustrated by a cohort study of couples with unexplained infertility in which the woman was initially treated with gonadotropin injections plus IUI for up to three cycles and then IVF was used to treat those who did not conceive [56]. The pregnancy rate with gonadotropin injections plus IUI was 15.7 percent per cycle and 29.8 percent per patient and the pregnancy rate in those who went on to IVF was 36.7 percent. (See "In vitro fertilization: Overview of clinical issues and questions".)

ALTERNATIVE TO IN VITRO FERTILIZATION — For women with unexplained infertility who do not pursue in vitro fertilization due to cost or other reasons, we typically offer laparoscopy as the next step after ovulation induction. Laparoscopy provides visualization of the pelvis, can identify causes for infertility and failed therapy, and allows for surgical intervention. Surgical treatment of conditions such as endometriosis or pelvic adhesions can improve fertility.

INEFFECTIVE TREATMENTS — Clinical trials of the treatment of unexplained infertility have shown that administration of either bromocriptine or danazol was not effective [57,58].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Male infertility (The Basics)" and "Patient education: Female infertility (The Basics)")

●Beyond the Basics topics (see "Patient education: Evaluation of infertility in couples (Beyond the Basics)" and "Patient education: Treatment of male infertility (Beyond the Basics)" and "Patient education: Ovulation induction with clomiphene or letrozole (Beyond the Basics)" and "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Unexplained infertility refers to the absence of a definable cause for a couple's failure to achieve pregnancy after 12 months of attempting conception (six months in women 35 years and older) despite a thorough evaluation. (See 'Definition and diagnosis' above.)

●Contributing etiologies – The infertility is probably due to subtle functional abnormalities in oocyte, sperm or endometrial function. (See 'Possible etiologies' above.)

●Approach – The management of couples with unexplained infertility usually starts with treatments that consume few resources, are low risk, and are patient directed (eg, lifestyle changes), and then moves sequentially to treatments requiring proportionately greater resources and risks (clomiphene or letrozole plus intrauterine insemination [IUI]), and finally to higher risk and high resource intensive interventions (in vitro fertilization [IVF], laparoscopy) (table 1). (See 'Our approach' above.)

•Lifestyle interventions – Lifestyle changes, such as discontinuing cigarette smoking and achieving a normal weight may increase fertility in women with unexplained infertility. (See 'Lifestyle changes' above.)

•Expectant management – Approximately 1 percent of couples with unexplained infertility will become pregnant per cycle with no intervention. Expectant management is a more appropriate option for couples in which the female partner is young (<32 years of age) than for couples with older female partners. For women >37 years of age, the ovarian follicular pool can become depleted during expectant management, resulting in untreatable infertility. (See 'Low-resource interventions' above.)

●Treatment options

•Ovulation induction – For treatment of women with unexplained infertility, we suggest three to four cycles of clomiphene citrate (CC) or letrozole plus IUI for initial therapy rather than gonadotropin injections with IUI or IVF (Grade 2B). CC/IUI is generally the first-line treatment for unexplained infertility because of its good clinical pregnancy rate, relatively low rate of multiple gestations, oral route of intake, lack of need for monitoring, and low cost. (See 'Clomiphene plus IUI' above.)

•In vitro fertilization (IVF) – For women who do not conceive with CC, AI, and IUI, we suggest IVF as the next step rather than gonadotropin therapy (Grade 2A). IVF results in the highest per-cycle pregnancy rate in the shortest time interval. Limitations of IVF include high cost and high rates of multiple gestations, unless single embryo transfer is used. (See 'In vitro fertilization' above.)

-IVF is the intervention that will result in the highest per-cycle pregnancy rate in the shortest time interval. It is also the most costly intervention and has a high rate of high-order multiple pregnancy unless single embryo transfer is performed. (See 'In vitro fertilization' above.)

•If IVF is not an option – For women who do not conceive with CC or AI/IUI and for whom IVF is not an option, the choice and order of treatment steps vary by author. (See 'Our approach' above.)

-The section editor and one author (MH) offer laparoscopy for women with pelvic symptoms or ovulation induction with a second oral agent or gonadotropins for asymptomatic women. For symptomatic women, treatment following laparoscopy is determined by the intraoperative findings. Gonadotropin ovulation induction and IUI are used for asymptomatic women because they are established in the treatment of unexplained infertility and have higher rates of conception compared with CC/IUI or aromatase inhibitors, although they also result in greater rates of multiple gestations, including triplet pregnancies and higher. (See 'Our approach' above and 'Gonadotropin injections with or without IUI' above.)

-One author (WG) performs laparoscopy, rather than gonadotropin/IUI, as the next treatment step because a number of these women will have findings of endometriosis and/or adhesive disease, regardless of symptoms, and surgical treatment of endometriosis is associated with improved fertility rates but does not increase the risk of multiple gestation. After laparoscopy another course of CC/IUI is initiated. (See 'Our approach' above.)

●Additional options – For women with unexplained infertility who do not conceive with CC or AI/IUI, IVF, gonadotropin/IUI, or laparoscopy, alternate treatment options include ovulation induction with the aromatase inhibitor letrozole, donor-egg pregnancy, gestational surrogacy, adoption, and cessation of treatment. Letrozole treatment for ovulation induction is an off-label use of this medication. At this point in treatment, the next step is determined by the patient after extensive counseling with her fertility team. (See 'Our approach' above.)