1. Introduction
2. The Diagnosis of Unexplained Infertility
3. Controversial Issues in Infertility Testing: Validity and Clinical Utility
   1. Laparoscopy
   2. PCT
   3. Antisperm Antibody Testing
4. More Advanced Tests for Infertility
   1. Tests Evaluating Endometrial Function
   2. Tests of Ovarian Reserve (Day 3 FSH or CCCT)
5. Management of Unexplained Infertility
   1. Expectant Management
   2. Options for Active Management
      1. Ovulation Induction Without IUI
         1. CC
         2. hMG
      2. Intrauterine Insemination With and Without Ovulatory Agents
         1. IUI
         2. CC/IUI
         3. hMG/IUI
      3. IVF
         1. IVF vs. Expectant Management
         2. IVF vs. IUI Alone or CC/IUI
         3. GIFT vs. hMG/IUI
         4. IVF or hMG/IUI vs. Expectant Management
         5. IVF vs. GIFT
         6. Summary of IVF data
         7. Fertilization Failure
      4. FSP
      5. Tubal Flushing
      6. Alternative Medical Therapies
6. Obstetric Outcome
7. Conclusion

INTRODUCTION

Unexplained infertility is the diagnosis of exclusion given to infertile couples who have had a complete infertility evaluation with no abnormal findings. The reported prevalence of unexplained infertility ranges from 6-58%¹ with the average incidence being reported as 15%.² This variation in the reported prevalence is mostly attributed to the differences in the definition of unexplained infertility used by medical professionals, the evaluation process that is considered "complete", and the interpretation of test results.

Thus far, there is no agreement in the medical community regarding which tests make up a standard infertility evaluation nor are there standard protocols for management of unexplained infertility. Differences in the interpretation of research data, in addition to the lack of prospective randomized trials, account for this variability in the diagnosis and treatment of unexplained infertility. This chapter will present the best available clinical evidence regarding the diagnosis and treatment of unexplained infertility.

THE DIAGNOSIS OF UNEXPLAINED INFERTILITY

In order to make the diagnosis of unexplained infertility, a complete infertility evaluation should be performed. There are multiple tests available for determining the cause of infertility; however, there is no consensus on which tests are essential before reaching the diagnosis of "unexplained" infertility.

Classically, infertility testing has included a semen analysis (SA), postcoital test (PCT), an assessment of ovulation, a hysterosalpingogram (HSG), antisperm antibody testing, and a laparoscopy.3 More recently the widespread use of all these tests has fallen out of favor, mostly because of the lack of clinical evidence to support their continued use. In 1992 the American Fertility Society (now known as American Society for Reproductive Medicine - ASRM) and the World Health Organization (WHO) recommended that infertile women be evaluated in five areas. These organizations described the complete basic workup as 1) a semen analysis, 2) assessment of ovulation, 3) evaluation of the uterine cavity and tubes, 4) the postcoital test, and 5) a laparoscopy (Table 1). ⁴ In the same year ESHRE (European Society of Human Reproduction and Embryology) grouped the basic infertility tests into three categories (Table 2). ESHRE's groups for infertility testing are based on the prognostic utility of these tests. ⁵ The ESHRE classification was updated in 1996 and 2000. ^6,7 For the purpose of this chapter the basic workup will be defined minimally as a good history and physical, HSG, SA and documentation of ovulation, unless otherwise specified. Only studies that used this evaluation as the minimum for basic infertility testing to diagnose patients with unexplained infertility will be discussed unless otherwise noted.

CONTROVERSIAL ISSUES IN INFERTILITY TESTING: VALIDITY AND CLINICAL UTILITY

Even among large organizations there is significant variability in the tests defined as part of a basic infertility workup. The role and importance of the PCT, antisperm antibodies and laparoscopy as a mandatory part of the basic infertility workup is controversial.

Laparoscopy

Pelvic pathology of the female reproductive tract is often a cause of infertility. Complete evaluation for the presence of adhesions and endometriosis involves invasive surgical techniques. Laparoscopy has traditionally been included as a mandatory step in the basic infertility evaluation to rule out pelvic disease. In an evaluation of 24 cases of "unexplained infertility", Drake et. al. found abnormal laparoscopic findings in 75% of patients (46% had endometriosis, 29% peritubal adhesions). In 1977, these authors concluded that the laparoscopy should be a mandatory step in an otherwise negative workup for infertility. ⁸ Since that time, laparoscopy has been traditionally considered an important diagnostic procedure in the evaluation of the infertile couple and considered complementary to the HSG. The superiority of laparoscopy over the HSG has been demonstrated in many studies for evaluating peritubal adhesions and endometriosis. ^4,9,10 However, in light of a normal HSG, the "mandatory" need for laparoscopy has been recently questioned by fertility specialists. ^5,6,11 It has been estimated that using laparoscopy as a standard test of tubal function would reduce the incidence of unexplained infertility from 10 to 3.5%.⁸ Gleicher argued that in the cases of a negative history for pelvic disease, normal exam, and normal HSG, that the probability of finding clinically relevant disease was low. ¹² He additionally stated that in order to perform a cost effective evaluation, gynecologists should perform laparoscopies on an as needed basis. Fatum et. al. agreed with Dr. Gliecher's opinion¹³ and went on to state that in patients with unexplained infertility and a negative history for pelvic disease they should be offered three to six cycles of ovulation induction with IUI as the next course of therapy rather than a laparoscopy.

It is now typical that infertility specialists will take a detailed history (question the patient for evidence of PID, STD's, dyspareunia, and dysmenorrhea), perform a detailed exam using the single digit technique described by Ripps et. al. ^{14, 15} and perform an HSG. If the history and testing are normal, most reproductive endocrinologists will forgo the laparoscopy and proceed with ovarian hyperstimulation with IUI.

Postcoital Test (PCT)

The postcoital test has been considered part of the basic infertility workup for over 100 years. ¹⁶ For several years now the role of PCT has been widely questioned. In fact, ASRM considers the PCT part of the standard infertility evaluation, but ESHRE considers the PCT a category 2 test (not consistently correlated with pregnancy, see Tables 1 and 2). Its utility has been limited by the fact that there is no universally agreed upon normal values and there are significant controversies around treatment protocols for abnormal results. In a review of the literature evaluating the benefit of the PCT, many of the studies validating its use have design flaws. These flaws include the use of infertile couples with various infertility diagnoses, no attempt to correlate the PCT results with subsequent pregnancy rates, and the failure to compare PCT results between fertile and infertile populations.^1,16-20 Despite these problems, a few studies warrant mentioning.^{1,16,17,19,20,21} In a study by Collins et. al., the authors found no differences in subsequent pregnancy rates among groups undergoing a PCT having no sperm, no motile sperm, one to five motile sperm, six to ten motile sperm, and eleven motile sperm per HPF on the PCT.²¹ These results question the utility of the PCT in predicting infertility and subsequent pregnancy rates. In a study evaluating only fertile couples, Kovacs et. al. found that 20% of fertile couples had either no sperm or less than one sperm per HPF on the PCT. This is about the same incidence of abnormal PCT that is found in the infertile population.¹⁷ These results further question the prognostic ability of the PCT. However, as shown in Table 3, significant differences in pregnancy rates were noted between the patients with normal PCT and abnormal PCT results. Additionally, it is important to note that the results of the PCT seldom make a difference in the clinical management of the infertile couple. Many physicians feel that the widespread use of intrauterine inseminations has made the PCT merely an academic exercise, because the treatment of the infertile couple is the same regardless of the results of the PCT. The above findings make it difficult to justify the PCT as an essential part of an infertility evaluation.

Antisperm Antibody Testing

Numerous methods are available to detect sperm antibodies. The mixed antiglobulin reaction (MAR) and the immunobead test are the two most commonly used methods. Both of these assays allow for direct assessment of antibody interaction with sperm surface antigens.

The sperm MAR is performed by mixing semen, human IgG coated latex particles, and IgG antiserum on a microscope slide. If antibodies are present on the sperm, the latex particles will bind to the sperm and the antisera and cause clumping. The immunobead test uses latex beads coated with antibodies against human IgG, IgM, and IgA. For the direct assay, washed sperm are mixed with beads on a glass slide. Results are recorded according to type of immunoglobulin bound and the location of the bead binding. The immunobead test can also be used to "indirectly" test serum, seminal plasma, follicular fluid, or cervical mucus for the presence of antibodies.

The WHO laboratory manual states that the immunobead test is considered positive when 20% or more of motile sperm are bound, with >50% sperm binding considered to be clinically significant.²² Additionally, the location of the immunobead binding has been shown to reflect sperm function in vitro. Antibodies that bind to the head region may interfere with gamete interaction. Immunobead binding restricted to the tail tip is not considered clinically significant.

Approximately 10% of male partners in infertile couples will have some degree of autoimmunity to sperm surface antigens.^{23, 24} Haas et. al.²⁵ evaluated sera from 624 men and women with unexplained infertility and has found that 7% of men had antisperm antibodies.

Review of retrospective and prospective analyses of pregnancy rates for couples with sperm antibodies questions the prognostic value of antisperm antibody screening for the diagnosis of infertility. Some studies have reported a significant association between antibody presence in male partners and spontaneous pregnancy rates, whereas others have not found an effect of antibodies on pregnancy rates.^25-30 The inconclusive and inconsistent results of these studies can be attributed to the presence of heterogeneous antibodies, the varying degree of their ability to impair fertility, as well as varying antibody titers.^23-30 It is now recognized that not all sperm antibodies impair fertilization. In addition, low levels of sperm antibodies have been shown to have poor prognostic value in predicting fertility.²⁹ Therefore, diagnosing someone as having antisperm antibodies in general does not have a clear prognostic significance.

Testing for sperm antibodies may help to explain the cause of infertility in some men, particularly those who have had vasectomy reversals, testicular trauma, or surgery. The results of the testing, however, seldom make a difference in the clinical management of the couple. The reason is that sperm antibodies may result in a state of subfertility, but rarely produce absolute infertility in couples. In addition, there are no proven treatments for this condition. Immunosuppressive therapy with corticosteroids has been suggested as treatment for men with antibodies. Whether fertility is improved by this method is unclear.³⁰ Washing sperm to get rid of antibodies is usually unsuccessful because of the high affinity of the antibody-antigen bond, although washing may prevent sperm agglutination. Most clinicians empirically use assisted reproductive procedures including IUI and IVF for treating couples with antisperm antibodies. Therefore, treatment options are the same as those for couples with otherwise unexplained infertility. In other words, the test outcome does not often change the recommended therapy. The prognosis for couples with these treatments (IUI and IVF) does not seem to be altered by the presence of sperm antibodies.³⁰

MORE ADVANCED TESTS FOR INFERTILITY

Various markers of subfertility have been described in the literature, some of which may be used in clinical practice. Over the past decade there has been great interest in the evaluation of embryo implantation and ovarian reserve. Subtle changes in the oocyte quality (as reflected by ovarian reserve) or the endometrium may be the cause of "unexplained" infertility.

Tests Evaluating Endometrial Function

Li et. al. examined the endometrial expression of HOXA-10 gene in normal fertile women and in women with unexplained infertility.³¹ These authors found a higher incidence of aberrant HOXA-10 expression in patients with unexplained infertility. The study suggested that altered development of the endometrium at a molecular level may contribute to the etiology of infertility.

A second study evaluating the role of the endometrium in unexplained infertility was described by Lessey and colleagues.³² These authors compared in phase and out of phase biopsies plus β-3 integrin levels in the endometrium of fertile control women to women with unexplained infertility. These authors found a significant reduction in β-3 integrins in the unexplained infertility group. It is important to note that both those infertile women with out of phase and in phase biopsies demonstrated this abnormal pattern of β-3 expression. It was also noted by these authors that atypical endometriosis was noted more frequently in women with in phase endometrium who lacked β-3 integrins.³²

Tests of Ovarian Reserve (Day 3 FSH or CCCT)

Some form of ovarian reserve screening has been a part of the patient evaluation for most patients with infertility since the description of the benefit of a day three FSH in predicting IVF success.³³ Although most women with abnormal ovarian function could be identified by a cycle day three FSH and estradiol alone, the use of the Clomiphene Citrate Challenge Test (CCCT) has improved the ability to detect patients with subtle ovarian dysfunction.

Ovarian reserve screening using the clomiphene citrate challenge test (CCCT) was first described by Navot et. al. in 1987³⁴ as a means to assess pregnancy potential. Since its original description, numerous studies have validated its use.^33-36 The CCCT has been used to predict which patients will respond poorly to gonadotropin stimulation for IUI or IVF cycles. In general, about 10% of infertile women will have an abnormal CCCT. As expected only 3% of women under 30 years of age and 26% of women 40 years of age or older will have an abnormal CCCT. Interestingly, 38% of women with unexplained infertility (basic workup plus a PCT, prolactin level, TSH, evaluation for luteal phase defects, and laparoscopy) were found to have an abnormal CCCT result.³⁶ Scott et. al. in his prospective analysis of the CCCT, concluded that significantly more women with the diagnosis of unexplained infertility and a normal CCCT became pregnant than women with unexplained infertility and an abnormal CCCT. Therefore, a CCCT may help predict which patients with unexplained infertility will respond to therapy.³⁶

MANAGEMENT OF UNEXPLAINED INFERTILITY

Unexplained infertility is a common clinical problem for which there is no standard treatment protocol. Very few randomized clinical trials are available to assess the benefit of treatment and treatment plans are often empiric. The definition of unexplained infertility, investigation protocols, and inclusion criteria vary among clinical trials in patients with unexplained infertility. Some studies include only patients under 38 years of age while other studies did not report age limits.³⁷ Some studies include couples with mild male factor infertility^84,85 and minimal endometriosis.^37-39 This variability amongst studies makes it difficulty to interpret data, and therefore most of the data presented will be limited by small sample size.

Expectant Management

Spontaneous conception in couples with unexplained infertility is well documented.^40-44 A cumulative live birth rate of 33% at 36 months was estimated from a Canadian study⁴⁵ and a study performed in the Netherlands suggested a live birth rate of 60% at 36 months without treatment.⁴⁶ The reported cumulative pregnancy rate without treatment varies in the literature and is based on the length of infertility, age of the female partner, and whether this is primary or secondary infertility.

Lenton and colleagues studied 80 untreated couples with primary unexplained infertility of at least two years duration.⁴² These authors found that after a basic evaluation (plus a laparoscopy with no abnormal findings) 43% of couples conceived before the study was completed. The maximum study length was eight years. Conceptions occurred at a rate of about 10% per year for the first two years then 5% per year after that. Women with secondary infertility seemed to fare better with a cumulative pregnancy rate of 89% after seven years of study. In patients with secondary infertility, there was a spontaneous pregnancy rate of 18% per year for the first five years then 10% per year, thereafter.⁴²

Age of the female partner also plays a role in predicting the spontaneous pregnancy rates in patients with unexplained infertility. In a multi-center trial of 470 couples with unexplained infertility (diagnosis made by basic evaluation plus laparoscopy), the authors found that the age of the infertile female and length of infertility affected the prognosis.⁴⁰ In this multi-center evaluation the average age of those obtaining pregnancy was 29.5 years and those not obtaining pregnancy was 30.4 years. The cumulative pregnancy rate was 42% in women <30 years of age and 31% in women >30 years of age. In this study the authors noted that if the duration of infertility was <36 months the pregnancy rate was 46% over the next seven years compared to 27% in couples with greater than 36 months of infertility.⁴⁰

Options for the Active Management of Unexplained Infertility

Obviously, the exact etiology of unexplained infertility remains unknown. Unexplained infertility most likely represents a broad range of defects in folliculogenesis, gamete development, fertilization, or embryo implantation. Due to the decreased reproductive capacity in couples with unexplained infertility, options to increase the number of gametes available for fertilization have been considered good treatment options.

A number of studies have sought to evaluate the use of ovulation induction with or without IUI in the treatment of unexplained infertility. The majority of these studies were not randomized. Below is a summary of the current data available on the use of ovulation induction with or without IUI for the treatment of unexplained infertility.

Ovulation Induction Without Intrauterine Insemination (IUI)

Clomiphene Citrate Without IUI: Several trials have been published evaluating the benefit of clomiphene citrate (CC) in the treatment of unexplained infertility.^38,47-52 Fisch et. al. evaluated the use of CC, human chorionic gonadotropin (hCG), and intercourse in the treatment of primary unexplained infertility.⁵¹ These authors found a significant improvement in pregnancy rates in 36 patients in their randomized trial. It is important to note in this trial that there were no pregnancies in the control (placebo) group. Hughes et. al. in a review of the literature⁴⁷ found that CC alone was slightly superior to no treatment in patients with unexplained infertility. The absolute treatment effect was small and may not be clinically significant. However, when counseling patients regarding the effectiveness of clomiphene, it is important to remember that the baseline cycle fecundity is 1-2% for patients with unexplained infertility without therapy, and the cycle fecundity with CC/intercourse would be enhanced to 2%.^48,50 This low pregnancy rate will dramatically limit the role of CC/intercourse in the treatment of unexplained infertility.

Human Menopausal Gonadotropins (HMG) Without IUI: Gonadotropins have been used for years for the treatment of unexplained infertility.⁵³ It is felt that ovarian stimulation increases the number of preovulatory follicles and it may correct subtle ovulatory dysfunction. In a randomized control trial of various therapies for the treatment of unexplained infertility, Guzick et. al. reported a pregnancy rate of 7.7% per cycle in the HMG/intercourse group, compared to a 17.1% rate in HMG/IUI groups. The lower pregnancy rate in the HMG alone group suggests that IUI may be beneficial for patients with unexplained infertility.⁴⁸

Intrauterine Insemination With or Without Ovulatory Agents

IUI Alone: For many years IUI has been widely used for a treatment option for couples with unexplained infertility. Its effectiveness has been heavily debated. In natural cycles (without the use of ovulation induction agents), it has been reported that IUI does not improve the probability of conception in patients with unexplained infertility when compared to timed intercourse.⁵⁴ It is therefore not a good treatment option for couples with unexplained infertility.

CC/IUI: Although IUI alone does not improve pregnancy rates when controlled ovarian hyperstimulation (COH) is added to the protocol, it appears to significantly improve the chance of conception.⁴⁸ Arici et. al. compared CC/hCG/IUI with spontaneous unstimulated cycle/ovulation predictor kit timed IUI. These authors found a twofold increase in pregnancy rates with the addition of CC.⁴⁹ Deaton et. al. in a randomized controlled trial treated patients with unexplained infertility or surgically treated endometriosis. This study utilized CC, 50 mg, utilized hCG when the lead follicle was 18 mm followed by IUI at 36 hours after hCG. These authors reported a significant benefit to CC/IUI. In the 148 CC/IUI treated cycles, the cycle fecundity was 9.5% compared to 3.3% in 150 untreated couples. ³⁸ Martinez and colleagues in a randomized prospective fashion compared four different treatment protocols for patients with unexplained infertility. The groups were 1) CC with an LH kit timed IUI, 2) CC with timed intercourse, 3) IUI in a spontaneous unstimulated cycle, and 4) timed intercourse (control). Cycle fecundity was 14% in the CC/IUI group, 3% in CC/intercourse group, 9% in the IUI group, and 0% in the control group. These authors confirmed the findings that CC/IUI improved pregnancy rates over CC or IUI alone. ⁵⁰ In a review of the subject it appears that patients with unexplained infertility undergoing CC/IUI therapy should be quoted an approximate pregnancy rate of 8-12% per cycle.

It is important to note that the age of the patient may play a role in the success of CC/IUI therapy. Agarwal et. al. found a significantly lower pregnancy rate per cycle in women over the age of 35 utilizing CC/IUI therapy. Additionally, this study also found that 96% of pregnancies occurred in the first four cycles (up to six cycles were studied), therefore CC/IUI should be limited to four cycles.⁵⁵

An important study to mention when discussing CC/IUI therapy is a study by Deaton et. al. These authors compared the pregnancy rate in patients treated with CC and IUI. This study evaluated the difference between using LH testing (ovulation predictor kit) and ultrasound monitoring with hCG to time the insemination. There was no difference in the pregnancy rate between these two groups.⁵⁶ Therefore, it may be more cost effective and less invasive to utilize LH testing to time inseminations in this group of patients.

Gonadotropins with IUI: Many reports in the literature support the effectiveness of hMG/IUI in the treatment of unexplained infertility.^57-59 Unfortunately, most of the studies evaluating the benefit are uncontrolled and retrospective.

Simon et. al. treated 87 couples with unexplained infertility and reported a cumulative pregnancy rate of 34% after 446 total cycles.⁵⁷ Nulsen and colleagues performed a randomized study comparing IUI in a natural cycle timed by LH kit with hMG/IUI in 119 couples. They found a cycle fecundity rate of 19.3% for couples with unexplained infertility treated with hMG/IUI compared to 2.4% in those treated with IUI alone.⁵⁶ In an uncontrolled study by Dodson et. al., the authors reported a 19% pregnancy rate per cycle in patients with unexplained infertility utilizing hMG/IUI therapy.⁵⁹ In a retrospective analysis of patients with unexplained infertility of greater than four years duration, Aboulghar et. al. found significant improvement in cumulative pregnancy rates with hMG/IUI therapy. In this review patients were treated with hMG/IUI for one to three cycles. There were 268 couples undergoing 463 hMG/IUI cycles, compared to 112 couples who did not have treatment. Cycle fecundity in the hMG/IUI group was 20%, with a cumulative pregnancy rate of 34.7%. This rate was significantly higher than the 8.9% cumulative pregnancy rate in the untreated group.⁶⁰

Interestingly, there are two large studies comparing the use of hMG/IUI to a GnRH-agonist (GnRH-a) down-regulated hMG/IUI cycle in patients with infertility.^61,62 In a retrospective study by Gagliardi and colleagues, the authors found a higher pregnancy rate in the GnRH down-regulated group. However, Manzi et. al. in a randomized prospective trial found similar pregnancy rates between these groups but a significantly higher live birth rate in the GnRH down-regulated group.⁶² The findings by Manzi et. al. were confirmed by other studies.^59,60,61 It may be that for select populations with subtle ovulatory defects there may be an advantage to the addition of the GnRH-agonist to improve the live birth rate.^62,66

In Vitro Fertilization (IVF)

IVF is a widely used treatment for unexplained infertility. With the increasing awareness of the role of expectant management and the benefits of less invasive procedures (IUI) it is extremely important to evaluate the role of IVF in the treatment of couples with unexplained infertility. Despite being empirical and expensive, IVF is considered to be an effective treatment option. IVF may also play a diagnostic role in couples with unexplained infertility by recognizing fertilization failure and poor embryo quality.

IVF vs. Expectant Management: In a study by Soliman et. al. the authors evaluated the pregnancy rate from a single cycle of IVF with expectant management of six months duration in patients with unexplained infertility.⁶⁷ These authors found that the pregnancy rate for expectant management was slightly higher than a single IVF cycle; however, these rates were not significantly different. This study is limited by its small sample size (N=14 expectant management, N=21 IVF). Additionally, since the time of this study (over 10 years ago) IVF pregnancy rates have dramatically improved. The lack of statistical difference may not currently be true with the current IVF success rates.

IVF vs. IUI alone or COH/IUI: Goverde et. al. compared the use of IVF to IUI and COH/IUI in couples with unexplained infertility.³⁷ This study included patients with minimal endometriosis and mild male factor infertility. The age of the female partner in this prospective trial was not discussed. These authors found no significant differences in the cumulative live birth rate per couple after 6 months between these three treatment options, although the pregnancy rate per cycle was significantly higher in the IVF group than the IUI or COH/IUI groups (12.2% vs. 7.4% vs. 8.7%, respectively). This was most likely due to the fact that couples in the IVF group were more likely to abandon treatment before six cycles (42% dropout rate vs. 15% and 16%, respectively for the IUI and COH/IUI groups) when compared to the IUI groups. Therefore, at the end of six months, regardless of the number of cycles of therapy completed, the cumulative pregnancy rates were similar between groups. It is important to note, however, that the cost per pregnancy was significantly lower in the IUI groups (IVF $14,679 vs. IUI $4,511-$5,710). This study was also limited by its small sample size (54 couples IUI and 59 couples IVF).

GIFT vs. hMG/IUI for Unexplained Infertility: There are six trials that evaluate GIFT vs. hMG/IUI in the treatment of unexplained infertility. It should be noted that none of these studies have sufficient power or confidence.^68-71 The authors presenting this data from these articles, however, suggest that there is no difference in pregnancy rate per couple between these two options.

IVF or hMG/IUI vs. Expectant Management: In a meta-analysis of 22 reported studies on hMG/IUI and IVF, Peterson et. al. found higher pregnancy rates in the treated groups when compared to expectant management.⁷²

IVF vs. GIFT: Tanbo et. al. compared pregnancy rates in women with unexplained infertility using GIFT vs. IVF. Tanbo found a significantly higher pregnancy rate with IVF compared to GIFT.³⁹ Tanbo et. al. also included patients with mild male factor infertility and minimal endometriosis. Other studies^68,70 have not shown this benefit, but the authors of these studies favored IVF as it is the least invasive of the two procedures.⁷³ Therefore, it seems that GIFT has a limited role in the treatment of unexplained infertility.

Summary of IVF Data: Probably the best review of the efficacy and cost effectiveness of the various therapies was published by the members of the Reproductive Medicine Network in 1998. In a retrospective analysis of 45 studies on the subject, these authors found a pregnancy rate per initiated cycle of 1.3-4.1% with no treatment, 3.8% with IUI alone, 5.6% with CC and intercourse, 8.3% with CC/IUI, 7.7% with hMG intercourse, 17.1% with hMG/IUI, 20.7% with IVF, and 27% with GIFT. These authors concluded that CC/IUI is a cost effective first line treatment for unexplained infertility and, if this treatment fails to result in pregnancy, patients should be offered hMG/IUI.⁴⁸

The existing data appear insufficient to suggest that IVF is more effective than other treatment options available for unexplained infertility. Adverse events such as OHSS and multiple pregnancy, in addition to cost, must be taken into consideration when IVF is considered as a treatment option. Until further evidence is available, IVF should not be considered a first line treatment option in patients with unexplained infertility, and should be reserved for those who fail COH with IUI.

Fertilization Failure In Unexplained Infertility: Fertilization failure or lower than expected fertilization rates at the time of IVF as a cause of infertility has been well documented in couples with unexplained infertility.^74-77 Despite the lower than normal fertilization rates, cleavage rates and implantation rates are similar.^76,77 In a well controlled prospective study of this subject, Aboulghar et. al.⁷⁶ performed IVF and ICSI on sibling oocytes of 22 patients with unexplained infertility. There was a total failure of fertilization in the IVF group in 5 of 22 patients (22.7%) and in 0% in the ICSI group. Gurgan et. al. confirmed this finding in his study of 157 IVF cycles⁷⁷ with failure of fertilization in 11.4% of couples with no failure of fertilization with ICSI. Patients with unexplained infertility who are proceeding to IVF should be counseled about the benefits of ICSI.

Fallopian Tube Sperm Perfusion (FSP)

Fallopian tube sperm perfusion is described as another method of intrauterine insemination.⁷⁸ With FSP a large volume of sperm suspension (4 ml) is injected to reach the tubes via the cervix by transcervical insemination. Several studies have reported higher pregnancy rates with this technique compared to the traditional IUI.^78-81 In a prospective randomized study Mamas, demonstrated a cycle fecundity of 12% with hMG/traditional IUI compared to 26% with hMG/FSP.⁷⁴ Trout and Kemmann confirmed these results.⁸⁰ However, it is important to note that there are several prospective randomized trials that show no benefit to FSP when compared to traditional IUI.^81,82 Secondary to this, most infertility programs still perform the traditional IUI.

Tubal Flushing

Couples with the diagnosis of unexplained infertility may benefit from a "tubal flushing" procedure. In an evaluation of this technique by Nugent et. al. the authors randomized couples to tubal flushing with an oil soluble media (lipiodol) or no therapy. There was a significantly higher pregnancy rate in the lipiodol group.⁸³ It has been well established in the past that the use of an oil-based media for HSG improves pregnancy rates post-procedure for patients with normal fallopian tubes.⁸⁴ The risks associated with using an oil-based media led to the abandonment of this therapy by most practitioners.

Alternative Medical Therapies

Many different medical therapies have been studied for the treatment of unexplained infertility, the majority of which lack sufficient evidence to support their use. The use of bromocriptine has been studied and has not been shown to improve pregnancy rates in women with unexplained infertility.⁸⁵ Similarly, Danazol has been evaluated. A Cochrane review of the studies examining the benefit of Danazol in the treatment of unexplained infertility, showed no benefit.⁸⁶

OBSTETRIC OUTCOME

Infertility and the use of assisted reproductive techniques has been thought to increase the risk of poor pregnancy outcome.^87,88 This is especially true when multiple pregnancies are factored in. In some poorly controlled studies evaluating women with unexplained infertility treated with assisted reproduction, it was found that women with unexplained infertility had a higher risk of intrauterine growth retardation (IUGR)⁸⁷ and low birth weight⁸⁸ when compared to fertile controls or women with unexplained infertility conceiving spontaneously. Some have guessed that infertility treatment may lead to placental insufficiency^87-89. However, in a well controlled trial by Isaksson et. al., no differences were noted in gestational duration, major congenital anomalies, perinatal mortality, or mean birth weight in women with unexplained infertility using fertility therapy compared to spontaneous pregnancies. Isaksson's data refutes the finding that unexplained infertility is associated with a poor pregnancy outcome.

CONCLUSION

Unexplained infertility is a difficult problem for both the infertile couple and their physician. As research advances and we better understand the molecular/genetic mechanisms involved in ovulation, fertilization, and embryo implantation, we will undoubtedly find more subtle causes of infertility. Fortunately, the current strategies used for the treatment of unexplained infertility work fairly well and will probably limit the practicability of more esoteric testing to academic use.

Key Points

1. Unexplained infertility is a diagnosis of exclusion given to infertile couples who have had a complete infertility evaluation with no abnormal findings.

2. The incidence of unexplained infertility is approximately 15%.

3. Spontaneous conception without treatment is well documented for couples with unexplained infertility. Conceptions occur at a rate of about 10% per year during the first two years, then 5% per year after that in couples with primary infertility. In couples with secondary infertility conceptions occur at a rate of 18% per year for the first five years then 10% per year.42

4. Options for active management including CC/IUI, hMG/IUI, and IVF. IUI appears to significantly improve pregnancy rates over treatment options using COH with intercourse.

5. Consideration should be given to the use of ICSI in patients undergoing IVF with the diagnosis of unexplained infertility. High rates of fertilization failure are seen in this group of patients, especially those failing to conceive with COH/IUI.

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Table 1. American Fertility Society Evaluation of Infertility (ASRM 1992)

1. Evidence of ovulation by BBT and/or midluteal phase serum progesterone

2. Normal semen parameters.

3. Normal sperm-mucus interaction with a postcoital test

4. Normal uterus and tubes by hysterosalpingogram (HSG).

5. Laparoscopy to evaluate the pelvic structures (hysteroscopy not required).

Table 2. ESHRE Workshop on Unexplained Infertility

Category 1: Tests with established correlation to pregnancy

1. Semen analysis
2. Documentation of tubal patency (HSG, laparoscopy)
3. Midluteal phase progesterone for documentation of ovulation

Category 2: Tests not consistently correlated with pregnancy

1. Zona free hamster egg penetration assay
2. Postcoital test (PCT)
3. Antisperm antibody testing

Category 3: Tests which do not correlate with pregnancy

1. Endometrial biopsy for dating
2. Varicocele assessment
3. Chlamydia testing

The 1996 and 2000 ESHRE Capri workshops concluded that a midluteal phase progesterone was the best test for confirming ovulation and that the primary investigation of the uterus and tubes should be the HSG.

Table 3. Postcoital Test

Table 4. Results of different randomized controlled trials comparing hMG/intrauterine insemination versus hMG/timed intercourse

Table 5. Shows the results of different randomized controlled trials comparing hMG/IUI versus IUI.

Table 6. Efficacy of various treatment options for unexplained infertility.

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