|REVIEW ARTICLE: ISSUE IN FOCUS
|Year : 2016 | Volume
| Issue : 4 | Page : 94-100
Unexplained infertility: An approach to diagnosis and management
Mohan S Kamath, Mogili Krishna Deepti
Department of Reproductive Medicine, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||22-Nov-2016|
Mohan S Kamath
Department of Reproductive Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
The cause of infertility is said to be unexplained when there is normal ovulatory function, semen analysis is normal, and tubal patency is established by hysterosalpingography or laparoscopy. Some of the factors that may contribute to the etiology of unexplained infertility are inability to identify the subtle reproductive abnormalities, endocrine/genetic/immunological disorders, minimal/mild endometriosis, and compromised ovarian and natural fecundability that may be less than normal. Prognostic factors in unexplained infertility include maternal age, duration of infertility, and previous obstetric history. The management options depend on various factors such as age of woman, duration of infertility, couples' preferences, and the health-care setting. The options available for treatment include expectant management, clomiphene citrate, super ovulation with intrauterine insemination, and in vitro fertilization/intracytoplasmic sperm injection.
Keywords: Clomiphene citrate, Intracytoplasmic sperm injection, intrauterine insemination, in vitro fertilization, unexplained infertility
|How to cite this article:|
Kamath MS, Deepti MK. Unexplained infertility: An approach to diagnosis and management. Curr Med Issues 2016;14:94-100
| Introduction|| |
The management of infertility has seen several significant advances over the years due to the new diagnostic tests to detect an underlying cause and more treatment options available. The treatment options recommended often depend on the etiology identified on standard tests done during the assessment of infertility. It is not uncommon, however, to have couples who fail to conceive despite all standard tests being reported "normal" - what is termed "unexplained infertility." The prevalence of unexplained infertility ranges from 8% to 37% , of infertile couples. It must be understood that the "standard" diagnostic tests that are routinely done in the assessment of infertility may not detect all possible etiologies. At the same time, however, advanced and expensive diagnostic tests may not necessarily be beneficial or alter management significantly. This review is aimed at presenting an approach to the problem of unexplained infertility in the setting of a general practice with an emphasis on management options which can be offered at the level of primary or secondary level care.
| Definition of Unexplained Infertility|| |
The cause of infertility is said to be unexplained when the following criteria are met:
- Normal ovulatory function is established by means of basal body temperature measurement, cervical mucus changes, serum luteinizing hormone (LH) surge or mid-luteal progesterone levels, or evidence of follicular rupture during ultrasound
- Semen analysis is normal
- Tubal patency is established by hysterosalpingography or laparoscopy. 
Some of the factors that may contribute to the etiology of unexplained infertility are as follows:
Inability to identify the subtle reproductive abnormalities
Most diagnostic tests in the assessment of infertility do not detect abnormalities that may be rare or subtle. Advanced tests may detect these etiologies and narrow down the cause of infertility. In reality, however, in most cases, advanced and expensive tests do not add anything significant to our understanding and do not significantly alter management and are offered only in research settings.
Endocrine/genetic/immunological disorders [Table 1].
This can be missed if woman is asymptomatic and hysterosalpingography (HSG) is done for tubal patency instead of diagnostic laparoscopy. Such cases may sometimes be diagnosed as unexplained infertility.
Compromised ovarian reserve
Ovarian reserve is defined as the functional potential of the ovary and reflects on the number and the quality of oocytes within it. It may be diminished in women who have a history of prior ovarian surgery, received gonadotoxic therapy, or are advanced in age. Patients with decreased ovarian reserve can have regular cycles, but spontaneous ovulation rates and response to ovulation induction treatments are diminished in these individuals.  The tests for ovarian reserve are described in Box 1.
Natural fecundability may be less than normal
Natural fecundability is the chance of obtaining clinical pregnancy in one menstrual cycle, and for young couples, it is around 20%. In unexplained infertility, the fecundability is less than normal.
| Prognostic Factors in Unexplained Infertility|| |
This is the most important prognostic factor. Ovarian reserve and therefore the chance of conception diminish with advanced age. In a young female (25 years and below), expectant management can be considered, especially if the duration of infertility is < 3 years which is not the case in advanced age (>35 years).
Duration of infertility
The success rate of interventions reduces with increase in the duration of infertility despite regular sexual intercourse. Customarily, infertility is considered if a couple fails to conceive after 1 year of regular intercourse. However, an active medical intervention is usually considered only after 2-3 years in unexplained infertility, especially in a young couple.
Previous obstetric history
In case a patient has conceived previously, it is considered as a good prognostic factor irrespective of pregnancy outcome for natural conception and treatment results.
| Evaluation of a Couple with Unexplained Infertility|| |
History and examination of both the partners
The couple should be present together at the time of evaluation as it is a problem of the couple and not of an individual. A good history is adequate in many cases to identify the cause of infertility and ovulatory function as shown in Appendixes 1 and 2 in the end of article.
The standard evaluation
Investigations should include a basic workup to assess the following:
- Tests of ovulatory function [Box 2]
- Husband's semen analysis
- Tests to assess tubal patency (HSG/laparoscopy/saline infusion sonography) [Box 3 and 4]
- Ultrasound of the pelvis.
| Management Options for Unexplained Infertility|| |
The management options depend on various factors such as age of woman, duration of infertility, couples' preferences, and health-care setting. The options are as follows:
- Expectant management
- Clomiphene citrate
- Superovulation with intrauterine insemination (IUI)
- In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).
| Expectant Management|| |
Expectant management plays an important role in limited resource settings, especially if the woman is relatively young (around 25 years) and the period of infertility is short. It is often the first line of treatment.
The average cycle fecundity (the probability of achieving live birth in a menstrual cycle) of 1.3% to 4.1% has been reported with expectant management.  The couple is advised to follow up regular intercourse during the fertile period.
One study showed that 60% of couples with unexplained infertility of 3 years duration would become pregnant within 3 years of expectant management if the woman was <25 years old.  Another study showed that for couples with unexplained infertility for 3 years, the cumulative pregnancy rate after 24 months without any treatment was 28%. If the woman was over 31 years of age, If the woman was over 31 years of age, this number reduces by 10% for each year afterward. 
Counseling the couple, presenting the facts, and allaying their fears are the important aspects of expectant management and many young women conceive without any treatment. However, this approach may not be practically applicable in societies where social expectations are high. For older women (above the age of 30 years) and in those with a longer infertility period, one must have a lower threshold for intervention.
| Clomiphene Citrate|| |
Clomiphene citrate is a very commonly used drug for ovulation induction. Its role in unexplained infertility is debatable. According to the American Society for Reproductive Medicine (ASRM) practice committee,  clomiphene citrate is associated with a small but significant treatment effect, i.e., one additional pregnancy with 40 cycles of clomiphene compared to no treatment. A Cochrane review  including 1159 patients and 7 trials has shown that there is no evidence of clomiphene citrate being more effective than no treatment or placebo. Therefore, our recommendation is not to use clomiphene in unexplained infertility.
However, in limited resources, empirical treatment with clomiphene citrate starting with 50 mg up to a maximum of 250 mg can be used for 3-6 cycles, especially in younger women. It can be given from day 2 of menstrual cycle for 5 days. The aim should be monofollicular growth to avoid complications such as ovarian hyperstimulation and multiple gestations.
| Intrauterine Insemination|| |
The rationale behind doing IUI in unexplained infertility is that it increases the gamete density (by sperm preparation and superovulation), brings together the gametes into close proximity (bypassing the cervix and by insemination into the uterine cavity). In general, superovulation IUI is advised in which ovarian stimulation is done with clomiphene, gonadotropin, or in combination to achieve more than one follicle development. Follicular monitoring is done and development of follicle is recorded by serial ultrasounds. Once the follicle size is optimal (>17 mm), the human chorionic gonadotropin is given as a trigger (5000 IU) to mimic artificial LH surge. The IUI is planned 34-38 h later. On the day of IUI, husband's semen sample is processed and it is injected in the uterine cavity using a catheter. Luteal support is generally advised in cases where gonadotropin has been used.
IUI can be done in a natural cycle or in a stimulated cycle (clomiphene citrate, gonadotropins, and clomiphene + gonadotropins). A recent Cochrane review published in 2012  suggests that IUI in stimulated cycles is better than IUI in natural cycles.
In a meta-analysis by van Rumste et al.,  the pregnancy rate was 8.4% for monofollicular growth and 15% for multifollicular growth. However, since the multiple pregnancy rates are higher in those with more than 2 follicles, the aim should be not more than 2-3 follicles during ovarian stimulation. A study published by Kamath et al. has shown pregnancy rates of 11.3% with stimulated IUI cycles in patients with unexplained infertility.
Pregnancy rates with IUI are higher with a higher follicular number [Table 2],  but this carries a risk of higher order pregnancy (more than 2). A disadvantage of superovulation IUI is that it is often difficult to control the number of follicles. IVF provides better control in this regard. It will be advisable to aim for 1-2 follicles and keep a low threshold for cancellation when superovulation IUI is being offered in low-resource setting. In case there is development of more than three follicles during stimulation, then couple should be counseled and cancellation of the treatment cycle should be advised. For those willing for cancellation, abstinence is advised for the next 2-3 weeks until the onset of menstrual cycle. In case the woman misses her cycles in these circumstances or following IUI, they are advised to check for pregnancy by urine pregnancy test. In case it is positive, they need to contact the clinician for further advice.
|Table 2: Pregnancy rates with intrauterine insemination (for all indications) in correlation with the number of follicles13 |
Click here to view
According to the ICMR guidelines, IUI in a stimulated cycle should not be done in a primary health center. Infertility clinics need ICMR accreditation to perform IUI. A maximum of 3 cycles of IUI can be done before referring the patient to a tertiary care center for further management.
| In Vitro Fertilization/Intracytoplasmic Sperm Injection|| |
IVF is an effective and expensive method of treatment for unexplained infertility. IVF involves controlled ovarian hyperstimulation (COH) with gonadotropins with the aim of obtaining between 5 and 10 mature oocytes. While women undergo COH, the hypothalamic-pituitary-ovarian axis is suppressed by giving gonadotropin-releasing hormone analogs which prevents premature LH surge and release. Once the follicles develop up to a size of 17 mm, the human chorionic gonadotropin (hCG) trigger is given to mimic LH surge as in the case of IUI, but the oocyte retrieval is planned after 35-36 h after hCG trigger. Oocyte retrieval is generally done under conscious sedation by using transvaginal ultrasound and it is a day care procedure. The mature oocytes are identified and fertilized using IVF or ICSI (generally for male factor indication).  The fertilized oocytes are cultured in incubators, and the developing embryos are then transferred back on day 2/3 or day 5 postoocyte retrieval.
The ASRM reports a pregnancy rate of 30.4% with IVF.  A recent Cochrane review  has shown that IVF is associated with higher live birth rates than expectant management (45.8% vs. 3.7%) and unstimulated IUI. Multiple pregnancy rates are lower with IVF because of a greater control over the number of follicles being fertilized, when compared to IUI.
IVF must be considered in a woman if age >35 years or with prolonged duration of infertility or if the cycles has undergone 3-4 cycles of IUI without conception.
| Conclusion|| |
Unexplained infertility poses a great challenge to both patients and treating physicians. Infertility is not only a medical condition but also has a significant negative psychological and social impact. In addition to the medical treatment, some couples may require additional psychological support and counseling. The pros and cons have to be discussed before going ahead with treatment. Any intervention or invasive diagnostic tests on the female partner to be withheld till semen analysis is available. Expectant management is associated with satisfactory pregnancy rates in selected group of patients. Clomiphene citrate has a limited role in unexplained infertility, probably in a low-resource setting. Superovulation with IUI is an effective second-line treatment, and IVF/ICSI is the final treatment option for unexplained infertility generally offered in a tertiary level center.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ray A, Shah A, Gudi A, Homburg R. Unexplained infertility: An update and review of practice. Reprod Biomed Online 2012;24:591-602.
Collins JA, Rowe TC. Age of the female partner is a prognostic factor in prolonged unexplained infertility: A multicenter study. Fertil Steril 1989;52:15-20.
Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril 2006;86 5 Suppl 1:S111-4.
Swart P, Mol BW, van der Veen F, van Beurden M, Redekop WK, Bossuyt PM. The accuracy of hysterosalpingography in the diagnosis of tubal pathology: A meta-analysis. Fertil Steril 1995;64:486-91.
Fatum M, Laufer N, Simon A. Investigation of the infertile couple: Should diagnostic laparoscopy be performed after normal hysterosalpingography in treating infertility suspected to be of unknown origin? Hum Reprod 2002;17:1-3.
Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, et al.
Efficacy of treatment for unexplained infertility. Fertil Steril 1998;70:207-13.
Simon A, Laufer N. Unexplained infertility: A reappraisal. Ass Reprod Rev 1993;3:26-36.
John A. Collins, Elizabeth A. Burrows, Andrew R. Willan. The prognosis for live birth among untreated infertile couples. Fertility and Sterility 1995;64 (1):22-8.
Effectiveness and treatment for unexplained infertility. The Practice Committee of the American Society for Reproductive Medicine. 2006.
Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev 2010;(1):CD000057. doi: 10.1002/14651858.
Veltman- Verhulst SM, Cohlen BJ, Hughes E, Heineman MJ. Intra uterine insemination for unexplained subfertility. Cochrane Database Syst Rev 2012;(9):CD001838. doi: 10.1002/14651858.
van Rumste MM, Custers IM, van der Veen F, van Wely M, Evers JL, Mol BW. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: A meta-analysis. Hum Reprod Update 2008;14:563-70.
Kamath MS, Bhave P, Aleyamma T, Nair R, Chandy A, Mangalaraj AM, et al.
Predictive factors for pregnancy after intrauterine insemination: A prospective study of factors affecting outcome. J Hum Reprod Sci 2010;3:129-34.
Johnson LN, Sasson IE, Sammel MD, Dokras A. Does intracytoplasmic sperm injection improve the fetility rate and decrease the total fertilization failure rate in couples with well-defined unexplained infertility? A systematic review and meta- analysis. Fertil Steril 2013;100:704-11
Pandian Z, Gibreel A, Bhattacharya S. In vitro fertilization for unexplained subfertility. Cochrane Database Syst Rev 2012;(4):CD003357. doi: 10.1002/14651858.
[Table 1], [Table 2]
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