Unexplained Infertility Thirty percent of couples are diagnosed with unexplained infertility, in which the basic infertility evaluation reveals normal semen parameters, evidence of ovulation, patent fallopian tubes, and no other obvious cause of infertility. Patients with unexplained infertility may be reassured that even after 12 months of failed attempts, 20% will conceive in the following 12 months and over 50% in the following 36 months. This suggests that in couples with the good prognostic factors of female age less than 30, less than 24 months of infertility, and a previous pregnancy in the same partnership, unexplained infertility may merely reﬂect the lower extreme of normal fertility. It is likely that current technology is limited in terms of diagnosing all causes for infertility, and the utility of evaluations other than basic testing in an infertile couple has yet to be proven (2,150,276).
Luteinized Unruptured Follicle Syndrome This condition involves luteinization of a follicle that has failed to rupture and release its oocyte, leading to a normal menstrual cycle but infertility. It is thought to occur in up to 25% of patients with unexplained infertility, more than twice the incidence in fertile women (138). The diagnosis may justify the use of IVF whereby follicles are aspirated and oocyte are retrieved and fertilized in vitro.
Immunologic Factors Although serum antiphospholipid antibodies and antithyroid antibodies are more prevalent among patients with unexplained infertility than among fertile women, the presence of antiphospholipid antibodies has not been found to adversely affect IVF outcomes, so screening is discouraged (277,278). The association between the presence of antithyroid antibodies and infertility is inconsistent, so screening is not recommended (279–282). Unexplained infertility has been associated with antisperm antibodies, but the extent to which these antibodies affect fertility treatment outcomes and whether IUI, ICSI, or glucocorticoids should be used remains unclear (280,282,283). A similar lack of consensus exists concerning the assessment of peripheral natural killer cell number and/or activity in infertility patients (276,282).
Decreased Endometrial Perfusion Using ultrasound-based endometrial Doppler studies, women with unexplained infertility have been shown to exhibit abnormal endometrial perfusion when compared to fertile women, but, at present, there is no direct link to fertility treatment outcomes and no recommendations to act on these findings (284).
Infection C. trachomatis and related clinical and subclinical infections have been discussed in the “Tubal Factor” section. To date, no consistent associations have been reported between chlamydial species, M. hominis, and unexplained infertility in men or women (207,285,286).
U. urealyticum and M. genitalium, however, may be more of a concern (287). Prophylactic doxycycline (100 mg twice daily for 4 weeks) given to infertile couples improved pregnancy rates only for those couples in which the male partner was able to clear a ureaplasma infection (288). Antimicrobial prophylaxis is often given for ART, but it is not clear the extent to which clearance of these organisms improves pregnancy rates (287,289).
Undiagnosed Pelvic Pathology Following a negative infertility workup, laparoscopy has been proposed to evaluate for peritubal adhesions and endometriosis. However, there is a lack of consensus as to the frequency of these abnormalities in women with unexplained infertility, and many practitioners will forgo laparoscopy in lieu of a few cycles of less invasive interventions in such patients (290–292).