Download PDF
Semin Reprod Med 2020; 38(01): 055-060
DOI: 10.1055/s-0040-1718709
Review Article

How and Why to Define Unexplained Infertility?

Karim S. Abdallah 
1   Department of Obstetrics and Gynecology, Women's Health Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt
2   Department of Obstetrics and Gynecology, Monash University, Clayton, Australia
,
Sarah Hunt
2   Department of Obstetrics and Gynecology, Monash University, Clayton, Australia
3   Department of Obstetrics and Gynecology, Monash Health, Clayton, Australia
4   Monash IVF, Richmond, Australia
,
Sayed A. Abdullah
1   Department of Obstetrics and Gynecology, Women's Health Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt
,
Ben W.J. Mol
2   Department of Obstetrics and Gynecology, Monash University, Clayton, Australia
5   Aberdeen Centre for Women's Health Research, University of Aberdeen, Aberdeen, United Kingdom
,
Mohamed A. Youssef
6   Department of Obstetrics and Gynecology, Kasr Al-Ainy Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Unexplained infertility represents up to 30% of all cases of infertility. It is a diagnosis of exclusion, where no cause for infertility may be identified in the investigation of the couple, be it anovulation, fallopian tube blockage, or severe male factor. Unexplained infertility therefore cannot be considered a diagnosis to which a specific treatment is directed, rather that it indicates a failure to reach a diagnosis of the true cause of infertility. In this review, we explore the evidence base and potential limitations of the current routine infertility assessment. We also aim to highlight the importance of considering the prognosis of each individual couple through the process of assessment and propose a reconsidered approach to treatment, targeted to the prognosis rather than the diagnosis. Ultimately, a better understanding of the mechanisms of infertility will reduce the number of couples diagnosed with “unexplained” infertility.

Keywords

unexplained infertility - definition - prognosis


Publication History

Article published online:
14 October 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Zegers-Hochschild F, Adamson GD, Dyer S. et al. The international glossary on infertility and fertility care, 2017. Hum Reprod 2017; 32 (09) 1786-1801
    CrossrefPubMedGoogle Scholar
  • 2 Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 2007; 22 (06) 1506-1512
    CrossrefPubMedGoogle Scholar
  • 3 Whiteford LM, Gonzalez L. Stigma: the hidden burden of infertility. Soc Sci Med 1995; 40 (01) 27-36
    CrossrefPubMedGoogle Scholar
  • 4 Downey J, Yingling S, McKinney M, Husami N, Jewelewicz R, Maidman J. Mood disorders, psychiatric symptoms, and distress in women presenting for infertility evaluation. Fertil Steril 1989; 52 (03) 425-432
    CrossrefPubMedGoogle Scholar
  • 5 Baldur-Felskov B, Kjaer SK, Albieri V. et al. Psychiatric disorders in women with fertility problems: results from a large Danish register-based cohort study. Hum Reprod 2013; 28 (03) 683-690
    CrossrefPubMedGoogle Scholar
  • 6 Hull MG, Glazener CM, Kelly NJ. et al. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 1985; 291 (6510): 1693-1697
    CrossrefPubMedGoogle Scholar
  • 7 Evers JL. Female subfertility. Lancet 2002; 360 (9327): 151-159
    CrossrefPubMedGoogle Scholar
  • 8 Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org, Practice Committee of the American Society for Reproductive Medicine. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril 2020; 113 (02) 305-322
    CrossrefPubMedGoogle Scholar
  • 9 Templeton AA, Penney GC. The incidence, characteristics, and prognosis of patients whose infertility is unexplained. Fertil Steril 1982; 37 (02) 175-182
    CrossrefPubMedGoogle Scholar
  • 10 Moghissi KS, Wallach EE. Unexplained infertility. Fertil Steril 1983; 39 (01) 5-21
    CrossrefPubMedGoogle Scholar
  • 11 National Institute for Health Care Excellence. Fertility Problems: Assessment and Treatment. NICE Clinical Guidelines [CG156]. United Kingdom: NICE; 2017
    Google Scholar
  • 12 ACOG Committee. Infertility workup for the women's health specialist: ACOG Committee Opinion, Number 781. Obstet Gynecol 2019; 133 (06) e377-e384
    CrossrefPubMedGoogle Scholar
  • 13 Gunn DD, Bates GW. Evidence-based approach to unexplained infertility: a systematic review. Fertil Steril 2016; 105 (06) 1566-1574
    CrossrefPubMedGoogle Scholar
  • 14 Mol BW, Tjon-Kon-Fat R, Kamphuis E, van Wely M. Unexplained infertility: Is it over-diagnosed and over-treated?. Best Pract Res Clin Obstet Gynaecol 2018; 53: 20-29
    CrossrefPubMedGoogle Scholar
  • 15 Ray A, Shah A, Gudi A, Homburg R. Unexplained infertility: an update and review of practice. Reprod Biomed Online 2012; 24 (06) 591-602
    CrossrefPubMedGoogle Scholar
  • 16 te Velde ER, Eijkemans R, Habbema HD. Variation in couple fecundity and time to pregnancy, an essential concept in human reproduction. Lancet 2000; 355 (9219): 1928-1929
    CrossrefPubMedGoogle Scholar
  • 17 Gleicher N, Barad D. Unexplained infertility: does it really exist?. Hum Reprod 2006; 21 (08) 1951-1955
    CrossrefPubMedGoogle Scholar
  • 18 Siristatidis C, Bhattacharya S. Unexplained infertility: does it really exist? Does it matter?. Hum Reprod 2007; 22 (08) 2084-2087
    CrossrefPubMedGoogle Scholar
  • 19 Buckett W, Sierra S. The management of unexplained infertility: an evidence-based guideline from the Canadian Fertility and Andrology Society. Reprod Biomed Online 2019; 39 (04) 633-640
    CrossrefPubMedGoogle Scholar
  • 20 King LS. What is a diagnosis?. JAMA 1967; 202 (08) 714-717
    CrossrefPubMedGoogle Scholar
  • 21 Leushuis E, van der Steeg JW, Steures P. et al. Reproducibility and reliability of repeated semen analyses in male partners of subfertile couples. Fertil Steril 2010; 94 (07) 2631-2635
    CrossrefPubMedGoogle Scholar
  • 22 van der Steeg JW, Steures P, Eijkemans MJ. et al. Collaborative Effort for Clinical Evaluation in Reproductive Medicine Study Group. Role of semen analysis in subfertile couples. Fertil Steril 2011; 95 (03) 1013-1019
    CrossrefPubMedGoogle Scholar
  • 23 World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. 2010
    PubMedGoogle Scholar
  • 24 Bonde JPE, Ernst E, Jensen TK. et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998; 352 (9135): 1172-1177
    CrossrefPubMedGoogle Scholar
  • 25 Patel AS, Leong JY, Ramasamy R. Prediction of male infertility by the World Health Organization laboratory manual for assessment of semen analysis: a systematic review. Arab J Urol 2017; 16 (01) 96-102
    CrossrefPubMedGoogle Scholar
  • 26 Guzick DS, Overstreet JW, Factor-Litvak P. et al. National Cooperative Reproductive Medicine Network. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001; 345 (19) 1388-1393
    CrossrefPubMedGoogle Scholar
  • 27 Bayar U, Basaran M, Atasoy N. et al. Sexual dysfunction in infertile couples: evaluation and treatment of infertility. J Pak Med Assoc 2014; 64 (02) 138-145
    PubMedGoogle Scholar
  • 28 Dancet EAF, D'Hooghe TM, Dreischor F. et al. The ‘Pleasure&Pregnancy’ web-based interactive educational programme versus expectant management in the treatment of unexplained subfertility: protocol for a randomised controlled trial. BMJ Open 2019; 9 (07) e025845
    CrossrefPubMedGoogle Scholar
  • 29 Su H-W, Yi Y-C, Wei T-Y, Chang T-C, Cheng C-M. Detection of ovulation, a review of currently available methods. Bioeng Transl Med 2017; 2 (03) 238-246
    CrossrefPubMedGoogle Scholar
  • 30 Prior JC, Naess M, Langhammer A, Forsmo S. Ovulation prevalence in women with spontaneous normal-length menstrual cycles–a population-based cohort from HUNT3, Norway. PLoS One 2015; 10 (08) e0134473
    CrossrefPubMedGoogle Scholar
  • 31 Ebner T, Moser M, Shebl O, Sommergruber M, Yaman C, Tews G. Blood clots in the cumulus-oocyte complex predict poor oocyte quality and post-fertilization development. Reprod Biomed Online 2008; 16 (06) 801-807
    CrossrefPubMedGoogle Scholar
  • 32 Mol BWJ, Swart P, Bossuyt PMM, van Beurden M, van der Veen F. Reproducibility of the interpretation of hysterosalpingography in the diagnosis of tubal pathology. Hum Reprod 1996; 11 (06) 1204-1208
    CrossrefPubMedGoogle Scholar
  • 33 Maheux-Lacroix S, Boutin A, Moore L. et al. Hysterosalpingosonography for diagnosing tubal occlusion in subfertile women: a systematic review with meta-analysis. Hum Reprod 2014; 29 (05) 953-963
    CrossrefPubMedGoogle Scholar
  • 34 Gürgan T, Kişnişçi HA, Yarali H. et al. Evaluation of the functional status of the fallopian tubes in unexplained infertility with radionuclide hysterosalpingography. Gynecol Obstet Invest 1991; 32 (04) 224-226
    CrossrefPubMedGoogle Scholar
  • 35 Tur-Kaspa I, Gal M, Hartman M, Hartman J, Hartman A. A prospective evaluation of uterine abnormalities by saline infusion sonohysterography in 1,009 women with infertility or abnormal uterine bleeding. Fertil Steril 2006; 86 (06) 1731-1735
    CrossrefPubMedGoogle Scholar
  • 36 Antón AG, Velasco JAG. Role of endometrial receptivity in unexplained infertility. In: Unexplained Infertility. Springer; 2015: 185-191
    CrossrefGoogle Scholar
  • 37 Galliano D, Pellicer A. Potential etiologies of unexplained infertility in females. In: Unexplained Infertility. Springer; 2015: 141-147
    CrossrefGoogle Scholar
  • 38 Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril 2012; 98 (03) 591-598
    CrossrefPubMedGoogle Scholar
  • 39 Smith S, Pfeifer SM, Collins JA. Diagnosis and management of female infertility. JAMA 2003; 290 (13) 1767-1770
    CrossrefPubMedGoogle Scholar
  • 40 Anderson K, Nisenblat V, Norman R. Lifestyle factors in people seeking infertility treatment - a review. Aust N Z J Obstet Gynaecol 2010; 50 (01) 8-20
    CrossrefPubMedGoogle Scholar
  • 41 Chaabane S, Sheehy O, Monnier P. et al. Ovarian stimulation, intrauterine insemination, multiple pregnancy and major congenital malformations: a systematic review and meta-analysis - the ART_Rev study. Curr Drug Saf 2016; 11 (03) 222-261
    CrossrefPubMedGoogle Scholar
  • 42 Danhof NA, Wang R, van Wely M, van der Veen F, Mol BWJ, Mochtar MH. IUI for unexplained infertility-a network meta-analysis. Hum Reprod Update 2020; 26 (01) 1-15
    CrossrefPubMedGoogle Scholar
  • 43 Dunson DB, Baird DD, Colombo B. Increased infertility with age in men and women. Obstet Gynecol 2004; 103 (01) 51-56
    CrossrefPubMedGoogle Scholar
  • 44 Hunault CC, Habbema JD, Eijkemans MJ, Collins JA, Evers JL, te Velde ER. Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models. Hum Reprod 2004; 19 (09) 2019-2026
    CrossrefPubMedGoogle Scholar
  • 45 van Eekelen R, Scholten I, Tjon-Kon-Fat RI. et al. Natural conception: repeated predictions over time. Hum Reprod 2017; 32 (02) 346-353
    CrossrefPubMedGoogle Scholar
  • 46 Thurston L, Abbara A, Dhillo WS. Investigation and management of subfertility. J Clin Pathol 2019; 72 (09) 579-587
    CrossrefPubMedGoogle Scholar
  • 47 Guzick DS, Grefenstette I, Baffone K. et al. Infertility evaluation in fertile women: a model for assessing the efficacy of infertility testing. Obstet Gynecol Surv 1995; 50 (09) 661-663
    CrossrefPubMedGoogle Scholar
  • 48 van der Steeg JW, Steures P, Eijkemans MJC. et al. CECERM Study Group (Collaborative Effort for Clinical Evaluation in Reproductive Medicine). Pregnancy is predictable: a large-scale prospective external validation of the prediction of spontaneous pregnancy in subfertile couples. Hum Reprod 2007; 22 (02) 536-542
    CrossrefPubMedGoogle Scholar
  • 49 Steures P, van der Steeg JW, Hompes PG. et al. Collaborative Effort on the Clinical Evaluation in Reproductive Medicine. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368 (9531): 216-221
    CrossrefPubMedGoogle Scholar
  • 50 Custers IM, van Rumste MM, van der Steeg JW. et al. CECERM. Long-term outcome in couples with unexplained subfertility and an intermediate prognosis initially randomized between expectant management and immediate treatment. Hum Reprod 2012; 27 (02) 444-450
    CrossrefPubMedGoogle Scholar
  • 51 Farquhar CM, Liu E, Armstrong S, Arroll N, Lensen S, Brown J. Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled, two-centre trial. Lancet 2018; 391 (10119): 441-450
    CrossrefPubMedGoogle Scholar
  • 52 van Eekelen R, van Geloven N, van Wely M. et al. Is IUI with ovarian stimulation effective in couples with unexplained subfertility?. Hum Reprod 2019; 34 (01) 84-91
    CrossrefPubMedGoogle Scholar
  • 53 Woodward B, Tomlinson M, Kirkman-Brown J. Replacing IUI with IVF for initial treatment of unexplained infertility: why this NICE recommendation is cause for concern. Hum Fertil (Camb) 2016; 19 (02) 80-84
    CrossrefPubMedGoogle Scholar
  • 54 Bensdorp AJ, Tjon-Kon-Fat RI, Bossuyt PM. et al. Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation. Bmj 2015 2015; 350: g7771
    PubMedGoogle Scholar
  • 55 Wang R, Danhof NA, Tjon-Kon-Fat RI. et al. Interventions for unexplained infertility: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2019; 9 (09) CD012692
    PubMedGoogle Scholar
  • 56 Hunt S, Abdallah KS, Ng E, Rombauts L, Vollenhoven B, Mol BW. Impairment of uterine contractility is associated with unexplained infertility. Semin Reprod Med 2020
    PubMedGoogle Scholar
  • 57 Dreyer K, Martins W. Tubal flushing treatment for unexplained infertility. Semin Reprod Med 2020
    PubMedGoogle Scholar