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American Society for Reproductive MedicineObstetrics and Gynecology2020advanced

Evidence-based Treatments for Couples with Unexplained Infertility

Published by American Society for Reproductive Medicine · ASRM Quality of Evidence and Strength of Recommendations

11Recommendations
96References
4Tables
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Summary

AI-generated

Up to 30% of couples experiencing infertility are diagnosed with unexplained infertility after a standard evaluation. Since no treatable cause is identified, treatment is by necessity empiric. Commonly used treatments include ovarian stimulation with oral medications or injectable gonadotropins with intrauterine insemination, and in vitro fertilization.

unexplained infertilityclomipheneletrozoleovarian stimulationIUIIVFASRMobstetrics and gynecology

Key Takeaways

  • 1
    For most couples with unexplained infertility, the best initial therapy is a course (typically 3 or 4 cycles) of OS and IUI, either with clomiphene or letrozole, followed by IVF for those couples unsuccessful in achieving a pregnancy with OS and IUI.
  • 2
    There is a pressing need for additional therapies to bridge the wide gap in effectiveness between OS and IUI with oral medications and IVF.
  • 3
    Further research is needed into methods to improve access to care, including ART treatments.

Key Recommendations

INTRAUTERINE INSEMINATION (IUI), NATURAL CYCLE

  • rec_1

    It is not recommended to perform IUI in natural cycles for the treatment of unexplained infertility. It is less effective than OS with IUI and likely no more effective than expectant management.

    StrongEvidence: Grade ATreatment

CLOMIPHENE CITRATE WITH INTERCOURSE

  • rec_2

    It is not recommended to use clomiphene citrate with timed intercourse as a treatment for unexplained infertility, as it is no more effective than expectant management.

    ModerateEvidence: Grade BTreatment

AROMATASE INHIBITORS WITH INTERCOURSE

  • rec_3

    It is not recommended to use letrozole with timed intercourse as a treatment for unexplained infertility, as it is no more effective than expectant management.

    ModerateEvidence: Grade BTreatment

GONADOTROPINS WITH INTERCOURSE

  • rec_4

    It is not recommended to use gonadotropins with timed intercourse in the treatment of unexplained infertility. Studies report either no difference in pregnancy outcomes compared to OS with oral agents or higher pregnancy rates associated with a higher risk of multiple-gestation pregnancy.

    ModerateEvidence: Grade BTreatment

CLOMIPHENE CITRATE WITH INTRAUTERINE INSEMINATION (IUI)

  • rec_5

    It is recommended to use clomiphene citrate with IUI in the treatment of couples with unexplained infertility.

    StrongEvidence: Grade ATreatment

AROMATASE INHIBITORS WITH INTRAUTERINE INSEMINATION (IUI)

  • rec_6

    It is recommended that letrozole with IUI treatments be considered as an alternative regimen for couples with unexplained infertility, as studies to date suggest similar efficacy. Of note, letrozole is not FDA approved for treatment of unexplained infertility, but is considered an effective and well tolerated option.

    StrongEvidence: Grade ATreatment

INTRAUTERINE INSEMINATION (IUI) WITH COMBINATION OF CLOMIPHENE CITRATE OR LETROZOLE AND GONADOTROPINS (LOW DOSE AND CONVENTIONAL DOSE)

  • rec_7

    It is not recommended to use letrozole or clomiphene citrate plus conventional-dose gonadotropins with IUI, as most studies associated with improved pregnancy rate over OS-IUI with oral medications are also associated with an increased risk of multiple-gestation pregnancy.

    ModerateEvidence: Grade BTreatment

INTRAUTERINE INSEMINATION (IUI) WITH LOW-DOSE GONADOTROPINS

  • rec_8

    It is not recommended to use low-dose gonadotropins with IUI in the treatment of unexplained infertility, as it is more complex and expensive, and likely no more effective than OS with oral medications with IUI.

    ModerateEvidence: Grade BTreatment

INTRAUTERINE INSEMINATION (IUI) WITH CONVENTIONAL-DOSE GONADOTROPINS

  • rec_9

    It is not recommended to use conventional-dose gonadotropins with IUI, as most studies associated with improved pregnancy rate over OS-IUI with oral medications are also associated with a high multiple-gestation pregnancy rate.

    StrongEvidence: Grade ATreatment

TIMING OF INTRAUTERINE INSEMINATION (IUI)

  • rec_10

    It is recommended that a single IUI be performed between 0 and 36 hours relative to hCG injection in OS with IUI treatments.

    ModerateEvidence: Grade BTreatment

IN VITRO FERTILIZATION (IVF) AND TREATMENT PARADIGMS

  • rec_11

    It is recommended that couples with unexplained infertility initially undergo a course (typically 3 or 4 cycles) of OS and IUI with oral agents. For those unsuccessful with OS and IUI treatments with oral agents, IVF is recommended rather than OS and IUI with gonadotropins.

    ModerateEvidence: Grade BTreatment

Scope & Objectives

Clinical Topic

Unexplained Infertility

Objectives

To provide evidence-based recommendations to practicing physicians and others regarding the effectiveness and safety of therapies for unexplained infertility.

Target Patient Population

Couples with unexplained infertility

Diagnostic Criteria

Demonstration of at least one patent fallopian tube, documentation of ovulation of the female partner, and a semen analysis with an adequate number of motile sperm for the male partner.

Target Providers

Practicing physiciansObstetriciansGynecologistsReproductive endocrinologists

Patient Criteria & Setting

Therapeutic Area

Reproductive Medicine

Guideline Scope

TreatmentEffectivenessSafety

Inclusion Criteria

  • Human studies
  • English language
  • Studies with a comparison group
  • Early/minimal endometriosis (stage 1 or 2)
  • Patients with intracytoplasmic sperm injection (ICSI) for non-male factor
  • >5 million total motile sperm (TMS) count
  • Spontaneous ovulatory cycles
  • Studies that compare a low dose (<150 IU) and conventional dose (>=150 IU) of gonadotropins in patients who received IUI

Exclusion Criteria

  • Animal studies
  • Non-English
  • Studies without a comparison group
  • Studies in which treatment/intervention is not clearly stated
  • Stage-3 or -4 endometriosis
  • Hysteroscopy/'endometrial scratch' focus
  • Modeling studies
  • Focus on passive uterine straightening
  • Severe male factor <5 million/ml TMS count on semen analysis
  • Tubal factor infertility
  • Polycystic ovary syndrome (PCOS) or anovulation
  • Focus on luteal progesterone/luteal support
  • Studies with patients who received IUI and overlapping doses of gonadotropins in the same arm
  • Studies that did not specify dose of gonadotropin
  • Treatment with tamoxifen
  • IUI with gonadotropin-releasing hormone (GnRH) agonists or antagonists for suppression
  • Acupuncture as treatment
  • Hysterosalpingo-foam sonography (HyFoSy)
  • Hysterosalpingography (HSG)
  • Diagnostic rather than therapeutic studies
  • Dexamethasone as adjunctive therapy

Special Populations

Women < 38 years of ageWomen >= 38 years of ageWomen < 40 years of age

Evidence Grading

System: ASRM Quality of Evidence and Strength of Recommendations

Evidence Levels

Grade_AHigh confidence in evidence. Larger or further study very unlikely to change reported effect.
Grade_BModerate confidence in evidence. Larger or further studies not likely to change reported effect but may more precisely identify magnitude of effect.
Grade_CLow confidence in evidence. Evidence lacking to support reported effect.
Quality_LowInsufficient sample size; discrepancies among reported data; errors in study design or analysis; missing significant information; unclear or inconsistent results; high risk of bias; high uncertainty about validity of conclusions.
Quality_HighTarget population clearly identified; sufficient sample size for the study design; clear description of study design; appropriate control(s); generalizable results; definitive conclusions; minimal risk of bias; limitations do not invalidate conclusions. Evidence primarily based on well-designed systematic reviews or meta-analyses of randomized controlled trials.
Quality_IntermediateTarget population; sufficient sample size but could benefit from larger studies; control group identified; reasonably consistent results which limitations do not invalidate; fairly definitive conclusions; low risk of bias. Evidence primarily based on small RCTs, systematic reviews/meta-analyses of combination of RCTs and observational studies, and/or well-designed observational studies.

Recommendation Strength

StrongStrong degree of confidence that stated recommendation reflects best practice approach. Recommendation based on consistent evidence of high quality, consideration that benefit outweighs potential risks, and consensus of expert task force and Practice Committee review.
ModerateModerate degree of confidence that stated recommendation reflects best practice approach. Recommendation based on limited evidence of high quality or mix of evidence of high and intermediate quality or consistent body of evidence mostly of intermediate quality, consideration that benefit outweighs potential risks, and consensus.
Weak/ConditionalLow degree of confidence in stated recommendation. Low quality or insufficient evidence to assess true measure of effect. Limited ability to assess benefit vs. risk of intervention.
No recommendationInsufficient available evidence, lack of confidence or consensus to provide a recommendation for clinical practice.

Safety & Contraindications

Monitoring Guidance

Ultrasound monitoring for timing of IUI does not improve pregnancy outcomes compared to urinary LH monitoring in clomiphene citrate-IUI treatments.

Authors & Contributors

Practice Committee of the American Society for Reproductive Medicine

Guideline Features

Dosing informationBased on systematic reviewMultidisciplinaryPatient involvement

Learning Context

Difficulty

advanced

Learning Paths

Unexplained InfertilityOvarian StimulationIntrauterine InseminationIn Vitro FertilizationReproductive EndocrinologyClomiphene CitrateLetrozoleGonadotropins