Interventions for unexplained infertility

a systematic review and network meta‐analysis

Rui Wang, Nora A. Danhof, Raissa I. Tjon-Kon-Fat, Marinus J.C. Eijkemans, Patrick M. M. Bossuyt, Monique H. Mochtar, Fulco Van Der Veen, Siladitya Bhattacharya, Ben Willem J. Mol, Madelon van Wely (Corresponding Author)

Research output: Contribution to journalReview article

Abstract

Background
Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS‐IUI, and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).

Existing systematic reviews have conducted head‐to‐head comparisons of these interventions using pairwise meta‐analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta‐analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision‐making.

Objectives
To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS‐IUI, and IVF/ICSI) in couples with unexplained infertility.

Search methods
We performed a systematic review and network meta‐analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials.

Selection criteria
We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS‐IUI, and IVF (or combined with ICSI).

Data collection and analysis
Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta‐analysis within a random‐effects multi‐variate meta‐analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta‐analysis, we used Confidence in Network Meta‐analysis (CINeMA) to evaluate the overall certainty of evidence.

Main results
We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta‐analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.

Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS‐IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low‐certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low‐certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low‐certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low‐certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS‐IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS‐IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate‐certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate‐certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS‐IUI (OR 1.11, 95% CI 0.78 to 1.60; low‐certainty evidence).

Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low‐certainty evidence) and OS‐IUI (OR 3.34 95% CI 1.09 to 10.29; moderate‐certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low‐certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS‐IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.

Trial results show insufficient evidence of a difference between IVF/ICSI and OS‐IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate‐certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS‐IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%.

Authors' conclusions
There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS‐IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS‐IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS‐IUI.
Original languageEnglish
Article numberCD012692
Number of pages127
JournalCochrane Database of Systematic Reviews
Volume2019
Issue number9
DOIs
Publication statusPublished - 5 Sep 2019

Fingerprint

Intracytoplasmic Sperm Injections
Fertilization in Vitro
Infertility
Insemination
Ovulation Induction
Odds Ratio
Multiple Pregnancy
Confidence Intervals
Live Birth
Randomized Controlled Trials
Ovarian Hyperstimulation Syndrome
Safety
Birth Rate
Therapeutics
Gynecology
MEDLINE
Fertility

Keywords

  • Birth Rate
  • Female
  • Fertility Agents, Female/therapeutic use
  • Fertilization in Vitro/methods
  • Humans
  • Infertility, Female/etiology
  • Network Meta-Analysis
  • Ovulation Induction/methods
  • Pregnancy
  • Pregnancy Rate
  • Randomized Controlled Trials as Topic
  • Reproductive Techniques, Assisted
  • Sperm Injections, Intracytoplasmic/methods

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Wang, R., Danhof, N. A., Tjon-Kon-Fat, R. I., Eijkemans, M. J. C., Bossuyt, P. M. M., Mochtar, M. H., ... van Wely, M. (2019). Interventions for unexplained infertility: a systematic review and network meta‐analysis. Cochrane Database of Systematic Reviews, 2019(9), [CD012692]. https://doi.org/10.1002/14651858.CD012692.pub2

Interventions for unexplained infertility : a systematic review and network meta‐analysis. / Wang, Rui; Danhof, Nora A.; Tjon-Kon-Fat, Raissa I.; Eijkemans, Marinus J.C.; Bossuyt, Patrick M. M.; Mochtar, Monique H.; Van Der Veen, Fulco ; Bhattacharya, Siladitya; Mol, Ben Willem J.; van Wely, Madelon (Corresponding Author).

In: Cochrane Database of Systematic Reviews, Vol. 2019, No. 9, CD012692, 05.09.2019.

Research output: Contribution to journalReview article

Wang, R, Danhof, NA, Tjon-Kon-Fat, RI, Eijkemans, MJC, Bossuyt, PMM, Mochtar, MH, Van Der Veen, F, Bhattacharya, S, Mol, BWJ & van Wely, M 2019, 'Interventions for unexplained infertility: a systematic review and network meta‐analysis', Cochrane Database of Systematic Reviews, vol. 2019, no. 9, CD012692. https://doi.org/10.1002/14651858.CD012692.pub2
Wang, Rui ; Danhof, Nora A. ; Tjon-Kon-Fat, Raissa I. ; Eijkemans, Marinus J.C. ; Bossuyt, Patrick M. M. ; Mochtar, Monique H. ; Van Der Veen, Fulco ; Bhattacharya, Siladitya ; Mol, Ben Willem J. ; van Wely, Madelon. / Interventions for unexplained infertility : a systematic review and network meta‐analysis. In: Cochrane Database of Systematic Reviews. 2019 ; Vol. 2019, No. 9.
@article{0d0292b36bca466f90fd9143c98a88b2,
title = "Interventions for unexplained infertility: a systematic review and network meta‐analysis",
abstract = "BackgroundClinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS‐IUI, and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head‐to‐head comparisons of these interventions using pairwise meta‐analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta‐analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision‐making.ObjectivesTo evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS‐IUI, and IVF/ICSI) in couples with unexplained infertility.Search methodsWe performed a systematic review and network meta‐analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials.Selection criteriaWe included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS‐IUI, and IVF (or combined with ICSI).Data collection and analysisTwo review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta‐analysis within a random‐effects multi‐variate meta‐analysis model. We presented treatment effects by using odds ratios (ORs) and 95{\%} confidence intervals (CIs). For the network meta‐analysis, we used Confidence in Network Meta‐analysis (CINeMA) to evaluate the overall certainty of evidence.Main resultsWe included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta‐analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS‐IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95{\%} CI 0.51 to 1.98; low‐certainty evidence; OR 1.21, 95{\%} CI 0.61 to 2.43; low‐certainty evidence; OR 1.61, 95{\%} CI 0.88 to 2.94; low‐certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low‐certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17{\%}, the chance following OS, IUI, OS‐IUI, and IVF would be 9{\%} to 28{\%}, 11{\%} to 33{\%}, 15{\%} to 37{\%}, and 14{\%} to 47{\%}, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS‐IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95{\%} CI 2.00 to 10.1; moderate‐certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate‐certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS‐IUI (OR 1.11, 95{\%} CI 0.78 to 1.60; low‐certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95{\%} CI 1.00 to 9.41; low‐certainty evidence) and OS‐IUI (OR 3.34 95{\%} CI 1.09 to 10.29; moderate‐certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95{\%} CI 0.68 to 10.43; low‐certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6{\%}, the chance following OS, OS‐IUI, and IVF/ICSI would be 0.6{\%} to 5.0{\%}, 0.6{\%} to 5.4{\%}, and 0.4{\%} to 5.5{\%}, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS‐IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95{\%} CI 0.92 to 6.76; 5 studies; 985 women; moderate‐certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS‐IUI is assumed to be 1.1{\%}, the chance following IVF/ICSI would be between 1.0{\%} and 7.2{\%}.Authors' conclusionsThere is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS‐IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS‐IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS‐IUI.",
keywords = "Birth Rate, Female, Fertility Agents, Female/therapeutic use, Fertilization in Vitro/methods, Humans, Infertility, Female/etiology, Network Meta-Analysis, Ovulation Induction/methods, Pregnancy, Pregnancy Rate, Randomized Controlled Trials as Topic, Reproductive Techniques, Assisted, Sperm Injections, Intracytoplasmic/methods",
author = "Rui Wang and Danhof, {Nora A.} and Tjon-Kon-Fat, {Raissa I.} and Eijkemans, {Marinus J.C.} and Bossuyt, {Patrick M. M.} and Mochtar, {Monique H.} and {Van Der Veen}, Fulco and Siladitya Bhattacharya and Mol, {Ben Willem J.} and {van Wely}, Madelon",
note = "Acknowledgements We would like to thank Marian Showell from the Cochrane Gynaecology and Fertility Group for conducting the database searches.",
year = "2019",
month = "9",
day = "5",
doi = "10.1002/14651858.CD012692.pub2",
language = "English",
volume = "2019",
journal = "Cochrane Database of Systematic Reviews",
issn = "1469-493X",
publisher = "Wiley",
number = "9",

}

TY - JOUR

T1 - Interventions for unexplained infertility

T2 - a systematic review and network meta‐analysis

AU - Wang, Rui

AU - Danhof, Nora A.

AU - Tjon-Kon-Fat, Raissa I.

AU - Eijkemans, Marinus J.C.

AU - Bossuyt, Patrick M. M.

AU - Mochtar, Monique H.

AU - Van Der Veen, Fulco

AU - Bhattacharya, Siladitya

AU - Mol, Ben Willem J.

AU - van Wely, Madelon

N1 - Acknowledgements We would like to thank Marian Showell from the Cochrane Gynaecology and Fertility Group for conducting the database searches.

PY - 2019/9/5

Y1 - 2019/9/5

N2 - BackgroundClinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS‐IUI, and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head‐to‐head comparisons of these interventions using pairwise meta‐analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta‐analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision‐making.ObjectivesTo evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS‐IUI, and IVF/ICSI) in couples with unexplained infertility.Search methodsWe performed a systematic review and network meta‐analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials.Selection criteriaWe included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS‐IUI, and IVF (or combined with ICSI).Data collection and analysisTwo review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta‐analysis within a random‐effects multi‐variate meta‐analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta‐analysis, we used Confidence in Network Meta‐analysis (CINeMA) to evaluate the overall certainty of evidence.Main resultsWe included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta‐analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS‐IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low‐certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low‐certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low‐certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low‐certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS‐IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS‐IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate‐certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate‐certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS‐IUI (OR 1.11, 95% CI 0.78 to 1.60; low‐certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low‐certainty evidence) and OS‐IUI (OR 3.34 95% CI 1.09 to 10.29; moderate‐certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low‐certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS‐IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS‐IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate‐certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS‐IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%.Authors' conclusionsThere is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS‐IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS‐IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS‐IUI.

AB - BackgroundClinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS‐IUI, and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head‐to‐head comparisons of these interventions using pairwise meta‐analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta‐analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision‐making.ObjectivesTo evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS‐IUI, and IVF/ICSI) in couples with unexplained infertility.Search methodsWe performed a systematic review and network meta‐analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials.Selection criteriaWe included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS‐IUI, and IVF (or combined with ICSI).Data collection and analysisTwo review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta‐analysis within a random‐effects multi‐variate meta‐analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta‐analysis, we used Confidence in Network Meta‐analysis (CINeMA) to evaluate the overall certainty of evidence.Main resultsWe included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta‐analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS‐IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low‐certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low‐certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low‐certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low‐certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS‐IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS‐IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate‐certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate‐certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS‐IUI (OR 1.11, 95% CI 0.78 to 1.60; low‐certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low‐certainty evidence) and OS‐IUI (OR 3.34 95% CI 1.09 to 10.29; moderate‐certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low‐certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS‐IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS‐IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate‐certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS‐IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%.Authors' conclusionsThere is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS‐IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS‐IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS‐IUI.

KW - Birth Rate

KW - Female

KW - Fertility Agents, Female/therapeutic use

KW - Fertilization in Vitro/methods

KW - Humans

KW - Infertility, Female/etiology

KW - Network Meta-Analysis

KW - Ovulation Induction/methods

KW - Pregnancy

KW - Pregnancy Rate

KW - Randomized Controlled Trials as Topic

KW - Reproductive Techniques, Assisted

KW - Sperm Injections, Intracytoplasmic/methods

UR - http://www.scopus.com/inward/record.url?scp=85072012977&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/interventions-unexplained-infertility-systematic-review-network-metaanalysis

U2 - 10.1002/14651858.CD012692.pub2

DO - 10.1002/14651858.CD012692.pub2

M3 - Review article

VL - 2019

JO - Cochrane Database of Systematic Reviews

JF - Cochrane Database of Systematic Reviews

SN - 1469-493X

IS - 9

M1 - CD012692

ER -