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. 2019 Sep 5;9(9):CD012692.
doi: 10.1002/14651858.CD012692.pub2.

Interventions for unexplained infertility: a systematic review and network meta-analysis

Rui Wang  1 , Nora A Danhof, Raissa I Tjon-Kon-Fat, Marinus Jc Eijkemans, Patrick Mm Bossuyt, Monique H Mochtar, Fulco van der Veen, Siladitya Bhattacharya, Ben Willem J Mol, Madelon van Wely
Affiliations

Interventions for unexplained infertility: a systematic review and network meta-analysis

Rui Wang et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

Conflict of interest statement

SB has not received money from any source to support the work leading up to this review. SB has received support for travel and accommodation for speaking at conferences. His institution and institutional colleagues have received support from pharmaceutical companies for educational activities such as hosting seminars and attending conferences. He receives an honorarium as Editor‐in‐Chief of Human Reproduction Open.

BWM is supported by an NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck, and Guerbet, and research grants from Guerbet and Merck.

RW, NAD, RIT, ME, PB, MHM, FvdV, and MvW have no interests to declare.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Box plot for the distribution of means of age in different studies across different comparisons.
5
5
Network plot for live birth. Each node represents an intervention, and the size of each node is proportional to the number of trials reporting such intervention. The widths of the lines are proportional to the numbers of trials comparing each pair of interventions.
6
6
Network meta‐analysis for live birth. Each diamond represents the estimate summary odds ratio of each comparison; each horizontal line represents the confidence interval of each comparison; blue vertical line represents line of no effect (odds ratio = 1). Odds ratio greater than 1 favours the first intervention; odds ratio less than 1 favours the second intervention.
7
7
Comparison‐adjusted funnel plot for live birth. (A: expectant management; B: OS; C: IUI; D: OS‐IUI; E: IVF/ICSI.)
8
8
Cumulative rankograms of interventions for live birth. Each cumulative rankogram illustrates the cumulative probability of each ranking (from the best to the worst rank) for each intervention in terms of live birth.
9
9
Subgroup analysis for live birth ‐ RCTs with a median duration of infertility ≤ 2 years.
10
10
Subgroup analysis for live birth ‐ RCTs with a median duration of infertility > 2 years.
11
11
Sensitivity analysis for live birth by exclusion of participants with missing outcome data. Each diamond represents the estimate summary odds ratio for each comparison; each horizontal line represents the confidence interval for each comparison; blue vertical line represents line of no effect (odds ratio = 1). Odds ratio greater than 1 favours the first intervention; odds ratio less than 1 favours the second intervention.
12
12
Sensitivity analysis for live birth by exclusion of abstract‐only publications. Each diamond represents the estimate summary odds ratio for each comparison; each horizontal lines represents the confidence interval for each comparison; blue vertical line represents line of no effect (odds ratio = 1). Odds ratio greater than 1 favours the first intervention; odds ratio less than 1 favours the second intervention.
13
13
Sensitivity analysis for live birth excluding RCTs involving expectant management from the network. Each diamond represents the estimate summary odds ratio for each comparison; each horizontal lines represents the confidence interval for each comparison; blue vertical line represents line of no effect (odds ratio = 1). Odds ratio greater than 1 favours the first intervention; odds ratio less than 1 favours the second intervention.
14
14
Sensitivity analysis for live birth by limiting to RCTs including couples with poor prognosis of natural conception. Each diamond represents the estimate summary odds ratio for each comparison; each horizontal lines represents the confidence interval for each comparison; blue vertical line represents line of no effect (odds ratio = 1). Odds ratio greater than 1 favours the first intervention; odds ratio less than 1 favours the second intervention.
15
15
Network plot for multiple pregnancy. Each node represents an intervention, and the size of each node is proportional to the number of trials reporting such interventions. The widths of lines are proportional to the numbers of trials comparing each pair of interventions.
16
16
Network meta‐analysis for multiple pregnancy. Each diamond represents the estimate summary odds ratio for each comparison; each horizontal line represents the confidence interval for each comparison; blue vertical line represents line of no effect (odds ratio = 1). Odds ratio greater than 1 favours the second intervention; odds ratio less than 1 favours the first intervention.
17
17
Cumulative rankograms of interventions for multiple pregnancy. Each cumulative rankogram illustrates the cumulative probability of each ranking (from the best to the worst rank) for each intervention in terms of multiple pregnancy .
18
18
Comparison‐adjusted funnel plot for multiple pregnancy. (A: expectant management or IUI; B: OS; C: OS‐IUI; D: IVF/ICSI.)
19
19
Network plot for clinical pregnancy. Each node represents an intervention, and the size of each node is proportional to the number of trials reporting such intervention. The widths of the lines are proportional to the numbers of trials comparing each pair of interventions.
20
20
Network meta‐analysis for clinical pregnancy. Each diamond represents the estimate summary odds ratio for each comparison; each horizontal line represents the confidence interval for each comparison; blue vertical line represents line of no effect (odds ratio = 1). Odds ratio greater than 1 favours the first intervention; odds ratio less than 1 favours the second intervention.
21
21
Cumulative rankograms of interventions for clinical pregnancy. Each cumulative rankogram illustrates the cumulative probability of each ranking (from the best to the worst rank) for each intervention in terms of clinical pregnancy.
22
22
Comparison‐adjusted funnel plot for clinical pregnancy.(A: expectant management; B: OS; C: IUI; D: OS‐IUI; E: IVF/ICSI.)
23
23
Forest plot of comparison: 2 Pairwise meta‐analysis for OHSS, outcome: 2.5 IVF/ICSI vs OS‐IUI.
1.1
1.1. Analysis
Comparison 1 Pairwise meta‐analyses for live birth, multiple pregnancy, and clinical pregnancy, Outcome 1 Live birth.
1.2
1.2. Analysis
Comparison 1 Pairwise meta‐analyses for live birth, multiple pregnancy, and clinical pregnancy, Outcome 2 Multiple pregnancy.
1.3
1.3. Analysis
Comparison 1 Pairwise meta‐analyses for live birth, multiple pregnancy, and clinical pregnancy, Outcome 3 Clinical pregnancy.
2.1
2.1. Analysis
Comparison 2 Pairwise meta‐analysis for OHSS, Outcome 1 OS‐IUI vs EM.
2.2
2.2. Analysis
Comparison 2 Pairwise meta‐analysis for OHSS, Outcome 2 OS‐IUI vs OS.
2.3
2.3. Analysis
Comparison 2 Pairwise meta‐analysis for OHSS, Outcome 3 OS‐IUI vs IUI.
2.4
2.4. Analysis
Comparison 2 Pairwise meta‐analysis for OHSS, Outcome 4 IVF/ICSI vs IUI.
2.5
2.5. Analysis
Comparison 2 Pairwise meta‐analysis for OHSS, Outcome 5 IVF/ICSI vs OS‐IUI.
3.1
3.1. Analysis
Comparison 3 Data analyses of RCTs that were not included in the network meta‐analysis, Outcome 1 Live birth.
3.2
3.2. Analysis
Comparison 3 Data analyses of RCTs that were not included in the network meta‐analysis, Outcome 2 Multiple pregnancy.
3.3
3.3. Analysis
Comparison 3 Data analyses of RCTs that were not included in the network meta‐analysis, Outcome 3 Clinical pregnancy.
See this image and copyright information in PMC

Update of

References

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Goverde 2000 {published data only}
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Guzick 1999 {published data only}
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Hughes 2004 {published data only}
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Janko 1998 {published data only}
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Karlstrom 1993 {published data only}
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Kirby 1991 {published data only}
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Melis 1995 {published data only}
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References to studies excluded from this review

Buvat 1993 {published data only}
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Martinez 1991 {published data only}
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Murdoch 1991 {published data only}
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Reindollar 2010 {published data only}
    1. Reindollar RH, Regan MM, Neumann PJ, Levine BS, Thornton KL, Alper MM, et al. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertility & Sterility 2010;94(3):888‐99. - PubMed
Shokeir 2006 {published data only}
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Soliman 1993 {published data only}
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Tjon Kon Fat 2014 {published data only}
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Zolghadri 2012 {published data only}
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References to ongoing studies

NCT01992731 {published data only}
    1. NCT01992731. IUI vs. IVF/ICSI in Women Aged 38‐42 Years: A Prospective Randomized Controlled Trial [IUI vs. IVF/ICSI in Women Aged 38‐42 Years: A Prospective Randomized Controlled Trial]. clinicaltrials.gov/ct2/show/NCT01992731 (first posted 25 November 2013).
NCT02001870 {published data only}
    1. NCT02001870. Comparison of the Efficiency of Intra‐uterine Insemination and in Vitro Fertilization in Women Over 37 Years (AMPAGE) [Comparison of the Efficiency of Intra‐uterine Insemination and in Vitro Fertilization in Women Over 37 Years (AMPAGE)]. clinicaltrials.gov/ct2/show/NCT02001870 (first posted 5 December 2013).
NCT02461173 {published data only}
    1. NCT02461173. Stimulated Intrauterine Insemination Cycles and Unstimulated Intrauterine Insemination Cycles in Couples With Unexplained Infertility [Comparison Between Stimulated Intrauterine Insemination Cycles and Unstimulated Intrauterine Insemination Cycles in Couples With Unexplained Infertility]. clinicaltrials.gov/ct2/show/NCT02461173 (first posted 3 June 2015).
NCT03455426 {published data only}
    1. NCT03455426. Intrauterine Insemination With Letrozole Versus Intrauterine Insemination in Natural Cycle. A Randomised Controlled Trial [Intrauterine Insemination With Letrozole Versus Intrauterine Insemination in Natural Cycle. A Randomised Controlled Trial]. clinicaltrials.gov/ct2/show/NCT03455426 (first posted 6 March 2018).
NTR5599 {published data only}
    1. NTR5599. Intrauterine Insemination for Unexplained or Mild Male Subfertility [Intrauterine Insemination for Unexplained or Mild Male Subfertility]. trialregister.nl/trialreg/admin/rctview.asp?TC=5599 2016; Vol. (registered 18 December 2015).

Additional references

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