In vitro fertilisation for unexplained subfertility

Zabeena Pandian; Ahmed Gibreel; Siladitya Bhattacharya

doi:10.1002/14651858.CD003357.pub4

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Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 3

Study flow diagram.

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Figure 4

Forest plot of comparison: 1 IVF versus expectant management, outcome: 1.1 Live birth rate per woman.

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Figure 5

Forest plot of comparison: 1 IVF versus expectant management, outcome: 1.2 Clinical pregnancy rate per woman.

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Figure 6

Forest plot of comparison: 2 IVF versus unstimulated IUI, outcome: 2.1 Live birth rate per woman.

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Figure 7

Forest plot of comparison: 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), outcome: 3.1 Live birth rate per woman.

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Figure 8

Forest plot of comparison: 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), outcome: 3.2 Clinical pregnancy rate per woman.

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Figure 9

Forest plot of comparison: 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), outcome: 3.3 Multiple pregnancy rate per woman.

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Analysis 1.1

Comparison 1 IVF versus expectant management, Outcome 1 Live birth rate per woman.

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Analysis 1.2

Comparison 1 IVF versus expectant management, Outcome 2 Clinical pregnancy rate per woman.

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Analysis 2.1

Comparison 2 IVF versus unstimulated IUI, Outcome 1 Live birth rate per woman.

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Analysis 2.2

Comparison 2 IVF versus unstimulated IUI, Outcome 2 Clinical pregnancy rate per woman.

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Analysis 2.3

Comparison 2 IVF versus unstimulated IUI, Outcome 3 Multiple pregnancy rate per woman.

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Analysis 3.1

Comparison 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), Outcome 1 Live birth rate per woman.

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Analysis 3.2

Comparison 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), Outcome 2 Clinical pregnancy rate per woman.

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Analysis 3.3

Comparison 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), Outcome 3 Multiple pregnancy rate per woman.

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Analysis 3.4

Comparison 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), Outcome 4 Incidence of OHSS per woman.

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Analysis 3.5

Comparison 3 IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC), Outcome 5 Miscarriage rate per woman.

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Summary of findings for the main comparison. IVF compared with expectant management for unexplained subfertility

IVF compared with expectant management for unexplained subfertility
Population: women with unexplained subfertility Settings: fertility clinic Intervention: IVF Comparison: expectant management
Outcomes	Plain language summary	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
		Assumed risk	Corresponding risk
		Expectant management	IVF
Live birth rate per woman IVF vs expectant management	There is inconclusive evidence to suggest that IVF may result in more births than expectant management	37 per 1000	458 per 1000 (90 to 879)	OR 22 (2.56 to 189.37)	51 (1 study)	⊕⊝⊝⊝ Very low^a
Pregnancy rate per woman IVF vs expectant management	There is inconclusive evidence to suggest that IVF may result in more clinical pregnancies than expectant management	127 per 1000	320 per 1000 (135 to 588)	OR 3.24 (1.07 to 9.8)	86 (2 studies)	⊕⊝⊝⊝ Very low^a
Multiple pregnancy rate	Not reported in the included studies
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; IVF: In vitro fertilisation; OR: Odds ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aThe GRADE quality rating was downgraded by 3 levels due to very serious imprecision, questionable applicability and (for the analysis of clinical pregnancy) serious inconsistency. Very few events were reported in the included studies (12 births and 18 pregnancies altogether). There was also substantial statistical heterogeneity (I²=80%) in the analysis of clinical pregnancies (with differing directions of effect) and applicability was unclear due to the long duration of unexplained infertility and use of co‐interventions.

Summary of findings for the main comparison. IVF compared with expectant management for unexplained subfertility

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Summary of findings 2. IVF compared with unstimulated IUI for unexplained subfertility

IVF compared with unstimulated IUI for unexplained subfertility
Population: women with unexplained subfertility Setting: fertility clinic Intervention: IVF Comparison: unstimulated IUI
Outcomes	Plain language summary	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
		Assumed risk	Corresponding risk
		Unstimulated IUI	IVF
Live birth rate IVF vs IUI	Evidence suggests that IVF may result in more births than insemination without using fertility drugs	160 per 1000	320 per 1000 (185 to 494)	OR 2.47 (1.19 to 5.12)	156 (2 studies)	⊕⊕⊝⊝ Low^a
Pregnancy rate IVF vs IUI	It is unclear whether there is a difference in the pregnancy rate resulting from IVF compared with insemination without using fertility drugs, due to insufficient evidence	121 per 1000	400 per 1000 (115 to 775)	OR 4.83 (0.94 to 24.95)	43 (1 study)	⊕⊕⊝⊝ Very low^b
Multiple pregnancy rate	It is unclear whether there is a difference in the multiple pregnancy rate resulting from IVF compared with insemination without using fertility drugs, due to insufficient evidence	30 per 1000	31 per 1000 (1 to 460)	OR 1.03 (0.04 to 27.29)	43 (1 study)	⊕⊝⊝⊝ Very low^c
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; IUI: Intrauterine insemination; OR: Odds ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aThe GRADE quality rating was downgraded by 2 levels due to serious imprecision: There were only 44 events. There was also substantial statistical heterogeneity (I²=60%), though the direction of effect was consistent. ^bThe GRADE quality rating was downgraded by 3 levels due to very serious imprecision, with only 8 events. The confidence interval is compatible with no difference between the groups or with a large benefit in the IVF group. ^cThe GRADE quality rating was downgraded by 3 levels due to very serious imprecision: there was only one event in this analysis

Summary of findings 2. IVF compared with unstimulated IUI for unexplained subfertility

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Summary of findings 3. IVF compared with IUI + superovulation for unexplained subfertility

IVF compared with IUI + superovulation for unexplained subfertility
Population: women with unexplained subfertility Setting: fertility clinic Intervention: IVF Comparison: IUI + superovulation
Outcomes	Plain language summary	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
		Assumed risk	Corresponding risk
		IUI + superovulation	IVF
Live birth rate in treatment‐naive women IVF vs IUI + gonadotropins	In treatment‐naive women there is no conclusive evidence of a difference in live birth rates between IVF and insemination using injectable fertility drugs	273 per 1000	308 per 1000 (264 to 360)	OR 1.27 (0.94 to 1.73)	745 (4 studies)	⊕⊕⊕⊝ Moderate^a
Live birth rate in pretreated women IVF vs IUI + gonadotropins	In women pretreated with oral fertility drugs IVF leads to more live births than insemination using injectable fertility drugs	219 per 1000	523 per 1000 (374 to 731)	OR 3.90 (2.32 to 6.57)	280 (1 study)	⊕⊕⊕⊝ Moderate^b
Live birth rate in treatment‐naive women IVF vs IUI + CC	In treatment‐naive women there is no conclusive evidence of a difference in live birth rates between IVF and insemination using injectable fertility drugs	154 per 1000	314 per 1000 (148 to 668)	OR 2.51 (0.96 to 6.55)	103 (1 study)	⊕⊕⊝⊝ Low^c
Multiple pregnancy rate	In treatment‐naive women there is no evidence of a difference in multiple pregnancy rates between IVF and insemination using injectable fertility drugs	58 per 1000	47 per 1000 (28 to 78)	OR 0.81 (0.47 to 1.39)	848 (4 studies)	⊕⊕⊕⊝ Moderate^d
Incidence of OHSS	In treatment‐naive women there is no evidence of a difference in OHSS rates between IVF and insemination using injectable fertility drugs	58 per 1000	66 per 1000 (26 to 158)	OR 1.15 (0.43 to 3.06)	324 (2 studies)	⊕⊕⊝⊝ Low^e
The basis for the assumed risk* is the median risk in the control groups. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CC: Clomiphene citrate; CI: Confidence interval; IUI: Intrauterine insemination; IVF: In vitro fertilisation; OHSS: Ovarian hyperstimulation syndrome; OR: Odds ratio ;RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aThe GRADE quality rating was downgraded by 1 level due to serious imprecision: the confidence interval is compatible with no difference between the interventions or with meaningful benefit from IVF. ^bThe GRADE quality rating was downgraded by 1 level due to the relatively small number of events (n=97) in the single included trial. ^cThe GRADE quality rating was downgraded by 2 levels due to very serious imprecision: there were only 24 events and the confidence interval is compatible with no difference between the interventions or with meaningful benefit from IVF ^dThe GRADE quality rating was downgraded by 1 level due to serious imprecision: the confidence interval is compatible with no difference between the interventions or with meaningful benefit in either arm. ^eThe GRADE quality rating was downgraded by 2 levels due to serious imprecision, risk of bias in one trial and the small number of events in the included trials. The confidence interval is compatible with no difference between the interventions or with meaningful benefit in either arm.

Summary of findings 3. IVF compared with IUI + superovulation for unexplained subfertility

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Comparison 1. IVF versus expectant management

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	22.0 [2.56, 189.37]

2 Clinical pregnancy rate per woman Show forest plot	2	86	Odds Ratio (M‐H, Fixed, 95% CI)	3.24 [1.07, 9.80]

Comparison 1. IVF versus expectant management

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Comparison 2. IVF versus unstimulated IUI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	2	156	Odds Ratio (M‐H, Fixed, 95% CI)	2.47 [1.19, 5.12]

2 Clinical pregnancy rate per woman Show forest plot	1	43	Odds Ratio (M‐H, Fixed, 95% CI)	4.83 [0.94, 24.95]

3 Multiple pregnancy rate per woman Show forest plot	1	43	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.04, 27.29]

Comparison 2. IVF versus unstimulated IUI

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Comparison 3. IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Treatment‐naive women IVF vs IUI + gonadotropins	4	745	Odds Ratio (M‐H, Fixed, 95% CI)	1.27 [0.94, 1.73]
1.2 Pretreated women IVF vs IUI + gonadotropins	1	280	Odds Ratio (M‐H, Fixed, 95% CI)	3.90 [2.32, 6.57]
1.3 Treatment‐naive women IVF vs IUI + CC	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	2.51 [0.96, 6.55]
2 Clinical pregnancy rate per woman Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Treatment‐naive women IVF vs IUI + gonadotropins	3	627	Odds Ratio (M‐H, Fixed, 95% CI)	1.45 [1.03, 2.03]
2.2 Treatment‐naive women IVF vs IUI + CC	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	4.59 [1.86, 11.35]
2.3 Pretreated women IVF vs IUI + gonadotropins	1	280	Odds Ratio (M‐H, Fixed, 95% CI)	14.13 [7.57, 26.38]
3 Multiple pregnancy rate per woman Show forest plot	4	848	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.47, 1.39]

3.1 Treatment‐naive women IUI + gonadotropins	4	745	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.45, 1.39]
3.2 Treatment‐naive women IVF vs IUI + CC	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	1.02 [0.20, 5.31]
4 Incidence of OHSS per woman Show forest plot	2	324	Odds Ratio (M‐H, Fixed, 95% CI)	1.15 [0.43, 3.06]

4.1 Treatment‐naive women IVF vs IUI + gonadotropins	2	221	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.36, 4.14]
4.2 Treatment‐naive women IVF vs IUI + CC	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	1.02 [0.20, 5.31]
5 Miscarriage rate per woman Show forest plot	1	206	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.59, 2.28]

5.1 Treatment‐naive women IVF vs IUI + CC	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.44, 3.02]
5.2 Treatment‐naive women IVF vs IUI+ gonadotropins	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.44, 3.02]

Comparison 3. IVF versus IUI + ovarian stimulation with gonadotropins or clomiphene (CC)

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