In vitro fertilisation for unexplained subfertility

Sesh Kamal Sunkara; Mohan S Kamath; Zabeena Pandian; Ahmed Gibreel; Siladitya Bhattacharya

doi:10.1002/14651858.CD003357.pub5

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Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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Figure 4

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

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Figure 5

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

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Figure 6

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

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Figure 7

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

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Figure 8

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

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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 2.4

Comparison 2: IVF versus unstimulated IUI, Outcome 4: Miscarriage rate

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Analysis 3.1

Comparison 3: IVF versus IUI + ovarian stimulation with gonadotropins or 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 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 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 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 CC, Outcome 5: Miscarriage rate per woman

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Summary of findings 1. IVF versus expectant management for unexplained subfertility

Outcomes	Plain language summary	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)
IVF versus expectant management for unexplained subfertility
Patient or population: women with unexplained subfertility Setting: fertility clinic Intervention: IVF Comparison: expectant management
		Assumed risk	Corresponding risk
		Expectant management	IVF
Live birth per woman randomised	We are uncertain whether IVF treatment may improve live birth rate compared with expectant management.	37 per 1000	458 per 1000 (90 to 879)	OR 22 (2.56 to 189.37)	51 (1 study)	⊕⊝⊝⊝ Very low ^1,2,3
Clinical pregnancy rate per woman randomised	We are uncertain whether IVF treatment may improve clinical pregnancy rate compared with expectant management.	122 per 1000	310 per 1000 (129 to 576)	OR 3.24 (1.07 to 9.8)	86 (2 studies)	⊕⊝⊝⊝ Very low ^{3, 4, 5}
Multiple pregnancy rate per woman randomised	No study reported this outcome.
OHSS rate per woman randomised	No study reported this outcome.
Miscarriage rate per woman randomised	No study reported this outcome.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. 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; OHSS: ovarian hyperstimulation syndrome; 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.
¹Serious risk of bias: downgraded by one level. Unclear risk of performance bias. ²Serious indirectness: downgraded by one level. Single study, small number of participants, and very wide confidence interval. ³Serious imprecision: downgraded by one level. Very wide confidence interval. ⁴Serious risk of bias: downgraded by one level. High risk of other bias and attrition bias, as well as unclear risk of bias for other domains. ⁵Serious inconsistency: downgraded by one level. High statistical heterogeneity (80%).

Summary of findings 1. IVF versus expectant management for unexplained subfertility

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Summary of findings 2. IVF versus unstimulated IUI for unexplained subfertility

Outcomes	Plain language summary	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)
IVF versus unstimulated IUI for unexplained subfertility
Population: women with unexplained subfertility Setting: fertility clinic Intervention: IVF Comparison: unstimulated IUI
		Assumed risk	Corresponding risk
		Unstimulated IUI	IVF
Live birth rate per woman randomised	IVF treatment may improve LBR compared with IUI 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 ^1,2,3
Clinical pregnancy rate per woman randomised	There is not enough evidence to determine whether there is a difference in clinical pregnancy rate between IVF and IUI without using fertility drugs.	121 per 1000	400 per 1000 (115 to 775)	OR 4.83 (0.94 to 24.95)	43 (1 study)	⊕⊝⊝⊝ Very low^1,2,4
Multiple pregnancy rate per woman randomised	There is not enough evidence to determine whether there is a difference in multiple pregnancy rate between IVF and IUI without using fertility drugs.	30 per 1000	31 per 1000 (1 to 460)	OR 1.03 (0.04 to 27.29)	43 (1 study)	⊕⊝⊝⊝ Very low ^1,2,4
OHSS rate per woman randomised	No study reported this outcome.
Miscarriage rate per woman randomised	There is not enough evidence to determine whether there is a difference in miscarriage rate between IVF and IUI without using fertility drugs.	61 per 1000	100 per 1000 (9 to 578)	OR 1.72 (0.14 to 21.25)	43 (1 study)	⊕⊝⊝⊝ Very low ^1,2,4
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; IVF: in vitro fertilisation; OHSS: ovarian hyperstimulation syndrome; 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.
¹Serious risk of bias: downgraded by one level. Unclear risk of performance bias. ²Serious imprecision: downgraded by one level. Very wide confidence interval. ³The statistical heterogeneity was moderate (60%), but the direction of effect was consistent, hence we did not downgrade for inconsistency. ⁴Serious indirectness: only one study reported the outcome.

Summary of findings 2. IVF versus unstimulated IUI for unexplained subfertility

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Summary of findings 3. IVF versus IUI + ovarian stimulation with gonadotropins or CC for unexplained subfertility

Outcomes		Plain language summary	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)
IVF versus IUI + ovarian stimulation with gonadotropins or CC for unexplained subfertility
Patient or population: women with unexplained subfertility Setting: fertility clinic Intervention: IVF Comparison: IUI + ovarian stimulation with gonadotropins or CC
			Assumed risk	Corresponding risk
			IUI + ovarian stimulation with gonadotropins or CC	IVF
Live birth rate per woman randomised	Treatment‐naive women: IVF vs IUI + gonadotropins	In treatment‐naive women, there may be little or no difference in live birth rate between IVF and IUI using injectable fertility drugs.	423 per 1000	466 per 1000 (390 to 542)	OR 1.19 (0.87 to 1.61)	731 (3 studies)	⊕⊕⊝⊝ Low ^1,2
	Treatment‐naive women: IVF vs IUI + gonadotropins (1 IVF to 1 IUI cycle)	In treatment‐naive women, there may be little or no difference in live birth rate between 1 cycle of IVF and 1 cycle of IUI using injectable fertility drugs.	261 per 1000	366 per 1000 (243 to 508)	OR 1.63 (0.91 to 2.92)	221 (2 studies)	⊕⊕⊝⊝ Low ^1,2
	Pretreated women: IVF vs IUI + gonadotropins	In women pretreated with oral fertility drugs, IVF may improve live birth rate compared to IUI using injectable fertility drugs.	219 per 1000	522 per 1000 (394 to 648)	OR 3.9 (2.32 to 6.57)	280 (1 study)	⊕⊕⊝⊝ Low^2,3
	Treatment‐naive women: IVF vs IUI + CC	In treatment‐naive women, there may be little or no difference in live birth rate between IVF and IUI using oral fertility drugs.	154 per 1000	313 per 1000 (149 to 544)	OR 2.51 (0.96 to 6.55)	103 (1 study)	⊕⊕⊝⊝ Low ^2,3
Clinical pregnancy rate per woman randomised	Treatment‐naive women: IVF vs IUI + gonadotropins	In treatment‐naive women, there may be little or no difference in clinical pregnancy rate between IVF and IUI using injectable fertility drugs.	481 per 1000	520 per 1000 (441 to 596)	OR 1.17 (0.85 to 1.59)	731 (3 studies)	⊕⊕⊝⊝ Low ^1,2,
	Treatment‐naive women: IVF vs IUI + gonadotropins (1 IVF to 1 IUI cycle)	In treatment‐naive women, there may be little or no difference in clinical pregnancy rate between 1 cycle of IVF and 1 cycle of IUI using injectable fertility drugs.	173 per 1000	490 per 1000 (280 to 704)	OR 4.59 (1.86 to 11.35)	103 (1 study)	⊕⊕⊝⊝ Low ^2,3
	Pretreated women: IVF vs IUI + gonadotropins	In women pretreated with oral fertility drugs, IVF may improve clinical pregnancy rate compared to IUI using injectable fertility drugs.	296 per 1000	856 per 1000 (761 to 917)	OR 14.13 (7.57 to 26.38)	280 (1 study)	⊕⊕⊝⊝ Low ^2,3
	Treatment‐naive women: IVF vs IUI + CC	In treatment‐naive women, there may be little or no difference in clinical pregnancy rate between IVF and IUI using oral fertility drugs.	212 per 1000	490 per 1000 (288 to 695)	OR 3.58 (1.51 to 8.49)	103 (1 study)	⊕⊕⊝⊝ Low ^2,3
Multiple pregnancy rate per woman randomised	Treatment‐naive women: IUI + gonadotropins	In treatment‐naive women, there may be little or no difference in multiple pregnancy rate between IVF and IUI using injectable fertility drugs.	40 per 1000	33 per 1000 (16 to 69)	OR 0.82 (0.38 to 1.77)	731 (3 studies)	⊕⊕⊝⊝ Low ^1,2
	Treatment‐naive women: IVF vs IUI + gonadotropins (1 IVF to 1 IUI cycle)	In treatment‐naive women, there may be little or no difference in multiple pregnancy rate between 1 cycle of IVF and 1 cycle of IUI using injectable fertility drugs.	180 per 1000	143 per 1000 (73 to 258)	OR 0.76 (0.36 to 1.58)	221 (2 studies)	⊕⊕⊝⊝ Low ^1,2
	Treatment‐naive women: IUI + CC	In treatment‐naive women, there may be little or no difference in multiple pregnancy rate between IVF and IUI using oral fertility drugs.	118 per 1000	79 per 1000 (22 to 243)	OR 0.64 (0.17 to 2.41)	102 (1 study)	⊕⊕⊝⊝ Low ^2,3
OHSS rate per woman randomised	Treatment‐naive women: IVF vs IUI + gonadotropins	In treatment‐naive women, it is unclear whether there is a difference in OHSS rate between IVF and IUI using injectable fertility drugs.	0 per 1000	0 per 1000 (0 to 0)	OR 6.86 (0.35 to 134.59)	207 (1 study)	⊕⊝⊝⊝ Very low ^1,2,3
	Treatment‐naive women: IVF vs IUI + gonadotropins (1 IVF to 1 IUI cycle)	In treatment‐naive women, there may be little or no difference in OHSS rate between 1 cycle of IVF and 1 cycle of IUI using injectable fertility drugs.	45 per 1000	54 per 1000 (17 to 164)	OR 1.22 (0.36 to 4.16)	221 (2 studies)	⊕⊕⊝⊝ Low ^1,2
	Treatment‐naive women: IVF vs IUI + CC	In treatment‐naive women, there may be little or no difference in OHSS rate between IVF and IUI using oral fertility drugs.	39 per 1000	59 per 1000 (10 to 281)	OR 1.53 (0.24 to 9.57)	102 (1 study)	⊕⊕⊝⊝ Low ^2,3
Miscarriage rate per woman randomised	Treatment‐naive women: IUI + gonadotropins	In treatment‐naive women, it is unclear whether there is a difference in miscarriage rate between IVF and IUI using injectable fertility drugs.	30 per 1000	9 per 1000 (1 to 85)	OR 0.31 (0.03 to 3.04)	207 (1 study)	⊕⊝⊝⊝ Very low ^1,2,3
	Treatment‐naive women: IVF vs IUI + gonadotropins (1 IVF to 1 IUI cycle)	In treatment‐naive women, there may be little or no difference in miscarriage rate between 1 cycle of IVF and 1 cycle of IUI using injectable fertility drugs.	192 per 1000	216 per 1000 (95 to 418)	OR 1.16 (0.44 to 3.02)	103 (1 study)	⊕⊕⊝⊝ Low^2,3
	Treatment‐naive women: IUI + CC	In treatment‐naive women, there may be little or no difference in miscarriage rate between IVF and IUI using oral fertility drugs.	157 per 1000	216 per 1000 (91 to 430)	OR 1.48 (0.54 to 4.05)	102 (1 study)	⊕⊕⊝⊝ Low^2,3
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. 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
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.
¹Serious risk of bias: downgraded by one level. Unclear risk of performance bias alone or with other bias. ²Serious imprecision: downgraded by one level. Wide confidence interval. ³Serious indirectness: downgraded by one level. Single study.

Summary of findings 3. IVF versus IUI + ovarian stimulation with gonadotropins or CC 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
1.1 Live birth rate per woman Show forest plot	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	22.00 [2.56, 189.37]

1.2 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
2.1 Live birth rate per woman Show forest plot	2	156	Odds Ratio (M‐H, Fixed, 95% CI)	2.47 [1.19, 5.12]

2.2 Clinical pregnancy rate per woman Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

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

2.4 Miscarriage rate Show forest plot	1	43	Odds Ratio (M‐H, Fixed, 95% CI)	1.72 [0.14, 21.25]

Comparison 2. IVF versus unstimulated IUI

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Live birth rate per woman Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1.1 Treatment‐naive women IVF vs IUI + gonadotropins (1 IVF to 2‐3 IUI cycles)	3	731	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.87, 1.61]
3.1.2 Treatment‐naive women IVF vs IUI + gonadotrophins (1 IVF to 1 IUI cycle)	2	221	Odds Ratio (M‐H, Fixed, 95% CI)	1.63 [0.91, 2.92]
3.1.3 Treatment‐naive women IVF vs IUI + CC	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	2.51 [0.96, 6.55]
3.1.4 Pretreated women IVF vs IUI + gonadotropins	1	280	Odds Ratio (M‐H, Fixed, 95% CI)	3.90 [2.32, 6.57]
3.2 Clinical pregnancy rate per woman Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.2.1 Treatment‐naive women IVF vs IUI + gonadotropins	3	731	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.85, 1.59]
3.2.2 Treatment‐naive women IVF vs IUI + gonadotrophins (1 IVF to 1 IUI cycle)	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	4.59 [1.86, 11.35]
3.2.3 Treatment‐naive women IVF vs IUI + CC	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	3.58 [1.51, 8.49]
3.2.4 Pretreated women IVF vs IUI + gonadotropins	1	280	Odds Ratio (M‐H, Fixed, 95% CI)	14.13 [7.57, 26.38]
3.3 Multiple pregnancy rate per woman Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.3.1 Treatment‐naive women IUI + gonadotropins	3	731	Odds Ratio (M‐H, Fixed, 95% CI)	0.82 [0.38, 1.77]
3.3.2 Treatment‐naive women IVF vs IUI + gonadotrophins (1 IVF to 1 IUI cycle)	2	221	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.36, 1.58]
3.3.3 Treatment‐naive women IVF vs IUI + CC	1	102	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.17, 2.41]
3.4 Incidence of OHSS per woman Show forest plot	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

3.4.1 Treatment‐naive women IVF vs IUI + gonadotropins	1	207	Odds Ratio (M‐H, Random, 95% CI)	6.86 [0.35, 134.59]
3.4.2 Treatment‐naive women IVF vs IUI + gonadotrophins (1 IVF to 1 IUI cycle)	2	221	Odds Ratio (M‐H, Random, 95% CI)	1.22 [0.36, 4.16]
3.4.3 Treatment‐naive women IVF vs IUI + CC	1	102	Odds Ratio (M‐H, Random, 95% CI)	1.53 [0.24, 9.57]
3.5 Miscarriage rate per woman Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.5.1 Treatment‐naive women IVF vs IUI + gonadotropins	1	207	Odds Ratio (M‐H, Fixed, 95% CI)	0.31 [0.03, 3.04]
3.5.2 Treatment‐naive women IVF vs IUI + gonadotrophins (1 IVF to 1 IUI cycle)	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.44, 3.02]
3.5.3 Treatment‐naive women IVF vs IUI + CC	1	102	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.54, 4.05]

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

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