Gonadotrophins for ovulation induction in women with polycystic ovary syndrome

Nienke S Weiss; Elena Kostova; Marleen Nahuis; Ben Willem J Mol; Fulco van der Veen; Madelon van Wely

doi:10.1002/14651858.CD010290.pub3

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Figure 1

Study flow diagram

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 4

Forest plot of comparison 1. Recombinant FSH (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), outcome: 1.1 Live birth rate per woman by urinary gonadotrophins

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Figure 5

Forest plot of comparison 1. Recombinant FSH (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), outcome: 1.8 Incidence of OHSS per woman by urinary gonadotrophins

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Figure 6

Forest plot of comparison 2. Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH), outcome: 2.1 Live birth rate per woman

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Analysis 1.1

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 1 Live birth rate per woman by urinary gonadotrophins.

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Analysis 1.2

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 2 Live birth rate per woman by sponsor.

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Analysis 1.3

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 3 Multiple pregnancy per woman by urinary gonadotrophins.

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Analysis 1.4

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 4 Multiple pregnancy per woman by sponsor.

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Analysis 1.5

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 5 Clinical pregnancy rate per woman by urinary gonadotrophins.

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Analysis 1.6

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 6 Incidence of multiple pregnancy per clinical pregnancy by urinary gonadotrophins.

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Analysis 1.7

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 7 Miscarriage rate per woman by urinary gonadotrophins.

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Analysis 1.8

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 8 Incidence of OHSS per woman by urinary gonadotrophins.

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Analysis 1.9

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 9 Total gonadotrophin dose per woman (IU) by urinary gonadotrophins.

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Analysis 1.10

Comparison 1 Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins), Outcome 10 Total duration of stimulation per woman (days) by urinary gonadotrophins.

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Analysis 2.1

Comparison 2 Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH), Outcome 1 Live birth rate per woman.

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Analysis 2.2

Comparison 2 Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH), Outcome 2 Multiple pregnancy per woman.

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Analysis 2.3

Comparison 2 Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH), Outcome 3 Multiple pregnancy per clinical pregnancy.

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Analysis 2.4

Comparison 2 Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH), Outcome 4 Clinical pregnancy rate per woman.

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Analysis 2.5

Comparison 2 Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH), Outcome 5 Miscarriage rate per woman.

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Analysis 2.6

Comparison 2 Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH), Outcome 6 Incidence of OHSS per woman.

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Analysis 3.1

Comparison 3 Gonadotrophins (FSH) versus continued clomiphene citrate (CC), Outcome 1 Live birth rate per woman.

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Analysis 3.2

Comparison 3 Gonadotrophins (FSH) versus continued clomiphene citrate (CC), Outcome 2 Multiple pregnancy per woman.

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Analysis 3.3

Comparison 3 Gonadotrophins (FSH) versus continued clomiphene citrate (CC), Outcome 3 Multiple pregnancy (per clinical pregnancy).

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Analysis 3.4

Comparison 3 Gonadotrophins (FSH) versus continued clomiphene citrate (CC), Outcome 4 Clinical pregnancy per woman.

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Analysis 3.5

Comparison 3 Gonadotrophins (FSH) versus continued clomiphene citrate (CC), Outcome 5 Miscarriages per woman.

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Analysis 3.6

Comparison 3 Gonadotrophins (FSH) versus continued clomiphene citrate (CC), Outcome 6 Incidence of OHSS per woman.

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Summary of findings for the main comparison. Recombinant follicle stimulating hormone versus urinary‐derived gonadotrophins for ovulation induction in women with polycystic ovarian syndrome

Recombinant follicle stimulating hormone versus urinary‐derived gonadotrophins for ovulation induction in women with polycystic ovarian syndrome
Patient or population: women with polycystic ovarian syndrome (PCOS) undergoing ovulation induction Settings: women visiting the outpatient clinic Intervention: recombinant follicle stimulating hormone (rFSH) Comparison: urinary‐derived gonadotrophins
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
Outcomes	Risk with urinary‐derived gonadotrophins	Risk with rFSH	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
Live birth rate per woman	157 per 1000	190 per 1000 (130 to 279)	RR 1.21 (0.83 to 1.78)	505 (5 studies)	⊕⊕⊝⊝ LOW ^a,b
Incidence of multiple pregnancy (per woman)	30 per 1000	25 per 1000 (14 to 48)	RR 0.86 (0.46 to 1.61)	1368 (8 studies)	⊕⊕⊝⊝ LOW ^a,b
Clinical pregnancy rate per woman	239 per 1000	251 per 1000 (210 to 303)	RR 1.05 (0.88 to 1.27)	1330 (8 studies)	⊕⊕⊝⊝ LOW ^a,b
Miscarriage rate per woman	47 per 1000	56 per 1000 (33 to 95)	RR 1.20 (0.71 to 2.04)	970 (7 studies)	⊕⊕⊝⊝ LOW ^a,b
Incidence of OHSS per woman	22 per 1000	33 per 1000 (12 to 96)	RR 1.48 (0.82 to 2.65)	1565 (10 studies)	⊕⊝⊝⊝ VERY LOW ^a,b,c
* The risk in the intervention group (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; RR: risk ratio; OHSS: ovarian hyperstimulation syndrome
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded one level for imprecision around the absolute effect ^bDowngraded one level for inconsistency in results across studies ^cDowngraded one level for inconsistent definition or for the lack of definition of OHSS

Summary of findings for the main comparison. Recombinant follicle stimulating hormone versus urinary‐derived gonadotrophins for ovulation induction in women with polycystic ovarian syndrome

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Summary of findings 2. Human menopausal gonadotrophin or highly purified human menopausal gonadotrophin versus urinary follicle stimulating hormone for ovulation induction in women with polycystic ovarian syndrome

Human menopausal gonadotrophin or highly purified human menopausal gonadotrophin versus urinary follicle stimulating hormone for ovulation induction in women with polycystic ovarian syndrome
Patient or population: women with polycystic ovarian syndrome (PCOS) undergoing ovulation induction Settings: women visiting the outpatient clinic Intervention: Human menopausal gonadotrophin (HMG) or highly purified HMG Comparison: urinary follicle stimulating hormone (uFSH)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
Outcomes	Risk with uFSH	Risk with HMG or HP‐HMG	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
Live birth rate per woman	179 per 1000	230 per 1000 (117 to 452)	RR 1.28 (0.65 to 2.52)	138 (3 studies)	⊕⊝⊝⊝ VERY LOW ^a,b
Incidence of multiple pregnancy (per woman)	23 per 1000	48 per 1000 (12 to 203)	RR 2.13 (0.51 to 8.91)	161 (4 studies)	⊕⊝⊝⊝ VERY LOW ^a,b
Clinical pregnancy rate per woman	203 per 1000	266 per 1000 (134 to 527)	RR 1.31 (0.66 to 2.59)	102 (3 studies)	⊕⊝⊝⊝ VERY LOW ^a,b
Miscarriage rate per woman	82 per 1000	27 per 1000 (5 to 161)	RR 0.33 (0.06 to 1.97)	98 (2 studies)	⊕⊝⊝⊝ VERY LOW ^a,b
Incidence of OHSS per woman	No events ^c	4/28 ^c	RR 7.07 (0.42 to 117.81)	53 (2 studies)	⊕⊝⊝⊝ VERY LOW ^a,b,d
* The risk in the intervention group (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; RR: risk ratio; OHSS: ovarian hyperstimulation syndrome
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngarded two levels for serious imprecision around the absolute effect (wide CI and small sample size) ^bDowngraded one level for inconsistency in results across studies ^cEvent rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group ^d Downgraded one level for inconsistent definition or for the lack of definition of OHSS; two of four studies did not report this outcome

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Summary of findings 3. Gonadotrophins compared to continued clomiphene citrate for ovulation induction

Gonadotrophins compared to continued clomiphene citrate for ovulation induction
Patient or population: anovulatory women with clomiphene citrate‐failure Setting: women visiting the outpatient clinic Intervention: gonadotrophins Comparison: continued clomiphene citrate (CC)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with continued CC	Risk with gonadotrophins	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Live birth rate per woman	413 per 1000	512 per 1000 (434 to 603)	RR 1.24 (1.05 to 1.46)	661 (1 study)	⊕⊕⊕⊝ MODERATE ^a
Incidence of multiple pregnancy per woman	24 per 1000	21 per 1000 (8 to 57)	RR 0.89 (0.33 to 2.40)	661 (1 study)	⊕⊕⊕⊝ MODERATE ^a
Clinical pregnancy rate per woman	446 per 1000	584 per 1000 (504 to 678)	RR 1.31 (1.13 to 1.52)	661 (1 study)	⊕⊕⊕⊝ MODERATE ^a
Miscarriages per woman	33 per 1000	73 per 1000 (37 to 147)	RR 2.23 (1.11 to 4.47)	661 (1 study)	⊕⊕⊝⊝ LOW ^a,b,c	There may be little or no difference when expressed per clinical pregnancy
Incidence of OHSS per woman	0 per 1000	0 per 1000 (0 to 0)	not estimable	661 (1 study)	⊕⊕⊝⊝ LOW ^a,b
*The risk in the intervention group (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; RR: risk ratio; OHSS: ovarian hyperstimulation syndrome
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^a Downgraded one level for risk of bias – no blinding performed ^b Downgraded one level for imprecision in result ^c Downgraded one level for inconsistency in outcome, i.e. there were more clinical pregnancies in the gonadotrophin group; there may be little or no difference when expressing miscarriage per clinical pregnancy

Summary of findings 3. Gonadotrophins compared to continued clomiphene citrate for ovulation induction

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Comparison 1. Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman by urinary gonadotrophins Show forest plot	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.83, 1.78]

1.1 rFSH versus HMG	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.68, 1.57]
1.2 rFSH versus uFSH	2	96	Risk Ratio (M‐H, Fixed, 95% CI)	2.66 [0.95, 7.43]
2 Live birth rate per woman by sponsor Show forest plot	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.83, 1.78]

2.1 Ferring	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.68, 1.57]
2.2 unknown	2	96	Risk Ratio (M‐H, Fixed, 95% CI)	2.66 [0.95, 7.43]
3 Multiple pregnancy per woman by urinary gonadotrophins Show forest plot	8	1368	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.46, 1.61]

3.1 rFSH versus HMG	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.49, 2.79]
3.2 rFSH versus uFSH	5	959	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.25, 1.59]
4 Multiple pregnancy per woman by sponsor Show forest plot	8	1368	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.67, 1.60]

4.1 Ferring	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.49, 2.79]
4.2 MSD ‐ Organon	1	172	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.68, 2.23]
4.3 Merck ‐ Serono	2	357	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.14, 1.80]
4.4 Unknown	2	430	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.19, 4.49]
5 Clinical pregnancy rate per woman by urinary gonadotrophins Show forest plot	8	1330	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.88, 1.27]

5.1 rFSH versus HMG	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.77]
5.2 rFSH versus uFSH	5	921	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.82, 1.25]
6 Incidence of multiple pregnancy per clinical pregnancy by urinary gonadotrophins Show forest plot	8	315	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.43, 1.32]

6.1 rFSH versus HMG	3	81	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.47, 2.09]
6.2 rFSH versus uFSH	5	234	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.24, 1.35]
7 Miscarriage rate per woman by urinary gonadotrophins Show forest plot	7	970	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.71, 2.04]

7.1 rFSH versus HMG	2	335	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.24, 3.70]
7.2 rFSH versus uFSH	5	635	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.71, 2.23]
8 Incidence of OHSS per woman by urinary gonadotrophins Show forest plot	10	1565	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.82, 2.65]

8.1 rFSH versus HMG	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.39, 3.20]
8.2 rFSH versus uFSH	7	1156	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.82, 3.39]
9 Total gonadotrophin dose per woman (IU) by urinary gonadotrophins Show forest plot	6	1046	Mean Difference (IV, Fixed, 95% CI)	‐105.44 [‐154.21, ‐56.68]

9.1 rFSH versus HMG	2	335	Mean Difference (IV, Fixed, 95% CI)	‐283.94 [‐449.10, ‐118.78]
9.2 rFSH versus uFSH	4	711	Mean Difference (IV, Fixed, 95% CI)	‐88.40 [‐139.44, ‐37.36]
10 Total duration of stimulation per woman (days) by urinary gonadotrophins Show forest plot	6	1122	Mean Difference (IV, Fixed, 95% CI)	‐0.66 [‐1.04, ‐0.28]

10.1 rFSH versus HMG	2	335	Mean Difference (IV, Fixed, 95% CI)	‐2.28 [‐3.49, ‐1.07]
10.2 rFSH versus uFSH	4	787	Mean Difference (IV, Fixed, 95% CI)	‐0.49 [‐0.88, ‐0.09]

Comparison 1. Recombinant follicle stimulating hormone (rFSH) versus urinary‐derived gonadotrophins (u‐gonadotrophins)

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Comparison 2. Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	3	138	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.65, 2.52]

2 Multiple pregnancy per woman Show forest plot	4	161	Risk Ratio (M‐H, Fixed, 95% CI)	2.13 [0.51, 8.91]

3 Multiple pregnancy per clinical pregnancy Show forest plot	3	22	Risk Ratio (M‐H, Fixed, 95% CI)	4.2 [0.21, 83.33]

4 Clinical pregnancy rate per woman Show forest plot	3	102	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.66, 2.59]

5 Miscarriage rate per woman Show forest plot	2	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.06, 1.97]

6 Incidence of OHSS per woman Show forest plot	2	53	Risk Ratio (M‐H, Fixed, 95% CI)	7.07 [0.42, 117.81]

Comparison 2. Human menopausal gonadotrophin (HMG) or highly purified HMG (HP‐HMG) versus urinary FSH (uFSH)

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Comparison 3. Gonadotrophins (FSH) versus continued clomiphene citrate (CC)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate per woman Show forest plot	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [1.05, 1.46]

2 Multiple pregnancy per woman Show forest plot	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.33, 2.44]

3 Multiple pregnancy (per clinical pregnancy) Show forest plot	1	340	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.25, 1.84]

4 Clinical pregnancy per woman Show forest plot	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [1.13, 1.52]

5 Miscarriages per woman Show forest plot	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	2.23 [1.11, 4.47]

6 Incidence of OHSS per woman Show forest plot	1	661	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.01, 0.01]

Comparison 3. Gonadotrophins (FSH) versus continued clomiphene citrate (CC)

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