Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation

Mohan S Kamath; Abha Maheshwari; Siladitya Bhattacharya; Kar Yee Lor; Ahmed Gibreel

doi:10.1002/14651858.CD008528.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 Clomiphene citrate or letrozole with or without gonadotropins in conjunction with or without midcycle antagonist versus gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population, outcome: 1.1 Live birth.

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Figure 5

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Figure 6

Funnel plot of comparison: 1 Clomiphene citrate or letrozole with gonadotropins in conjunction with or without midcycle antagonist versus gonadotropins with GnRH protocols in IVF and ICSI cycles in general population, outcome: 1.4 Clinical pregnancy rate.

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Figure 7

Forest plot of comparison: 2 Clomiphene citrate or letrozole with or without gonadotropins in conjunction with or without midcycle antagonist versus gonadotropins (with GnRH agonist or midcycle antagonist) in IVF and ICSI cycles in poor responders, outcome: 2.1 Live birth.

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Analysis 1.1

Comparison 1 Clomiphene citrate or letrozole with or without gonadotropins in conjunction with or without midcycle antagonist versus gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population, Outcome 1 Live birth.

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Analysis 1.2

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Analysis 1.3

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Analysis 1.4

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Analysis 1.5

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Analysis 1.6

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Analysis 1.7

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Analysis 1.8

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Analysis 1.9

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Analysis 1.10

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Analysis 1.11

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Analysis 2.1

Comparison 2 Clomiphene citrate or letrozole with or without gonadotropins in conjunction with or without midcycle antagonist versus gonadotropins (with GnRH agonist or midcycle antagonist) in IVF and ICSI cycles in poor responders, Outcome 1 Live birth.

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Analysis 2.2

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Analysis 2.3

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Analysis 2.4

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Analysis 2.5

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Analysis 2.6

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Analysis 2.7

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Analysis 2.8

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Summary of findings for the main comparison. Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population for controlled ovarian stimulation

Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population for controlled ovarian stimulation
Patient or population: Women undergoing controlled ovarian stimulation in IVF and ICSI cycles (general population) Setting: Assisted reproduction clinic Intervention: Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) Comparison: Gonadotropins (with GnRH agonists or midcycle antagonist)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with gonadotropins (with GnRH agonists or midcycle antagonist)	Risk with clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist)	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Live birth per woman	235 per 1000	216 per 1000 (155 to 299)	RR 0.92 (0.66 to 1.27)	493 (4 RCTs)	⊕⊕⊝⊝ LOW^1,2
Ovarian hyperstimulation syndrome per woman	63 per 1000	14 per 1000 (7 to 27)	Peto OR 0.21 (0.11 to 0.41)	1067 (5 RCTs)	⊕⊕⊝⊝ LOW^1,3
Clinical pregnancy rate per woman	248 per 1000	248 per 1000 (213 to 288)	RR 1.00 (0.86 to 1.16)	1998 (12 RCTs)	⊕⊕⊕⊝ MODERATE¹
Cancellation rate per woman	80 per 1000	150 per 1000 (114 to 196)	RR 1.87 (1.43 to 2.45)	1784 (9 RCTs)	⊕⊕⊝⊝ LOW^1,4
Mean number of gonadotropin ampoules used per woman	The mean number of ampoules used in the control group ranged from 18 to 50.	In all studies CC plus gonadotropins was associated with use of fewer ampoules. The mean difference ranged from 5.6 to 24.6 ampoules	‐	1098 (6 RCTs)	⊕⊕⊕⊝ MODERATE^1,5
Mean number of oocytes retrieved per woman	The mean number of oocytes retrieved in the control group ranged from 5 to 17.	In seven studies CC plus gonadotropins was associated with retrieval of fewer oocytes, with the mean difference ranging from 1.02 to 6.20 oocytes. The difference was statistically significant in five of these studies. The eighth study found no evidence of a difference between the groups	‐	1481 (8 RCTs)	⊕⊕⊕⊝ MODERATE^1,5
*The risk in the intervention group (and its 95% confidence interval) is based on the mean risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GnRH: gonadotropin‐releasing hormone; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
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 the effect.
¹Downgraded one level (serious risk of bias). All included studies had unclear risk of bias for allocation concealment. ²Downgraded one level (serious imprecision). Confidence interval is wide and compatible with benefit in either group, or with no effect. ³Downgraded one level (serious imprecision). Small number of events. ⁴Downgraded one level (serious inconsistency). I² 61%. ⁵Not downgraded for inconsistency. Although there was significant statistical heterogeneity, this referred to the magnitude of difference rather than direction of evidence.

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Summary of findings 2. Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonist or midcycle antagonist) in IVF and ICSI cycles in poor responders for controlled ovarian stimulation

Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) compared to gonadotropins (with GnRH agonist or midcycle antagonist) in IVF and ICSI cycles in poor responders for controlled ovarian stimulation
Patient or population: Women undergoing controlled ovarian stimulation in IVF and ICSI cycles (poor responders) Setting: Assisted reproduction clinic Intervention: Clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist) Comparison: Gonadotropins (with GnRH agonist or midcycle antagonist)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with gonadotropins (with GnRH agonist or midcycle antagonist)	Risk with clomiphene citrate or letrozole with or without gonadotropins (with or without midcycle antagonist)	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Live birth per woman	49 per 1000	57 per 1000 (24 to 137)	RR 1.16 (0.49 to 2.79)	357 (2 RCTs)	⊕⊕⊝⊝ LOW^1,2
Clinical pregnancy rate per woman	128 per 1000	109 per 1000 (82 to 143)	RR 0.85 (0.64 to 1.12)	1462 (8 RCTs)	⊕⊕⊝⊝ LOW^1,2
Cancellation rate per woman	145 per 1000	212 per 1000 (171 to 263)	RR 1.46 (1.18 to 1.81)	1601 (10 RCTs)	⊕⊕⊝⊝ LOW^1,3
Mean number of gonadotropin ampoules used per woman	The mean number of ampoules used in the control group ranged from 39 to 71.	There were fewer ampoules used in the intervention groups (CC plus gonadotropins: MD ‐23.98, 95% CI ‐27.41 to ‐20.56; participants = 87; studies = 2); letrozole plus gonadotropins: MD ‐46.24, 95% CI ‐50.93 to ‐41.55; participants = 49; studies = 1).	‐	136 (3 RCTs)	⊕⊕⊕⊝ MODERATE^1,4
Mean number of oocytes retrieved per woman	The mean number oocytes retrieved in the control group ranged from 2 to 5.	In three of four studies CC plus gonadotropins versus gonadotropins in an agonist protocol was associated with retrieval of fewer oocytes, with the mean difference ranging from 0.75 to 2.10 oocytes. The difference was statistically significant in two of these studies. One study found no evidence of difference between CC plus gonadotropin versus gonadotropin in an antagonist protocol. Of three studies comparing letrozole plus gonadotrophins, one study reported significantly lower oocyte retrieval while the other two studies found no clear evidence of a difference.	‐	1203 (8 RCTs)	⊕⊕⊕⊝ MODERATE^1,4
*The risk in the intervention group (and its 95% confidence interval) is based on the mean risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GnRH: gonadotropin‐releasing hormone; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
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 the effect.
¹Downgraded one level (serious risk of bias). Many of the included studies had unclear risk of bias for allocation concealment. ²Downgraded one level (serious imprecision). Confidence interval is wide and compatible with benefit in either group, or with no effect. ³Downgraded one level (serious inconsistency). I² 64%. ⁴Not downgraded for inconsistency. Although there was high statistical heterogeneity, this referred to the magnitude of difference rather than direction of evidence.

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Table 1. Cycle characteristics of the included trials

Study ID	Downregulation used	Type of FSH used	Starting dose of FSH	Dose of clomiphene citrateor letrozole	Cycle monitoring	Luteal support	Timing of hCG
Ashrafi 2005	Buserelin	hMG	150 to 225 IU/day	100 mg CC	Ultrasound	Progesterone	Leading follicle 17 mm
Bastu 2016	Antagonist (cetrorelix subcutaneous)	hMG and recombinant FSH	hMG and recombinant FSH but in different doses: Group 1: 225 IU hMG + 225 IU rFSH Group 2: 150 IU hMG + 150 IU rFSH Group 3: 5mg Ltz + 150 IU rFSH	5 mg Ltz	Ultrasound	Progesterone	Leading follicle > 17 mm
Elnashar 2016	Antagonist (ganirelix (Orgalutran) subcutaneous) for the Ltz group and triptorelin subcutaneous in the agonist control group	FSH	75 IU for the Ltz group versus 150 to 225 IU for the control FSH/agonist group	10 mg Ltz	Not mentioned	Not mentioned	Not mentioned
Fenichel 1988	Triptorelin intramuscular	hMG	hMG 125 to 300 IU/day	200 mg CC	Ultrasound and oestradiol	hCG	Leading follicle 17 mm
Fujimoto 2014	Ganirelix	hMG	Not mentioned	100 mg CC	Not mentioned	Not mentioned	Not mentioned
Galal 2012	Not mentioned	hMG	150 to 225 IU	10 mg Ltz	Not mentioned	Not mentioned	Not mentioned
Ghosh Dastidar 2010	Not mentioned	Recombinant FSH	100 to 150 IU in the CC + gonadotropins group; 200 to 225 IU in the gonadotropins + GnRH agonist group)	Not mentioned	Not mentioned	Not mentioned	Not mentioned
Grochowski 1999	Triptorelin intramuscular depot	hMG	150 to 225 IU/day	100 mg CC	Ultrasound and oestradiol	Progesterone	Leading follicle 18 mm
Harrison 1994	Triptorelin intramuscular and buserelin intranasal	hMG	150 IU/day	100 mg CC	Ultrasound and oestradiol	Progesterone	Leading follicle 17 mm
Jindal 2013	Antagonist (cetrorelix subcutaneous) for the Ltz or CC group and GnRH agonist for the control group, type not mentioned	Not mentioned	Not mentioned	Not mentioned	Not mentioned	Not mentioned	Not mentioned
Jutras 1991	Leuprorelin	hMG	150 IU/day	50 mg CC	Ultrasound and oestradiol	Not mentioned	Leading follicle 15 mm
Karimzadeh 2010	Buserelin	Recombinant FSH	150 to 225 IU/day	100 mg CC	Ultrasound	Progesterone	Leading follicle 18 mm
Kingsland 1992	Buserelin nasal spray	hMG	According to age (225 IU for women < 35 years and 300 IU for women > 35 years)	100 mg CC	Ultrasound and oestradiol	hCG	Leading follicle 17 mm
Lee 2012	Antagonist (cetrorelix subcutaneous)	hMG	225 IU	2.5 mg Ltz	Ultrasound and oestradiol	Progesterone	Leading follicle 18 mm
Lin 2006	Antagonist (cetrorelix subcutaneous)	hMG	150 to 300 IU/day	100 mg CC	Ultrasound, serum oestradiol, LH, and progesterone	Progesterone	Leading follicle 18 mm
Long 1995	Leuprorelin (Lupron)	hMG	150 IU/day	50 mg CC	Ultrasound and oestradiol	None	Leading follicle 15 mm
Mohsen 2013	Antagonist (cetrorelix subcutaneous) for the Ltz group and agonist (leuprorelin) for the conventional agonist group	hMG	150 IU for the Ltz group versus 300 IU for the control hMG/agonist group	2.5 mg Ltz	Ultrasound and oestradiol	Progesterone	18 mm
Mukherjee 2012	Antagonist (ganirelix (Orgalutran) subcutaneous)	Recombinant FSH	75 IU for the Ltz group versus 150 to 225 IU for the control FSH/antagonist group	5 mg Ltz	Ultrasound and oestradiol	Progesterone	18 mm
Nabati 2016	The type of antagonist used was not mentioned in the study while the agonist used in the control group was buserelin	Recombinant FSH	300 IU for the Ltz group versus 450 IU for the control FSH/agonist group	5 mg Ltz	Ultrasound	Progesterone	17 mm
Pilehvari 2016	Antagonist (cetrorelix subcutaneous)	hMG	150 IU for the CC group versus 300 IU for the control hMG/antagonist group	100 mg CC	Ultrasound	Progesterone	17 to 18 mm
Ragni 2012	Buserelin	Recombinant FSH	450 IU	150 mg CC	Ultrasound and oestradiol	Progesterone	18 to 20 mm
Revelli 2014	Antagonist (cetrorelix or ganirelix (Orgalutran) subcutaneous); agonist was leuprorelin	hMG	150 IU for the CC group versus 300 to 450 IU for the control hMG/antagonist group	100 mg CC	Ultrasound and oestradiol	Progesterone	18 to 20 mm
Schimberni 2016	Antagonist (cetrorelix subcutaneous)	Recombinant FSH	450 IU for both groups	100 mg CC	Ultrasound and oestradiol	Progesterone	18 mm
Tummon 1992	Leuprorelin subcutaneous	hMG	According to body weight (less than 52 kg would start with 75 IU/day, 52 to 75 kg would start with 112.5 IU/day, and 150 IU/day for women who weighed more than 75 kg)	100 mg CC	Ultrasound and oestradiol	Progesterone	Leading follicle 16 mm
Weigert 2002	Buserelin	Recombinant FSH	150 IU/day	100 mg	Ultrasound	Progesterone	Leading follicle 18 mm
Youssef 2011	Buserelin	hMG	225 to 300 IU/day	100 mg	Ultrasound	Progesterone	Not mentioned
CC: clomiphene citrate FSH: follicle‐stimulating hormone GnRH: gonadotropin‐releasing hormone hCG: human chorionic gonadotropin hMG: human menopausal gonadotropin LH: luteinising hormone Ltz: letrozole rFSH: recombinant follicle‐stimulating hormone

Table 1. Cycle characteristics of the included trials

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Comparison 1. Clomiphene citrate or letrozole with or without gonadotropins in conjunction with or without midcycle antagonist versus gonadotropins (with GnRH agonists or midcycle antagonist) in IVF and ICSI cycles in general population

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth Show forest plot	4	493	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.66, 1.27]

1.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol.	4	493	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.66, 1.27]
1.2 Clomiphene citrate ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Letrozole ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Ovarian hyperstimulation syndrome Show forest plot	5	1067	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.21 [0.11, 0.41]

2.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	4	973	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.23 [0.11, 0.47]
2.2 Clomiphene citrate ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Letrozole ± gonadotropins ± antagonist vs. antagonist protocol	1	94	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.14 [0.03, 0.68]
3 Ongoing pregnancy rate Show forest plot	6	758	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.77, 1.30]

3.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	6	758	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.77, 1.30]
3.2 Clomiphene citrate ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Letrozole ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Clinical pregnancy rate Show forest plot	12	1998	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.86, 1.16]

4.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	9	1784	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.88, 1.23]
4.2 Clomiphene citrate± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.12, 0.72]
4.4 Letrozole ± gonadotropins ± antagonist vs. antagonist protocol	2	134	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.71, 1.94]
5 Cancellation rate Show forest plot	9	1784	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.43, 2.45]

5.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	9	1784	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.43, 2.45]
5.2 Clomiphene citrate ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.4 Letrozole ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Mean number of ampoules used Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	6		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Clomiphene citrate ± gonadotropins ± antagonist vs. antagonist protocol	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.4 Letrozole ± gonadotropins ± antagonists vs. antagonist protocol	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Mean number of oocytes retrieved Show forest plot	8		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	8		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Clomiphene citrate ± gonadotropins ± antagonist vs. antagonist protocol	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Letrozole ± gonadotropins ± antagonists vs agonist protocol	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.4 Letrozole ± gonadotropins ± antagonist vs. antagonist protocol	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Multiple pregnancy rate Show forest plot	5	791	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.39, 1.43]

8.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	4	697	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.40, 1.57]
8.2 Clomiphene citrate ± gonadotropins ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.4 Letrozole ± gonadotropins ± antagonist vs. antagonist protocol	1	94	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.04, 3.82]
9 Rate of miscarriage Show forest plot	7	1116	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.61, 1.47]

9.1 Clomiphene citrate ± gonadotropins ± antagonists vs. agonist protocol	6	1022	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.61, 1.75]
9.2 Clomiphene citrate ± gonadotropins ± antagonists vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Letrozole ± gonadotropins ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.4 Letrozole ± gonadotropins ± antagonists vs. antagonists protocol	1	94	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.35, 1.66]
10 Rate of ectopic pregnancy Show forest plot	2	223	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.56 [0.47, 120.94]

10.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	2	223	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.56 [0.47, 120.94]
10.2 Clomiphene citrate ± gonadotrophins ± antagonists vs. antagonist protocol	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.3 Letrozole ± gonadotropins ± antagonists vs. agonists protocol	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.4 Letrozole ± gonadotropins ± antagonists vs. antagonist protocol	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Rate of foetal abnormalities Show forest plot	1	74	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

11.1 Clomiphene citrate ± gonadotropins ± antagonists vs. GnRHagonists or antagonist protocol	1	74	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Letrozole ± gonadotropins ± antagonists vs. GnRH agonist or antagonist protocol	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

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Comparison 2. Clomiphene citrate or letrozole with or without gonadotropins in conjunction with or without midcycle antagonist versus gonadotropins (with GnRH agonist or midcycle antagonist) in IVF and ICSI cycles in poor responders

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth Show forest plot	2	357	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.49, 2.79]

1.1 Clomiphene citrate ± gonadotropin ± antagonist vs. agonist protocol	1	304	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.24, 2.32]
1.2 Clomiphene citrate ± gonadotrophin ± antagonists vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Letrozole ± gonadotrophin ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Letrozole ± gonadotropin ± antagonist vs. antagonist protocol	1	53	Risk Ratio (M‐H, Fixed, 95% CI)	2.60 [0.55, 12.22]
2 Ongoing pregnancy rate Show forest plot	2	748	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.58, 1.28]

2.1 Clomiphene citrate ± gonadotropin ± antagonist vs. agonist protocol	1	695	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.52, 1.19]
2.2 Clomiphene citrate ± gonadotrophin ± antagonists vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Letrozole ± gonadotrophin ± antagonists vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Letrozole ± gonadotropin ± antagonists vs. antagonist protocol	1	53	Risk Ratio (M‐H, Fixed, 95% CI)	2.60 [0.55, 12.22]
3 Clinical pregnancy rate Show forest plot	8	1462	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.64, 1.12]

3.1 Clomiphene citrate ± gonadotropins ± antagonist vs. agonist protocol	3	1069	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.66, 1.27]
3.2 Clomiphene citrate ± gonadotrophin ± antagonists vs. antagonists protocol	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.05, 12.84]
3.3 Letrozole ± gonadotropin ± antagonists vs. agonists protocol	3	221	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.29, 1.13]
3.4 Letrozole ± gonadotropin ± antagonists vs. antagonists protocol	1	95	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.38, 2.86]
4 Cancellation rate Show forest plot	10	1601	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [1.18, 1.81]

4.1 Clomiphene citrate ± gonadotropin ± antagonist vs. agonist protocol	4	1155	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.20, 2.10]
4.2 Clomiphene citrate ± gonadotropin ± antagonists vs. antagonists protocol	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.39, 1.53]
4.3 Letrozole ± gonadotropin ± antagonist vs. agonists protocol	3	221	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [1.10, 3.13]
4.4 Letrozole ± gonadotropin ± antagonists vs. antagonists protocol	2	148	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.67, 2.01]
5 Mean number of ampoules used Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.1 Clomiphene citrate ± gonadotropin ± antagonists vs. agonist protocol	2	87	Mean Difference (IV, Fixed, 95% CI)	‐23.98 [‐27.41, ‐20.56]
5.2 Clomiphene citrate ± gonadotrophin ± antagonist vs. antagonist protocol	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Letrozole ± gonadotropin ± antagonist vs. agonist protocol	1	49	Mean Difference (IV, Fixed, 95% CI)	‐46.24 [‐50.93, ‐41.55]
5.4 Letrozole ± gonadotrophin ± antagonist vs. antagonist protocol	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Mean number of oocytes retrieved. Show forest plot	8		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6.1 Clomiphene citrate ± gonadotropin ± antagonists vs. agonist protocol	4		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Clomiphene citrate ± gonadotropin ± antagonist vs. antagonist protocol	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Letrozole ± gonadotropin ± antagonists vs. agonist protocol	3		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.4 Letrozole ± gonadotropin ± antagonists vs. antagonist protocol	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Multiple pregnancy rate Show forest plot	1	304	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.05, 5.75]

7.1 Clomiphene citrate ± gonadotropin ± antagonist vs. agonist protocol	1	304	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.05, 5.75]
7.2 Clomiphene citrate ± gonadotrophin ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Letrozole ± gonadotrophin ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.4 Letrozole ± gonadotrophin ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Rate of miscarriage Show forest plot	3	818	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.45, 2.12]

8.1 Clomiphene citrate ± gonadotropin ± antagonists vs. agonist protocol	2	765	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.55, 3.01]
8.2 Clomiphene citrate ± gonadotrophin ± antagonist vs. antagonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.3 Letrozole ± gonadotrophin ± antagonist vs. agonist protocol	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.4 Letrozole ± gonadotropin ± antagonists vs. antagonist protocol	1	53	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.73]

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