. 2019 Nov 11;13(4):257–270. doi: 10.22074/ijfs.2020.5608

Table 1.

Results of main medical interventions


Review	Population	Outcomes assessed	Comparison	Outcomes with significant results
Letrozole

Abu Hashim et al. (32), 2015	CC resistant PCOS	Live birth	CC+metformin vs. Letrozole	Live birth/woman	OR: 0.21, 95% CI: 0.05 to 0.87
		Pregnancy
		Ovulation
		Miscarriage
		Multiple pregnancy
		OHSS
Franik et al. (39), 2014	PCOS, reproductive age	Live birth	Letrozole vs. CC (BMI >25 kg/m²)	Live birth/woman	OR: 1.67, 95% CI: 1.31 to 2.11
		Pregnancy	Letrozole vs. CC (with or without adjuncts followed by timed intercourse)	Live birth/woman	OR: 1.64, 95% CI: 1.32 to 2.04
		Miscarriage	Letrozole vs. CC (with or without adjuncts followed by IUI)	Pregnancy/woman	OR: 1.71, 95% CI: 1.30 to 2.25
		Multiple pregnancy	Letrozole vs. CC (overall with or without adjuncts followed by timed intercourse)	Pregnancy/woman	OR: 1.40, 95% CI: 1.18 to 1.65
		OHSS	Letrozole vs. CC+rFSH and rFSH only	Pregnancy/woman	OR: 1.66, 95% CI: 1.23 to 2.22
		OHSS	Letrozole+metformin vs. CC+metformin	Live birth/woman	OR: 4.5, 95% CI: 1.09 to 18.50
He and Jiang (20), 2011	PCOS	Pregnancy	Letrozole vs. CC	Mature follicles/cycle	SMD: 1.41, 95% CI: 1.54 to 1.28
		Ovulation
		Miscarriage
		Multiple pregnancy
		OHSS	Letrozole vs. CC	Ovulation/cycle	RR: 1.29, 95% CI: 1.12 to 1.49
		Mature follicles	Letrozole vs. CC	Ovulation/cycle	RR: 1.29, 95% CI: 1.12 to 1.49
Misso et al. (49), 2012	PCOS	Live birth	Letrozole long-term (10 days) vs. Letrozole short-term (5 days)	Pregnancy/cycle	Higher in long-term (10 days)
		Pregnancy	Letrozole vs. Anastrozole	Ovulation/cycle	Higher in letrozole
		Ovulation	Letrozole vs. Anastrozole	Pregnancy/woman	Higher in letrozole
		Miscarriage	Letrozole vs. CC	Ovulation/woman	OR: 2.90, 95% CI: 1.72 to 4.88
		Multiple pregnancies	Letrozole vs. LOD	Ovulation/cycle	Higher in letrozole
		Adverse events
		Cost effectiveness
Roque et al. (27), 2015	PCOS (therapy naïve)	Live birth	Letrozole vs. CC	Live birth/woman	RR: 1.55, 95% CI: 1.26 to 1.90
		Clinical pregnancy
		Ovulation
		Miscarriage
		Multiple pregnancy	Letrozole vs. CC	Pregnancy/woman	RR: 1.38, 95% CI: 1.05 to 1.83
CC
Abu Hashim et al. (32), 2015	CC resistant PCOS	Live birth	CC+metformin vs. Gonadotrophins	Live birth/woman	OR: 0.33, 95% CI: 0.13 to 0.85
		Pregnancy	CC+metformin vs. Gonadotrophins	Ovulation/woman	OR: 0.25, 95% CI: 0.15 to 0.41
		Ovulation	CC+metformin vs. CC + NAC	Ovulation/woman	OR: 8.93, 95% CI: 4.61 to 17.32
		Miscarriage	CC+metformin vs. Gonadotrophins	Pregnancy/woman	OR: 0.45, 95% CI: 0.27 to 0.75
		Multiple pregnancy	CC+metformin vs. CC + NAC	Pregnancy/woman	OR: 5.28, 95% CI: 1.91 to 14.62
		OHSS	CC+metformin vs. CC + NAC	Pregnancy/woman	OR: 5.28, 95% CI: 1.91 to 14.62
Brown and Farquhar (46), 2017	WHO group 2 anovulation	Live birth	CC vs. Placebo	Pregnancy/woman	OR: 5.91, 95% CI: 1.77 to 19.68
		Pregnancy	CC vs. Gonadotrophins	Live birth/woman	OR: 0.64, 95% CI: 0.41 to 0.98
		Ovulation	CC vs. Gonadotrophins	Pregnancy/woman	OR: 0.61, 95% CI: 0.40 to 0.93
		Miscarriage	CC 5 day vs. CC 10 day	Live birth/woman	OR: 0.10, 95% CI: 0.02 to 0.45
		Multiple pregnancy	CC 5 day vs. CC 10 day	Pregnancy/woman	OR: 0.18, 95% CI: 0.06 to 0.55
		OHSS	CC+DEX vs. CC	Pregnancy/woman	OR: 6.2, 95% CI: 2.20 to 17.48
		Adverse effects	Early CC vs. late CC	Pregnancy/woman	OR: 2.81, 95% CI: 1.02 to 7.75
		Adverse effects	CC+OCP vs. CC	Pregnancy/woman	OR: 27.18, 95% CI: 3.14 to 235.02
Ding et al. (36), 2016	PCOS	Pregnancy	Late CC vs. Early CC	Mature follicles/cycle	MD: 1.82, 95% CI: 0.86 to 2.78
		Ovulation
		Miscarriage
		Number of follicles
Farquhar et al. (19), 2012	CC resistant PCOS	Live birth	LOD vs. CC+metformin	Live birth/woman	OR: 0.44, 95% CI: 0.24 to 0.82
		Pregnancy	LOD vs. CC+metformin	Costs	MD: 3711.3, 95% CI: 3585.17 to 3837.43
		Ovulation
		Miscarriage
		Multiple pregnancy
		OHSS
		Costs
Gill et al. (33), 2014	CC resistant PCOS, reproductive age	Pregnancy	CC+metformin vs. CC	Ovulation/woman	Higher in CC+metformin
Gill et al. (33), 2014	CC resistant PCOS, reproductive age	Ovulation	CC+metformin vs. CC	Pregnancy/woman	Higher in CC+metformin
Palomba et al. (24), 2009	PCOS	Live birth	Metformin vs. CC+metformin	Live birth/woman	OR: 0.23, 95% CI: 0.13 to 0.40
		Pregnancy	Metformin vs. CC+metformin	Ovulation/woman	OR: 0.23, 95% CI: 0.15 to 0.34
		Ovulation	Metformin vs. CC+metformin	Pregnancy/woman	OR: 0.23, 95% CI: 0.14 to 0.37
		Miscarriage
		Adverse events
Siebert et al. (28), 2012	PCOS (therapy naïve)	Live birth	Metformin vs. CC	Live birth/woman	OR: 0.48, 95% CI: 0.31 to 0.73
		Pregnancy	Metformin vs. CC	Ovulation/woman	OR: 0.48, 95% CI: 0.41 to 0.57
		Ovulation	CC+metformin vs. CC	Ovulation/woman	OR: 1.6, 95% CI: 1.2 to 2.1
		Ovulation	CC+metformin vs. CC	Pregnancy/woman	OR: 1.3, 95% CI: 1.0 to 1.6
Tang et al. (41), 2012	PCOS	Live birth	Metformin vs. CC (BMI≥ 30)	Live birth/woman	OR: 0.3, 95% CI: 0.17 to 0.52
			Metformin vs. CC (BMI ≥ 30)	Ovulation/woman	OR: 0.43, 95% CI: 0.36 to 0.51
		Pregnancy	CC+metformin vs. CC (CC resistant PCOS)	Ovulation/woman	OR: 4.86, 95% CI: 2.43 to 9.74
		Ovulation	CC+metformin vs. CC (BMI<30)	Ovulation/woman	OR: 1.75, 95% CI: 1.27 to 2.39
		Miscarriage	CC+metformin vs. CC (BMI≥30)	Ovulation/woman	OR: 1.78, 95% CI: 1.51 to 2.1
		Multiple pregnancy	Metformin vs. CC (BMI ≥ 30)	Pregnancy/woman	OR: 0.34, 95% CI: 0.21 to 0.55
		Menstrual frequency	Metformin vs. CC (BMI <30)	Pregnancy/woman	OR: 1.94, 95% CI: 1.19 to 3.16
			CC+metformin vs. CC	Pregnancy/woman	OR: 1.51, 95% CI: 1.17 to 1.96
			CC+metformin vs. CC (BMI ≥30)	Pregnancy/woman	OR: 1.76, 95% CI: 1.26 to 2.47
			CC+metformin vs. CC	Side effects	OR: 3.31, 95% CI: 2.11 to 5.20
			CC+metformin vs. CC	Side effects (GIT)	OR: 3.4, 95% CI: 2.08 to 5.54
Thakker et al. (47), 2015	PCOS	Live birth	NAC vs. Placebo (CC resistant PCOS)	Live birth/woman	OR: 3.0, 95% CI: 1.05 to 8.6
		Ovulation	NAC vs. Placebo (CC resistant PCOS)	Ovulation/woman	OR: 8.4, 95% CI: 4.5 to 15.67
		Miscarriage, Multiple pregnancy OHSS	NAC vs. Placebo (CC resistant PCOS)	Pregnancy/woman	OR: 4.83, 95% CI: 2.30 to 10.13
		Menstrual regularity	NAC vs. Placebo (CC resistant PCOS)	Pregnancy/woman	OR: 4.83, 95% CI: 2.30 to 10.13
Xiao et al. (3), 2012	PCOS, <35 years	Pregnancy	Metformin vs. CC	Ovulation/woman	OR: 0.48, 95% CI: 0.26 to 0.87
		Ovulation	Metformin+CC vs. CC	Pregnancy/woman	OR: 1.56, 95% CI: 1.16 to 2.08
		Miscarriage	Metformin+CC vs. CC	Pregnancy/woman	OR: 1.56, 95% CI: 1.16 to 2.08
Insulin sensitizers
Tang et al. (41), 2012	PCOS	Live birth	Metformin vs. Placebo	Side effects (GIT)	OR: 4.27, 95% CI: 2.4 to 7.59
		Clinical pregnancy	Metformin vs. Placebo (BMI < 30)	Menstrual frequency	OR: 21.15, 95% CI: 1.01 to 445.0
		Ovulation	Metformin vs. Placebo (BMI ≥30)	Menstrual frequency	OR: 1.57, 95% CI: 1.03 to 2.41
		Miscarriage	Metformin vs. Placebo (BMI<30)	Pregnancy/woman	OR: 2.35, 95% CI: 1.44 to 3.82
		Multiple pregnancy	Metformin vs. Placebo	Menstrual frequency	OR: 1.72, 95% CI: 1.14 to 2.61
		Menstrual frequency	Metformin vs. Placebo	Ovulation/woman	OR: 1.81, 95% CI: 1.13 to 2.93
		Menstrual frequency	Metformin vs. Placebo	Pregnancy/woman	OR: 2.31, 95% CI: 1.52 to 3.51
Feng et al. (52), 2015	PCOS, pregnant and took metformin to get conception	GDM, PE, Miscarriage, Premature delivery	Metformin during pregnancy vs. Placebo	Miscarriage	RR: 0.32, 95% CI: 0.19 to 0.56
Feng et al. (52), 2015	PCOS, pregnant and took metformin to get conception	GDM, PE, Miscarriage, Premature delivery	Metformin during pregnancy vs. Placebo	Preterm birth	RR: 0.4, 95% CI: 0.18 to 0.91
Tan et al. (58), 2016	PCOS and pregnant	GDM, PIH/PE, Miscarriage Preterm delivery	Metformin during pregnancy vs. Placebo	GDM	OR: 0.28, 95% CI: 0.10 to 0.75
			Metformin during pregnancy vs. Placebo	Miscarriage	OR: 0.20, 95% CI: 0.12 to 0.31
		Fetal abnormality, Fetal birth weight	Metformin during pregnancy vs. Placebo	Preterm birth	OR: 0.33, 95% CI: 0.18 to 0.60
			Metformin during pregnancy vs. Placebo (Non RCTs)	GDM	OR: 0.14, 95% CI: 0.09 to 0.24
			Metformin during pregnancy vs. Placebo (Non RCTs)	PIH/PE	OR: 0.28, 95% CI: 0.16 to 0.48
Zhuo et al. (54), 2014	PCOS and pregnant	GDM	Metformin during pregnancy vs. Placebo	GDM	OR: 0.19, 95% CI: 0.13 to 0.27
Zeng et al. (53), 2016	PCOS and pregnant	Live birth	Metformin during pregnancy vs. Placebo	GDM	OR: 0.02, 95% CI: 0.14 to 0.87
		Miscarriage	Metformin during pregnancy vs. Placebo	IUGR	OR: 0.17, 95% CI: 0.08 to 0.33
		Preterm delivery GDM	Metformin during pregnancy vs. Placebo	Live birth/woman	OR: 5.23, 95% CI: 3.12 to 8.75
		PIH/PE	Metformin during pregnancy vs. Placebo	Miscarriage	OR: 0.19, 95% CI: 0.12 to 0.28
		IUGR	Metformin during pregnancy vs. Placebo	PIH/PE	OR: 0.22, 95% CI: 0.13 to 0.38
		Fetal malformation	Metformin during pregnancy vs. Placebo	Preterm birth	OR: 0.37, 95% CI: 0.20 to 0.68
		Neonatal death Macrosomia	Metformin during pregnancy vs. Placebo	Preterm birth	OR: 0.37, 95% CI: 0.20 to 0.68
Li et al. (22), 2011	PCOS	Pregnancy	Metformin vs. Thiazolidinediones (3 months duration)	Side effects	OR: 8.88, 95% CI: 3.54 to 22.27
		Ovulation	Metformin vs. Thiazolidinediones (3 months duration)	Side effects	OR: 8.88, 95% CI: 3.54 to 22.27
		Menstrual regularity	Metformin vs. Thiazolidinediones (6 months duration)	Side effects	OR: 12.22, 95% CI: 3.53 to 42.31
Thakker et al.(47), 2015	PCOS	Live birth	NAC vs. Metformin	Ovulation/woman	OR: 0.13, 95% CI: 0.08 to 0.22
		Ovulation	NAC vs. Metformin	Pregnancy/woman	OR: 0.4, 95% CI: 0.23 to 0.71
		Miscarriage, Multiple pregnancy OHSS
		Menstrual regularity
Al Khalifah et al. (34), 2016	Adolescents with PCOS (11-19 year old)	Menstrual regulation	OCP vs. Metformin	Menstrual frequency	MD; 0.27, 95% CI: -0.33 to -0.21
Fang et al. (37), 2017	PCOS	Dominant follicles Menstrual regularity	Vitamin D + metformin vs. Metformin	Menstrual frequency	OR: 1.85, 95% CI: 1.01 to 3.39
Pundir et al. (38), 2017	PCOS	Live birth Clinical pregnancy	Inositol vs. Placebo	Ovulation/woman	RR: 2.3, 95% CI: 1.1 to 4.7
		Ovulation Miscarriage	Inositol vs. Placebo	Menstrual frequency	RR: 6.8, 95% CI: 2.8 to 16.6
		Menstrual regulation	Pioglitazone vs. Placebo	Menstrual frequency	OR: 8.88, 95% CI: 2.35 to 33.61
		Menstrual regulation	Roziglitazone vs. Placebo	Menstrual frequency	OR: 5.59, 95% CI: 2.20 to 14.19

BMI; Body mass index, CC; Clomiphene citrate, DEX; Dexamethasone, GDM; Gestational diabetes mellitus, GIT; Gastrointestinal tract, IUGR; Intra-uterine growth restriction, IUI; Intra uterine insemination, LOD; Laparoscopic ovarian drilling, MD; Mean difference, NAC; N-acetyl cysteine, OCP; Oral contraceptive pills, OHSS; Ovarian hyper-stimulation syndrome, OR: Odds ratio, PCOS; Polycystic ovary syndrome, PIH/PE; Pregnancy induced hypertension/Preeclampsia, RCT; Randomized controlled trial, rFSH: Recombinant follicle stimulating hormone, RR; Risk ratio, SMD; Standardized mean difference, and WHO; World Health Organization.