Metformina durante la inducción de la ovulación con gonadotrofinas seguida del coito programado o la inseminación intrauterina para la subfertilidad asociada con el síndrome de ovario poliquístico
Appendices
Appendix 1. CGF search strategy
Gynaecology and Fertility group specialised register
PROCITE Platform
From inception until 8 June 2016
Keywords CONTAINS "polycystic ovary morphology" or "polycystic ovary syndrome" or "PCOS" or "anovulation" or "Oligo‐amenorrhea" or "oligo‐ovulation" or "oligo‐ovulatory" or "oligoamenorrhea" or "oligoanovulatory" or "oligohypomenorrhea" or "Amenorrhea" or "amenorrhea‐outcome" or "amenorrhoea" or Title CONTAINS "polycystic ovary morphology" or "polycystic ovary syndrome" or "PCOS" or "anovulation" or "Oligo‐amenorrhea" or "oligo‐ovulation" or "oligo‐ovulatory" or "oligoamenorrhea" or "oligoanovulatory" or "oligohypomenorrhea" or "Amenorrhea" or "amenorrhea‐outcome" or "amenorrhoea"
AND
Keywords CONTAINS "metformin" or "glucophage" or Title CONTAINS "metformin" or "glucophage"
AND
Keywords CONTAINS "superovulation" or "superovulation induction" or "IUI" or "insemination, intrauterine " or "Intrauterine Insemination" or "ART" or "artificial insemination" or "assisted reproduction techniques" or "subfertility‐Female" or "subfertility" or "anovulation" or "infertile"or "infertility" or "ovulation" or "timed intercourse" or "intercourse" or "ovulation induction" or "ovulation stimulation" or "Ovarian hyperstimulation syndrome" or "ovarian hyperstimulation" or "ovarian response" or "ovarian responsiveness" or "pregnancy" or "Ovarian stimulation" or "ovarian stimulation syndrome" or "controlled ovarian hyperstimulation" or "controlled ovarian stimulation" or "COH" or "COH IUI" or Title CONTAINS "superovulation" or "superovulation induction" or "IUI" or "insemination, intrauterine " or "Intrauterine Insemination" or "ART" or "artificial insemination" or "assisted reproduction techniques" or "subfertility‐Female" or "subfertility" or "anovulation" or "infertile" or "infertility" or "pregnancy"
(192 hits)
Appendix 2. CENTRAL CRSO search strategy
Web platform
From inception until 8 June 2016
#1 MESH DESCRIPTOR Polycystic Ovary Syndrome EXPLODE ALL TREES 857
#2 (Polycystic Ovar*):TI,AB,KY 1599
#3 PCOS:TI,AB,KY 1212
#4 (stein‐leventhal or leventhal):TI,AB,KY 15
#5 PCOD:TI,AB,KY 24
#6 anovulat*:TI,AB,KY 435
#7 MESH DESCRIPTOR Anovulation EXPLODE ALL TREES 110
#8 (oligo ovulat*):TI,AB,KY 10
#9 oligoovulat*:TI,AB,KY 4
#10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 1996
#11 MESH DESCRIPTOR Metformin EXPLODE ALL TREES 1702
#12 (dimethylbiguanidium or dimethylguanylguanidine or glucophage or glucovance):TI,AB,KY 36
#13 Metformin:TI,AB,KY 4034
#14 #11 OR #12 OR #13 4035
#15 #10 AND #14 561
#16 MESH DESCRIPTOR Ovulation Induction EXPLODE ALL TREES 1119
#17 ovulat*:TI,AB,KY 2819
#18 (ovar* respons*):TI,AB,KY 393
#19 MESH DESCRIPTOR Infertility, Female EXPLODE ALL TREES 1025
#20 fertility:TI,AB,KY 1636
#21 (infertil* or subfertil*):TI,AB,KY 3976
#22 (ovarian hyperstimulation syndrome):TI,AB,KY 381
#23 MESH DESCRIPTOR Ovarian Hyperstimulation Syndrome EXPLODE ALL TREES 161
#24 pregnancy:TI,AB,KY 24768
#25 (ovarian stimulation):TI,AB,KY 1072
#26 intercourse:TI,AB,KY 1364
#27 (intrauterine insemination):TI,AB,KY 581
#28 IUI:TI,AB,KY 457
#29 (artificial insemination):TI,AB,KY 166
#30 #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 29173
#31 #15 AND #30 277
Appendix 3. MEDLINE search strategy
Database: Ovid MEDLINE(R) Epub Ahead of Print, In Process & Other Non‐Indexed Citations, Ovid MEDLINE (R) Daily, and Ovid MEDLINE (R) 1946‐Present
From inception until 8 June 2016
1 exp Polycystic Ovary Syndrome/ (11492)
2 Polycystic Ovar$.tw. (12559)
3 PCOS.tw. (7815)
4 (stein‐leventhal or leventhal).tw. (708)
5 PCOD.tw. (271)
6 (ovar$ adj degeneration).tw. (44)
7 (sclerocystic adj ovar$).tw. (98)
8 anovulat$.tw. (4936)
9 exp Anovulation/ (2063)
10 oligo ovulat$.tw. (77)
11 oligoovulat$.tw. (49)
12 or/1‐11 (19239)
13 exp Metformin/ (9039)
14 (dimethylbiguanidium or dimethylguanylguanidine or glucophage or glucovance).tw. (120)
15 Metformin.tw. (12783)
16 or/13‐15 (14306)
17 16 and 12 (1342)
18 exp Ovulation Induction/ (11272)
19 ovulat$.tw. (34281)
20 ovar$ respons$.tw. (2249)
21 exp Infertility, Female/ (25439)
22 fertility.tw. (61511)
23 infertil$.tw. (48621)
24 ovarian hyperstimulation syndrome.tw. (2276)
25 pregnancy.tw. (313830)
26 ovarian stimulation.tw. (4552)
27 intercourse.tw. (16667)
28 intrauterine insemination.tw. (1974)
29 IUI.tw. (1380)
30 artificial insemination.tw. (5535)
31 or/18‐30 (445218)
32 17 and 31 (708)
33 randomized controlled trial.pt. (420633)
34 controlled clinical trial.pt. (90997)
35 randomized.ab. (358562)
36 randomised.ab. (70923)
37 placebo.tw. (178464)
38 clinical trials as topic.sh. (177470)
39 randomly.ab. (256508)
40 trial.ti. (156075)
41 (crossover or cross‐over or cross over).tw. (69484)
42 or/33‐41 (1090726)
43 exp animals/ not humans.sh. (4260951)
44 42 not 43 (1005502)
45 32 and 44 (293)
Appendix 4. Embase search strategy
OVID platform
From inception until 8 June 2016
1 exp ovary polycystic disease/ (19944)
2 Polycystic Ovar$.tw. (16539)
3 PCOS.tw. (11206)
4 (stein‐leventhal or leventhal).tw. (696)
5 PCOD.tw. (340)
6 (ovar$ adj degeneration).tw. (41)
7 (sclerocystic adj ovar$).tw. (95)
8 anovulat$.tw. (5539)
9 exp Anovulation/ (4387)
10 oligo ovulat$.tw. (87)
11 oligoovulat$.tw. (68)
12 or/1‐11 (27471)
13 exp Metformin/ (42485)
14 (dimethylbiguanidium or dimethylguanylguanidine or glucophage or glucovance).tw. (1609)
15 Metformin.tw. (21275)
16 or/13‐15 (43864)
17 12 and 16 (3173)
18 exp ovulation induction/ (11594)
19 ovulat$.tw. (35504)
20 ovar$ respons$.tw. (3127)
21 exp female infertility/ or exp infertility therapy/ (114547)
22 fertility.tw. (69709)
23 infertil$.tw. (63999)
24 ovarian hyperstimulation syndrome.tw. (3104)
25 pregnancy.tw. (375837)
26 ovarian stimulation.tw. (7035)
27 intercourse.tw. (19759)
28 intrauterine insemination.tw. (2802)
29 IUI.tw. (2382)
30 artificial insemination.tw. (5181)
31 or/18‐30 (560584)
32 17 and 31 (1768)
33 Clinical Trial/ (858094)
34 Randomized Controlled Trial/ (404847)
35 exp randomization/ (70570)
36 Single Blind Procedure/ (22197)
37 Double Blind Procedure/ (128704)
38 Crossover Procedure/ (47202)
39 Placebo/ (275451)
40 Randomi?ed controlled trial$.tw. (136119)
41 Rct.tw. (20323)
42 random allocation.tw. (1528)
43 randomly allocated.tw. (24807)
44 allocated randomly.tw. (2113)
45 (allocated adj2 random).tw. (757)
46 Single blind$.tw. (17385)
47 Double blind$.tw. (162039)
48 ((treble or triple) adj blind$).tw. (555)
49 placebo$.tw. (232908)
50 prospective study/ (334857)
51 or/33‐50 (1574988)
52 case study/ (37932)
53 case report.tw. (305862)
54 abstract report/ or letter/ (961247)
55 or/52‐54 (1298029)
56 51 not 55 (1533942)
57 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5531185)
58 56 not 57 (1474848)
59 32 and 58 (759)
Appendix 5. PsycINFO search strategy
OVID platform
From inception until 8 June 2016
1 exp Endocrine Disorders/ (17257)
2 Polycystic Ovar$.tw. (319)
3 PCOS.tw. (201)
4 (stein‐leventhal or leventhal).tw. (268)
5 PCOD.tw. (5)
6 (sclerocystic adj ovar$).tw. (1)
7 anovulat$.tw. (137)
8 or/1‐7 (17809)
9 Metformin.tw. (308)
10 glucophage.tw. (1)
11 9 or 10 (308)
12 8 and 11 (112)
13 exp Ovulation/ (334)
14 ovulat$.tw. (1378)
15 ovar$ respons$.tw. (5)
16 fertility.tw. (5905)
17 infertil$.tw. (2892)
18 ovarian hyperstimulation syndrome.tw. (4)
19 pregnancy.tw. (30627)
20 ovarian stimulation.tw. (17)
21 intercourse.tw. (8237)
22 intrauterine insemination.tw. (19)
23 IUI.tw. (28)
24 artificial insemination.tw. (239)
25 or/13‐24 (46095)
26 12 and 25 (7)
Appendix 6. CINAHL search strategy
EBSCO platform
From inception until 8 June 2016
| # | Query | Results |
| S46 | S33 AND S45 | 74 |
| S45 | S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 | 942,089 |
| S44 | TX allocat* random* | 4,203 |
| S43 | (MH "Quantitative Studies") | 13,027 |
| S42 | (MH "Placebos") | 9,083 |
| S41 | TX placebo* | 33,240 |
| S40 | TX random* allocat* | 4,203 |
| S39 | (MH "Random Assignment") | 38,641 |
| S38 | TX randomi* control* trial* | 83,441 |
| S37 | TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) | 754,151 |
| S36 | TX clinic* n1 trial* | 169,477 |
| S35 | PT Clinical trial | 77,334 |
| S34 | (MH "Clinical Trials+") | 183,704 |
| S33 | S18 AND S32 | 167 |
| S32 | S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 | 145,671 |
| S31 | TX artificial insemination | 448 |
| S30 | TX IUI | 78 |
| S29 | TX intrauterine insemination | 146 |
| S28 | TX intercourse | 3,690 |
| S27 | TX ovarian stimulation | 206 |
| S26 | TX pregnancy | 134,106 |
| S25 | TX ovarian hyperstimulation syndrome | 247 |
| S24 | TX infertil* | 7,277 |
| S23 | TX fertility | 6,780 |
| S22 | (MM "Infertility") | 3,645 |
| S21 | TX ovar* N2 respons* | 117 |
| S20 | TX ovulat* | 1,529 |
| S19 | (MM "Ovulation Induction") | 236 |
| S18 | S13 AND S17 | 291 |
| S17 | S14 OR S15 OR S16 | 3,962 |
| S16 | TX(dimethylbiguanidium or dimethylguanylguanidine or glucophage or glucovance) | 43 |
| S15 | TX Metformin | 3,951 |
| S14 | (MM "Metformin") | 1,630 |
| S13 | S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 | 2,765 |
| S12 | TX oligoovulat* | 7 |
| S11 | TX (oligo ovulat*) | 3 |
| S10 | (MM "Anovulation") | 84 |
| S9 | TX anovulat* | 350 |
| S8 | TX (sclerocystic N2 ovar*) | 1 |
| S7 | TX (sclerocystic N2 ovar*) | 0 |
| S6 | TX (ovar* N2 degeneration) | 4 |
| S5 | TX PCOD | 13 |
| S4 | TX (stein‐leventhal or leventhal) | 628 |
| S3 | TX PCOS | 652 |
| S2 | TX (Polycystic Ovar*) | 1,905 |
| S1 | (MM "Polycystic Ovary Syndrome") | 1,217 |
Appendix 7. General search terms for other databases
PCOS, metformin, ovulation induction, FSH, CC resistance
Appendix 8. Search terms for the WHO portal and clinicaltrials.gov
PCOS and metformin ‐ no ongoing trials were found
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 dichotomous outcome, outcome: 1.1 live birth rate (per woman).
Forest plot of comparison: 1 Metformin versus placebo co‐treatment for assisted reproduction, outcome: 1.2 Multiple pregnancy rate (per woman).
Forest plot of comparison: 1 Metformin versus placebo co‐treatment for assisted reproduction, outcome: 1.3 Ongoing pregnancy rate (per woman).
Forest plot of comparison: 1 Metformin versus placebo co‐treatment for assisted reproduction, outcome: 1.4 Clinical pregnancy rate.
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 1 Live birth rate (per woman).
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 2 Multiple pregnancy rate (per woman).
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 3 Ongoing pregnancy rate (per woman).
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 4 Clinical pregnancy rate.
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 5 Miscarriage rate (per clinical pregnancy).
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 6 Ovulation rate (per started cycle).
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 7 OHSS rate (per woman).
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 8 Cycle cancellation rate (per started cycle).
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 9 Adverse effects.
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 10 FSH dose per cycle.
Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 11 Duration of stimulation days per cycle.
| Metformin versus placebo co‐treatment for assisted reproduction for subfertility associated with polycystic ovary syndrome | ||||||
| Patient or population: patients with subfertility associated with polycystic ovary syndrome | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo co‐treatment | Metformin co‐treatment | |||||
| Live birth rate (per woman) | 267 per 1000 | 457 per 1000 190 more per 1000 (42 to 345) | OR 2.31 | 180 | ⊕⊕⊝⊝ | |
| Multiple pregnancy rate (per woman) | 52 per 1000 | 26 per 1000 23 fewer per 1000 (44 fewer to 25 more) | OR 0.55 (0.15 to 1.95) | 232 | ⊕⊕⊝⊝ | |
| Ongoing pregnancy rate (per woman) | 217 per 1000 | 393 per 1000 189 more per 1000 (57 to 336) | OR 2.46 | 232 | ⊕⊕⊝⊝ | |
| Clinical pregnancy rate (per woman) | 252 per 1000 | 444 per 1000 206 more per 1000 (78 to 340) | OR 2.51 | 264 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aLimited sample size, limited precision, lack of blinding of participants and of outcome assessors. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Live birth rate (per woman) Show forest plot | 2 | 180 | Odds Ratio (M‐H, Random, 95% CI) | 2.31 [1.23, 4.34] |
| 2 Multiple pregnancy rate (per woman) Show forest plot | 4 | 232 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.55 [0.15, 1.95] |
| 3 Ongoing pregnancy rate (per woman) Show forest plot | 4 | 232 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.46 [1.36, 4.46] |
| 4 Clinical pregnancy rate Show forest plot | 5 | 264 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.51 [1.46, 4.31] |
| 5 Miscarriage rate (per clinical pregnancy) Show forest plot | 3 | 84 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.19, 2.01] |
| 6 Ovulation rate (per started cycle) Show forest plot | 3 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 7 OHSS rate (per woman) Show forest plot | 2 | 180 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.01, 8.23] |
| 8 Cycle cancellation rate (per started cycle) Show forest plot | 4 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 9 Adverse effects Show forest plot | 2 | 90 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.78 [0.39, 8.09] |
| 10 FSH dose per cycle Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 11 Duration of stimulation days per cycle Show forest plot | 5 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
