Sistema intrauterino liberador de levonorgestrel para la hiperplasia endometrial
Appendices
Appendix 1. Cochrane Gynaecology and Fertility Group Specialised Register search strategy
Searched 08 May 2020
PROCITE platform
Keywords CONTAINS "Levonorgestrel"or"Levonorgestrel‐Therapeutic‐Use"or"levonorgestrel‐releasing intrauterine system" or "levonorgestrel‐releasing intrauterine device" or "levonorgestrel intrauterine system" or "intrauterine contraceptive devices" or "intrauterine device" or "intrauterine devices" or "Intrauterine Devices, Medicated" or "Mirena" or "LNG‐IUS" or "Nova T 380" or "LNG20" or "IUD" or Title CONTAINS "Levonorgestrel" or "Levonorgestrel‐Therapeutic‐Use" or "levonorgestrel‐releasing intrauterine system" or "levonorgestrel‐releasing intrauterine device" or "levonorgestrel intrauterine system" or "intrauterine contraceptive devices" or "intrauterine device" or "intrauterine devices" or "Intrauterine Devices, Medicated" or "Mirena" or "LNG‐IUS" or "Nova T 380"or "LNG20" or "IUD"
AND
Keywords CONTAINS "endometrial abnormalities" or "endometrial hyperplasia" or "endometrial thickness" or "endometrial vascularity" or "hyperplasia" or "proliferation" or "endometrial proliferation" or "endometrial safety" or "endometrial" or "endometrial bleeding" or "endometrial adhesions" or "endometrial cancer" or "endometrial activity" or "endometrial assessment" or "endometrial dysfunction" or "endometrioma" or "Endometrium" or "endometrium profile" or "endometrial parameters" or "endometrial pathology" or "endometrial response" or Title CONTAINS "endometrial abnormalities" or "endometrial hyperplasia" or "endometrial thickness" or "endometrial vascularity" or "hyperplasia" or "proliferation" or "endometrial proliferation" or "endometrial safety"
(90 records)
Appendix 2. CENTRAL via Cochrane Register of Studies Online (CRSO) search strategy
Searched 08 May 2020
Web platform
#1 MESH DESCRIPTOR Levonorgestrel EXPLODE ALL TREES 874
#2 d‐norgestrel:TI,AB,KY 18
#3 MESH DESCRIPTOR Intrauterine Devices, Medicated EXPLODE ALL TREES 390
#4 Levonorgestrel:TI,AB,KY 1710
#5 (LNG‐IUS or LNG‐IUD):TI,AB,KY 306
#6 Levonova*:TI,AB,KY 2
#7 Mirena*:TI,AB,KY 148
#8 Fibroplant*:TI,AB,KY 1
#9 (LNG releasing*):TI,AB,KY 13
#10 (progest* adj5 intrauterine):TI,AB,KY 53
#11 ( intrauterine device*):TI,AB,KY 1260
#12 ( intra‐uterine device*):TI,AB,KY 79
#13 ( intra‐uterine system*):TI,AB,KY 13
#14 ( intrauterine system*):TI,AB,KY 365
#15 (Skyla or Jaydess):TI,AB,KY 19
#16 (IUS or IUD):TI,AB,KY 1287
#17 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 3065
#18 MESH DESCRIPTOR Endometrial Hyperplasia EXPLODE ALL TREES 144
#19 (endometri* adj4 hyperplas*):TI,AB,KY 559
#20 (atypi* adj2 hyperplas*):TI,AB,KY 166
#21 (simple adj2 hyperplas*):TI,AB,KY 59
#22 (complex adj2 hyperplas*):TI,AB,KY 32
#23 (endometri* adj2 proliferat*):TI,AB,KY 121
#24 (endometri* adj2 thick*):TI,AB,KY 1528
#25 (endometri* adj5 (biops* or histolog*)):TI,AB,KY 1069
#26 (proliferat* adj4 endometri*):TI,AB,KY 131
#27 endometrium:TI,AB,KY 3653
#28 (endometri* adj2 histopatholog*):TI,AB,KY 38
#29 (endometri* adj5 effect*):TI,AB,KY 1155
#30 (endometri* adj2 safe*):TI,AB,KY 152
#31 MESH DESCRIPTOR Carcinoma, Endometrioid EXPLODE ALL TREES 67
#32 #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 5234
#33 #17 AND #32 293
Appendix 3. MEDLINE search strategy
Searched from 1946 to 08 May 2020
OVID platform
1 exp Levonorgestrel/ (4234)
2 d‐norgestrel.tw. (249)
3 exp Intrauterine Devices, Medicated/ (3335)
4 Levonorgestrel.tw. (4645)
5 (LNG‐IUS or LNG‐IUD).tw. (857)
6 Levonova$.tw. (7)
7 Mirena$.tw. (294)
8 Femilis$.tw. (8)
9 Fibroplant$.tw. (20)
10 LNG releasing.tw. (39)
11 (progest$ adj5 intrauterine).tw. (448)
12 (progest$ adj5 intra‐uterine).tw. (32)
13 intrauterine device$.tw. (5432)
14 intra‐uterine device$.tw. (401)
15 intrauterine system$.tw. (1183)
16 intra uterine system$.tw. (51)
17 (Skyla$ or Jaydess$).tw. (299)
18 (IUS or IUD).tw. (8023)
19 or/1‐18 (16538)
20 exp Endometrial Hyperplasia/ (3503)
21 exp Endometrial Neoplasms/ or exp Carcinoma, Endometrioid/ (21496)
22 (endometri$ adj4 hyperplas$).tw. (4624)
23 (atypi$ adj2 hyperplas$).tw. (5202)
24 (atypi$ adj2 endometri$).tw. (963)
25 (endometri$ adj2 proliferat$).tw. (2125)
26 (endometri$ adj2 thick$).tw. (3062)
27 (endometri$ adj5 (biops$ or histology)).tw. (5790)
28 (proliferat$ adj4 endometri$).tw. (3489)
29 endometrium.tw. (27399)
30 (endometri$ adj2 histopatholog$).tw. (262)
31 (endometri$ adj5 effect$).tw. (5147)
32 (endometri$ adj2 safety).tw. (177)
33 (simple adj2 hyperplas*).tw. (781)
34 (complex adj2 hyperplas*).tw. (678)
35 Adenocarcinoma/ and endometri*.tw. (6197)
36 or/20‐35 (59323)
37 19 and 36 (1425)
38 randomized controlled trial.pt. (505145)
39 controlled clinical trial.pt. (93658)
40 randomized.ab. (477973)
41 randomised.ab. (95504)
42 placebo.tw. (212999)
43 clinical trials as topic.sh. (191053)
44 randomly.ab. (332311)
45 trial.ti. (217423)
46 (crossover or cross‐over or cross over).tw. (84430)
47 or/38‐46 (1350659)
48 exp animals/ not humans.sh. (4696480)
49 47 not 48 (1243161)
50 37 and 49 (213)
Appendix 4. Embase search strategy
Searched from 1980 to 08 May 2020
OVID platform
1 exp LEVONORGESTREL/ (11652)
2 d‐norgestrel.tw. (83)
3 exp intrauterine contraceptive device/ (15930)
4 Levonorgestrel.tw. (5951)
5 (LNG‐IUS or LNG‐IUD).tw. (1409)
6 Levonova$.tw. (38)
7 Mirena$.tw. (1591)
8 Femilis$.tw. (16)
9 Fibroplant$.tw. (25)
10 LNG releasing.tw. (45)
11 (progest$ adj5 intrauterine).tw. (517)
12 (progest$ adj5 intra‐uterine).tw. (61)
13 intrauterine device$.tw. (6315)
14 intra‐uterine device$.tw. (478)
15 intra?uterine system$.tw. (1749)
16 (Skyla or Jaydess).tw. (113)
17 (IUS or IUD).tw. (8304)
18 or/1‐17 (27340)
19 exp endometrium hyperplasia/ (7263)
20 exp endometrium carcinoma/ or exp endometrioid carcinoma/ (22237)
21 (endometri$ adj4 hyperplas$).tw. (6178)
22 (proliferat$ adj4 endometri$).tw. (4532)
23 (endometri$ adj4 atypi$).tw. (2317)
24 (atypi$ adj2 hyperplas$).tw. (7358)
25 (atypi$ adj2 endometri$).tw. (1472)
26 (endometri$ adj2 proliferat$).tw. (2833)
27 (endometri$ adj2 thick$).tw. (5316)
28 (endometri$ adj5 (biops$ or histology)).tw. (8748)
29 (proliferat$ adj4 endometri$).tw. (4532)
30 endometrium.tw. (33319)
31 (endometri$ adj2 histopatholog$).tw. (436)
32 (endometri$ adj5 effect$).tw. (6983)
33 (endometri$ adj2 safety).tw. (267)
34 (simple adj2 hyperplas$).tw. (1081)
35 (complex adj2 hyperplas$).tw. (1108)
36 or/19‐35 (70950)
37 18 and 36 (2127)
38 Clinical Trial/ (963610)
39 Randomized Controlled Trial/ (597076)
40 exp randomization/ (86768)
41 Single Blind Procedure/ (38692)
42 Double Blind Procedure/ (168832)
43 Crossover Procedure/ (62819)
44 Placebo/ (335555)
45 Randomi?ed controlled trial$.tw. (226140)
46 Rct.tw. (36646)
47 random allocation.tw. (2000)
48 randomly.tw. (436022)
49 randomly allocated.tw. (34759)
50 allocated randomly.tw. (2530)
51 (allocated adj2 random).tw. (812)
52 Single blind$.tw. (24445)
53 Double blind$.tw. (201171)
54 ((treble or triple) adj blind$).tw. (1132)
55 placebo$.tw. (300426)
56 prospective study/ (595141)
57 or/38‐56 (2411231)
58 case study/ (68239)
59 case report.tw. (398561)
60 abstract report/ or letter/ (1092750)
61 or/58‐60 (1549189)
62 57 not 61 (2357423)
63 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5963145)
64 62 not 63 (2193804)
65 37 and 64 (537)
Appendix 5. PsycINFO search strategy
Searched from 1806 to 08 May 2020
OVID platform
1 exp Intrauterine Devices/ (141)
2 d‐norgestrel.tw. (1)
3 Levonorgestrel.tw. (117)
4 (LNG‐IUS or LNG‐IUD).tw. (37)
5 Levonova$.tw. (0)
6 Mirena$.tw. (11)
7 Femilis$.tw. (1)
8 Fibroplant$.tw. (0)
9 LNG releasing.tw. (1)
10 (progest$ adj5 intrauterine).tw. (13)
11 (progest$ adj5 intra‐uterine).tw. (1)
12 intrauterine device$.tw. (300)
13 intra‐uterine device$.tw. (9)
14 intra‐uterine system$.tw. (1)
15 (Skyla or Jaydess).tw. (0)
16 (IUS or IUD).tw. (376)
17 or/1‐16 (640)
18 (endometrial or endometrium).tw. (395)
19 17 and 18 (13)
Appendix 6. CINAHL search strategy
Searched from 1961 to 08 May 2020
EBSCO platform
| # | Query | Results |
| S49 | S20 AND S36 AND S48 | 312 |
| S48 | S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47 | 1,597,464 |
| S47 | TX allocat* random* | 13,234 |
| S46 | (MH "Quantitative Studies") | 30,435 |
| S45 | (MH "Placebos") | 13,694 |
| S44 | TX placebo* | 71,188 |
| S43 | TX random* allocat* | 13,234 |
| S42 | (MH "Random Assignment") | 68,046 |
| S41 | TX randomi* control* trial* | 220,864 |
| S40 | 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*) ) | 1,215,600 |
| S39 | TX clinic* n1 trial* | 294,158 |
| S38 | PT Clinical trial | 110,668 |
| S37 | (MH "Clinical Trials+") | 318,742 |
| S36 | S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 | 6,140 |
| S35 | TX (IUS or IUD) | 2,092 |
| S34 | TX (Skyla or Jaydess) | 94 |
| S33 | TX intrauterine system* | 789 |
| S32 | TX intra‐uterine system* | 26 |
| S31 | TX intra‐uterine device* | 78 |
| S30 | TX intrauterine device* | 4,197 |
| S29 | TX progest* N5 intra‐uterine | 12 |
| S28 | TX (progest* N5 intrauterine) | 150 |
| S27 | TX LNG releasing | 173 |
| S26 | TX LNG‐IUD | 60 |
| S25 | TX LNG‐IUS | 259 |
| S24 | TX mirena | 160 |
| S23 | TX levonorgestrel | 2,202 |
| S22 | (MM "Intrauterine Devices") | 2,055 |
| S21 | (MM "Levonorgestrel") | 965 |
| S20 | S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 | 66,530 |
| S19 | TX (endometri* N2 safety) | 85 |
| S18 | TX(endometri* N5 effect*) | 1,547 |
| S17 | TX (endometri* N2 histopatholog*) | 112 |
| S16 | TX endometrium | 4,307 |
| S15 | TX(endometri* N2 thick*) | 762 |
| S14 | TX(endometri* N2 proliferat*) | 266 |
| S13 | TX(complex N2 hyperplas*) | 127 |
| S12 | TX(simple N2 hyperplas*) | 70 |
| S11 | TX(atypi* N2 endometri*) | 235 |
| S10 | TX(atypi* N2 hyperplas*) | 749 |
| S9 | TX (endometri* N2 effect*) | 982 |
| S8 | TX (endometri* N2 safety) | 85 |
| S7 | TX endometrium | 4,307 |
| S6 | TX (bleed* or spotting*) | 45,491 |
| S5 | TX (hysteroscop* or hysterectomy) | 14,474 |
| S4 | TX (endometri* N5 (biops$ or histology)) | 294 |
| S3 | TX (endometri* N3 cancer*) | 4,604 |
| S2 | TX (endometri* N3 carcinoma) | 1,332 |
| S1 | TX endometri* N2 hyperplas* | 635 |
PRISMA flow diagram of the systematic literature search
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 LNG‐IUS versus non‐intrauterine progestogen, outcome: 1.1 Regression of EH; by length of follow‐up.
Funnel plot of comparison: 1 LNG‐IUS versus non‐intrauterine progestogen, outcome: 1.1 Regression of EH; by length of follow‐up.
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 1: Regression of EH; by length of follow‐up
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 2: Hysterectomy; histologically and non‐histologically indicated
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 3: Adverse effects associated with hormones
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 4: Withdrawal secondary to adverse effects
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 5: Satisfaction with treatment
Comparison 2: LNG‐IUS versus no treatment, Outcome 1: Regression of EH
| LNG‐IUS compared to non‐intrauterine progestogen for endometrial hyperplasia | ||||||
| Patient or population: endometrial hyperplasia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with non‐intrauterine progestogen | Risk with LNG‐IUS | |||||
| Regression of EH; by length of follow‐up ‒ Short follow‐up ≤ 6 months | 723 per 1000 | 885 per 1000 | OR 2.94 | 1108 | ⊕⊕⊕⊝ | |
| Regression of EH; by length of follow‐up ‒ Long follow‐up ≥ 1 year | 513 per 1000 | 800 per 1000 | OR 3.80 | 138 | ⊕⊕⊝⊝ | |
| Hysterectomy; histologically and non‐histologically indicated | 263 per 1000 | 85 per 1000 | OR 0.26 | 452 | ⊕⊕⊝⊝ | |
| Adverse effects associated with hormones: Nausea Weight gain | 383 per 1000 | 570 per 1000 | OR 2.13 | 428 | ⊕⊝⊝⊝ | |
| 213 per 1000 | 124 per 1000 | OR 0.52 | 428 | ⊕⊕⊝⊝ | ||
| 65 per 1000 | 82 per 1000 | OR 1.28 | 318 | ⊕⊝⊝⊝ | ||
| Withdrawal secondary to adverse effects | 54 per 1000 | 23 per 1000 | OR 0.41 | 360 | ⊕⊕⊝⊝ | |
| Satisfaction with treatment | 531 per 1000 | 857 per 1000 | OR 5.28 | 202 | ⊕⊝⊝⊝ | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 1 level for serious risk of bias: 6 in 10 studies high risk for detection bias as outcome assessors were not blinded, various studies with unclear selection bias and selection bias 2 Downgraded 1 level for serious risk of bias: high risk as not stated if pathologists measuring EH regression were blinded, and unclear allocation concealment and reporting bias. 3 Substantial heterogeneity for this comparison (I² = 66%), but the quality of the evidence was not downgraded for inconsistency, as the direction of effect was consistent. 4 Downgraded 1 level for serious imprecision with few events and wide confidence intervals. 5 Downgraded 1 level for serious risk of bias: all 4 studies high risk as participants/assessors were not blinded for outcome assessment of subjective measures and in 2 studies blinding of the pathologist was not mentioned. Selective reporting assessed as unclear in 3 of studies. 6 Downgraded 1 level for serious risk of bias: all studies with high risk of performance and detection bias (no blinding of participants to LNG‐IUS and self‐evaluation of adverse effects); other studies with high risk of attrition bias, and unclear allocation concealment and selective reporting. 7 Downgraded 1 level for serious inconsistency; unexplained inconsistency, with point estimates widely different in studies and confidence intervals not overlapping. 8 Downgraded 1 level for serious risk of bias: all 4 studies with high risk of performance and detection bias, 1 study with high risk of attrition bias, 2 studies with unclear allocation concealment and 3 with unclear selective reporting, 1 study with unclear selection bias. 9 Downgraded 2 levels for very serious risk of bias: both studies with high risk of performance and detection bias, 1 in 2 studies with high risk of attrition bias, both studies with unclear allocation concealment and selective reporting, 1 study with unclear selection bias. 10 Downgraded 1 level for serious imprecision: small sample size. | ||||||
| LNG compared to no treatment for endometrial hyperplasia | ||||||
| Patient or population: women with endometrial hyperplasia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with no treatment | Risk with LNG‐IUS | |||||
| Regression of EH ‐ Short | 270 per 1000 | 967 per 1000 | OR 78.41 | 190 | ⊕⊕⊝⊝ | |
| Adverse effects associated with LNG‐IUS | No study reported on this outcome in this comparison | |||||
| Hysterectomy | No study reported on this outcome in this comparison | |||||
| Adverse effects associated with hormones | No study reported on this outcome in this comparison | |||||
| Withdrawal secondary to adverse effects | No study reported on this outcome in this comparison | |||||
| Satisfaction | No study reported on this outcome in this comparison | |||||
| Cost of treatment | No study reported on this outcome in this comparison | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 1 level for serious risk of bias: unclear allocation concealment and selective reporting. 2 Downgraded 1 level for serious imprecision: small sample size and wide confidence interval. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Regression of EH; by length of follow‐up Show forest plot | 10 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Short follow‐up ≤ 6 months | 10 | 1108 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.94 [2.10, 4.13] |
| 1.1.2 Long follow‐up ≥ 1 year | 1 | 138 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.80 [1.75, 8.23] |
| 1.2 Hysterectomy; histologically and non‐histologically indicated Show forest plot | 4 | 452 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.26 [0.15, 0.46] |
| 1.3 Adverse effects associated with hormones Show forest plot | 4 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Bleeding/spotting | 3 | 428 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.13 [1.33, 3.43] |
| 1.3.2 Nausea | 3 | 428 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.28, 0.95] |
| 1.3.3 Weight gain | 3 | 318 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.56, 2.96] |
| 1.4 Withdrawal secondary to adverse effects Show forest plot | 4 | 360 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.12, 1.35] |
| 1.5 Satisfaction with treatment Show forest plot | 2 | 202 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.28 [2.51, 11.10] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Regression of EH Show forest plot | 1 | 190 | Odds Ratio (M‐H, Fixed, 95% CI) | 78.41 [22.86, 268.97] |
