Interventions to prevent or treat heavy menstrual bleeding or pain associated with intrauterine-device use

Background Heavy menstrual bleeding and pain are common reasons women discontinue intrauterine device (IUD) use. Copper IUD (Cu IUD) users tend to experience increased menstrual bleeding, whereas levonorgestrel IUD (LNG IUD) users tend to have irregular menstruation. Medical therapies used to reduce heavy menstrual bleeding or pain associated with Cu and LNG IUD use include non‐steroidal anti‐inflammatory drugs (NSAIDs), anti‐fibrinolytics and paracetamol. We analysed treatment and prevention interventions separately because the expected outcomes for treatment and prevention interventions differ. We did not combine different drug classes in the analysis as they have different mechanisms of action. This is an update of a review originally on NSAIDs. The review scope has been widened to include all interventions for treatment or prevention of heavy menstrual bleeding or pain associated with IUD use.

To evaluate all randomized controlled trials (RCTs) that have assessed strategies for treatment and prevention of heavy menstrual bleeding or pain associated with IUD use, for example, pharmacotherapy and alternative therapies. Search methods We searched CENTRAL, MEDLINE, Embase and CINAHL to January 2021. Selection criteria We included RCTs in any language that tested strategies for treatment or prevention of heavy menstrual bleeding or pain associated with IUD (Cu IUD, LNG IUD or other IUD) use. The comparison could be no intervention, placebo or another active intervention. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, and extracted data. Primary outcomes were volume of menstrual blood loss, duration of menstruation and painful menstruation. We used a random‐effects model in all meta‐analyses. Review authors assessed the certainty of evidence using GRADE. Main results This review includes 21 trials involving 3689 participants from middle‐ and high‐income countries. Women were 18 to 45 years old and either already using an IUD or had just had one placed for contraception. The included trials examined NSAIDs and other interventions. Eleven were treatment trials, of these seven were on users of the Cu IUD, one on LNG IUD and three on an unknown type. Ten were prevention trials, six focused on Cu IUD users, and four on LNG IUD users. Sixteen trials had high risk of detection bias due to subjective assessment of pain and bleeding. Treatment of heavy menstrual bleeding Cu IUD Vitamin B1 resulted in fewer pads used per day (mean difference (MD) −7.00, 95% confidence interval (CI) −8.50 to −5.50) and fewer bleeding days (MD −2.00, 95% CI –2.38 to −1.62; 1 trial; 110 women; low‐certainty evidence) compared to placebo. The evidence is very uncertain about the effect of naproxen on the volume of menstruation compared to placebo (odds ratio (OR) 0.09, 95% CI 0.00 to 1.78; 1 trial, 40 women; very low‐certainty evidence). Treatment with mefenamic acid resulted in less volume of blood loss compared to tranexamic acid (MD −64.26, 95% CI −105.65 to −22.87; 1 trial, 94 women; low‐certainty evidence). However, there was no difference in duration of bleeding with treatment of mefenamic acid or tranexamic acid (MD 0.08 days, 95% CI −0.27 to 0.42, 2 trials, 152 women; low‐certainty evidence). LNG IUD The use of ulipristal acetate in LNG IUD may not reduce the number of bleeding days in 90 days in comparison to placebo (MD −9.30 days, 95% CI −26.76 to 8.16; 1 trial, 24 women; low‐certainty evidence). Unknown IUD type Mefenamic acid may not reduce volume of bleeding compared to Vitex agnus measured by pictorial blood assessment chart (MD −2.40, 95% CI −13.77 to 8.97; 1 trial; 84 women; low‐certainty evidence). Treatment of pain Cu IUD Treatment with tranexamic acid and sodium diclofenac may result in little or no difference in the occurrence of pain (OR 1.00, 95% CI 0.06 to 17.25; 1 trial, 38 women; very low‐certainty evidence). Unknown IUD type Naproxen may reduce pain (MD 4.10, 95% CI 0.91 to 7.29; 1 trial, 33 women; low‐certainty evidence). Prevention of heavy menstrual bleeding Cu IUD We found very low‐certainty evidence that tolfenamic acid may prevent heavy bleeding compared to placebo (OR 0.54, 95% CI 0.34 to 0.85; 1 trial, 310 women). There was no difference between ibuprofen and placebo in blood volume reduction (MD −14.11, 95% CI −36.04 to 7.82) and duration of bleeding (MD −0.2 days, 95% CI −1.40 to 1.0; 1 trial, 28 women, low‐certainty evidence). Aspirin may not prevent heavy bleeding in comparison to paracetamol (MD −0.30, 95% CI −26.16 to 25.56; 1 trial, 20 women; very low‐certainty evidence). LNG IUD Ulipristal acetate may increase the percentage of bleeding days compared to placebo (MD 9.50, 95% CI 1.48 to 17.52; 1 trial, 118 women; low‐certainty evidence). There were insufficient data for analysis in a single trial comparing mifepristone and vitamin B. There were insufficient data for analysis in the single trial comparing tranexamic acid and mefenamic acid and in another trial comparing naproxen with estradiol. Prevention of pain Cu IUD There was low‐certainty evidence that tolfenamic acid may not be effective to prevent painful menstruation compared to placebo (OR 0.71, 95% CI 0.44 to 1.14; 1 trial, 310 women). Ibuprofen may not reduce menstrual cramps compared to placebo (OR 1.00, 95% CI 0.11 to 8.95; 1 trial, 20 women, low‐certainty evidence). Authors' conclusions Findings from this review should be interpreted with caution due to low‐ and very low‐certainty evidence. Included trials were limited; the majority of the evidence was derived from single trials with few participants. Further research requires larger trials and improved trial reporting. The use of vitamin B1 and mefenamic acid to treat heavy menstruation and tolfenamic acid to prevent heavy menstruation associated with Cu IUD should be investigated. More trials are needed to generate evidence for the treatment and prevention of heavy and painful menstruation associated with LNG IUD. Plain language summary Medications for heavy menstrual bleeding and pain related to intrauterine devices used for birth control

Heavy menstrual bleeding and cramping are the most common reasons why women stop using an intrauterine device (IUD) for birth control. We reviewed studies to find out whether pain relief or other medicines, or other methods could reduce bleeding and pain related to IUD use. Study characteristics The evidence is up‐to‐date to January 2021. We included studies that investigated the treatment or prevention of heavy menstrual bleeding or pain related to IUD use. The treatment could be compared with another medicine, no treatment or a placebo (dummy medicine). Key results This review includes 21 studies with 3689 women. Eleven studies investigated treatment, while 10 looked at prevention of heavy bleeding and pain. Most of the evidence was obtained from single studies with few participants. We have little to no confidence in the results of the studies. Our confidence is limited because some studies involved only a few people, had varied interventions or had no clear reports on how the study was conducted. Treatment of heavy menstrual bleeding Copper IUD Vitamin B1 may reduce the duration of bleeding, number of spotting days and number of pads used per day while. Mefenamic acid may reduce the volume but not the duration of bleeding when compared to tranexamic acid. Naproxen may not reduce the amount of menstrual bleeding associated with copper IUD. Levonorgestrel IUD Among levonorgestrel IUD users, ulipristal may not reduce the duration of bleeding. Unknown IUD type In one study with an unknown IUD type, we found that mefenamic acid may not reduce the volume of menstrual bleeding. Treatment of painful menstruation Copper IUD Treatment with tranexamic acid and sodium diclofenac may not reduce the occurrence of painful menstruation associated with copper IUD. Unknown IUD type Naproxen may reduce pain associated with an unknown IUD type Prevention of heavy menstrual bleeding Copper IUD Tolfenamic acid may prevent heavy menstrual bleeding while ibuprofen made little to no difference to the volume and duration of menstrual bleeding when compared to placebo. Aspirin in comparison to paracetamol, may not prevent the occurrence of heavy menstrual bleeding. Levonorgestrel IUD Studies on tranexamic acid, estradiol, naproxen and mifepristone could not tell us whether they prevented heavy menstrual bleeding associated with levonorgestrel IUD use. Prevention of painful menstruation Copper IUD Tolfenamic acid and ibuprofen may not be effective to prevent painful menstruation compared with placebo. Authors' conclusions Heavy menstrual bleeding among copper IUD users may be treated with vitamin B and mefenamic acid while tranexamic acid and diclofenac may not alleviate painful menstruation. As for levonorgestrel IUD users, ulipristal may not reduce or prevent heavy menstrual bleeding. Tolfenamic acid may prevent heavy menstrual bleeding but not pain associated with levonorgestrel IUD. Our confidence in the evidence is low to very low. More studies are needed in the future to generate higher‐quality evidence regarding effective medicines to treat and prevent heavy menstrual bleeding and painful menstruation associated with IUD use. Evidence from further studies is likely to change our results. Summary of findings Summary of findings 1. Interventions (vitamin B1, mefenamic acid, tranexamic acid) compared to placebo or active comparators (desmopressin, sodium diclofenac, flavonoids) for the treatment of heavy menstrual bleeding associated with Cu IUD. | Interventions versus comparisons | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Certainty of the evidence (GRADE) | | | Risk with comparisons | Risk with interventions | |||| | Vitamin B1 vs placebo | ||||| | Menstrual blood loss Number of pads (diary record) Follow‐up: 1 month after completion of intervention for 3 months | The mean number of pads was 19 pads | MD 7 pads fewer (8.5 fewer to 5.5 fewer) | ‐ | 110 (1 RCT) | ⨁⨁◯◯ Lowa,b | | Duration of bleeding Number of bleeding days (diary record) Follow‐up: 1 month after completion of intervention for three months | The mean duration of bleeding was 8 days | MD 2 days fewer (2.38 fewer to 1.62 fewer) | ‐ | 110 (1 RCT) | ⨁⨁◯◯ Lowa,b | | Adverse events or side effects | None reported | |||| | Mefenamic acid vs tranexamic acid | ||||| | Menstrual blood loss Volume blood loss (pictorial chart in mL) Follow‐up: after 3rd month of intervention | The mean volume of menstrual blood loss was 160 mL | MD 64.26 mL lower (105.65 lower to 22.87 lower) | ‐ | 94 (1 RCT) | ⨁⨁◯◯ Lowc | | Duration of bleeding Number of bleeding days (menstrual record) Follow‐up: after 3rd month of intervention Recorded on daily diary | The mean number of bleeding days was 3.5 to 6.4 days | MD 0.08 days more (0.27 fewer to 0.42 more) | ‐ | 152 (2 RCTs) | ⨁⨁◯◯ Lowd | | Adverse events or side effects | No data available | |||| | Mefenamic acid vs desmopressin | ||||| | Menstrual blood loss Mean reduction of PBAC score Follow‐up: after 3rd month of intervention | The mean reduction of PBAC score was 40.5% in desmopressin and 45.7% in mefenamic acid | 24 (1 RCT) | ⨁◯◯◯ Very lowb,e | || | Tranexamic acid vs sodium diclofenac | ||||| | Menstrual blood loss Volume of blood loss (alkaline hematin method) Follow‐up: each intervention cycle (cross‐over) for 5 menstrual cycles | The mean blood loss was 102mL | MD 42.7mL lower (73.33 lower to 12.07 lower) | ‐ | 38 (1 RCT) | ⨁◯◯◯ Very lowc,f | | Duration of bleeding Follow‐up: each intervention cycle (cross‐over) for 5 menstrual cycles | The mean duration of bleeding was 5.1 days | MD 0 days (0.62 lower to 0.62 higher) | ‐ | 38 (1 RCT) | ⨁◯◯◯ Very lowb,f | | Side effects: gastrointestinal disturbances (diarrhoea, lower abdominal pain), headache and sweating | 316 per 1000 | 684 per 1000 (356 to 895) | OR 4.69 (1.2 to 18.44) | 38 (1 RCT) | ⨁◯◯◯ Very lowb,f | | Tranexamic acid vs flavonoids | ||||| | Menstrual blood loss PBAC score Follow‐up: each cycle for 3 menstrual cycles | The mean PBAC score was 125 | MD 32 lower (39.84 lower to 24.16 lower) | ‐ | 100 (1 RCT) | ⨁⨁◯◯ Lowb,g | | Menstrual blood loss Number of pads per day Follow‐up: each cycle for 3 menstrual cycles | The mean number of pads was 3 pads per day | MD 0.5 pads lower (0.91 lower to 0.09 lower) | ‐ | 100 (1 RCT) | ⨁⨁◯◯ Lowb,g | | Duration of bleeding Number of bleeding days Follow‐up: each cycle for 3 menstrual cycles | The mean number of bleed days was 6.8 days | MD 1.4 days lower (1.93 lower to 0.87 lower) | ‐ | 100 (1 RCT) | ⨁⨁◯◯ Lowb,g | | Side effects: headache Follow‐up: each cycle for 3 menstrual cycles | 160 per 1000 | 99 per 1000 (33 to 268) | OR 0.58 (0.18 to 1.92) | 100 (1 RCT) | ⨁⨁◯◯ Lowb,g | | Side effects: vomiting Follow‐up: each cycle for 3 menstrual cycles | 180 per 1000 | 140 per 1000 (33 to 268) | OR 0.74 (0.25 to 2.18) | 100 (1 RCT) | ⨁⨁◯◯ Lowb,g | | Tranexamic acid vs active comparators (mefenamic acid, flavonoid, sodium diclofenac) | ||||| | Duration of bleeding Number of bleeding days Follow‐up: 2‐5 menstrual cycles | The mean number of bleeding days was 5.1 to 6.8 days | MD 0.27 days lower (1.14 lower to 0.6 higher) | ‐ | 290 (4 RCTs) | ⨁◯◯◯ Very lowf,h | CI: confidence interval; MD: mean difference; OR: odds ratio; PBAC: pictorial blood assessment chart; RCT: randomized controlled trial; vs: versus aDowngraded one level due to unclear risk of selection bias. bDowngraded one level for imprecision as effects were measured by one trial. cDowngraded two levels for imprecision as effects were measured by one trial and the confidence interval was wide. dDowngraded two levels due to unclear risk of selection bias and high risk of detection bias. eDowngraded two levels due to high risk of performance bias and detection bias. fDowngraded two levels due to unclear risk of selection, performance and reporting bias and high risk of detection bias. gDowngraded one level due to high risk of detection bias. hDowngraded one level for inconsistency due to high statistical heterogeneity. Summary of findings 2. Ulipristal acetate compared to placebo for the treatment of heavy menstrual bleeding associated with LNG IUD. | Interventions vs comparisons | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (trials) | Certainty of the evidence (GRADE) | | | Risk with comparisons | Risk with interventions | |||| | Ulipristal acetate vs placebo | ||||| | Duration of bleeding Total bleeding in 90 days (bleeding calendar) Follow‐up: 30, 60 and 90 days after treatment initiation | The mean total of bleeding days in 90 days was 29.8 to 39.1 days | MD 9.3 days lower (26.76 lower to 8.16 higher) | ‐ | 24 (1 RCT) | ⨁◯◯◯ Very lowa,b | CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomized controlled trial; vs: versus aDowngraded one level due to high risk of detection bias. bDowngraded two levels for imprecision as effects were only measured from one trial with small number of participants. Summary of findings 3. Mefanamic acid compared to Vitex agnus for the treatment of heavy menstrual bleeding associated with unknown IUD type. | Interventions vs comparisons | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Certainty of the evidence (GRADE) | ||| | Risk with comparisons | Risk with interventions | |||||| | Mefenamic acid vs Vitex agnus | ||||||| | Menstrual blood loss PBAC score Follow‐up: monthly for 4 months | The mean PBAC score was 89.7 | 2.4 lower (13.77 lower to 8.97 higher | ‐ | 84 (1 RCT) | ⨁⨁◯◯ Lowa,b | || | Side effects: nausea Follow‐up: monthly for 4 months | 24 per 1000 | 24 per 1000 (1 to 287) | OR 1.00 (0.06 to 16.53) | 84 (1 RCT) | ⨁⨁◯◯ Lowc | || | Side effects: abdominal pain Follow‐up: monthly for 4 months | 24 per 1000 | 8 per 1000 (0 to 167) | OR 0.33 (0.01 to 8.22) | 84 (1 RCT) | ⨁⨁◯◯ Lowc | CI: confidence interval; MD: mean difference; OR: odds ratio; PBAC: pictorial blood assessment chart; RCT: randomized controlled trial; vs: versus aDowngraded one level due to unclear reporting bias. bDowngraded one level for imprecision as effects were measured by only one trial. cDowngraded two levels for imprecision as effects were measured from only one trial and confidence interval was wide. Summary of findings 4. Tranexamic acid compared to sodium diclofenac for the treatment of pain associated with Cu IUD. | Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Certainty of the evidence (GRADE) | | | Risk with comparisons | Risk with interventions | |||| | Tranexamic acid vs sodium diclofenac | ||||| | Pelvic pain Follow‐up: each intervention cycle (cross over) for 5 menstrual cycles | 53 per 1000 | 53 per 1000 (3 to 489) | OR 1.00 (0.06 to 17.25) | 38 (1 RCT) | ⨁◯◯◯ Very lowa,b | CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomized controlled trial; vs: versus aDowngraded two levels due to unclear risk of selection, performance and reporting bias and high risk of detection bias. bDowngraded one level for imprecision as effect measures were from one small trial. Summary of findings 5. Naproxen compared to placebo for the treatment of pain associated with unknown IUD type. | Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Certainty of the evidence (GRADE) | | | Risk with comparisons | Risk with interventions | |||| | Naproxen vs placebo | ||||| | Overall pain relief score (4‐point scale) Follow‐up: each cycle for 3 menstrual cycles | The mean overall pain relief score was 7.9 | MD 4.1 higher (0.91 higher to 7.29 higher) | ‐ | 33 (1 RCT) | ⨁⨁◯◯ Lowa,b | | Daily pain relief score (6‐point scale) Follow‐up: each cycle for 3 menstrual cycles | The mean daily pain relief score was 10.8 | 3.1 higher (0.27 higher to 5.93 higher) | ‐ | 33 (1 RCT) | ⨁⨁◯◯ Lowa,b | | Need for additional analgesia (self‐recorded) Follow‐up: each cycle for 3 menstrual cycles | 313 per 1000 | 116 per 1000 (22 to 450) | OR 0.29 (0.05 to 1.80) | 33 (1 RCT) | ⨁⨁◯◯ Lowa,b | | Side effects: gastrointestinal symptoms Follow‐up: each cycle for 3 menstrual cycles | 48 per 1000 | 95 per 1000 (9 to 557) | OR 2.11 (0.18 to 25.17) | 33 (1 RCT) | ⨁⨁◯◯ Lowa,b | CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomized controlled trial; vs: versus aDowngraded two levels due to unclear risk of selection, performance and reporting bias as well as high risk of detection bias. bDowngraded one level for imprecision as effect measures were from one small trial. Summary of findings 6. Interventions (ibuprofen, tolfenamic acid, aspirin, tranexamic acid) compared to placebo or active comparators (paracetamol, tranexamic acid) for the prevention of heavy menstrual bleeding associated with Cu IUD. | Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Certainty of the evidence (GRADE) | Outcomes | | Ibuprofen vs placebo | ||||| | Menstrual blood loss (alkaline hematin method) Follow‐up: 3 months | The mean menstrual blood loss was 44.7 to 109.2 mL | MD 14.11 mL lower (36.04 lower to 7.82 higher) | ‐ | 40 (1 RCT) | ⨁◯◯◯ Very lowa,b | | Duration of bleeding (menstrual diary) Follow‐up: 3 months | The mean duration of bleed was 6.4 days | MD 0.2 days lower (0.14 lower to 1 higher) | ‐ | 28 (1 RCT) | ⨁◯◯◯ Very lowc,d | | Side effects: eye and mouth swelling, stomach cramps, fatigue, irritability (diary record) Follow‐up: 3 months | 38 per 1000 | 79 per 1000 (20 to 271) | OR 2.15 (0.5 to 9.31) | 68 (2 RCTs) | ⨁⨁◯◯ Lowa,d | | Tolfenamic acid vs placebo | ||||| | Menstrual blood loss Menstruation "more abundant than normal" (questionnaire) Follow‐up: 3 months | 658 per 1000 | 510 per 1000 (396 to 621) | OR 0.54 (0.34 to 0.85) | 310 (1 RCT) | ⨁◯◯◯ Very lowd,e | | Side effects: dyspepsia, diarrhoea, headache, fatigue (questionnaire) Follow‐up: 3 months | 129 per 1000 | 66 per 1000 (20 to 200) | OR 0.48 (0.14 to 1.69) | ⨁◯◯◯ Very lowd,e | | | Aspirin vs paracetamol | ||||| | Menstrual blood loss (alkaline hematin method) Follow‐up: 3 cycles | The mean menstrual blood loss was 49.5 mL | MD 0.3mL lower (26.16 lower to 25.56 higher) | ‐ | 20 (1 RCT) | ⨁◯◯◯ Very lowd,f | | Adverse events or side effects | Not reported | |||| | 2 g tranexamic acid vs 1 g tranexamic acid | ||||| | Menstrual blood loss % occurrence of heavy menstrual bleeding (alkaline hematin method) Follow‐up: each cycle for 3 menstrual cycles | 2 g tranexamic acid: 20 1 g tranexamic acid: 11.76 | 64 (1 RCT) | ⨁◯◯◯ Very lowd,g | || | Menstrual blood loss % occurrence heavy menstrual bleeding (PBAC score) Follow‐up: each cycle for 3 menstrual cycles | 2 g tranexamic acid: 26.79 1 g tranexamic acid: 45.83 | 175 (1 RCT) | ⨁◯◯◯ Very lowd,g | || | Adverse events or side effects | Not reported | CI: confidence interval; MD: mean difference; OR: odds ratio; PBAC: pictorial blood assessment chart; RCT: randomized controlled trial; vs: versus aDowngraded one level due to unclear risk of selection and reporting bias. bDowngraded two levels due to substantially wide confidence interval and effects measures from only one small trial. cDowngraded two levels due to unclear risk of selection, performance and reporting bias as well as high risk of detection bias. dDowngraded one level for imprecision as effect measures were from one trial. eDowngraded two levels due to unclear risk of selection, performance, attrition and reporting bias as well as high risk of detection bias. fDowngraded two levels due to unclear risk of selection, performance and reporting bias as well as high risk of other sources of bias (4 out of 10 women on intrauterine devices had prior to intervention, prolonged bleeding time, increased capillary fragility and/or a history of bleeding tendencies). gDowngraded two levels due to unclear risk of selection and performance bias, high risk of detection bias. Summary of findings 7. Interventions (ulipristal acetate, tranexamic acid, mifepristone, naproxen) compared placebo or active comparators (mefenamic acid, vitamin B, estradiol) for the prevention of heavy menstrual bleeding associated with LNG IUD. | Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Certainty of the evidence (GRADE) | | | Risk with comparisons | Risk with interventions | |||| | Ulipristal acetate vs placebo | ||||| | Percentage days bleeding or spotting (questionnaire) Follow‐up: 1, 3 and 6 months after IUD insertion | The mean percentage days bleeding or spotting was 20.7 | MD 9.5% higher (1.48 higher to 17.52 higher) | ‐ | 118 (1 RCT) | ⨁⨁◯◯ Lowa,b | | Adverse events or side effects | Not reported | |||| | Tranexamic acid vs mefenamic acid | ||||| | Menstrual blood loss | No data reported | |||| | Duration of bleeding Median number of bleed days (diary) Follow‐up: 90 days of study assessment followed by 30 days | Tranexamic acid: 8 Mefenamic acid: 10 | 168 (1 RCT) | ⨁⨁◯◯ Lowa,c | || | Side effects: gastrointestinal disorders, headache, breast tenderness, musculoskeletal disorders Follow‐up: 90 days of study assessment followed by 30 days | 468 per 1000 | 468 per 1000 | OR 1.00 (0.49 to 2.02) | 168 (1 RCT) | ⨁⨁◯◯ Lowa,c | | Mifepristone vs vitamin B | ||||| | Menstrual blood loss | No data reported | |||| | Duration of bleeding % spotting and bleeding days Follow‐up: 1, 3 and 6 months after IUD insertion | Mifepristone: fewer women reported bleeding or spotting. Fewer days with normal or heavy intensity bleeding Vitamin B: more bleeding or spotting days | 58 (1 RCT) | ⨁◯◯◯ Very lowa,d | || | Adverse events or side effects | Not reported | |||| | Naproxen vs estradiol | ||||| | Menstrual blood loss | Not reported | |||| | Duration of bleeding Median number of bleeding and spotting days (diary) Follow‐up: every 4 weeks for 16 weeks | Naproxen: 27.5 Estradiol: 44 | 106 (1 RCT) | ⨁◯◯◯ Very lowa,e | || | Side effects: gastroesophageal reflux Follow‐up: every 4 weeks for 16 weeks | 0 per 1000 | 0 per 1000 | OR 3.22 (0.13 to 81.19) | 86 (1 RCT) | ⨁◯◯◯ Very lowa,e | CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomized controlled trial; vs: versus aDowngraded one level for imprecision as effects were measured from one trial. bDowngraded one level due to unclear risk of performance bias. cDowngraded one level due to high risk of detection bias dDowngraded two levels due to high risk of detection bias and unclear risk of performance bias. eDowngraded two levels due to high risk of performance bias and detection bias. Summary of findings 8. Interventions (ibuprofen, tolfenamic acid) compared to placebo for the prevention of pain associated with Cu IUD. | Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Certainty of the evidence (GRADE) | | | Risk with comparisons | Risk with interventions | |||| | Ibuprofen vs placebo | ||||| | Reduction in painful menstruation Follow‐up: end of 1st, 2nd and 3rd months | 200 per 1000 | 200 per 1000 (27 to 691) | OR 1.00 (0.11 to 8.95) | 20 (1 RCT) | ⨁⨁◯◯ Lowa,b | | Tolfenamic acid vs placebo | ||||| | Menstruation "more painful than normal" Follow‐up: 3 months | 387 per 1000 | 310 per 1000 (217 to 476) | OR 0.71 (0.44 to 1.44) | 310 (1 RCT) | ⨁◯◯◯ Very lowc,d | CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomized controlled trial; vs: versus aDowngraded one level due to unclear risk of selection and reporting bias. bDowngraded one level for imprecision as effect measures were from one relatively small trial. cDowngraded one level for imprecision as effect measures were from one trial. dDowngraded two levels due to unclear risk of selection, performance, attrition and reporting bias as well as high risk of detection bias.

The intrauterine device (IUD) is one of the most commonly used methods of reversible contraception worldwide, accounting for 17% of contraceptive use. In 2019, it was used by 159 million women worldwide, up from 133 million women in 1994 (United Nations 2019). The estimated prevalence of IUD use among women of reproductive age (15 to 49 years) in 2019 was 10.7% in Asia, 8.1% in Europe and 4.6% in Latin America and the Caribbean. The highest prevalence of IUD use in 2019 is in the Democratic People’s Republic of Korea (46.9%) and Uzbekistan (36.9%). Among women of reproductive age, IUDs are used by 151 million married women (20%) in contrast to eight million (6%) unmarried women (United Nations 2019). Two types of IUD are commonly available: copper‐containing IUDs (Cu IUD) and levonorgestrel‐releasing IUDs (LNG IUD). Adolescent and adult women who desire a highly effective contraceptive method, which is long term and reversible, are eligible for IUD use (Francis 2017). IUD use has no restrictions for women who may have co‐morbidities including but not limited to benign ovarian tumours, breast disease, cervical cancer, cirrhosis, history of deep vein thrombosis, diabetes mellitus, epilepsy, migraine, hypertension, ischaemic heart disease, inflammatory bowel disease, multiple sclerosis, obesity, ovarian cancer, active smoking, thyroid disorders, tuberculosis and valvular heart disease (Gaffield 2016; Tepper 2016). Benefits of IUDs include highly effective pregnancy prevention. IUDs are long‐acting and rapidly reversible, with few side effects, few contraindications, reduced risk of cervical and ovarian cancer and do not require regular adherence to maintain their effectiveness (Cortessis 2017; Heinemann 2015; WHO 2015). However, despite their many benefits, IUD use is also associated with side effects such as heavier menstrual bleeding, prolonged or unscheduled bleeding, spotting, amenorrhoea and cramping (Bayer 2017). These side effects contribute to fear among women wanting to initiate IUD use as well as discontinuation among existing IUD users, as these effects are disturbing and affect quality of life (Diedrich 2015). Description of the condition Use of IUDs is associated with heavy menstrual bleeding and pain and these are the most commonly reported reasons for IUD removal within the first six months after insertion (Grunloh 2013). Heavy menstrual bleeding is defined based on a woman’s perception of increased daily or total menstrual volume or flow regardless of the duration, frequency and regularity (NICE 2018). This definition is subjective but a volume that impedes a woman’s physical, social, emotional or material quality of life is truly heavy. Previously, heavy menstrual bleeding was defined as a menstrual blood loss of more than 80 mL. However, in 2011, the International Federation of Gynaecology and Obstetrics (FIGO) developed new definitions and terminology for abnormal uterine bleeding symptoms as well as a new classification of underlying causes of abnormal uterine bleeding in the reproductive years (Munro 2011). Normal menstruation is defined as a frequency of 24 to 38 days, regularity of seven to nine days or less, duration of eight days or less and a subjective clinical definition of volume, which does not interfere with a woman’s physical, social, emotional or material quality of life. Research definition for normal volume is 80 mL vaginal blood loss per cycle or less. Any symptomatic variation from normal menstruation is thus, abnormal uterine bleeding (Munro 2011; NICE 2018). Heavy menstrual bleeding can be specified more objectively for research reasons by direct or indirect methods for determining menstrual blood loss. The volumetric description of heavy menstrual bleeding is less than 80 mL per cycle and can be assessed using the alkaline hematin method from menstrual sanitary pads and tampons after careful collection or a semi‐quantitative method using pictorial blood loss assessment charts (PBAC; Hallberg 1964; Higham 1990; Newton 1977). Description of the intervention Several interventions have been studied for the treatment of heavy menstrual bleeding and pain associated with IUD use, among which are nonsteroidal anti‐inflammatory drugs (NSAIDs), such as mefenamic acid; naproxen; indomethacin; aspirin; and antifibrinolytics, such as tranexamic acid. Other interventions studied include hormones such as desmopressin and estradiol, vitamins, flavonoids, paracetamol, and alternative therapies. How the intervention might work Increased fibrinolytic activity and increased prostaglandin release play a role in bleeding and pain associated with Cu IUD use (Godfrey 2013; Ylikorkala 1994). Endometrial concentrations of some prostaglandin metabolites correlate with measured blood loss in Cu IUD users (Ylikorkala 1994). As for LNG IUD, it has been hypothesized that progesterone causes increased fragility of the superficial vessels of the endometrium as well as endometrial atrophy (Hickey 2002). NSAIDs act as inhibitors of prostaglandin synthetase and decrease the release of endometrial prostaglandin, while tranexamic acid exerts its antifibrinolytic effect by inhibiting the endometrial plasminogen activator, preventing fibrinolysis and the breakdown of clots (Alanwar 2018; Saharkhiz 2017). NSAIDs and fibrinolytic agent such as tranexamic acid have been recommended by the World Health Organization's (WHO) Selected Practice Recommendations for Contraceptive Use as possible treatments for heavy menstrual bleeding among Cu IUD users (WHO 2015). Flavonoids have been shown to inhibit the release of the inflammatory mediators prostaglandin E2, prostaglandin F2a, thromboxane A2 and prostacyclin and thus reduce capillary hyper‐fragility, increase lymphatic drainage, normalize capillary permeability and strengthen capillary resistance (Lyseng‐Williamson 2003; Manthey 2000). These mechanisms of action are thought to reduce heavy menstrual bleeding and pain associated with Cu and LNG IUD use. Why it is important to do this review IUD users give the reasons for discontinuation of IUD use as heavy menstrual bleeding and pain associated with IUDs. The discontinuation of IUD use due to pain was 28% (LNG IUD) to 35% (Cu IUD), while due to heavy bleeding it was 9% (LNG IUD) and 19% (Cu IUD) (Grunloh 2013). This percentage is large and in turn affects many women, given the current use of IUDs worldwide (159 million women; United Nations 2019). As IUDs are highly effective, safe, cost‐effective and well tolerated by most women, strategies to treat and prevent heavy menstrual bleeding and pain associated with its use should be sought to ensure uptake of this contraceptive method and reduce discontinuation rates.

To evaluate all randomized controlled trials (RCTs) that have assessed strategies for treatment and prevention of heavy menstrual bleeding or pain associated with IUD use, for example, pharmacotherapy and alternative therapies.

Criteria for considering studies for this review Types of studies We included all RCTs in any language that compared any intervention for treating heavy menstrual bleeding or pain associated with any IUD use. We excluded cohort trials and before‐after trials. Interventions for pain during IUD insertion have been examined in another Cochrane Review (Lopez 2015). The intervention could be compared with no intervention, placebo or another active intervention. We excluded pathological causes of heavy menstrual bleeding and post‐menopausal bleeding. Types of participants We included women of reproductive age (15 to 49 years) of any gravidity and parity who were using an IUD for contraception. Types of interventions We included any pharmacological or other interventions used either for the treatment or the prevention of heavy menstrual bleeding or pain, or both, associated with IUD use. Comparisons included placebo, no intervention or another active intervention. Types of intervention may include NSAIDs, antifibrinolytics, hormones, other drugs or complementary alternative therapies. Types of outcome measures Primary outcomes We searched the Core Outcome Measures in Effectiveness Trials (COMET) database (www.comet-initiative.org), to see if a core outcome set had been developed for the outcomes in heavy menstrual bleeding. We found one ongoing trial in the Core Outcomes in Women’s and Newborn health (CROWN) initiative (www.comet-initiative.org/Studies/Details/789). Therefore, after discussion between the review authors, we have chosen the primary and secondary outcomes below. Volume of menstrual blood loss: outcome measures for bleeding included quantitative measurements of blood loss (Hallberg 1964), semi‐quantitative assessments of blood loss by PBAC scores (Higham 1990; Reid 2000), or IUD discontinuation (Hubacher 2006) and number of sanitary pads used for bleeding. Participant perceptions of bleeding being more abundant than usual using categorical scales or menstrual diary cards could also be included. Duration of bleeding: duration of bleeding in number of bleeding or spotting days Painful menstruation: level of pain could be reported on Likert scales, pain scores, qualitatively or any pain reduction Secondary outcomes IUD removal Haemoglobin levels Need for additional analgesia Quality of life measured by any validated scales Side effects and adverse events Search methods for identification of studies The Cochrane Fertility Regulation Information Specialist conducted a search for all published, unpublished, and ongoing trials, without restrictions on language or publication status till 28 January 2021. The search strategies for each database were modelled on the search strategy designed for MEDLINE Ovid (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily), available in Appendix 1. Electronic searches We searched the following databases from their inception. EBM Reviews Ovid (1974 to 28 January 2021) Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 12) MEDLINE Ovid (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily) (1946 to 28 January 2021) Embase.com (1974 to 28 January 2021) CINAHL (1982 to 28 January 2021) LILACs lilacs.bvsalud.org/en/ (1982 to 28 January 2021) Global Health Ovid (inception to 28 January 2021) Scopus (inception to 28 January 2021) We searched the following trials registries: The World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) (up to 28 January 2021) ClinicalTrials.gov (www.clinicaltrials.gov) (up to 28 January 2021) We searched the following grey literature sites: Guttmacher Institute (www.guttmacher.org/united-states/abortion) (up to 28 January 2021) International Planned Parenthood Federation (www.ippf.org/) (up to 28 January 2021) Ibis Reproductive Health (ibisreproductivehealth.org/) (up to 28 January 2021) Women on Waves (www.womenonwaves.org/) (up to 28 January 2021) Marie Stopes International (www.mariestopes.org/) (up to 28 January 2021) Population Council (www.popcouncil.org/) (up to 28 January 2021) Population Services International (www.psi.org/) (up to 28 January 2021) Ipas (www.ipas.org/) (up to 28 January 2021) Searching other resources We checked the bibliographies of included trials and any relevant systematic reviews identified for further references to relevant trials. We contacted experts and organizations in the field to obtain additional information on relevant trials. We wrote to authors of published trial reports to solicit other published or unpublished trials that we may have missed. We also contacted trial report authors as needed to supplement published information. Data collection and analysis For this update, we applied the techniques below to evaluate the reports that we discovered as a result of the updated search, and we went back over the trial reports in the 2011 publication to assign them to the proper comparison and to revise their risk of bias. Selection of studies Two review authors independently assessed and abstracted data from the trials identified to improve accuracy. We resolved any discrepancies or disagreements through discussion or by involving a third review author if needed. Data extraction and management Two review authors extracted the data for the eligible trials. We solved inconsistencies through discussion or, if necessary, we sought advice from the third review author. We entered data into Review Manager 5 software (Review Manager 2020), and checked accuracy. When any information was doubtful, we tried to contact authors of the original reports for further details. Assessment of risk of bias in included studies Two review authors independently assessed risk of bias for each trial using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We resolved any disagreement by discussion, or by involving a third review author. The biases related to this review were: selection bias (random sequence generation; allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other forms of bias (such as baseline imbalance, selective reporting of subgroups, or potential influence from funders). Conclusions were assigned to each of these domains (Higgins 2017). We graded each risk of bias domain as 'low', 'unclear' or 'high', We described all judgements fully and presented the conclusions in the Risk of bias in included studies. We assessed the likely magnitude and direction of the bias and whether it was likely to impact the findings. We explored impact of bias by performing sensitivity analysis. We also noted funding source for trials and declaration of interest by trial authors. Measures of treatment effect For continuous variables, we computed the mean difference (MD) with 95% confidence interval (CI). We used standardized mean difference (SMD) if trials in the meta‐analysis used different measurement scales. We would interpret SMD as 0.2 small effect, 0.5 moderate effect and 0.8 a large effect (Cohen 1988). For dichotomous outcomes, we calculated odds ratio (OR) with 95% CI. We used a random‐effects model in meta‐analysis. We presented data as provided by the trial authors, for trials that reported in medians, ranges and percentages. Unit of analysis issues We checked included trials for unit of analysis errors, and we did not encounter any of these. If we had encountered any cluster‐RCTs we intended to adjust the results from trials showing unit of analysis errors based on the mean cluster size and intra‐cluster correlation coefficient (Higgins 2021a). Dealing with missing data For included trials, we noted levels of attrition. We had proposed to investigate the influence of including trials with high levels of missing data in the whole assessment of treatment effect by using sensitivity analysis. For all outcomes, we conducted analyses, as far as feasible, on an intention‐to‐treat basis. Assessment of heterogeneity We deemed whether the clinical and methodological qualities of the included trials were adequately similar for meta‐analysis to provide a meaningful summary. Where we were able to carry out meta‐analyses, we checked for heterogeneity by visually inspecting the forest plots for evidence of poor overlap of the 95% CIs. More accurately, we used the Chi2 test (with a P value less than 0.10 being evidence of significance) and the I2 statistic value (Higgins 2003). The Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021), suggested a rough guide for interpretation of I2 statistic values: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% was considerable heterogeneity. Where we found substantial heterogeneity (I2 statistic > 50%), we aimed to look at possible sources involving variations in trial quality, inclusion criteria or intervention regimes among trials. Assessment of reporting biases We aimed to minimize the likelihood of reporting bias by conducting a comprehensive search for eligible trials with no restriction to language or publication status and by being alert to duplication of data. Despite these efforts, it is still possible that we may have missed some trials, so our conclusions should be interpreted with some caution. If we found 10 or more trials for the primary outcomes, we planned to use a funnel plot to explore the possibility of small‐trial effects. Data synthesis We carried out statistical analysis using Review Manager 5 software (Review Manager 2020). We applied a random‐effects model in meta‐analysis for merging data as we believed it was acceptable to presume that there was clinical heterogeneity due to the huge difference in the type of intervention used (Deeks 2021). There was also variation in the subjective assessment of volume of menstrual blood loss and level of pain. These variations directed us to believe that the underlying treatment effects would differ between trials. Cross‐over trials are a suitable design to evaluate stable, chronic conditions (Higgins 2021b). We therefore anticipated trials with cross‐over design in this review, as bleeding or pain associated with IUD use is a recurrent condition. However, to date, the reporting of cross‐over trials is variable, and the data needed to include a paired analysis in a meta‐analysis is often unpublished. We made an a priori decision to include only data from the first period if available and to report the rest of the cross‐over data in the review. Subgroup analysis and investigation of heterogeneity Where data were available, we planned to undertake subgroup analyses according to type and dose of interventions. However, there were insufficient trials to undertake subgroup analyses. Sensitivity analysis Akin to the previous review, we did not perform sensitivity analyses due to the inability to aggregate the included trials. We intended to do sensitivity analysis when there was high risk of bias for sequence generation and allocation concealment of included trials. Future updates may undertake this analysis if there are an adequate number of relevant trials. Summary of findings and assessment of the certainty of the evidence Assessing the certainty of evidence using the GRADE approach We used the GRADE approach to assess the certainty of the body of evidence for this update, relating to the following outcomes for the main comparisons. Menstrual blood loss Duration of bleeding Level of pain We used the GRADEPro GDT development tool (GRADEpro GDT), to import data from Review Manager 5 (Review Manager 2020), to create the summary of findings tables. Using the GRADE approach, we generated a summary of the intervention effect and measure of certainty for each of the above outcomes. The GRADE approach uses five considerations (trial limitations, consistency of effect, indirectness, imprecision and publication bias) to assess the certainty of the body of evidence for each outcome. We downgraded the evidence from 'high certainty' by one level for serious (or by two levels for very serious) weaknesses, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies; Table 9; Table 10. 1. Summary of treatment trials interventions. | Trial | Experimental Intervention | Comparison Intervention | IUD type | Duration of intervention | Follow‐up | Outcome | | Effectiveness trials | |||||| | Bleeding trials | |||||| | Davies 1981 RCT with cross‐over | Oral naproxen 1250 mg/day | Oral naproxen 500 mg on 1st day then 750 mg on subsequent days Placebo | Unknown | 4 cycles Each participant took 2 of the 3 treatments, each for 2 menstrual cycles. Each regimen was begun on the 1st day of menstrual bleeding and continued for a total of 5 days. | After every 2 menstrual cycles | Percentage reduction in menstrual blood loss | | Fava 2020 RCT | Oral ulipristal acetate 5 mg/day for 5 days | Oral placebo | LNG IUD | 5 days, bleeding was assessed at 30 days, 60 days and 70 days | 90 days | Total bleeding days | | Jafari 2014 RCT | Oral vitamin B1 100 mg/day during the 2nd, 3rd and 4th months following insertion of the IUD | Oral placebo during the 2nd, 3rd and 4th months following insertion of the IUD | Cu IUD | 3 cycles | 1 month after completion of intervention | Number of pads used Number of spotting days Duration of bleeding | | Pain trials | |||||| | Buttram 1979 RCT | Oral naproxen sodium 550 mg initially, then 275 mg every 6 hours as needed for uterine pain | Placebo (lactose) | Unknown IUD type | 3 cycles | No details | Overall and daily pain relief score (6‐point Likert scale) | | Lalos 1983 RCT with cross‐over | Oral naproxen 500 mg followed by 250 mg 2‐4 times a day, with a maximum of 1250 mg, taken at the first sign of menstrual distress. | Oral placebo taken at the first sign of menstrual distress. | Cu IUD | 4 cycles Participant took an intervention for 2 cycles then crossed over to the other intervention for 2 cycles | After 2nd and 4th menstrual cycle | Pain relief (5‐point Likert scale) | | Comparative effectiveness trials | |||||| | Bleeding trials | |||||| | Alanwar 2018 RCT | Oral tranexamic acid 500 mg, 1 tablet 6‐hourly during the 1st 3 days of menstrual bleeding | Oral micronized flavonoid 500 mg, 1 tablet 6‐hourly during the 1st 3 days of menstrual bleeding | Cu IUD | 3 cycles | No details | PBAC score Number of pads used/day Number of bleeding days | | Kaviani 2013 RCT | Oral mefenamic acid, 250 mg; 1 capsule every 8 hours on the first 3 days of menstruation | Oral tranexamic acid, 250 mg; 1 capsule every 8 hours on the first 3 days of menstruation | Cu IUD | 2 cycles | No details | PBAC score Number of bleeding days | | Mercorio 2003 RCT | Desmopressin 300 mcg intranasal spray each morning for the first 5 days after start of menstruation | Oral mefenamic acid 1500 mg/day for the first 5 days after the start of menstruation. | Cu IUD | 3 months | Monthly for 3 months | PBAC score | | Saharkhiz 2017 RCT | Oral tranexamic acid 500 mg 3 times/day for 3‐5 days based on the duration of bleeding | Oral mefenamic acid 500 mg 3 times/day for 3‐5 days based on the duration of bleeding | Cu IUD | 3 months | Monthly for 3 months | Volume of blood loss Duration of bleeding | | Yavarikia 2013 RCT | Oral mefenamic acid 250 mg 3 times/day from the 1st day of menstruation until day 8 | Oral Vitex agnus 3 times/day from the 1st day of menstruation until day 8 | Unknown IUD type | 4 months | No details | PBAC score | | Ylikorkala 1983 RCT with cross‐over | Oral tranexamic acid 4.5 g/day for 5 days | Oral sodium diclofenac 150 mg on day 1 then 75 mg/day on days 2‐4 Placebo | Cu IUD | 5 months Each participant received placebo for 1 month, 2 months of tranexamic acid, and 2 months of sodium diclofenac | No details | Menstrual blood loss (alkaline hematin) Duration of bleeding | | Cu IUD: copper intrauterine device; HMB: heavy menstrual bleeding; IUD: intrauterine device; LNG IUD: levonorgestrel intrauterine device; PBAC: pictorial blood loss assessment chart | 2. Summary of prevention trials interventions. | Trial | Experimental intervention | Comparison intervention | IUD type | Duration of intervention | Follow‐up | Outcomes | | Effectiveness trials | |||||| | Bleeding trials | |||||| | Makarainen 1986 RCT | Oral ibuprofen 1200 mg/day at the beginning of menstruation and to continue to end of bleeding for a maximum of 10 days. | Oral placebo at the beginning of menstruation and to continue to end of bleeding for a maximum of 10 days. | Cu IUD | 3 cycles | No details | Menstrual blood loss (alkaline hematin) Length of menstruation | | Roy 1981 RCT with cross‐over | Oral ibuprofen 1600 mg/day starting with bleeding and continuing until end of bleeding or maximum of 7 days | Placebo starting with bleeding and continuing until end of bleeding or maximum of 7 days | Cu IUD Cu Lippes loop | 3 cycles Each participant had 1 month of observation, 1 month on ibuprofen or placebo, and 1 month crossed over to the alternative treatment. | End of month 1, 2, 3 | Menstrual blood loss (alkaline hematin) | | Warner 2010 RCT | Oral CDB‐2914 50 mg/day | Oral placebo | LNG IUD | Intervention taken for 3 consecutive days with separate treatments starting 21, 49 and 77 days after LNG IUD insertion | 1,3 and 6 months after IUD insertion | Percentage days bleeding/ spotting, removal of LNG IUD within 6 months; the longest run of amenorrhoea in the 64 days after third treatment, side effects | | Bleeding and pain trials | |||||| | Hubacher 2006 RCT | Oral ibuprofen 1200 mg/day to be taken with the first 6 menstruations after IUD insertion and for a maximum of 5 days at a time. | Oral placebo to be taken with the first 6 menstruations after IUD insertion and for a maximum of 5 days at a time. | Cu IUD | 6 cycles | 6, 13, 26 and 52 weeks after IUD insertion | IUD removal within 12 months of insertion due to HMB/pain | | Ylikorkala 1978 RCT | Oral tolfenamic acid 600 mg/day starting at IUD insertion and continuing for 7 days; this was to be repeated during the next 3 menstruations. | Placebo starting at IUD insertion and continuing for 7 days; this was to be repeated during the next 3 menstruations | Cu IUD | 3 cycles | No details | Number of pads used, menstruation more abundant than normal, clots, menstruation more painful than normal | | Comparative effectiveness trials | |||||| | Bleeding trials | |||||| | Hahn 1979 RCT with cross‐over | Oral aspirin 1500 mg/day | Oral paracetamol 1500 mg/day Placebo | Cu IUD | 3 cycles Interventions taken on day 1 of menstruation and continued for the duration of bleeding. Each participant received each treatment in alternating order. | No details | Menstrual blood loss (alkaline hematin) | | Lin 2007 RCT | Oral tranexamic acid 2 g/day, taken for the 1st 5 days of 3 consecutive cycles after IUD insertion | Oral tranexamic acid 1 g/day, taken for the 1st 5 days of 3 consecutive cycles after IUD insertion | Cu IUD | 3 cycles | No details | Percentage occurrence of HMB by alkaline hematin and PBAC | | Madden 2012 RCT | Oral naproxen 500 mg twice a day first 5 days of a 4‐week period | Transdermal estradiol 0.1 mg on day after insertion of IUD, changing it weekly Oral placebo twice a day | LNG IUD | First 12 weeks of IUD use | Telephone surveys at 4, 8, and 16 weeks and an in‐person follow‐up visit at 12 weeks | Median bleed days, patient satisfaction, continuation rates of IUD | | Papaikonomou 2018 RCT | Oral 50 mg mifepristone every other day starting on the 1st day of the menstrual cycle for the pre‐treatment period | Oral vitamin B every other day starting on the 1st day of the menstrual cycle for the pre‐treatment period | LNG IUD | 2 months (corresponding to 2 menstrual cycles i.e. 2 × 28 days) prior to insertion and until 3 days (± 2 days) following the LNG IUD insertion | Monthly for the first 3 months, 6 months post‐LNG IUD insertion and 12 months end‐of‐trial evaluation | Bleeding and spotting days | | Sordal 2013 RCT | Oral tranexamic acid 1500 mg/day, taken on the 1st day of a bleeding or spotting episode until bleeding or spotting stopped | Oral mefenamic acid 1500 mg/day, taken on the 1st day of a bleeding or spotting episode until bleeding or spotting stopped Oral placebo (lactose and magnesium stearate), taken on the 1st day of a bleeding or spotting episode until bleeding or spotting stopped | LNG IUD | 90 days | No details | Median reduction of bleed days and length of bleed days, satisfaction with drug/placebo, occurrence of pain, number of days pain medication used to alleviate pain, adverse effects | | Cu IUD: copper intrauterine device; HMB: heavy menstrual bleeding; IUD: intrauterine device; LNG IUD: levonorgestrel intrauterine device; PBAC: pictorial blood loss assessment chart |

of the search For this update, we retrieved 591 records from the search conducted in January 2021. We also re‐examined trials from the previous version of the review (Grimes 2006): there were 15 included trials, 10 excluded trials, and two ongoing trials. We excluded 11 trials (Figure 1). Eight trials were awaiting classification due to inability to retrieve full texts; six from the previous review (Di Lieto 1987; Jensen 1998; Massey 1974; Toppozada 1982; Wu 2000; Yarkoni 1984), and two from our new search (Bayer 2013; Wang 2013). There were no ongoing trials. Included studies This update includes 21 trials with a total of 3689 participants. Of those, 11 trials were included in the previous review (Buttram 1979; Davies 1981; Hahn 1979; Hubacher 2006; Lalos 1983; Lin 2007; Mercorio 2003; Roy 1981; Warner 2010; Ylikorkala 1978; Ylikorkala 1983). One trial was excluded from the previous review (Makarainen 1986), and we included nine new trials from the updated search (Alanwar 2018; Fava 2020; Jafari 2014; Kaviani 2013; Madden 2012; Papaikonomou 2018; Saharkhiz 2017; Sordal 2013; Yavarikia 2013). See Figure 1 for the PRISMA flow diagram (Page 2021). Of the 20 included trials, five trials with a total of 104 participants were randomized controlled trials (RCTs) with cross‐over design (Davies 1981; Hahn 1979; Lalos 1983; Roy 1981; Ylikorkala 1983). The number of participants in each trial ranged from 19 to 2019. The 20 trials were undertaken in 10 countries. Four trials were conducted in Iran (Jafari 2014; Kaviani 2013; Saharkhiz 2017; Yavarikia 2013), three in the USA (Buttram 1979; Madden 2012; Roy 1981), three in Sweden (Hahn 1979; Lalos 1983; Papaikonomou 2018), three in Finland (Makarainen 1986; Ylikorkala 1978; Ylikorkala 1983), two in the UK (Davies 1981; Warner 2010), one in Egypt (Alanwar 2018), one in Chile (Hubacher 2006), one in China (Lin 2007), one in Brazil (Fava 2020) and one in Italy (Mercorio 2003). One trial (Sordal 2013), involved three countries, which were Denmark, Ireland and Norway. Six trials were multi‐centre trials (Hubacher 2006; Jafari 2014; Kaviani 2013; Lin 2007; Saharkhiz 2017; Sordal 2013). Participants’ age ranged from 15 to 49 years old. Cu IUD was used by participants in 12 trials (Alanwar 2018; Hahn 1979; Hubacher 2006; Jafari 2014; Kaviani 2013; Lalos 1983; Lin 2007; Makarainen 1986; Mercorio 2003; Saharkhiz 2017; Ylikorkala 1978; Ylikorkala 1983), Cu IUD and Lippes Loop in one trial (Roy 1981), and LNG IUD in five trials (Fava 2020; Madden 2012; Papaikonomou 2018; Sordal 2013; Warner 2010). Three trials did not state the type of IUD used (Buttram 1979; Davies 1981; Yavarikia 2013). See Characteristics of included studies. Treatment trials Seven trials were among Cu IUD users. There were two effectiveness trials (Jafari 2014; Lalos 1983), and five comparative effectiveness trials (Alanwar 2018; Kaviani 2013; Mercorio 2003; Saharkhiz 2017; Ylikorkala 1983). Five trials focused on the treatment of heavy menstrual bleeding associated with IUD use (Alanwar 2018; Jafari 2014; Kaviani 2013; Mercorio 2003; Saharkhiz 2017), one trial on the treatment of pain associated with IUD use (Lalos 1983), and one trial on treatment of pain and bleeding associated with IUD use (Ylikorkala 1983). LNG IUD was used in one treatment of bleeding effectiveness trial (Fava 2020). Details are in Characteristics of included studies. The IUD type was uncertain in two treatment of bleeding effectiveness trials (Davies 1981; Yavarikia 2013), and one treatment of pain comparative effectiveness trial (Buttram 1979). Table 9 summarizes the experimental and comparison interventions for the treatment trials. Additional details are given in Characteristics of included studies. The following are the interventions for the treatment of bleeding and pain. Cu IUD - Treatment of heavy menstrual bleeding Vitamin B1 versus placebo Naproxen versus placebo Mefenamic acid versus tranexamic acid Mefenamic acid versus desmopressin Tranexamic acid versus diclofenac Tranexamic acid versus flavonoids Tranexamic acid versus active comparators (mefenamic acid, flavonoids, diclofenac) - Treatment of pain Tranexamic acid versus diclofenac LNG IUD - Treatment of heavy menstrual bleeding Ulipristal versus placebo Treatment of pain ‐ none Unknown IUD type - Treatment of heavy menstrual bleeding Higher dose versus lower dose naproxen Mefenamic acid versus Vitex agnus - Treatment of pain Naproxen versus placebo Treatment of heavy bleeding associated with IUD use Cu IUD The five treatment of bleeding trials included a total of 544 Cu IUD users, with sample size ranging from 24 to 210 women. The age of the women ranged from 18 to 49 years old. One trial studied oral vitamin B1 compared to placebo (dried starch; Jafari 2014). The dose of vitamin B was 100 mg per day taken during the second through fourth month of menstruation. Three trials studied NSAIDs (Kaviani 2013; Mercorio 2003; Saharkhiz 2017). Two trials compared mefenamic acid to tranexamic acid (Kaviani 2013; Saharkhiz 2017). The dose of mefenamic acid used was 750 mg per day in comparison tranexamic acid 750 mg per day for the first three days of menstruation for a total of two menstrual cycles (Kaviani 2013), while the other trial used 1500 mg mefenamic acid compared to 1500 mg tranexamic acid for three to five days, depending on the duration of bleeding, for three cycles (Saharkhiz 2017). An Italian RCT compared oral mefenamic acid 1500 mg per day to intranasal desmopressin 300 mcg per day for the first five days of menstruation for a duration of three cycles (Mercorio 2003). One trial studied oral tranexamic acid at a dose of 2 g per day compared to oral flavonoids at a dose of 2 g per day, taken on the first three days of menstruation for duration of three cycles (Alanwar 2018). Five trials assessed menstrual blood loss by applying PBAC (Alanwar 2018; Jafari 2014; Kaviani 2013; Mercorio 2003). One trial (Saharkhiz 2017), evaluated menstrual blood loss using a different pictorial chart, where each pad was perceived as lightly (10 mL), mildly (20 mL), moderately (30 mL), or completely saturated (40 mL). LNG IUD One trial among 30 LNG IUD users compared 5 mg oral ulipristal acetate per day, taken for five days, to oral placebo (Fava 2020). Duration of bleeding was reported as the number of days until bleeding stopped as well as the number of bleeding days in 90 days. Unknown IUD type One trial compared naproxen sodium at 1250 mg to 500 mg on the first day then 750 mg on subsequent days or placebo on day one to five of menstruation, for a total of two menstrual cycles per intervention (Davies 1981). No method of blood loss quantification was reported. Another trial compared oral mefenamic acid 750 mg per day to oral Vitex agnus 750 mg per day for the first eight days of menstruation for a duration of four months (Yavarikia 2013). Blood loss was assessed using a PBAC. Treatment of pain associated with IUD use Cu IUD One trial involving 21 Cu IUD users examined the use of naproxen sodium against placebo for the treatment of pain (Lalos 1983). This trial was a cross‐over design that compared oral naproxen at a dose of 500 mg initially followed by 250 mg two to four times per day as needed for two cycles followed by placebo for two cycles or vice versa. Pain was assessed using a Likert scale with scale of five being excellent relief and scale of one being worst pain. Unknown IUD type One trial with an unknown IUD type randomized 35 women to receive either naproxen sodium (550 mg initially, then 275 mg every six hours as needed) versus a placebo (lactose) for three consecutive menstrual cycles (Buttram 1979). Pain was assessed by a self‐administered six‐point Likert scale with 6 being excellent relief and 1 being no relief. Treatment of bleeding and pain associated with IUD use Cu IUD One trial assessed treatment of heavy menstrual bleeding and pain associated with IUD use (Ylikorkala 1983). The trial consisted of 19 women on Cu IUD, studied during five cycles. In randomized order, they received for two cycles oral tranexamic acid, 1.5 g three times daily for five days; in another two cycles they received sodium diclofenac, 50 mg three times daily on the first day followed by 25 mg three times daily for four days and placebo for five days in another cycle. Ylikorkala 1983 assessed menstrual blood loss using the alkaline hematin method, but did not describe the method for pain assessment. Prevention trials There were 10 prevention trials (Hahn 1979; Hubacher 2006; Lin 2007; Madden 2012; Makarainen 1986; Papaikonomou 2018; Roy 1981; Sordal 2013; Warner 2010; Ylikorkala 1978). Six were effectiveness trials, while four were comparative effectiveness, as detailed below (see Characteristics of included studies and Table 10). Four trials in women with Cu IUD were effectiveness trials (Hubacher 2006; Makarainen 1986; Roy 1981; Ylikorkala 1978), while two were comparative effectiveness trial (Hahn 1979; Lin 2007). Three trials examined prevention of heavy menstrual bleeding associated with Cu IUD (Hahn 1979; Lin 2007; Makarainen 1986), while another three trials looked at the prevention of both bleeding and pain (Hubacher 2006; Roy 1981; Ylikorkala 1978). Four trials assessed the prevention of bleeding associated with LNG IUD use (Madden 2012; Papaikonomou 2018; Sordal 2013; Warner 2010). Only one was an effectiveness trial (Warner 2010). Table 10 summarizes the experimental and comparison interventions for the 10 prevention trials. Additional details are given in Characteristics of included studies. Prevention of pain ‐ There were 11 treatment trials. Five were effectiveness trials, while six were comparative effectiveness, as detailed below (see Characteristics of included studies; Table 9) The following are the interventions for the prevention of bleeding and pain: Cu IUD - Prevention of heavy menstrual bleeding Ibuprofen versus placebo Tolfenamic acid versus placebo Aspirin versus paracetamol 2 g tranexamic acid versus 1 g tranexamic acid - Prevention of pain Ibuprofen versus placebo Tolfenamic acid versus placebo LNG IUD - Prevention of heavy menstrual bleeding CDB‐2914 (ulipristal) versus placebo Tranexamic acid versus mefenamic acid Mifepristone versus vitamin B1 Naproxen versus estradiol Prevention of pain ‐ none Prevention of heavy menstrual bleeding associated with IUD use Cu IUD One trial examined oral ibuprofen (1200 mg per day) against placebo for three cycles (Makarainen 1986), while another trial compared different doses of oral tranexamic acid (2 g per day versus 1 g per day; Lin 2007). One trial compared aspirin to paracetamol for the prevention of heavy bleeding (Hahn 1979). Aspirin, 1500 mg per day was compared to 1500 mg paracetamol taken from day one of menstruation and continued for the duration of bleeding for a total of three menstrual cycles. Two trials assessed menstrual blood loss using the alkaline hematin method (Hahn 1979; Makarainen 1986), while another trial utilized a PBAC and the alkaline hematin method (Lin 2007). LNG IUD Two trials examined NSAIDs for the prevention of bleeding associated with LNG IUD (Madden 2012; Sordal 2013). One trial compared the use of oral mifepristone, 50 mg every other day, to vitamin B, starting on the first day of the menstrual cycle for the pre‐treatment period until three days (± 2 days) following the LNG IUD insertion (Papaikonomou 2018). One trial compared a selective progesterone receptor modulator, Ulipristal acetate to placebo (Warner 2010). Women were randomized to receive oral ulipristal acetate 50 mg per day or placebo, taken for three consecutive days, with separate treatments starting 21, 49 and 77 days after IUD insertion. One trial compared oral naproxen 1 g per day for the first five days to transdermal estradiol 0.1 mg weekly or oral placebo (Madden 2012), while the other trial utilized oral tranexamic acid 1500 mg per day against oral mefenamic acid 1500 mg per day and placebo (Sordal 2013). The duration of the intervention in both trials was for three menstrual cycles. Four trials used diaries to record bleeding days and pattern (Madden 2012; Papaikonomou 2018; Sordal 2013; Warner 2010). Prevention of bleeding and pain associated with IUD use Cu IUD Three trials, with a total of 2199 participants, evaluated prevention of bleeding and pain associated with Cu IUD use (Hubacher 2006; Roy 1981; Ylikorkala 1978). Two trials compared ibuprofen to placebo; Hubacher 2006 utilized oral ibuprofen at a dose of 1200 mg per day and Roy 1981 at a dose of 1600 mg per day. One prevention trial compared oral tolfenamic acid 600 mg to placebo (Ylikorkala 1978). One trial assessed menstrual blood loss using the alkaline hematin method (Roy 1981). Subjective assessment of pain in diaries (Roy 1981) and bleeding pattern records (Ylikorkala 1978) were reported. Sources of trial funding Fifteen trials reported their sources of funding (Fava 2020; Hubacher 2006; Jafari 2014; Kaviani 2013; Lin 2007; Madden 2012; Makarainen 1986; Papaikonomou 2018; Roy 1981; Saharkhiz 2017; Sordal 2013; Warner 2010; Yavarikia 2013; Ylikorkala 1978; Ylikorkala 1983). Four trials received funding from universities (Jafari 2014; Kaviani 2013; Saharkhiz 2017; Yavarikia 2013), four trials were funded by pharmaceutical companies (Lin 2007; Roy 1981; Sordal 2013; Warner 2010), three from government research funding bodies (Hubacher 2006; Papaikonomou 2018; Ylikorkala 1983), and one from a charitable private trust (Ylikorkala 1978). Two trials received funding from both a pharmaceutical company and government research funding body (Madden 2012; Makarainen 1986), and one trial partially from a grant and research council (Fava 2020). Six trials did not report their funding (Alanwar 2018; Buttram 1979; Davies 1981; Hahn 1979; Lalos 1983; Mercorio 2003). Declaration of interests Seven trials reported their declaration of interests as ‘none’ (Alanwar 2018; Jafari 2014; Kaviani 2013; Madden 2012; Papaikonomou 2018; Saharkhiz 2017; Yavarikia 2013). One trial (Fava 2020), reported a conflict of interest for being a member of a foundation and receiving honorarium by a pharmaceutical company as a speaker. Thirteen trials did not report on declarations of interest by researchers (Buttram 1979; Davies 1981; Hahn 1979; Hubacher 2006; Lalos 1983; Lin 2007; Makarainen 1986; Mercorio 2003; Roy 1981; Sordal 2013; Warner 2010; Ylikorkala 1978; Ylikorkala 1983). See Characteristics of included studies. Excluded studies In this update, we excluded 11 trials for several reasons, including seven trials which were non‐randomized controlled trials (Batar 1978; Dreher 1980; Grunloh 2013; Guillebaud 1978; Hidalgo 2002; Lal 2010; Toppozoda 1987). We excluded four trials as they did not meet the inclusion criteria. Abbas 2018, Baldwin 2016, and Tavakolian 2015 reported pain perception during IUD insertion, while Van der Heijden 2017 did not fulfil the inclusion criteria for type of intervention. See Characteristics of excluded studies. Risk of bias in included studies Summaries of assessments of bias in included studies are shown in Figure 2 and Figure 3. Details of the appraisals made on risk of bias are described below. Allocation Twelve trials described the method they used to generate the randomization sequence, thus meeting the criteria for low risk of bias (Alanwar 2018; Fava 2020; Hubacher 2006; Jafari 2014; Kaviani 2013; Madden 2012; Mercorio 2003; Papaikonomou 2018; Saharkhiz 2017; Sordal 2013; Warner 2010; Yavarikia 2013). Randomization was mostly undertaken by a computer‐generated list of random numbers. For allocation concealment, we found 10 trials to have low risk of bias (Alanwar 2018; Fava 2020; Madden 2012; Makarainen 1986; Mercorio 2003; Papaikonomou 2018; Saharkhiz 2017; Warner 2010; Yavarikia 2013; Ylikorkala 1978). Eight out of 21 trials met the criteria for low risk of selection bias (both random sequence generation and allocation concealment; Alanwar 2018; Fava 2020; Madden 2012; Mercorio 2003; Papaikonomou 2018; Saharkhiz 2017; Warner 2010; Yavarikia 2013). Nine trials had unclear random sequence generation (Buttram 1979; Davies 1981; Hahn 1979; Lalos 1983; Lin 2007; Makarainen 1986; Roy 1981; Ylikorkala 1978; Ylikorkala 1983), while 11 trials had unclear allocation concealment (Buttram 1979; Davies 1981; Hahn 1979; Hubacher 2006; Jafari 2014; Kaviani 2013; Lalos 1983; Lin 2007; Roy 1981; Sordal 2013; Ylikorkala 1983). There were no trials with high risk of selection bias. Blinding Performance bias Ten trials met the criteria for low risk of performance bias that ensured blinding of participants and investigators because the control groups had treatment regimens identical in appearance to the experimental intervention (Alanwar 2018; Buttram 1979; Fava 2020; Hubacher 2006; Jafari 2014; Kaviani 2013; Roy 1981; Saharkhiz 2017; Sordal 2013; Yavarikia 2013). We found two trials to have high risk of performance bias because the route of administration of the experimental intervention was transdermal (Madden 2012), and intranasal (Mercorio 2003), without similar route of administration in the controls. We judged nine other trials to have unclear risk of performance bias because there were insufficient details to infer who was blinded (Davies 1981; Hahn 1979; Lalos 1983; Lin 2007; Makarainen 1986; Papaikonomou 2018; Warner 2010; Ylikorkala 1978; Ylikorkala 1983). Detection bias We considered 16 trials to have high risk of detection bias because their assessments of bleeding and pain outcomes were subjective (Alanwar 2018; Buttram 1979; Fava 2020; Jafari 2014; Kaviani 2013; Lalos 1983; Lin 2007; Madden 2012; Makarainen 1986; Mercorio 2003; Papaikonomou 2018; Saharkhiz 2017; Sordal 2013; Warner 2010; Ylikorkala 1978; Ylikorkala 1983). In these trials, the participants assessed the outcome by filling in the questionnaires and PBACs and recording their symptoms in diaries. Four trials met the criteria for low risk of detection bias, with the use of alkaline hematin tests in laboratories (Hahn 1979; Hubacher 2006; Roy 1981; Yavarikia 2013). One trial had unclear risk of detection bias because they did not describe their methods of outcome measurement and there were no other details regarding blinding of outcome assessors (Davies 1981). Incomplete outcome data Eighteen trials had low risk of attrition bias because there were either no missing data or they excluded the missing data from analysis, or they applied the intention‐to‐treat principle (Alanwar 2018; Buttram 1979; Fava 2020; Hahn 1979; Hubacher 2006; Jafari 2014; Kaviani 2013; Lalos 1983; Lin 2007; Madden 2012; Makarainen 1986; Papaikonomou 2018; Roy 1981; Saharkhiz 2017; Sordal 2013; Warner 2010; Yavarikia 2013; Ylikorkala 1983). Three trials had unclear risk of attrition bias because they did not provide details regarding missing data (Davies 1981; Mercorio 2003; Ylikorkala 1978). Selective reporting The majority of the included trials published only data. There was no access to the trial registration reports or trial protocols. Under these conditions, we were not able to evaluate whether trial authors had overlooked reporting findings for all their pre‐specified outcomes. Thus, we considered 13 trials to have an unclear risk of reporting bias (Buttram 1979; Davies 1981; Hahn 1979; Hubacher 2006; Kaviani 2013; Lalos 1983; Lin 2007; Makarainen 1986; Mercorio 2003; Roy 1981; Yavarikia 2013; Ylikorkala 1978; Ylikorkala 1983). The remaining eight trials met the criteria for low risk of reporting bias because they listed their pre‐specified outcomes in their protocols or trial registration reports (Alanwar 2018; Fava 2020; Jafari 2014; Madden 2012; Papaikonomou 2018; Saharkhiz 2017; Sordal 2013; Warner 2010). Other potential sources of bias We deemed most of the included trials to have low risk of bias in this domain as they appeared free from other sources of bias. We judged one trial, which was a cross‐over design, to be high risk due to differences in baseline characteristics because four out of 10 participants on IUD had prolonged bleeding time, increased capillary fragility or a history of bleeding tendencies prior to intervention (Hahn 1979). Two trials had unclear risk of bias because the baseline characteristics were not available (Davies 1981; Mercorio 2003). Effects of interventions See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8 Primary outcomes Treatment trials Treatment of heavy menstrual bleeding associated with IUD use Cu IUD Vitamin B1 versus placebo: vitamin B1 may reduce the number of pads used per day (MD −7.0 pads, 95% CI −8.50 to −5.50, P < 0.001; 1 trial, 110 participants; Analysis 1.1), number of spotting days (MD −1.60 days, 95% CI −1.94 to −1.26, P < 0.001; 1 trial, 110 participants; Analysis 1.2) and number of bleeding days in comparison to placebo (MD −2.00 days, 95% CI −2.38 to −1.62; P < 0.001; 1 trial, 110 participants; Analysis 1.3). This evidence was low certainty, downgraded for serious risk of bias and imprecision. Naproxen versus placebo: there may be little or no difference between naproxen and placebo for heavier menstrual flow (OR 0.09, 95% CI 0.00 to 1.78; P = 0.11; 1 trial; 40 participants; Analysis 2.1) but the evidence is uncertain. The result was assessed as very low certainty, downgraded for very serious risk of bias and serious imprecision. Mefenamic acid versus tranexamic acid: mefenamic acid may reduce the volume of menstrual blood loss in comparison to tranexamic acid (MD −64.26 mL, 95% CI −105.65 to −22.87; P = 0.002; 1 trial, 94 participants; Analysis 1.1). The certainty of evidence was low, downgraded for very serious risk of bias and serious imprecision (Table 1). Mefenamic acid may have lower pictorial blood loss assessment chart (PBAC) score in contrast to tranexamic acid (MD −8.19, 95% CI −25.24 to 8.86; P = 0.35; 1 trial, 58 participants; Analysis 3.2) but the evidence is very uncertain. The certainty of evidence was very low, downgraded for very serious risk of bias and serious imprecision. There may be little or no difference in the number of bleeding days between mefenamic acid and tranexamic acid (MD 0.08 days, 95% CI −0.27 to 0.42; P = 0.66, I2 = 0; 2 trials, 152 participants; Analysis 3.3). Evidence was of low certainty, downgraded for serious imprecision (Table 1). Mefenamic acid versus desmopressin: the evidence is very uncertain about the effect of mefenamic acid compared to desmopressin and there were insufficient data available for analysis. It was reported that the mean reduction in PBAC score was 45.7% in the mefenamic acid group and 40.5% in the desmopressin group (1 trial, 24 participants; Analysis 4.1). Evidence was very low certainty, downgraded due to very serious risk of bias and serious imprecision (Table 1). Tranexamic acid versus sodium diclofenac: tranexamic acid may reduce the volume of menstrual blood loss in comparison to sodium diclofenac (MD −42.70 mL, 95% CI −73.33 to −12.07; P = 0.006; 1 trial, 38 participants; Analysis 5.1) but the evidence is very low certainty, downgraded for serious risk of bias and imprecision (Table 1). There may be little or no difference in the duration of bleeding between tranexamic acid and sodium diclofenac (MD 0.00 95% CI −0.62 to 0.62; P = 1.0; 1 trial, 38 participants; Analysis 5.2) but the evidence is very uncertain. Evidence was of very low certainty, downgraded for serious risk of bias and imprecision (Table 1). Tranexamic acid versus flavonoids: tranexamic acid may be associated with a modest reduction in PBAC score compared with oral flavonoids (MD −32.0, 95% CI −39.84 to −24.16; P < 0.001; 1 trial, 100 participants; Analysis 6.1). The certainty of evidence was low, downgraded for serious risk of bias and imprecision (Table 1). Tranexamic acid may result in fewer pads used per day (MD −0.50 pads, 95% CI −0.91 to −0.09; P = 0.02; 1 trial, 100 participants; Analysis 6.2) and fewer bleeding days in comparison to flavonoids (MD −1.40 days, 95% CI −1.93 to −0.87; 1 trial, 100 participants; Analysis 6.3). The certainty of evidence was assessed as low, downgraded for serious risk of bias and imprecision (Table 1). Tranexamic acid versus active comparators (mefenamic acid, flavonoid, sodium diclofenac): the evidence is very uncertain about the effect of tranexamic acid compared to controls in the number of bleeding days (MD −0.27 95% CI −1.14 to 0.60; P = 0.54, I2 = 87%; 4 trials, 290 participants; Analysis 7.1). The certainty of evidence was very low, downgraded for serious risk of bias and inconsistency (Table 1). This was a composite analysis as other trials had different interventions and outcomes, which could not be analysed together. 4.1. Analysis. Comparison 4: Mefenamic acid vs desmopressin (Cu IUD, treatment for HMB), Outcome 1: Mean reduction of PBAC score (%) | Mean reduction of PBAC score (%) | || | Study | desmopressin | mefenamic acid | | Mercorio 2003 | 40.5 | 45.7 | LNG IUD Ulipristal acetate versus placebo: the evidence is very uncertain about the effect of ulipristal acetate compared with placebo on the duration of bleeding (MD −3.30 days, 95% CI −9.07 to 2.47; P = 0.26, 1 trial, 24 participants; Analysis 8.1) and number of bleeding days in 90 days (MD −9.30 days, 95% CI −26.76 to 8.16; P = 0.30, 1 trial, 24 participants; Analysis 8.2). This evidence was very low certainty, downgraded for serious risk of bias and serious imprecision as well as inconsistency (Table 2). Unknown IUD type High‐dose naproxen versus low‐dose naproxen: the evidence is very uncertain about the effect of different naproxen doses on menstrual blood loss; there were insufficient data available for analysis. One trial involving 34 users of an unknown type of IUD reported that naproxen 1250 mg per day for five days had higher percentage (31.6%) of menstrual blood loss in comparison to 500 mg on day one then 750 mg per day for five days (9.5%) (Davies 1981; Analysis 9.1). Mefenamic acid versus Vitex agnus: mefenamic acid may not differ from Vitex agnus in PBAC score (MD −2.40, 95% CI −13.77 to 8.97; P = 0.68; 1 trial, 84 participants; Analysis 10.1). The certainty of evidence was low, downgraded due to serious risk of bias and imprecision (Table 3). 9.1. Analysis. Comparison 9: High‐dose naproxen vs low‐dose naproxen (unknown IUD, treatment of HMB), Outcome 1: Blood loss reduction (%) | Blood loss reduction (%) | || | Study | High dose naproxen | Low dose naproxen | | Davies 1981 | 31.6 | 9.5 | Treatment of pain associated with IUD use Cu IUD Tranexamic acid versus sodium diclofenac: there may be little or no difference between tranexamic acid and sodium diclofenac for the occurrence of pelvic pain (OR 1.0, 95% CI 0.06 to 17.25; P = 1.00; 1 trial, 38 participants; Analysis 11.1) but the evidence is very uncertain. The evidence was very low certainty, downgraded for serious risk of bias and imprecision (Table 4). Unknown IUD type Naproxen versus placebo: compared to placebo, naproxen may be associated with lower overall pain relief scores (MD 4.1, 95% CI 0.91 to 7.29; P = 0.01; 1 trial, 33 participants; Analysis 12.1) and lower daily pain relief score (MD 3.1, 95% CI 0.27 to 5.93; P = 0.03; 1 trial, 33 participants; Analysis 12.2). Evidence for both outcomes was low certainty, downgraded for serious risk of bias and imprecision (Table 5). Prevention trials Prevention of heavy menstrual bleeding associated with IUD use Cu IUD Ibuprofen versus placebo: the trial arms did not differ significantly in reduction of blood loss volume, measured by alkaline hematin method, for ibuprofen and placebo (MD −14mL.11, 95% CI −36.04 to 7.82; P = 0.21; 2 trials, 40 participants; Analysis 13.1). Subgroup analysis by type of IUD (Lippes loop and Cu IUD) also revealed no difference. The evidence was of low certainty, downgraded for serious risk of bias and imprecision (Table 6). In another trial (Makarainen 1986), there was no difference in duration of bleeding between ibuprofen and placebo (MD −0.20 days, 95% CI −1.40 to 1.00; P = 0.74; 1 trial; 28 participants; Analysis 13.2). The evidence was of very low certainty, downgraded for very serious risk of bias and serious imprecision (Table 6). The median blood loss in this trial was 51 mL in the ibuprofen group with Fincoid IUD and 47 mL with the multiload copper‐375 IUD in comparison to 49 mL in the placebo group with Fincoid IUD and 62 mL with the multiload copper‐375 IUD (Analysis 13.3). Tolfenamic acid versus placebo: tolfenamic acid resulted in fewer pads used per day (MD −1.00 pads, 95% CI −1.57 to −0.43; P < 0.001; 1 trial, 122 participants; Analysis 14.1), fewer occurrences of menstruation that were "more abundant than normal" in comparison to placebo (OR 0.54, 95% CI 0.34 to 0.85; P = 0.008; 1 trial, 181 events; Analysis 14.2) and fewer blood clots (OR 0.43, 95% CI 0.27 to 0.68, P < 0.001; 1 trial, 150 events; Analysis 14.3). Evidence was very low certainty; downgraded for serious risk of bias and imprecision (Table 6). Aspirin versus paracetamol: there was no evidence of a difference between aspirin and paracetamol to reduce the volume of menstrual blood loss (MD −0.30, 95% CI −26.16 to 25.56; P = 0.98; 1 trial, 20 participants; Analysis 15.1). This evidence was of very low certainty, downgraded for very serious risk of bias and serious imprecision (Table 6). Higher dose of tranexamic acid versus lower dose of tranexamic acid: one trial conducted among 175 Cu IUD users compared 1 g tranexamic acid to 2 g tranexamic acid for the prevention of bleeding (Lin 2007). The percentage occurrence of heavy menstrual bleeding was 20% in the 2 g tranexamic acid arm versus 11.76% in the 1 g tranexamic acid arm as measured by the alkaline hematin method (Analysis 16.1). The PBAC score was also lower in the 2 g tranexamic acid group (26.79%) in comparison to 1 g tranexamic acid (45.83%; Analysis 16.1). The evidence was very low certainty, downgraded for serious risk of bias and imprecision (Table 6). 13.3. Analysis. Comparison 13: Ibuprofen vs placebo (Cu IUD, prevention of HMB), Outcome 3: Median menstrual blood loss (alkaline hematin) | Median menstrual blood loss (alkaline hematin) | || | Study | Ibuprofen | Placebo | | Fincoid | || | Makarainen 1986 | 51 | 49 | | ML Cu 375 | || | Makarainen 1986 | 47 | 62 | 16.1. Analysis. Comparison 16: 2 g tranexamic vs 1 g tranexamic (Cu IUD, prevention HMB), Outcome 1: Occurence of HMB (%) | Occurence of HMB (%) | || | Study | 2g tranexamic | 1g tranexamic | | Alkaline hematin | || | Lin 2007 | 20 | 11.76 | | PBAC | || | Lin 2007 | 26.79 | 45.83 | LNG IUD Ulipristal acetate (CBD‐2914) versus placebo: ulipristal acetate may increase the percentage bleeding or spotting days in comparison to placebo (MD 9.50, 95% CI 1.48 to 17.52; P = 0.02; 1 trial, 118 participants; Analysis 17.1). However, the certainty of evidence was low, downgraded for serious risk of bias and very serious imprecision (Table 7). Tranexamic acid versus mefenamic acid and placebo: one trial that compared tranexamic acid, mefenamic acid and placebo had insufficient data for analysis (Sordal 2013). The median number of bleed days reported was 8 days in the tranexamic acid group, 10 in the mefenamic acid group and 11.5 in the placebo group (Analysis 18.1). Evidence was low certainty, downgraded for serious risk of bias and imprecision (Table 7). Mifepristone versus vitamin B: there were insufficient data for analysis in the trial comparing mifepristone and vitamin B, which reported that fewer participants in the mifepristone group reported bleeding or spotting (Papaikonomou 2018; Analysis 20.1). The evidence was of very low certainty, downgraded for very serious risk of bias and imprecision (Table 7). Naproxen versus estradiol: one trial provided insufficient data for analysis of number of bleeding days for naproxen compared with estradiol (Madden 2012). The median number of bleeding days in the naproxen arm was 27.5 in comparison to 44 days in the estradiol arm (Analysis 19.1). Evidence was very low certainty, downgraded for very serious risk of bias and imprecision (Table 7). 18.1. Analysis. Comparison 18: Tranexamic acid vs mefenamic acid (LNG IUD, prevention of HMB), Outcome 1: Median number of bleeding days | Median number of bleeding days | ||| | Study | tranexamic acid (n=55) | mefenamic acid (n=57) | placebo (n=56) | | Sordal 2013 | 8 | 10 | 11.5 | 20.1. Analysis. Comparison 20: Mifepristone vs vitamin B (LNG IUD, prevention of HMB), Outcome 1: Percentage bleeding and spotting days | Percentage bleeding and spotting days | || | Study | Mifepristone | Vitamin B | | Papaikonomou 2018 | Fewer women reported bleeding or spotting. Less days with normal or heavy intensity bleeding | More bleeding or spotting days. | 19.1. Analysis. Comparison 19: Naproxen vs estradiol (LNG IUD, prevention of HMB), Outcome 1: Median number of bleeding and spotting days | Median number of bleeding and spotting days | ||| | Study | Naproxen (n=35) | Estradiol (n=34) | Placebo (n=37) | | Madden 2012 | 27.5 | 44 | 32 | Prevention of pain Cu IUD Tolfenamic acid versus placebo: there may be little or no difference between tolfenamic acid and placebo in reduction of the occurrence of menstruation that was "more painful than normal" but the evidence is very uncertain (OR 0.71, 95% CI 0.44 to 1.14; P = 0.15; 1 trial, 108 events; Analysis 21.1). Evidence was very low certainty, downgraded for serious risk of bias and imprecision (Table 8). Ibuprofen versus placebo: there may be little or no difference between ibuprofen and placebo in the reduction of menstrual cramps (OR 1.0, 95% CI 0.11 to 8.95, P = 1.00; 1 trial, 4 events; Analysis 22.1). The evidence was low certainty, downgraded for serious risk of bias and imprecision (Table 8). Secondary outcomes Treatment trials IUD removal No treatment trials assessed IUD removal due to bleeding or pain. Haemoglobin levels One trial reported on pre‐ and post‐haemoglobin levels of all Cu IUD participants, but data were insufficient for analysis because the trial did not compare tranexamic acid and sodium diclofenac (Ylikorkala 1983). The mean (standard error) for pre‐intervention blood haemoglobin concentrations was 124.8 (1.9) g/L while for post‐intervention it was 124.7 (1.8) g/L. Need for additional analgesia One trial that compared naproxen to placebo for the treatment of pain associated with IUD use (unknown type of IUD) reported the use of additional analgesia (Buttram 1979). There was no difference between naproxen and placebo for the use of additional analgesia (OR 0.29, 95% CI 0.05 to 1.80; P = 0.19; 1 trial, 33 participants, 7 events; Analysis 12.4). Quality of life No treatment trial reported quality of life. Side effects Four treatment trials among Cu IUD users reported side effects but it was not possible to analyze the data due to differences in various side effects, interventions and control. In a small trial by Mercorio 2003, it was difficult to estimate the difference between mefenamic acid and desmopressin, with no effect on the occurrence of headache and insomnia (OR 0.11, 95% CI 0.00 to 2.36, P = 016; 1 trial, 24 participants, 3 events; Analysis 4.2). In another trial that compared tranexamic acid and sodium diclofenac for the occurrence of side effects (gastrointestinal symptoms, headache, sweating), tranexamic acid increased the odds of the occurrence of side effects compared to sodium diclofenac (OR 4.69, 95% CI 1.20 to 18.44; P = 0.03; 1 trial, 38 participants, 19 events; Analysis 5.3; Ylikorkala 1983). The occurrence of headache (OR 0.58, 95% CI 0.18 to 1.92; P = 0.38; 1 trial, 100 participants, 13 events; Analysis 6.4) and vomiting (OR 0.74, 95% CI 0.25 to 2.18; P = 0.59; 1 trial, 100 participants, 16 events; Analysis 6.4) also did not differ in a trial comparing tranexamic acid and oral flavonoids (Alanwar 2018). There was also no difference in the occurrence of side effects in a trial that compared naproxen and placebo (OR 1.91, 95% CI 0.72 to 5.06; P = 0.19; 1 trial, 336 participants, 16 events; Analysis 2.2; Lalos 1983). In another trial comparing mefenamic acid and Vitex agnus (Yavarikia 2013), where the IUD type was not known, the occurrence of nausea (OR 1.00, 95% CI 0.06 to 16.53; P = 1.0; 1 trial, 84 participants, 2 events; Analysis 10.2) and abdominal pain (OR 0.33, 95% CI 0.01 to 8.22; P = 0.50; 1 trial; 84 participants, 1 event; Analysis 10.2) did not differ. Prevention trials IUD removal One prevention trial assessed the effect of ibuprofen and placebo among Cu IUD users on IUD removal due to pain or increased blood loss (Hubacher 2006). There was no difference between ibuprofen and placebo on IUD removal due to pain or increased blood loss by 26 weeks (OR 0.96, 95% CI 0.66 to 1.38; P = 0.81; 1 trial, 1962 participants, 120 events; Analysis 23.1) and by 52 weeks (OR 1.25, 95% CI 0.39 to 1.69; P = 0.14; 1 trial, 1962 participants, 190 events; Analysis 23.2). Haemoglobin levels No prevention trial assessed haemoglobin levels. Need for additional analgesia No prevention trial assessed need for analgesia. Quality of life No prevention trial assessed quality of life. Side effects Four prevention trials provided data for side effects but it was not feasible to pool data for analysis due to differences in side effects, interventions and control. Three trials were in Cu IUD users (Makarainen 1986; Roy 1981; Ylikorkala 1978), while one trial was among LNG IUD users (Madden 2012). There was no difference in the occurrence of side effects between ibuprofen and placebo in two trials (OR 2.15, 95% CI 0.5 to 9.31; P = 0.30, I2 = 0%; 2 trials, 108 participants, 8 events; Analysis 13.4; Makarainen 1986; Roy 1981). In another trial comparing tolfenamic acid and placebo (Ylikorkala 1978), there was no difference in the occurrence of side effects (OR 0.42, 95% CI 0.02 to 9.29; P = 0.58; 1 trial, 366 participants, 14 events; Analysis 21.2). The occurrence of dyspepsia and diarrhoea (OR 9.96, 95% CI 0.52 to 189.04; P = 0.13; 1 trial, 122 participants, 4 events; Analysis 21.2) were more common with tolfenamic acid but the estimate was not statistically significant and the confidence interval was wide. The occurrence of headache (OR 0.09, 95% CI 0.00 to 1.60; P = 0.10; 1 trial, 122 participants, 5 events; Analysis 21.2) and depression (OR 0.09, 95% CI 0.00 to 1.60, P = 0.10; 1 trial, 122 participants, 5 events; Analysis 21.2) did not differ between tolfenamic acid and placebo. There was no difference in the occurrence of gastroesophageal reflux between naproxen and estradiol among LNG IUD users (OR 3.22, 95% CI 0.13 to 81.19; P = 0.48; 1 trial, 86 participants, 1 event; Analysis 19.3).

Summary of main results This updated review includes 21 trials involving 3689 participants. Trials were mostly conducted in upper‐middle‐ to high‐income countries. There were 11 treatment trials (seven Cu IUD, one LNG IUD, three unknown IUD type), involving 767 participants, and 10 prevention trials (six Cu IUD, four LNG IUD), involving 2922 participants. This review has also extended its interventions to not just include NSAIDs but any interventions that were assessed to treat or prevent heavy menstrual bleeding or pain, or both, induced by IUD. Treatment trials Treatment of heavy menstrual bleeding associated with Cu IUD use Vitamin B1 versus placebo: in one trial involving 126 participants, 100 mg vitamin B1 may reduce the number of pads used per day, number of spotting days and duration of bleeding in comparison to placebo (Jafari 2014). Since the evidence was from one trial, we cannot draw definitive conclusions. Naproxen versus placebo: there may be little or no difference between oral naproxen (500 mg followed by 250 mg two to four times per day as needed) and oral placebo in the amount of menstrual flow according to one small trial involving 40 participants but the effect is very uncertain (Lalos 1983). Mefenamic acid versus tranexamic acid: oral mefenamic acid at 1500 mg per day may reduce the volume of menstrual blood loss in comparison to oral tranexamic acid 1500 mg per day but this evidence is based on one trial with 94 participants, thus, we cannot draw definitive conclusions (Saharkhiz 2017). Mefenamic acid and tranexamic acid may not reduce the duration of bleeding (Kaviani 2013; Saharkhiz 2017). This evidence however, was based on two trials involving a total of 152 participants. Mefenamic acid versus desmopressin: there were insufficient data for analysis. Tranexamic acid versus sodium diclofenac: based on one trial involving 38 participants (Ylikorkala 1983), oral tranexamic acid at 4.5 g per day for five days may reduce the volume of menstrual blood loss but not the duration of bleeding in comparison to oral sodium diclofenac 150 mg on day 1 then 75 mg for four days. Tranexamic acid versus flavonoids: oral tranexamic acid 500 mg, six‐hourly, taken for the first three days of menstruation, had a lower PBAC score, fewer number of pads used per day and fewer bleeding days in comparison to flavonoids. This evidence was also from a single trial involving 100 participants (Alanwar 2018). Tranexamic acid versus comparisons: oral tranexamic acid (at various doses and regimes) may reduce the number of bleeding days in comparison to control (Alanwar 2018; Kaviani 2013; Saharkhiz 2017; Ylikorkala 1983). There was substantial heterogeneity due to the various doses of tranexamic acid and type of comparisons used (mefenamic acid, flavonoid, sodium diclofenac). Treatment of heavy menstrual bleeding associated with LNG IUD use Ulipristal acetate versus placebo: oral ulipristal acetate 5 mg per day taken for five days made no difference in comparison to placebo to the duration of days until bleeding stops and total bleeding days in 90 days for bleeding associated with LNG IUD use. However, this evidence was also from one small trial involving 30 participants (Fava 2020). Treatment of heavy menstrual bleeding associated with unknown IUD type Higher dose naproxen versus lower dose naproxen: there were insufficient data for analysis. One trial (Davies 1981), compared oral naproxen 1250 mg per day for five days to 500 mg then 750 mg for five days and reported that the higher dose of naproxen reduced menstrual blood loss more than the lower dose (32% versus 22%). Mefenamic acid versus Vitex agnus: the PBAC score did not differ significantly between oral mefenamic acid and Vitex agnus for the treatment of bleeding associated with LNG IUD based on one trial involving 84 participants (Yavarikia 2013). Treatment of pain associated with Cu IUD use Tranexamic acid versus sodium diclofenac: there was no difference between oral tranexamic acid and oral sodium diclofenac for pain in one trial involving 38 participants (Ylikorkala 1983). Treatment of pain associated with unknown IUD type Naproxen versus placebo: oral naproxen may provide overall and daily pain relief in comparison to placebo, but this evidence was also based on one trial with 33 participants thus definitive conclusions can’t be drawn (Buttram 1979). Prevention trials Prevention of heavy menstrual bleeding associated with Cu IUD use Ibuprofen versus placebo: prophylactic oral ibuprofen did not reduce menstrual blood loss (Roy 1981) or duration of bleeding (Makarainen 1986). There were insufficient data to pool these two trials together for further analysis. Tolfenamic acid versus placebo: prophylactic tolfenamic acid at a dose of 600 mg per day may be effective to reduce the number of pads used, the number of occurrences of menstruation that were "more abundant than normal" and blood clots compared to placebo. The evidence was from one trial with 160 participants (Ylikorkala 1978). Aspirin versus paracetamol: there was no significant difference between oral aspirin and oral paracetamol for the prevention of bleeding associated with Cu IUD, based on one small trial involving 20 participants (Hahn 1979). Higher dose of tranexamic acid versus lower dose of tranexamic acid: there were insufficient data for analysis. One trial, involving 175 participants, compared 2 g prophylactic oral tranexamic acid versus 1 g and reported a lower percentage of heavy menstrual bleeding occurrence in the 2 g arm than in the 1 g arm (20% versus 11.76% via alkaline hematin method and 26.79% versus 45.83% via PBAC score; Lin 2007). Prevention of bleeding associated with LNG IUD Ulipristal acetate (CBD‐2914) versus placebo: ulipristal acetate, a selective progesterone receptor modulator at a dose of 50 mg per day taken for three consecutive days with separate treatments starting from 21, 49 and 77 days after IUD insertion may not be effective to reduce the percentage bleeding/spotting days. This evidence was generated from a single trial involving 118 participants (Warner 2010). Tranexamic acid versus mefenamic acid and placebo: there were insufficient data for analysis. One trial including 187 participants (Sordal 2013), reported that the median number of bleed days in the prophylactic tranexamic acid group was 8 days while in the mefenamic acid group it was 10 days, and 11.5 days with placebo. Mifepristone versus vitamin B: there were insufficient data for analysis in the trial comparing prophylactic mifepristone and vitamin B (Papaikonomou 2018). Naproxen versus estradiol: there were insufficient data for analysis. The median number of bleeding days in the naproxen arm was 27.5 in comparison to 44 days in the estradiol arm from the trial conducted by Madden 2012 involving 129 women. The occurrence of gastroesophageal reflux was more common in the naproxen group but findings were not statistically significant with a wide confidence interval. Prevention of pain associated with Cu IUD use Tolfenamic acid versus placebo: there was no difference between prophylactic oral tolfenamic acid and placebo in the occurrence of more painful menstruation among 160 Cu IUD users in one trial conducted by Ylikorkala 1978. Ibuprofen versus placebo: there was also no difference in oral ibuprofen and placebo to prevent menstrual cramps associated with Cu IUD use. This evidence was from one small trial involving 20 participants (Roy 1981) thus, further research is necessary. Overall completeness and applicability of evidence This review included a heterogeneous literature due to the broad review objective and scope. The heterogeneity related to the intent of the intervention either for prophylaxis or treatment, the various interventions and comparators, the different intervention regimens, reporting of outcomes and limited number of trials, and the different IUD types studied. Due to the considerable heterogeneity we could not combine the data using meta‐analysis. Therefore, the overall completeness of evidence in this review is limited. In terms of applicability in clinical practice based on evidence in this review, there is still insufficient evidence to draw conclusions regarding a specific drug or regimen for the treatment or prevention of heavy menstrual bleeding or pain associated with IUD use. In agreement with the previous review, mefenamic acid and tranexamic acid may reduce heavy menstrual bleeding associated with Cu IUD use. Vitamin B1 may reduce heavy menstrual bleeding while naproxen may reduce pain among Cu IUD users. Prophylactic tolfenamic acid could possibly reduce heavy menstrual bleeding associated with Cu IUD use. There was no evidence for the effectiveness of ulipristal and Vitex agnus to treat bleeding and pain associated with LNG IUD and ulipristal acetate to prevent heavy menstrual bleeding. With regard to side effects, there were only two trials that had sufficient data for analysis. The occurrence of dyspepsia and headache was more frequent with tolfenamic acid while gastroesophageal reflux was more common with naproxen. The evidence for side effects was limited, with wide confidence intervals. It was not possible to rule out possible harms and establish the side effects of treatments. Quality of the evidence We used GRADE to evaluate the certainty of evidence for each primary and secondary outcome, as reported in the summary of findings tables. The methodological quality of the evidence varied from very low to low. The major limitations were risk of bias and imprecision. Risk of bias was mostly serious due to unclear selection (allocation concealment), detection (unclear blinding of outcome assessors and self‐reporting of subjective assessments such as pain) and reporting bias (unpublished protocols). Most of the evidence had serious imprecision as effect measures were mostly obtained from a single trial for each of the comparisons. Larger, properly designed trials of the interventions are essential in order to achieve conclusions on the comparative efficacy of treatments. Potential biases in the review process We are mindful of possible biases in the reviewing process and have undertaken several measures to curb bias, such as having two review authors independently extracting data. Publication of an updated protocol prior to undertaking this review would have been better but all review authors have approved the protocol changes prior to initiating the review. We deem that all relevant trials are now incorporated but cannot dismiss the likelihood that additional trials may be unpublished or published in sources not accessible to our search. Hence, publication bias cannot be wholly disregarded. Agreements and disagreements with other studies or reviews There are several systematic reviews previously published for pain and bleeding unrelated to IUD use. There was insufficient evidence to determine whether NSAIDs reduced volumes of menstrual blood loss in comparison to combined oral contraceptives for heavy menstrual bleeding unrelated to IUD use (Lethaby 2019). In another systematic review for participants with primary pain, NSAIDs were effective for pain relief but had more side effects particularly gastrointestinal symptoms (Marjoribanks 2015). We found low‐ to very low‐certainty evidence that mefenamic acid, tranexamic acid and vitamin B1 may reduce heavy menstrual bleeding associated with Cu IUD use, while naproxen may relieve pain. Trials investigating NSAIDs in this review had various interventions and outcome measures. Thus, no conclusions can be drawn regarding the preferred NSAID. There is limited evidence in terms of the possible effectiveness of NSAIDs, or whether a specific NSAID or regimen might be most effective to reduce pain associated with IUD use. Therefore, the choice of NSAID might be driven by other considerations such as cost, dosage and regimen, drug interactions, and patient’s preference, as well as side effects. Research regarding the interventions to treat and prevent heavy bleeding and pain associated with LNG IUD use remains limited. Authors' conclusions Implications for practice. Even though 210 trials met the criteria for inclusion, the shortcomings in several of the trials must be emphasized. The trials were predominantly small and for numerous outcomes the results were obtained from only one trial. The most effective non‐steroidal anti‐inflammatory drug (NSAID) and regimen is still uncertain. If treatment with NSAID did not deliver the anticipated improvement in bleeding, tranexamic acid may well be considered. Our low‐certainty evidence also suggests that tolfenamic acid may be used prophylactically to reduce heavy menstrual bleeding but not pain with Cu IUD use. Evidence on the use of prophylactic ibuprofen and aspirin for CDB‐2914 (ulipristal acetate) within the first six months of Cu IUD insertion to reduce heavy menstrual bleeding and pain was limited and more research is needed to inform clinical practice. CDB‐2914 (ulipristal acetate) may also not be effective for the prevention of levonorgestrel intrauterine device (LNG IUD)‐associated heavy menstrual bleeding. Women initiated on NSAIDs or tranexamic acid should be made aware of the potential side effects, such as gastrointestinal discomfort and headache, as the use of tranexamic acid increased the odds for the occurrence these side effects in comparison to sodium diclofenac. Further large trials should be conducted over a longer duration to establish their effectiveness and safety. Implications for research. As evidence was scarce for the majority of analyses in this review, larger, high‐quality randomized controlled trials (RCTs) are essential to establish the effectiveness as well as the optimum dose and regimen of mefenamic acid and tranexamic acid to reduce heavy menstrual bleeding, naproxen to reduce pain, along with prophylactic tolfenamic acid for heavy menstrual bleeding associated with Cu IUD use. Future trials should also collect comprehensive data on side effects and potential adverse effects. Currently, there are no trials investigating the use of other NSAIDs such as celecoxib and etoricoxib for the prevention and treatment of heavy menstrual bleeding or pain, or both, associated with IUD use. Future RCTs can be designed to assess the effectiveness and safety of these NSAIDs. Trials should also investigate the use of NSAIDs, tranexamic acid or other interventions for the treatment and prevention of heavy bleeding and pain associated with LNG IUD. As intrauterine devices (IUDs) are used as long‐term contraceptives and can be in place for an average of five years, future RCTs should assess their interventions throughout a similar duration of follow‐up. Longer follow‐up may also facilitate better assessment of adverse events. In addition, the National Institute for Health and Care Excellence (NICE) in the UK has recommended that any intervention for heavy menstrual bleeding should also be intended to enhance quality of life (NICE 2018). However, no trials in this review assessed the effect of interventions on quality of life. Forthcoming trials should include these measures using validated questionnaires such as the Menstrual Bleeding Questionnaire (Matteson 2015), to adequately represent women’s experiences and incorporate these measures as primary outcomes rather than solely quantifying the amount of blood loss objectively or semi‐objectively. It is of utmost importance that these upcoming trials report in detail the methods used, to allow comprehensive risk of bias assessment. Full results should also be presented with a summary of effect measures to ease analysis. What's new | Date | Event | Description | |---|---|---| | 4 August 2022 | New citation required and conclusions have changed | Updated review includes new evidence which changed the conclusion. | | 19 May 2021 | New search has been performed | This update includes 21 trials involving 3689 women of which 11 were treatment trials and 10 were prevention trials. | History Protocol first published: Issue 2, 2006 Review first published: Issue 4, 2006 | Date | Event | Description | |---|---|---| | 28 January 2021 | New search has been performed | Searches were updated | | 18 August 2011 | New search has been performed | Searches were updated. No new trials for inclusion were found. Updated one ongoing study Madden 2011 and added another Bayer 2011. | | 20 February 2009 | New search has been performed | Searches were updated; searches of clinical trials databases were added. A trial was added to 'ongoing studies' that had not yet begun enrollment. | | 15 April 2008 | Amended | Converted to new review format. | | 30 September 2006 | New citation required and conclusions have changed | Substantive amendment |

We wish to acknowledge the authors of a previous protocol, Grimes DA, Hubacher D, Lopez LM, Schulz KF (Grimes 2006). The new review authors would like to thank the Cochrane Fertility Regulation review group for their support and guidance with this review. Appendices Appendix 1. Search strategies, 2020 update Cochrane Central Register of Controlled Trials (CENTRAL; Ovid EBM Reviews) January 2020 1 (IUB or IUBs or IUC or IUCs or IUD or IUDs or IUCD or IUCDs or IUS or IUSs or CuIUB or Cu‐IUB or CuIUBs or Cu‐IUBs or CuIUD or Cu‐IUD or CuIUDs or Cu‐IUDs or CuIUC or Cu‐IUC or CuIUCs or Cu‐IUCs or CuIUCD or Cu‐IUCD or CuIUDs or Cu‐IUDs or CuIUS or Cu‐IUS or CuIUSs or Cu‐IUSs or LNGIUC or LNGIUCs or LNGIUCD or LNGIUCDs or LNGIUD or LNGIUDs or LNGIUS or LNGIUSs or PPIUC or PPIUCs or PPIUCD or PPIUCDs or PPIUD or PPIUDs or PPIUS or PPIUSs).ti. (488) 2 ((intrauterine or intra‐uterine) adj3 (ball or balls or coil or coils or contraceptive or contraception or device or devices or system or systems)).ti. (878) 3 (Jaydess or Kyleena or Liletta or Mirena or Skyla or Copper‐T or CuSafe or Cu‐Safe or Cu375 or Cu‐375 or CuT380* or Cu‐T380* or FlexiT or Flexi‐T or Gyne or Gynefix or Gyneplus or IUB* or Liberte or "Lippes Loop" or Load‐375 or MLCu* or Mini‐TT or MiniTT or Mona Lisa or Multiload or Multi‐load or MultiSafe or Multi‐Safe or MYCu or NeoSafe or Neo‐Safe or NovaT or Nova‐T or Paragard or TCu or TSafe or T‐Safe or T380* or T‐380* or TT380* or TT‐380* or UT380 or UT‐380).ti. (316) 4 or/1‐3 (1372) 5 (analges* or antagonist* or "pain control" or "pain relief" or "pain reliever" or "pain relievers" or NSAID or NSAIDs or tenaculum or ((nonsteroidal or non‐steroidal) adj1 (antiinflammatory or anti‐inflammatory)) or adapalene or alclofenac or ampyrone or antipyrine or apazone or arylpropionic or aspirin or "acetylsalicylic‐acid" or baofuxin or benzydamine or bufexamac or celecoxib or clofazimine or clonixin or "Cox 2" or curcumin or cyclooxygenase or cyclo‐oxygenase or desmopressin or dapsone or diclofenac or diflunisal or dipyrone or epirizole or etanercept or etodolac or etoricoxib or fenamate* or fenoprofen or feprazone or flurbiprofen or flufenamic or glycyrrhizic or ibuprofen or indomethacin or indoprofen or inhibit* or ketoprofen or ketorolac or lumiracoxib$ or masoprocol or meclofenamic or mefenamic or meloxicam or mesalamine or nabumetone or naprosyn or naproxen or niflumic or norpregnadienes or olopatadine hydrochloride or oxaprozin or oxyphenbutazone or paracetamol or parecoxib$ or pentosan or phenylbutazone or piroxicam or prenazone or prophylaxis or prophylactic or prostaglandin or rofecoxib$ or salicylate* or sulfasalazine or sulphonanilide$ or sulindac or suprofen or thiamine or tolfenamic or tolmetin or tranexam?c or trasylol or valdecoxib$).ti,ab. (241691) 6 and/4‐5 (245) 7 6 not ("animal model" or "animal models" or bovine or canine or capra or cat or cats or cattle or cow or cows or dog or dogs or equine or feline or goat or goats or horse or mice or mouse or ovine or pig or pigs or porcine or rabbit or rabbits or rat or rats or rattus or sheep or sow or sows).ti. (244) MEDLINE ALL (Ovid) 1946 to 20 February 2020 1 Intrauterine Devices/ or Intrauterine Devices, Medicated/ or Intrauterine Devices, Copper/ (11362) 2 (IUB or IUBs or IUC or IUCs or IUD or IUDs or IUCD or IUCDs or IUS or IUSs or CuIUB or Cu‐IUB or CuIUBs or Cu‐IUBs or CuIUD or Cu‐IUD or CuIUDs or Cu‐IUDs or CuIUC or Cu‐IUC or CuIUCs or Cu‐IUCs or CuIUCD or Cu‐IUCD or CuIUDs or Cu‐IUDs or CuIUS or Cu‐IUS or CuIUSs or Cu‐IUSs or LNGIUC or LNGIUCs or LNGIUCD or LNGIUCDs or LNGIUD or LNGIUDs or LNGIUS or LNGIUSs or PPIUC or PPIUCs or PPIUCD or PPIUCDs or PPIUD or PPIUDs or PPIUS or PPIUSs).ti,ab,kf. (10663) 3 ((intrauterine or intra‐uterine) adj3 (ball or balls or coil or coils or contraceptive or contraception or device or devices or system or systems)).ti,ab,kf. (9192) 4 (Jaydess or Kyleena or Liletta or Mirena or Skyla or Copper‐T or CuSafe or Cu‐Safe or Cu375 or Cu‐375 or CuT380* or Cu‐T380* or FlexiT or Flexi‐T or Gyne or Gynefix or Gyneplus or IUB* or Liberte or "Lippes Loop" or Load‐375 or MLCu* or Mini‐TT or MiniTT or Mona Lisa or Multiload or Multi‐load or MultiSafe or Multi‐Safe or MYCu or NeoSafe or Neo‐Safe or NovaT or Nova‐T or Paragard or TCu or TSafe or T‐Safe or T380* or T‐380* or TT380* or TT‐380* or UT380 or UT‐380).ti,ab,kf. (3496) 5 or/1‐4 (18799) 6 Anti‐Inflammatory Agents, Non‐Steroidal/ or Cyclooxygenase Inhibitors/ or Cyclooxygenase 2 Inhibitors/ or "4,5‐Dihydro‐1‐(3‐(trifluoromethyl)phenyl)‐1H‐pyrazol‐3‐amine"/ or Adapalene/ or Adapalene, Benzoyl Peroxide Drug Combination/ or Ampyrone/ or Antipyrine/ or Apazone/ or Aspirin/ or Bufexamac/ or Celecoxib/ or Clonixin/ or Curcumin/ or Diclofenac/ or Diflunisal/ or Dipyrone/ or Epirizole/ or Etanercept/ or Etodolac/ or Etoricoxib/ or Fenoprofen/ or Feprazone/ or Flurbiprofen/ or Ibuprofen/ or Indomethacin/ or Indoprofen/ or Ketoprofen/ or Ketorolac/ or Ketorolac Tromethamine/ or Masoprocol/ or Meclofenamic Acid/ or Mefenamic Acid/ or Meloxicam/ or Mesalamine/ or Nabumetone/ or Naproxen/ or Niflumic Acid/ or Olopatadine Hydrochloride/ or Oxaprozin/ or Oxyphenbutazone/ or Phenylbutazone/ or Piroxicam/ or Prostaglandin Antagonists/ or Salicylates/ or Sodium Salicylate/ or Sulfasalazine/ or Sulindac/ or Suprofen/ or Thiamine/ or Tolmetin/ or Tranexamic Acid/ (209751) 7 (analges* or antagonist* or "pain control" or "pain relief" or "pain reliever" or "pain relievers" or NSAID or NSAIDs or ((nonsteroidal or non‐steroidal) adj1 (antiinflammatory or anti‐inflammatory)) or adapalene or alclofenac or ampyrone or antipyrine or apazone or arylpropionic or aspirin or "acetylsalicylic‐acid" or baofuxin or benzydamine or bufexamac or celecoxib or clofazimine or clonixin or "Cox 2" or curcumin or cyclooxygenase or cyclo‐oxygenase or desmopressin or dapsone or diclofenac or diflunisal or dipyrone or epirizole or etanercept or etodolac or etoricoxib or fenamate* or fenoprofen or feprazone or flurbiprofen or flufenamic or glycyrrhizic or ibuprofen or indomethacin or indoprofen or inhibit* or ketoprofen or ketorolac or lumiracoxib$ or masoprocol or meclofenamic or mefenamic or meloxicam or mesalamine or nabumetone or naprosyn or naproxen or niflumic or norpregnadienes or olopatadine hydrochloride or oxaprozin or oxyphenbutazone or paracetamol or parecoxib$ or pentosan or phenylbutazone or piroxicam or prenazone or prophylaxis or prophylactic or prostaglandin or rofecoxib$ or salicylate* or sulfasalazine or sulphonanilide$ or sulindac or suprofen or thiamine or tolfenamic or tolmetin or tranexam?c or trasylol or valdecoxib$).ti,ab,kf,rn. (3018163) 8 or/6‐7 (3031564) 9 (controlled clinical trial or randomized controlled trial or comparative study).pt. (2276529) 10 (blind or blinded or control* or groups or placebo or random* or trial).ti,ab,oa. (5763664) 11 (meta‐analysis or systematic review).pt. (182738) 12 (meta‐analy* or metaanaly* or ((evidence or systematic) adj2 (review or synthesis))).ti,kf. (188827) 13 or/9‐12 (7143280) 14 13 not ((exp Animals/ not Humans/) or ("animal model" or "animal models" or bovine or canine or capra or cat or cats or cattle or cow or cows or dog or dogs or equine or feline or goat or goats or horse or mice or mouse or ovine or pig or pigs or porcine or rabbit or rabbits or rat or rats or rattus or sheep or sow or sows).ti.) (5647953) 15 and/5,8,14 (537) Embase.com #1 'intrauterine contraceptive device'/de OR 'levonorgestrel releasing intrauterine system'/exp OR 'copper intrauterine device'/exp OR 'multiload copper intrauterine device'/exp (19,888) #2 iub:ti,ab,kw OR iubs:ti,ab,kw OR iuc:ti,ab,kw OR iucs:ti,ab,kw OR iud:ti,ab,kw OR iuds:ti,ab,kw OR iucd:ti,ab,kw OR iucds:ti,ab,kw OR ius:ti,ab,kw OR iuss:ti,ab,kw OR cuiub:ti,ab,kw OR 'cu iub':ti,ab,kw OR cuiubs:ti,ab,kw OR 'cu iubs':ti,ab,kw OR cuiud:ti,ab,kw OR 'cu iud':ti,ab,kw OR cuiuc:ti,ab,kw OR 'cu iuc':ti,ab,kw OR cuiucs:ti,ab,kw OR 'cu iucs':ti,ab,kw OR cuiucd:ti,ab,kw OR 'cu iucd':ti,ab,kw OR cuiuds:ti,ab,kw OR 'cu iuds':ti,ab,kw OR cuius:ti,ab,kw OR 'cu ius':ti,ab,kw OR cuiuss:ti,ab,kw OR 'cu iuss':ti,ab,kw OR lngiuc:ti,ab,kw OR lngiucs:ti,ab,kw OR lngiucd:ti,ab,kw OR lngiucds:ti,ab,kw OR lngiud:ti,ab,kw OR lngiuds:ti,ab,kw OR lngius:ti,ab,kw OR lngiuss:ti,ab,kw OR ppiuc:ti,ab,kw OR ppiucs:ti,ab,kw OR ppiucd:ti,ab,kw OR ppiucds:ti,ab,kw OR ppiud:ti,ab,kw OR ppiuds:ti,ab,kw OR ppius:ti,ab,kw OR ppiuss:ti,ab,kw (11,890) #3 ((intrauterine OR 'intra uterine') NEAR/3 (ball OR balls OR coil OR coils OR contraceptive OR contraception OR device OR devices OR system OR systems)):ti,ab,kw (12,449) #4 jaydess:ti,ab,kw OR kyleena:ti,ab,kw OR liletta:ti,ab,kw OR mirena:ti,ab,kw OR skyla:ti,ab,kw OR 'copper t':ti,ab,kw OR cusafe:ti,ab,kw OR 'cu safe':ti,ab,kw OR cu375:ti,ab,kw OR 'cu 375':ti,ab,kw OR cut380*:ti,ab,kw OR 'cu t380*':ti,ab,kw OR flexit:ti,ab,kw OR 'flexi t':ti,ab,kw OR gyne:ti,ab,kw OR gynefix:ti,ab,kw OR gyneplus:ti,ab,kw OR iub*:ti,ab,kw OR liberte:ti,ab,kw OR 'lippes loop':ti,ab,kw OR 'load 375':ti,ab,kw OR mlcu*:ti,ab,kw OR 'mini tt':ti,ab,kw OR minitt:ti,ab,kw OR 'mona lisa':ti,ab,kw OR multiload:ti,ab,kw OR 'multi load':ti,ab,kw OR multisafe:ti,ab,kw OR 'multi safe':ti,ab,kw OR mycu:ti,ab,kw OR neosafe:ti,ab,kw OR 'neo safe':ti,ab,kw OR novat:ti,ab,kw OR 'nova t':ti,ab,kw OR paragard:ti,ab,kw OR tcu:ti,ab,kw OR tsafe:ti,ab,kw OR 't safe':ti,ab,kw OR t380*:ti,ab,kw OR 't 380*':ti,ab,kw OR tt380*:ti,ab,kw OR 'tt 380*':ti,ab,kw OR ut380:ti,ab,kw OR 'ut 380':ti,ab,kw (5,404) #5 #1 OR #2 OR #3 OR #4 (27,836) #6 'nonsteroid antiinflammatory agent'/exp OR 'prostaglandin receptor blocking agent'/exp OR '3 amino 1 (3 trifluoromethylphenyl) 2 pyrazoline'/de OR 'adapalene'/de OR 'adapalene plus benzoyl peroxide'/de OR '4 aminophenazone'/de OR 'phenazone'/de OR 'azapropazone'/de OR 'curcumin'/de OR 'dipyrone'/de OR 'etanercept'/de OR 'indometacin'/de OR 'ketorolac trometamol'/de OR 'nordihydroguaiaretic acid'/de OR 'mesalazine'/de OR 'olopatadine'/de OR 'salicylic acid derivative'/exp OR 'salazosulfapyridine'/de OR 'tranexamic acid'/de (841,263) #7 analges*:ti,ab,kw OR antagonist*:ti,ab,kw OR 'pain control':ti,ab,kw OR 'pain relief':ti,ab,kw OR 'pain reliever':ti,ab,kw OR 'pain relievers':ti,ab,kw OR nsaid:ti,ab,kw OR nsaids:ti,ab,kw OR (((nonsteroidal OR 'non steroidal') NEAR/1 (antiinflammatory OR 'anti inflammatory')):ti,ab,kw) OR adapalene:ti,ab,kw OR alclofenac:ti,ab,kw OR ampyrone:ti,ab,kw OR antipyrine:ti,ab,kw OR apazone:ti,ab,kw OR arylpropionic:ti,ab,kw OR aspirin:ti,ab,kw OR 'acetylsalicylic‐acid':ti,ab,kw OR baofuxin:ti,ab,kw OR benzydamine:ti,ab,kw OR bufexamac:ti,ab,kw OR celecoxib:ti,ab,kw OR clofazimine:ti,ab,kw OR clonixin:ti,ab,kw OR 'cox 2':ti,ab,kw OR curcumin:ti,ab,kw OR cyclooxygenase:ti,ab,kw OR 'cyclo oxygenase':ti,ab,kw OR desmopressin:ti,ab,kw OR dapsone:ti,ab,kw OR diclofenac:ti,ab,kw OR diflunisal:ti,ab,kw OR dipyrone:ti,ab,kw OR epirizole:ti,ab,kw OR etanercept:ti,ab,kw OR etodolac:ti,ab,kw OR etoricoxib:ti,ab,kw OR fenamate*:ti,ab,kw OR fenoprofen:ti,ab,kw OR feprazone:ti,ab,kw OR flurbiprofen:ti,ab,kw OR flufenamic:ti,ab,kw OR glycyrrhizic:ti,ab,kw OR ibuprofen:ti,ab,kw OR indomethacin:ti,ab,kw OR indoprofen:ti,ab,kw OR inhibit*:ti,ab,kw OR ketoprofen:ti,ab,kw OR ketorolac:ti,ab,kw OR lumiracoxib?:ti,ab,kw OR masoprocol:ti,ab,kw OR meclofenamic:ti,ab,kw OR mefenamic:ti,ab,kw OR meloxicam:ti,ab,kw OR mesalamine:ti,ab,kw OR nabumetone:ti,ab,kw OR naprosyn:ti,ab,kw OR naproxen:ti,ab,kw OR niflumic:ti,ab,kw OR norpregnadienes:ti,ab,kw OR 'olopatadine hydrochloride':ti,ab,kw OR oxaprozin:ti,ab,kw OR oxyphenbutazone:ti,ab,kw OR paracetamol:ti,ab,kw OR parecoxib?:ti,ab,kw OR pentosan:ti,ab,kw OR phenylbutazone:ti,ab,kw OR piroxicam:ti,ab,kw OR prenazone:ti,ab,kw OR prophylaxis:ti,ab,kw OR prophylactic:ti,ab,kw OR prostaglandin?:ti,ab,kw OR rofecoxib?:ti,ab,kw OR salicylate*:ti,ab,kw OR sulfasalazine:ti,ab,kw OR sulphonanilide*:ti,ab,kw OR sulindac:ti,ab,kw OR suprofen:ti,ab,kw OR thiamine:ti,ab,kw OR tolfenamic:ti,ab,kw OR tolmetin:ti,ab,kw OR tranexam?c:ti,ab,kw OR trasylol:ti,ab,kw OR valdecoxib*:ti,ab,kw (3,769,595) #8 #6 OR #7 (4,236,328) #9 'crossover procedure':de OR 'double‐blind procedure':de OR 'randomized controlled trial':de OR 'single‐blind procedure':de OR random*:de,ab,ti OR factorial*:de,ab,ti OR crossover*:de,ab,ti OR ((cross NEXT/1 over*):de,ab,ti) OR placebo*:de,ab,ti OR ((doubl* NEAR/1 blind*):de,ab,ti) OR ((singl* NEAR/1 blind*):de,ab,ti) OR assign*:de,ab,ti OR allocat*:de,ab,ti OR volunteer*:de,ab,ti (2,541,220) #10 'meta analysis'/de OR 'network meta‐analysis'/de OR 'systematic review'/de (326,469) #11 'meta analy*':ti OR metaanaly*:ti OR (((evidence OR systematic) NEAR/2 (review OR synthesis)):ti) OR 'meta analy*':kw OR metaanaly*:kw OR (((evidence OR systematic) NEAR/2 (review OR synthesis)):kw) (236,552) #12 #9 OR #10 OR #11 (2,758,267) #13 #5 AND #8 AND #12 (574) #14 #13 NOT ('animal model':ti OR 'animal models':ti OR bovine:ti OR canine:ti OR capra:ti OR cat:ti OR cats:ti OR cattle:ti OR cow:ti OR cows:ti OR dog:ti OR dogs:ti OR equine:ti OR feline:ti OR goat:ti OR goats:ti OR horse:ti OR mice:ti OR mouse:ti OR ovine:ti OR pig:ti OR pigs:ti OR porcine:ti OR rabbit:ti OR rabbits:ti OR rat:ti OR rats:ti OR rattus:ti OR sheep:ti OR sow:ti OR sows:ti) (563) Scopus ( ( ( TITLE ( iub OR iubs OR iuc OR iucs OR iud OR iuds OR iucd OR iucds OR ius OR iuss OR cuiub OR cu‐iub OR cuiubs OR cu‐iubs OR cuiud OR cu‐iud OR cuiuds OR cu‐iuds OR cuiuc OR cu‐iuc OR cuiucs OR cu‐iucs OR cuiucd OR cu‐iucd OR cuiuds OR cu‐iuds ) OR TITLE ( cuius OR cu‐ius OR cuiuss OR cu‐iuss OR lngiuc OR lngiucs OR lngiucd OR lngiucds OR lngiud OR lngiuds OR lngius OR lngiuss OR ppiuc OR ppiucs OR ppiucd OR ppiucds OR ppiud OR ppiuds OR ppius OR ppiuss ) OR TITLE ( ( ( intrauterine OR intra‐uterine ) PRE/3 ( ball OR balls OR coil OR coils OR contraceptive OR contraception OR device OR devices OR system OR systems ) ) ) OR TITLE ( jaydess OR kyleena OR liletta OR mirena OR skyla OR copper‐t OR cusafe OR cu‐safe OR cu375 OR cu‐375 OR cut380* OR cu‐t380* OR flexit OR flexi‐t OR gyne OR gynefix OR gyneplus OR iub* OR liberte OR "Lippes Loop" OR load‐375 ) OR TITLE ( mlcu* OR mini‐tt OR minitt OR "Mona Lisa" OR multiload OR multi‐load OR multisafe OR multi‐safe OR mycu OR neosafe OR neo‐safe OR novat OR nova‐t OR paragard OR tcu OR tsafe OR t‐safe OR t380* OR t‐380* OR tt380* OR tt‐380* OR ut380 OR ut‐380 ) ) ) AND ( ( TITLE‐ABS‐KEY ( analges* OR antagonist* OR "pain control" OR "pain relief" OR "pain reliever" OR "pain relievers" OR nsaid OR nsaids OR ( ( nonsteroidal OR non‐steroidal ) PRE/1 ( antiinflammatory OR anti‐inflammatory ) ) OR adapalene OR alclofenac OR ampyrone OR antipyrine ) OR TITLE‐ABS‐KEY ( apazone OR arylpropionic OR aspirin OR "acetylsalicylic‐acid" OR baofuxin OR benzydamine OR bufexamac OR celecoxib OR clofazimine OR clonixin OR "Cox 2" OR curcumin OR cyclooxygenase OR cyclo‐oxygenase OR desmopressin OR dapsone OR diclofenac ) OR TITLE‐ABS‐KEY ( diflunisal OR dipyrone OR epirizole OR etanercept OR etodolac OR etoricoxib OR fenamate* OR fenoprofen OR feprazone OR flurbiprofen OR flufenamic OR glycyrrhizic OR ibuprofen OR indomethacin OR indoprofen OR inhibit* OR ketoprofen OR ketorolac ) OR TITLE‐ABS‐KEY ( lumiracoxib* OR masoprocol OR meclofenamic OR mefenamic OR meloxicam OR mesalamine OR nabumetone OR naprosyn OR naproxen OR niflumic OR norpregnadienes OR olopatadine AND hydrochloride OR oxaprozin OR oxyphenbutazone OR paracetamol OR parecoxib* ) OR TITLE‐ABS‐KEY ( pentosan OR phenylbutazone OR piroxicam OR prenazone OR prophylaxis OR prophylactic OR prostaglandin OR rofecoxib* OR salicylate* OR sulfasalazine OR sulphonanilide* OR sulindac OR suprofen OR thiamine OR tolfenamic OR tolmetin OR tranexam?c OR trasylol ) OR TITLE‐ABS‐KEY ( valdecoxib* ) ) ) ) AND ( TITLE‐ABS‐KEY ( blind OR blinded OR control* OR groups OR placebo OR random* OR trial ) ) (509) Global Health (Ovid) 1973 to 2020 Week 07 1 (IUB or IUBs or IUC or IUCs or IUD or IUDs or IUCD or IUCDs or IUS or IUSs or CuIUB or Cu‐IUB or CuIUBs or Cu‐IUBs or CuIUD or Cu‐IUD or CuIUDs or Cu‐IUDs or CuIUC or Cu‐IUC or CuIUCs or Cu‐IUCs or CuIUCD or Cu‐IUCD or CuIUDs or Cu‐IUDs or CuIUS or Cu‐IUS or CuIUSs or Cu‐IUSs or LNGIUC or LNGIUCs or LNGIUCD or LNGIUCDs or LNGIUD or LNGIUDs or LNGIUS or LNGIUSs or PPIUC or PPIUCs or PPIUCD or PPIUCDs or PPIUD or PPIUDs or PPIUS or PPIUSs).ti,ab. (1162) 2 ((intrauterine or intra‐uterine) adj3 (ball or balls or coil or coils or contraceptive or contraception or device or devices or system or systems)).ti,ab. (1392) 3 (Jaydess or Kyleena or Liletta or Mirena or Skyla or Copper‐T or CuSafe or Cu‐Safe or Cu375 or Cu‐375 or CuT380* or Cu‐T380* or FlexiT or Flexi‐T or Gyne or Gynefix or Gyneplus or IUB* or Liberte or "Lippes Loop" or Load‐375 or MLCu* or Mini‐TT or MiniTT or Mona Lisa or Multiload or Multi‐load or MultiSafe or Multi‐Safe or MYCu or NeoSafe or Neo‐Safe or NovaT or Nova‐T or Paragard or TCu or TSafe or T‐Safe or T380* or T‐380* or TT380* or TT‐380* or UT380 or UT‐380).ti,ab. (201) 4 or/1‐3 (1985) 5 (analges* or antagonist* or "pain control" or "pain relief" or "pain reliever" or "pain relievers" or NSAID or NSAIDs or tenaculum or ((nonsteroidal or non‐steroidal) adj1 (antiinflammatory or anti‐inflammatory)) or adapalene or alclofenac or ampyrone or antipyrine or apazone or arylpropionic or aspirin or "acetylsalicylic‐acid" or baofuxin or benzydamine or bufexamac or celecoxib or clofazimine or clonixin or "Cox 2" or curcumin or cyclooxygenase or cyclo‐oxygenase or desmopressin or dapsone or diclofenac or diflunisal or dipyrone or epirizole or etanercept or etodolac or etoricoxib or fenamate* or fenoprofen or feprazone or flurbiprofen or flufenamic or glycyrrhizic or ibuprofen or indomethacin or indoprofen or inhibit* or ketoprofen or ketorolac or lumiracoxib$ or masoprocol or meclofenamic or mefenamic or meloxicam or mesalamine or nabumetone or naprosyn or naproxen or niflumic or norpregnadienes or olopatadine hydrochloride or oxaprozin or oxyphenbutazone or paracetamol or parecoxib$ or pentosan or phenylbutazone or piroxicam or prenazone or prophylaxis or prophylactic or prostaglandin or rofecoxib$ or salicylate* or sulfasalazine or sulphonanilide$ or sulindac or suprofen or thiamine or tolfenamic or tolmetin or tranexam?c or trasylol or valdecoxib$).ti,ab. (373116) 6 and/4‐5 (60) 7 6 not ("animal model" or "animal models" or bovine or canine or capra or cat or cats or cattle or cow or cows or dog or dogs or equine or feline or goat or goats or horse or mice or mouse or ovine or pig or pigs or porcine or rabbit or rabbits or rat or rats or rattus or sheep or sow or sows).ti. (57) 8 (blind or blinded or control* or groups or placebo or random* or trial).ti,ab. (1018071) 9 (meta‐analy* or metaanaly* or ((evidence or systematic) adj2 (review or synthesis))).ti. (36292) 10 or/8‐9 (1031128) 11 and/7,10 (25) LILACS Words: IUB OR IUBs OR IUC OR IUCs OR IUD OR IUDs OR IUCD OR IUCDs OR IUS OR IUSs OR CuIUB OR Cu‐IUB OR CuIUBs OR Cu‐IUBs OR CuIUD OR Cu‐IUD OR CuIUDs OR Cu‐IUDs OR CuIUC OR Cu‐IUC OR CuIUCs OR Cu‐IUCs OR CuIUCD OR Cu‐IUCD OR CuIUDs OR Cu‐IUDs OR CuIUS OR Cu‐IUS OR CuIUSs OR Cu‐IUSs OR LNGIUC OR LNGIUCs OR LNGIUCD OR LNGIUCDs OR LNGIUD OR LNGIUDs OR LNGIUS OR LNGIUSs OR PPIUC OR PPIUCs OR PPIUCD OR PPIUCDs OR PPIUD OR PPIUDs OR PPIUS OR PPIUSs OR ((intrauterine OR intra‐uterine) AND (ball OR balls OR coil OR coils OR contraceptive OR contraception OR device OR devices OR system OR systems)) OR Jaydess OR Kyleena OR Liletta OR Mirena OR Skyla OR Copper‐T OR CuSafe OR Cu‐Safe OR Cu375 OR Cu‐375 OR CuT380 OR Cu‐T380 OR FlexiT OR Flexi‐T OR Gyne OR Gynefix OR Gyneplus OR IUB OR Liberte OR Lippes OR Load‐375 OR MLCu OR Mini‐TT OR MiniTT OR Mona Lisa OR Multiload OR Multi‐load OR MultiSafe OR Multi‐Safe OR MYCu OR NeoSafe OR Neo‐Safe OR NovaT OR Nova‐T OR Paragard OR TCu OR TSafe OR T‐Safe OR T380 OR T‐380 OR TT380 OR TT‐380 OR UT380 OR UT‐380 AND Words: analges? OR antagonist? OR "pain control" OR "pain relief" OR "pain reliever" OR "pain relievers" OR NSAID OR NSAIDs OR nonsteroidal OR non‐steroidal OR adapalene OR alclofenac OR ampyrone OR antipyrine OR apazone OR arylpropionic OR aspirin OR "acetylsalicylic‐acid" OR baofuxin OR benzydamine OR bufexamac OR celecoxib OR clofazimine OR clonixin OR "Cox 2" OR curcumin OR cyclooxygenase OR cyclo‐oxygenase OR desmopressin OR dapsone OR diclofenac OR diflunisal OR dipyrone OR epirizole OR etanercept OR etodolac OR etORicoxib OR fenamate? OR fenoprofen OR feprazone OR flurbiprofen OR flufenamic OR glycyrrhizic OR ibuprofen OR indomethacin OR indoprofen OR inhibit? OR ketoprofen OR ketorolac OR lumiracoxib? OR masoprocol OR meclofenamic OR mefenamic OR meloxicam OR mesalamine OR nabumetone OR naprosyn OR naproxen OR niflumic OR norpregnadienes OR olopatadine hydrochloride OR oxaprozin OR oxyphenbutazone OR paracetamol OR parecoxib? OR pentosan OR phenylbutazone OR piroxicam OR prenazone OR prophylaxis OR prophylactic OR prostaglandin OR rofecoxib? OR salicylate? OR sulfasalazine OR sulphonanilide? OR sulindac OR suprofen OR thiamine OR tolfenamic OR tolmetin OR tranexam?c OR trasylol OR valdecoxib? (49) Appendix 2. Previous search strategies 2011 Search strategies MEDLINE via PubMed (2009 to 17 Aug 2011) (intrauterine devices OR intrauterine system* OR IUD* OR IUC* OR IUS) AND (NSAID* OR anti inflammatory agents, nonsteroidal) CENTRAL (2009 to 17 Aug 2011) contracept* in Title, Abstract or Keywords AND (non‐steroidal anti‐inflammatory OR NSAID*) in Title, Abstract or Keywords POPLINE (17 Aug 2011 and past five years) (iud*/iuc*/intrauterine device*) & (NSAID*/nonsteroidal anti inflammatory agent*) LILACS (17 Aug 2011) intrauterine devices or intrauterine device or dispositivos intrauterinos or dispositivos Intra‐uterinos OR IUD or iuds OR IUC or IUCD or iucds [Words] and bleeding or pain [Words] ClinicalTrials.gov (01 Jan 2009 to 18 Aug 2011) Search terms: non‐steroidal anti‐inflammatory OR NSAID* Intervention: contraceptive OR contraception ICTRP Title or Intervention: non‐steroidal anti‐inflammatory OR NSAID Condition: contraception OR contraceptive 2006 Search strategies MEDLINE via PubMed (intrauterine devices OR intrauterine system* OR IUD* OR IUCD* OR IUS) AND (NSAID* OR anti inflammatory agents, nonsteroidal) CENTRAL contracept* AND (non‐steroidal anti‐inflammatory OR NSAID*) in Title, Abstract or Keywords POPLINE (iud*/iucd*/intrauterine device*) & (NSAID*/nonsteroidal anti inflammatory agent*) LILACS intrauterine devices or intrauterine device or dispositivos intrauterinos or dispositivos Intra‐uterinos OR IUD or iuds OR IUCD or iucds [Words] and bleeding or pain [Words] Embase (INTRAUTERINE CONTRACEPTIVE DEVICE or INTRAUTERINE(1N)DEVICE? or IUD? OR IUCD?) and (NONSTEROID ANTI INFLAMMATORY AGENT or NONSTEROID ANTI INFLAMMATORY DRUG or NONSTEROID ANTIINFLAMMATORY AGENT or NONSTEROIDAL(1N)ANTI(1N)INFLAMMATORY(1N) AGENT or NONSTEROIDAL(1N)ANTI(1N)INFLAMMATORY(1N)DRUG or NONSTEROIDAL(1N)ANTIINFLAMMATORY(1N)AGENT? or NONSTEROIDAL(1N)ANTIINFLAMMATORY(1N)DRUG? or NSAID?) CINAHL (intrauterine device* or IUD* or IUCD*) and (non?steroidal anti?inflammatory agent? or non?steroidal anti?inflammatory drug? or non?steroidal anti?inflammatory agent* or non?steroidal anti?inflammatory drug* or NSAID*) ClinicalTrials.gov Search terms: non‐steroidal anti‐inflammatory OR NSAID Condition: contraceptive OR contraception ICTRP Title or Intervention: non‐steroidal anti‐inflammatory OR NSAID Condition: contraception OR contraceptive Data and analyses Comparison 1. Vitamin B1 vs placebo (Cu IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 1.1 Number of pads/day | 1 | 110 | Mean Difference (IV, Random, 95% CI) | ‐7.00 [‐8.50, ‐5.50] | | 1.2 Number of spotting days | 1 | 110 | Mean Difference (IV, Random, 95% CI) | ‐1.60 [‐1.94, ‐1.26] | | 1.3 Number of bleeding days | 1 | 110 | Mean Difference (IV, Random, 95% CI) | ‐2.00 [‐2.38, ‐1.62] | Comparison 2. Naproxen vs placebo (Cu IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 2.1 "More" menstrual flow | 1 | 40 | Odds Ratio (M‐H, Random, 95% CI) | 0.09 [0.00, 1.78] | | 2.2 Side effects | 1 | 336 | Odds Ratio (M‐H, Random, 95% CI) | 1.91 [0.72, 5.06] | | 2.2.1 Irregular flow | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 2.24 [0.36, 13.78] | | 2.2.2 Fluor | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 3.15 [0.12, 81.74] | | 2.2.3 Tender vagina | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 3.15 [0.12, 81.74] | | 2.2.4 Gastrointestinal symptoms | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 2.11 [0.18, 25.17] | | 2.2.5 Dizziness | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 3.15 [0.12, 81.74] | | 2.2.6 Trembling legs | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 3.15 [0.12, 81.74] | | 2.2.7 Blurry vision | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 1.00 [0.06, 17.12] | | 2.2.8 Sore lips | 1 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 0.32 [0.01, 8.26] | Comparison 3. Mefenamic acid vs tranexamic acid (Cu IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 3.1 Volume of blood loss | 1 | 94 | Mean Difference (IV, Random, 95% CI) | ‐64.26 [‐105.65, ‐22.87] | | 3.2 PBAC score | 1 | 58 | Mean Difference (IV, Random, 95% CI) | ‐8.19 [‐25.24, 8.86] | | 3.3 Number of bleeding days | 2 | 152 | Mean Difference (IV, Random, 95% CI) | 0.08 [‐0.27, 0.42] | Comparison 4. Mefenamic acid vs desmopressin (Cu IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 4.1 Mean reduction of PBAC score (%) | 1 | Other data | No numeric data | | | 4.2 Side effects: headache and insomnia | 1 | 24 | Odds Ratio (M‐H, Random, 95% CI) | 0.11 [0.00, 2.36] | Comparison 5. Tranexamic acid vs sodium diclofenac (Cu IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 5.1 Menstrual blood loss (alkaline hematin) | 1 | 38 | Mean Difference (IV, Random, 95% CI) | ‐42.70 [‐73.33, ‐12.07] | | 5.2 Duration of menstruation | 1 | 38 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.62, 0.62] | | 5.3 Side effects | 1 | 38 | Odds Ratio (M‐H, Random, 95% CI) | 4.69 [1.20, 18.44] | Comparison 6. Tranexamic acid vs flavonoids (Cu IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 6.1 PBAC score | 1 | 100 | Mean Difference (IV, Random, 95% CI) | ‐32.00 [‐39.84, ‐24.16] | | 6.2 Number of pads/day | 1 | 100 | Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐0.91, ‐0.09] | | 6.3 Number of bleeding days | 1 | 100 | Mean Difference (IV, Random, 95% CI) | ‐1.40 [‐1.93, ‐0.87] | | 6.4 Side effects | 1 | 200 | Odds Ratio (M‐H, Random, 95% CI) | 0.67 [0.30, 1.48] | | 6.4.1 Headache | 1 | 100 | Odds Ratio (M‐H, Random, 95% CI) | 0.58 [0.18, 1.92] | | 6.4.2 Vomiting | 1 | 100 | Odds Ratio (M‐H, Random, 95% CI) | 0.74 [0.25, 2.18] | Comparison 7. Tranexamic acid vs active comparators (mefenamic acid, flavonoids, diclofenac) (Cu IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 7.1 Number of bleeding days | 4 | 290 | Mean Difference (IV, Random, 95% CI) | ‐0.27 [‐1.14, 0.60] | Comparison 8. Ulipristal acetate vs placebo (LNG IUD, treatment of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 8.1 Duration of days until bleeding stops | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | ‐3.30 [‐9.07, 2.47] | | 8.2 Total bleeding in 90 days | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | ‐9.30 [‐26.76, 8.16] | Comparison 9. High‐dose naproxen vs low‐dose naproxen (unknown IUD, treatment of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 9.1 Blood loss reduction (%) | 1 | Other data | No numeric data | Comparison 10. Mefenamic acid vs Vitex agnus (unknown IUD, treatment for HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 10.1 PBAC score | 1 | 84 | Mean Difference (IV, Random, 95% CI) | ‐2.40 [‐13.77, 8.97] | | 10.2 Side effects | 1 | 168 | Odds Ratio (M‐H, Random, 95% CI) | 0.62 [0.07, 5.13] | | 10.2.1 Nausea | 1 | 84 | Odds Ratio (M‐H, Random, 95% CI) | 1.00 [0.06, 16.53] | | 10.2.2 Abdominal pain | 1 | 84 | Odds Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 8.22] | Comparison 11. Tranexamic acid vs sodium diclofenac (Cu IUD, treatment for pain). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 11.1 Pelvic pain | 1 | 38 | Odds Ratio (M‐H, Random, 95% CI) | 1.00 [0.06, 17.25] | Comparison 12. Naproxen vs placebo (unknown IUD, treatment for pain). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 12.1 Overall pain relief score | 1 | 33 | Mean Difference (IV, Random, 95% CI) | 4.10 [0.91, 7.29] | | 12.2 Daily pain relief score | 1 | 33 | Mean Difference (IV, Random, 95% CI) | 3.10 [0.27, 5.93] | | 12.3 Pain relief | 1 | 40 | Odds Ratio (M‐H, Random, 95% CI) | 2.79 [0.77, 10.04] | | 12.4 Need for analgesia | 1 | 33 | Odds Ratio (M‐H, Random, 95% CI) | 0.29 [0.05, 1.80] | Comparison 13. Ibuprofen vs placebo (Cu IUD, prevention of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 13.1 Menstrual blood loss (alkaline hematin) | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐14.11 [‐36.04, 7.82] | | 13.1.1 Cu IUD | 1 | 20 | Mean Difference (IV, Random, 95% CI) | ‐9.47 [‐34.45, 15.51] | | 13.1.2 Lippes Loop | 1 | 20 | Mean Difference (IV, Random, 95% CI) | ‐29.68 [‐75.44, 16.08] | | 13.2 Duration of bleeding | 1 | 28 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐1.40, 1.00] | | 13.3 Median menstrual blood loss (alkaline hematin) | 1 | Other data | No numeric data | | | 13.3.1 Fincoid | 1 | Other data | No numeric data | | | 13.3.2 ML Cu 375 | 1 | Other data | No numeric data | | | 13.4 Side effects | 2 | 108 | Odds Ratio (M‐H, Random, 95% CI) | 2.15 [0.50, 9.31] | | 13.4.1 Eye and mouth swelling | 1 | 40 | Odds Ratio (M‐H, Random, 95% CI) | 3.15 [0.12, 82.16] | | 13.4.2 Stomach cramps | 1 | 40 | Odds Ratio (M‐H, Random, 95% CI) | 3.15 [0.12, 82.16] | | 13.4.3 Tired, irritable | 1 | 28 | Odds Ratio (M‐H, Random, 95% CI) | 1.67 [0.25, 11.07] | Comparison 14. Tolfenamic vs placebo (Cu IUD, prevention of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 14.1 Number of pads/day | 1 | 122 | Mean Difference (IV, Random, 95% CI) | ‐1.00 [‐1.57, ‐0.43] | | 14.2 Menstruation "more abundant than normal" | 1 | 310 | Odds Ratio (M‐H, Random, 95% CI) | 0.54 [0.34, 0.85] | | 14.3 Clots in menstrual blood | 1 | 310 | Odds Ratio (M‐H, Random, 95% CI) | 0.43 [0.27, 0.68] | Comparison 15. Aspirin vs paracetamol (Cu IUD, prevention of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 15.1 Menstrual blood loss (alkaline hematin) | 1 | 20 | Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐26.16, 25.56] | Comparison 16. 2 g tranexamic vs 1 g tranexamic (Cu IUD, prevention HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 16.1 Occurence of HMB (%) | 1 | Other data | No numeric data | | | 16.1.1 Alkaline hematin | 1 | Other data | No numeric data | | | 16.1.2 PBAC | 1 | Other data | No numeric data | Comparison 17. Ulipristal acetate (CDB‐2914) vs placebo (LNG IUD, prevention of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 17.1 Percentage days bleeding or spotting | 1 | 118 | Mean Difference (IV, Random, 95% CI) | 9.50 [1.48, 17.52] | | 17.2 Longest consecutive run of days without bleeding or spotting | 1 | 118 | Mean Difference (IV, Random, 95% CI) | ‐1.90 [‐6.93, 3.13] | Comparison 18. Tranexamic acid vs mefenamic acid (LNG IUD, prevention of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 18.1 Median number of bleeding days | 1 | Other data | No numeric data | Comparison 19. Naproxen vs estradiol (LNG IUD, prevention of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 19.1 Median number of bleeding and spotting days | 1 | Other data | No numeric data | | | 19.2 Satisfied with bleeding pattern at 12 weeks | 1 | 73 | Odds Ratio (M‐H, Random, 95% CI) | 1.10 [0.40, 3.03] | | 19.3 Side effects | 1 | 86 | Odds Ratio (M‐H, Random, 95% CI) | 3.22 [0.13, 81.19] | | 19.3.1 Gastroesophageal reflux disease (GERD) | 1 | 86 | Odds Ratio (M‐H, Random, 95% CI) | 3.22 [0.13, 81.19] | Comparison 20. Mifepristone vs vitamin B (LNG IUD, prevention of HMB). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 20.1 Percentage bleeding and spotting days | 1 | Other data | No numeric data | Comparison 21. Tolfenamic acid vs placebo (Cu IUD, prevention of pain). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 21.1 Menstruation "more painful than normal" | 1 | 310 | Odds Ratio (M‐H, Random, 95% CI) | 0.71 [0.44, 1.14] | | 21.2 Side effects | 1 | 366 | Odds Ratio (M‐H, Random, 95% CI) | 0.42 [0.02, 9.29] | | 21.2.1 Dyspepsia and diarrhoea | 1 | 122 | Odds Ratio (M‐H, Random, 95% CI) | 9.96 [0.52, 189.04] | | 21.2.2 Headache | 1 | 122 | Odds Ratio (M‐H, Random, 95% CI) | 0.09 [0.00, 1.60] | | 21.2.3 Depression | 1 | 122 | Odds Ratio (M‐H, Random, 95% CI) | 0.09 [0.00, 1.60] | Comparison 22. Ibuprofen vs placebo (Cu IUD, prevention of pain). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 22.1 Reduction in menstrual cramps | 1 | 20 | Odds Ratio (M‐H, Random, 95% CI) | 1.00 [0.11, 8.95] | Comparison 23. Ibuprofen vs placebo (Cu IUD,prevention of bleed and pain, IUD removal). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 23.1 IUD removal by 26 weeks due to pain or increased blood loss | 1 | 1962 | Odds Ratio (M‐H, Random, 95% CI) | 0.96 [0.66, 1.38] | | 23.2 IUD removal due to pain or increased blood loss by 52 weeks | 1 | 1962 | Odds Ratio (M‐H, Random, 95% CI) | 1.25 [0.93, 1.69] | Characteristics of studies Characteristics of included studies [ordered by study ID] Alanwar 2018. | Study characteristics | || | Methods | RCT with 2 treatment groups | | | Participants | 100 women aged 18‐49 years old who presented with HMB secondary to use of the TCu 380A IUD Location/setting: family planning and gynaecology outpatient clinics at the Ain Shams University Maternity Hospital, Cairo, Egypt Type of IUD: Cu IUD Inclusion criteria: HMB (defined as a score > 100 on a PBAC) Exclusion criteria: HMB prior to IUD insertion, any systemic or local cause of HMB such as haemorrhagic blood disease, fibroids, adenomyosis, or uterine or cervical polyps, iron deficiency anaemia and displaced IUD | | | Interventions | Oral tranexamic acid 500 mg vs oral micronized flavonoid 500 mg tablets, 1 tablet 6‐hourly during the first 3 days of menstrual bleeding (total 2 g of tranexamic acid/day vs 2 g of micronized flavonoid/day) Duration: 3 cycles | | | Outcomes | Primary outcome: difference in PBAC scores between the groups Secondary outcome: difference in PBAC scores before and after treatment in each group, the number of bleeding days (menstruation lasting up to 5 days was considered normal), the number of pads used/day and any drug side effects Women recorded their PBAC scores on diaries | | | Notes | The trial was registered at ClinicalTrials.gov NCT02616731 Sample size power calculations provided No report on funding No conflicts of interest declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "A statistician, not otherwise involved in the study, prepared a computer‐generated random table using the MedCalc 14 program" | | Allocation concealment (selection bias) | Low risk | Quote: "serially‐numbered, closed opaque envelopes" | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "To ensure double‐blinding, both study medications were administered by a research assistant in closed packets identical in shape and colour. Therefore, both the investigators and the patients were blinded to the nature of the used drug. To avoid any bias, blinding was not revealed until the end of the study." | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "complete the PBAC charts at home daily during menstruation" Comment: subjective outcome, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No loss to follow‐up | | Selective reporting (reporting bias) | Low risk | All trial outcomes listed were reported | | Other bias | Low risk | The trial appears to be free of other sources of bias | Buttram 1979. | Study characteristics | || | Methods | RCT | | | Participants | 35 women with either uterine pain starting after IUD insertion or prior menstrual pain exacerbated by IUD insertion Location/setting: USA Type of IUD: unknown type Inclusion criteria: normal physical examination, and, if necessary for pain evaluation, normal laparoscopy Exclusion criteria: women with cycle irregularities | | | Interventions | Naproxen sodium 550 mg initially, then 275 mg every 6 h as needed for uterine pain vs a placebo (lactose) Duration: 3 cycles | | | Outcomes | Uterine pain as judged by 6‐point Likert scale Women recorded on diaries | | | Notes | No protocol published Method of randomization not specified; no mention of allocation concealment Sample size calculation not provided Funding not reported Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Quote: "randomly and sequentially assigned" | | Allocation concealment (selection bias) | Unclear risk | No mention | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "this study was a double blind..." | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "the patients were instructed to keep detailed records on ..." Comment: subjective outcome, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "Of the 35 subjects originally enrolled, two left the trial for personal reasons. Data were analysed for the remaining 33 subjects." | | Selective reporting (reporting bias) | Unclear risk | No protocol published | | Other bias | Low risk | The trial appears to be free of other sources of bias | Davies 1981. | Study characteristics | || | Methods | RCT with cross‐over | | | Participants | 48 women of reproductive age using IUDs in England, UK Type of IUD: unknown Inclusion criteria: measured MBL averaging at least 80 mL per cycle over 2 pre‐treatment cycles. Participants had regular cycles, were healthy, and had a normal pelvic examination. | | | Interventions | 3 treatment arms:naproxen 1250 mg/day naproxen 500 mg on first day then 750 mg on subsequent days placebo Each participant took 2 of the 3 treatments, each for 2 menstrual cycles. Each regimen was begun on the first day of menstrual bleeding and continued for a total of 5 days. Duration: four cycles | | | Outcomes | Percentage reduction of MBL. Method of measurement not described | | | Notes | No protocol published Complex design with small number of participants Method of randomization not stated, and no mention of allocation concealment No sample size calculation provided Funding and declarations of conflicts of interest not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No mention | | Allocation concealment (selection bias) | Unclear risk | No mention | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No mention | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No mention | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No data on lost participants | | Selective reporting (reporting bias) | Unclear risk | No protocol published | | Other bias | Unclear risk | Cross‐over design. No baseline characteristics | Fava 2020. | Study characteristics | || | Methods | Randomized, double‐blind, placebo‐controlled pilot trial | | | Participants | 30 women aged 18‐45 years old who had been using LNG IUD for at least 1 year with complaints of abnormal uterine bleeding Location/setting: Department of Obstetrics and Gynecology, University of Campinas Medical School (UNICAMP), Campinas, Brazil Type of IUD: LNG IUD Duration of trial: 1 September 2016 to 30 September 2018 Inclusion criteria: on LNG IUD for at least 1 year but 14 days’ bleeding) or frequent (< 24 days between menstrual periods) in the previous month Exclusion criteria: use of carbamazepine or topiramate, childbirth within the previous 6 months, previous history of abnormal uterine bleeding before LNG IUD placement, any haematological inherited disorder, or use of anticoagulant drugs, uterine fibroids, endometrial polyps | | | Interventions | 5 mg ulipristal acetate vs placebo pills for 5 days Followed up for 90 days | | | Outcomes | Days before bleeding stopped, days free of bleeding, total bleeding days in 30, 60 and 90 days. Endometrial thickness at 90 days All women received a bleeding calendar with instructions to record all bleeding episodes daily for 90 days after beginning treatment | | | Notes | Protocol lodged ClinicalTrials.gov: NCT03186586 Sample size power calculations provided This trial received partial financial support from the Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP) award No. 2015/20504‐9 and the National Research Council (CNPq), grant #573747/2008‐3 The LNG IUD devices were donated by the International Contraceptive Access Foundation, Turku, Finland under an unrestricted grant. Donors were not involved in the design of the trial protocol, the trial itself, data analysis, or manuscript writing One of the authors is an advisory member without remuneration of the ICA Foundation Board of Trustees, Finland, and has received an honorarium from Bayer Pharma as a speaker | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "randomly assigned (1:1) to one of two groups using sealed envelopes prepared according to a computerized randomization program by a person not involved in the study." | | Allocation concealment (selection bias) | Low risk | Quote: "using sealed envelopes", "pills that were visually indistinguishable" | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "Women and healthcare professionals were blinded to the treatment type, and we opened the codes after the last woman completed the study." | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "All women received a bleeding calendar with instructions to record all bleeding episodes daily" Comment: subjective, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "Five women in the placebo group were lost to follow‐up after several attempts to contact them by phone call or text message. Consequently, we analysed the outcomes for 25 women" | | Selective reporting (reporting bias) | Low risk | All outcomes listed were reported | | Other bias | Low risk | Appears free from other sources of bias | Hahn 1979. | Study characteristics | || | Methods | RCT with cross‐over | | | Participants | 37 women aged 20‐40 years in Sweden, 10 of whom were using Cu IUDs Location/setting: Sweden Type of IUD: Cu IUD | | | Interventions | 3 treatment arms:Aspirin 1500 mg/day Paracetamol 1500 mg/day Placebo Interventions taken on day 1 of menstruation and continued for the duration of bleeding Each participant received each treatment in alternating order Duration: 3 cycles | | | Outcomes | MBL measured by alkaline hematin method | | | Notes | No protocol published Sample size was one of convenience Funding and declarations of conflicts of interest not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No details | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Blinding was not likely to have led to detection bias as alkaline hematin was measured in laboratory | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No loss to follow‐up | | Selective reporting (reporting bias) | Unclear risk | No protocol published.No objectives stated in published trial | | Other bias | High risk | Cross‐over design 4 out of 10 women on IUD had prior to intervention, prolonged bleeding time, increased capillary fragility and/or a history of bleeding tendencies | Hubacher 2006. | Study characteristics | || | Methods | RCT | | | Participants | 2019 women aged 18‐49 years old, having a T380A Cu IUD inserted Location/setting: Chile Type of IUD: Cu IUD Inclusion criteria: women who were literate, no previous IUD use, > 6 weeks postpartum if recently pregnant, and without contraindications to an IUD or ibuprofen | | | Interventions | Ibuprofen 1200 mg/day vs placebo, to be taken with the first 6 menstruations after IUD insertion and for a maximum of 5 days at a time Duration: 6 cycles | | | Outcomes | The primary outcome was IUD removal within 12 months of insertion. Participants were followed up at 6, 13, 26, and 52 weeks after insertion ‐ follow‐up forms filled to record current IUD use, reason for visit and removal | | | Notes | No protocol published Sample size was calculated to achieve 85% power to detect a reduction in discontinuation from 16% to 11% with an alpha of 0.025 (1‐sided hypothesis) This trial was supported by a grant from the National Institutes of Health. Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "randomly assigned to group A or B using random permuted block sizes of 20, 10, 4 and 2" | | Allocation concealment (selection bias) | Unclear risk | No mention | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "Participants, clinicians and the research team were blinded to the true identity of the tablets" "identical appearing placebo and ibuprofen tablets" | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The test results were concealed from everyone on the research team." "Blinding was maintained throughout data analysis" Comment: unlikely blinding was broken | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "2019 women enrolled...A total of 57 participants did not have IUD inserted…34 minor protocol violations...data from these participants were not excluded from subsequent analyses" Comment: intention to treat | | Selective reporting (reporting bias) | Unclear risk | All trial outcomes listed were reported, although no trial protocol was published or lodged | | Other bias | Low risk | Appears free from other bias | Jafari 2014. | Study characteristics | || | Methods | RCT | | | Participants | 126 women Setting: 2 public health clinics in Borujerd, Iran Type of IUD: Cu IUD Inclusion criteria: basic literacy, first time use of the TCu380A IUD, a history of normal menstrual bleeding with duration of 3‐7 days without spotting, a menstrual cycle lasting 26‐30 days, use of 10‐14 sanitary pads per cycle before IUD insertion, and a gravidity ranging between 1 and 4 Those who met criteria were scheduled for IUD insertion. During follow‐up, those that claimed volume of MBL/number of pads increased or had spotting were recruited into the trial and randomized. Exclusion criteria: systemic disease | | | Interventions | 100 mg vitamin B1/day during the 2nd, 3rd and 4th months following insertion of the IUD vs placebo Duration: 3 cycles | | | Outcomes | Amount of MBL using Higham scale Number of pads used, number of spotting days and duration of bleeding Women recorded on checklists provided | | | Notes | The trial was registered with the Iranian Clinical Trials centre (IRCT 2012073010451N1) No sample size calculation provided Financial support from Vice‐Chancellor in Research Affairs of Azad University, Iran No conflicts of interest | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote:"Participants were assigned in a 1:1 ratio to the use of vitamin B1 or placebo, in accordance with a random table produced by an Excel program" | | Allocation concealment (selection bias) | Unclear risk | No mention | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote:"This double‐blind, randomised controlled trial" "person who was unaware of the purpose of the study" | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "note the amount of menstrual blood lost using the Higham scale" Comment: subjective outcome as reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote:"Sixteen women withdrew from the study (14 in the control group and two in the intervention group), and 110 completed the study" Comment: withdrawn participants were not included in analysis | | Selective reporting (reporting bias) | Low risk | All trial outcomes listed were reported | | Other bias | Low risk | Appears free from other bias | Kaviani 2013. | Study characteristics | || | Methods | RCT | | | Participants | 84 women using IUD (TCu‐380) with complaints of severe menstrual bleeding Location/setting: health clinics of Bandar Abbas, southern Iran Type of IUD: Cu IUD Inclusion criteria: used IUD (TCu‐380) and had confirmed menorrhagia Exclusion criteria: intrauterine organic lesions, liver and renal disorders, moderate and severe anaemia, chlamydia infection, endometrial abscission, thromboembolic and coagulation problems, had used other methods of contraception/tranexamic acid or mefenamic acid | | | Interventions | 250 mg mefenamic acid vs 250 mg tranexamic acid; 1 capsule every 8 h on the first 3 days of menstruation (750 mg mefenamic acid/day vs 750 mg tranexamic acid/day) Duration: 2 cycles | | | Outcomes | Amount of bleeding (PBAC) and number of bleeding days Women recorded on PBAC charts | | | Notes | No protocol published No sample size calculation provided Financial support from Shiraz University of Medical Sciences No conflicts of interest | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "Randomization was done, as follows: the women were asked to choose one number from 1 to 84; the women who selected 42 and less received tranexamic acid capsules and mefenamic acid were given to those with higher than 42" | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | No details on who was blinded, however blinding may not have been broken | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "For every person, personal characteristics, results of examination and tests and treatment type were collected using questionnaires" Comment: subjective outcome, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No loss to follow‐up Quote: "After one month 7 women in the tranexamic acid group and 19 women in the mefenamic acid group who did not response to treatment in first menstrual cycle, were excluded" Comment: excluded women were not included in analysis | | Selective reporting (reporting bias) | Unclear risk | All outcomes listed were reported. No protocol lodged | | Other bias | Low risk | Appears free from other bias | Lalos 1983. | Study characteristics | || | Methods | RCT with cross‐over | | | Participants | 21 women in Sweden with primary period pain aggravated by insertion of a Cu IUD (either a T or the Cu‐7) Location/setting: Sweden Type of IUD: Cu IUD Inclusion criteria included severe period pain, regular menstrual cycles, and normal gynaecological examination | | | Interventions | Naproxen 500 mg followed by 250 mg 2‐4 times a day, with a maximum of 1250 mg, vs placebo for 2 cycles, then vice versa for 2 cycles. The drug was started at the first sign of menstrual distress. Duration: 4 cycles | | | Outcomes | Pain assessed by a 5‐point Likert scale | | | Notes | No protocol published Sample‐size calculation not provided Informed consent was verbal, not written Conflicts of interest not declared Funding not stated | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | Quote: "the tablets of Naproxen ... were similarly shaped as the placebo tablets" | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No details on who was blinded Quote: "the tablets of Naproxen ... were similarly shaped as the placebo tablets" | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Subjective outcome of pain as reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "One woman did not complete the study...and has been excluded from the final analysis of the study" | | Selective reporting (reporting bias) | Unclear risk | No protocol published. No objectives stated in published trial | | Other bias | Low risk | Cross‐over design but no carry‐over effect seen | Lin 2007. | Study characteristics | || | Methods | RCT with 3 treatment groups | | | Participants | 175 Chinese women Location/setting: 4 Maternal and Child Health (MCH) Centres in Shanghai, China Type of IUD: Cu IUD Inclusion criteria: aged 20‐40 years with regular menstrual cycles and attending for a Cu IUD insertion Exclusion criteria: medical histories of organic diseases, concomitant disease influencing menstruation, contraindication to tranexamic acid, intake of any medications in the latest month which may alter MBL, and intake of contraceptive pills in the last 3 months | | | Interventions | Treatment groups:2 g treatment group (oral tranexamic acid, 1 g, twice daily) half dosage treatment group (oral tranexamic acid 500 mg, twice daily) placebo group All were taken for the first 5 days of 3 consecutive cycles after IUD insertion Duration: 3 cycles | | | Outcomes | MBL was primarily assessed with the score obtained from a PBAC. Some women were further randomly sampled to collect used sanitary towels for a more precise measure of MBL via the alkaline hematin method | | | Notes | No protocol published No sample size calculation provided Financial support from Daiichi Pharmaceutical Company Ltd Conflicts of Interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Quote: "Eligible women were randomly allocated to..." Comment: no details on how randomisation was done | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "..double blind..." Comment: no details on who was blinded | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "Menstrual blood loss was primarily assessed with the score obtained from a pictorial blood loss assessment chart, which takes into account the degree to which each item of sanitary protection is soiled with blood, as well as the total number of pads or tampons used. Some of the subjects were further randomly sampled to collect used sanitary towels for a more precise measure of menstrual blood loss, the alkaline hematin method" Comment: MBL was a subjective outcome, not all underwent alkaline hematin method | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "Women randomised and at least completing the first follow‐up were admitted to intention‐to‐treat (ITT) analysis population, based on which results were primarily presented, and those who had taken 80% of prescribed pills were included in the per protocol (PP) analysis population" | | Selective reporting (reporting bias) | Unclear risk | Outcomes listed were reported. No protocol lodged | | Other bias | Low risk | Appears free from other source of bias | Madden 2012. | Study characteristics | || | Methods | RCT with 3 treatment groups, single‐blind | | | Participants | 129 women Type of IUD: LNG IUD Location/setting: USA Inclusion criteria: English‐speaking, willing to avoid additional use of exogenous hormones (e.g. oral contraceptives) and NSAIDs for the duration of the trial, and willing to comply with the trial protocol by adhering to the medication regimen, keeping the bleeding diary, attending follow‐up visits, and completing the telephone surveys as scheduled. Exclusion criteria: known or suspected pregnancy; contraindications to oestrogen or NSAID use; current use of medications that alter oestrogen metabolism; current regular use of a NSAID; current diagnosis of menorrhagia, metrorrhagia, symptomatic uterine fibroids, or endometrial polyps; use of DMPA within the previous 6 months; postpartum in the past 4 weeks; induced or spontaneous abortion in the past 4 weeks; currently breastfeeding; or previous use of the LNG IUD | | | Interventions | Treatment groups:oral naproxen 500 mg twice a day first 5 days of a 4‐week period transdermal estradiol 0.1 mg on day after insertion of IUD, changing it weekly oral placebo twice a day Duration: first 12 weeks of LNG IUD use | | | Outcomes | Number of bleeding and spotting days, patient satisfaction, continuation rates of IUD ‐ trial diaries to record bleeding and spotting and medication compliance Women recorded bleeding, spotting and medication compliance on diaries | | | Notes | The trial was registered with clinicaltrials.gov NCT00789802 Sample size calculation provided Funding by Bayer Healthcare, National Institute of Health & Human Development, National Institute of Health and National Centre for Research Resources Participants were compensated for participation No conflicts of interest | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "randomisation scheme using computer generated number tables" | | Allocation concealment (selection bias) | Low risk | Quote: "The treatment arm assignments were contained in sequentially numbered, opaque envelopes opened by the research nurse" | | Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "The naproxen and placebo arms were blinded to the participant and the research team; the estradiol arm was open label as no transdermal placebo was available" | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Subjective outcome, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Intention to treat | | Selective reporting (reporting bias) | Low risk | Objectives published in protocol reported | | Other bias | Low risk | Trial appears free from other source of bias | Makarainen 1986. | Study characteristics | || | Methods | RCT | | | Participants | 28 women, aged between 24‐45 years old with Cu IUD (either Fincoid 350 or ML Cu375) Type of IUD: Cu Location/setting: Finland | | | Interventions | Ibuprofen 1200 mg/day or placebo at the beginning of menstruation and to continue to end of bleeding for a maximum of 10 days Duration: 3 cycles | | | Outcomes | MBL measured by alkaline hematin method and questionnaires and length of menstruation | | | Notes | No protocol published No sample size calculation provided Research was funded by Emil Aaltonen Foundations, Orion Corporation Research Foundation, Finland's Cultural Fund and Medipolar and Farmos Group Ltd Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Quote: "After insertion, the woman received at random.." Comment: no details on randomisation technique | | Allocation concealment (selection bias) | Low risk | Quote: "sealed envelope" | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "double‐blind manner" Comment: no details on who was blinded | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "the women filled in questionnaires on the duration of bleed, pain..." Comment: no details on blinding of outcome assessors Subjective outcome of pain, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "Thus results from 28 women were included in final analysis" | | Selective reporting (reporting bias) | Unclear risk | Outcome listed reported. No protocol lodged | | Other bias | Low risk | Appears to be free from other sources of bias | Mercorio 2003. | Study characteristics | || | Methods | RCT without blinding | | | Participants | 24 women aged 20‐40 years with IUD‐associated menorrhagia Type of IUD: Cu IUD Location/setting: Italy Inclusion criteria: PBAC assessment for 2 treatment cycles indicating menorrhagia (score of ≥ 100) Exclusion criteria: gynaecological pathology, family or personal history of bleeding disorders, or prior use of trial drugs | | | Interventions | Desmopressin 300 mcg intranasal spray each morning for the first 5 days after start of menstruation vs mefenamic acid 1500 mg/day for the first 5 days after the start of menstruation Duration: 3 months | | | Outcomes | PBAC recorded on menstrual charts | | | Notes | No protocol lodged Sample size calculation not provided No baseline characteristics Funding not stated Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "The subjects were allocated to either the desmopressin or mefenamic acid group according to a schedule provided by an envelope system developed using computer analysis" | | Allocation concealment (selection bias) | Low risk | Quote: "The subjects were allocated to either the desmopressin or mefenamic acid group according to a schedule provided by an envelope system developed using computer analysis" | | Blinding of participants and personnel (performance bias) All outcomes | High risk | Intranasal desmopressin vs oral mefenamic acid | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Subjective outcome of MBL, self‐reported by patients | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No details on lost data | | Selective reporting (reporting bias) | Unclear risk | Listed outcomes reported, no protocol lodged | | Other bias | Unclear risk | No baseline characteristics of subjects | Papaikonomou 2018. | Study characteristics | || | Methods | Prospective, randomized, double blind, placebo‐controlled trial | | | Participants | 58 women Location/setting: Sweden Type of IUD: LNG IUD Inclusion criteria: healthy, opting for LNG‐IUS 52 mg for contraception, aged 18–43 with regular and normal menstrual cycles lasting 24–35 days, with no contraindications to LNG‐IUS or mifepristone Exclusion criteria: current signs of pelvic inflammatory disease, pregnancy, breastfeeding or use of hormonal contraception or Cu IUD within 2 months prior to trial start, a history of malignant disorder of the breast or other malignancy, unexplained irregular vaginal bleeding, untreated genital infection, abnormal laboratory values, or abnormal gynaecological ultrasound and Pap smear findings at baseline | | | Interventions | 50 mg mifepristone was to be taken orally every other day starting on the first day of the menstrual cycle for the pre‐treatment period vs oral vitamin B Duration: 2 months (corresponding to 2 menstrual cycles (i.e. 2 × 28 days) prior to insertion and until 3 days (± 2 days) following the LNG‐IUD insertion | | | Outcomes | Primary outcome: days of bleeding and spotting in both groups at 3 months following LNG‐IUD 52 mg insertion Secondary outcomes: bleeding patterns during the 6 months following insertion, early removal of LNG‐IUD within 6 months, continued use at 6 months and satisfaction with the contraceptive method at 6 and 12 months as well as side effects of mifepristone and/or LNG IUD 52 mg Women kept daily diaries of vaginal bleeding, adverse events and use of concomitant medications | | | Notes | Protocol lodged (EudraCT number 2009‐009014‐40) Sample size calculation provided This trial was funded by the Swedish Research Council No conflicts of interest | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "...were randomised at a ratio of 1:1 in blocks of 10, ..according to a computer‐generated randomisation list" | | Allocation concealment (selection bias) | Low risk | Quote: "...dispensing opaque identical sequentially numbered pill packs prepared.." "...visually indistinguishable..." | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "We designed this double blind randomised controlled trial..." Comment: no details on who was blinded | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "Bleeding was graded on a five‐point scale as none (0), spotting (1), mild (2, less than normal menstruation), moderate (3, similar to normal menstruation) or severe (4, heavier than normal menstruation)." "The study participants were asked to a keep daily diary..." "Women were asked about their vaginal bleeding pattern (improved/no effect/worse).." Comment: subjective assessment by participants, no details on blinding of outcome assessors | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "These missing data were excluded from the analysis." | | Selective reporting (reporting bias) | Low risk | Listed outcomes reported | | Other bias | Low risk | Appears free from other sources of bias | Roy 1981. | Study characteristics | || | Methods | Cross‐over RCT | | | Participants | 20 women, aged 18‐33 years without bleeding or other complaints; 10 used Cu IUDs and 10 used Lippes Loop Location/setting: USA Type of IUD: Cu IUD and Lippes Loop Inclusion criteria: having used the IUD for at least 5 months and being free of side effects Exclusion criteria: previous salpingitis, undiagnosed bleeding, uterine anomalies, multiple fibroids, and contraindications to ibuprofen | | | Interventions | Ibuprofen 1600 mg/day starting with bleeding and continuing until end of bleeding or maximum of 7 days vs placebo Each participant had 1 month of observation, 1 month on ibuprofen or placebo, and 1 month crossed over to the alternative treatment. Duration: 3 cycles | | | Outcomes | MBL measured by alkaline hematin method Women completed menstrual diaries and collected all sanitary pads/ tampons into plastic bags during each cycle | | | Notes | No protocol published Sample size was based on feasibility rather than power calculation Research supported in part by grant from the Upjohn Company, Kalamazoo, Michigan Conlicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Quote: "..the subjects were assigned to group 1 (initial ibuprofen) or to group 2 (initial placebo) following a scheme designed to ensure equal and random patient distribution" | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "the study was double blind with regard to placebo and drug..." | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Blinding was not likely to have led to detection bias as alkaline hematin was measured in laboratory | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No loss to follow‐up | | Selective reporting (reporting bias) | Unclear risk | Outcome listed reported. No protocol lodged | | Other bias | Low risk | Cross‐over trial but no carry‐over effect seen | Saharkhiz 2017. | Study characteristics | || | Methods | Parallel RCT | | | Participants | 210 women aged 18‐40 years Setting: 6 health centres of Shahid Beheshti University of Medical Sciences in Tehran Type of IUD: Cu IUD Trial duration: June 2012‐December 2014 Inclusion criteria: women who had > 7 days of menstrual bleeding or menstrual blood volume of > 80 mL Exclusion criteria: history of anatomical abnormalities such as uterine myoma; adenomyosis; coagulopathy, such as thromboembolism or stroke; anticoagulant therapy; drug sensitivity; gastrointestinal bleeding; genital infection; endometritis; and other confounding factors that can lead to increased bleeding. | | | Interventions | 2 x 250 mg capsules of tranexamic acid 3 times/day (total 750 mg/day) vs 2 x 250 mg capsules of mefenamic acid (total 750 mg/day) 3 times/day, 3‐5 days based on the duration of bleeding Duration: 3 months | | | Outcomes | Primary outcome: days of menstruation, volume of MBL, and the sequence of bleeding Secondary outcome: haemoglobin (Hb) concentration on admission and at the end of the treatment Women filled in questionnaires monthly for 3 months | | | Notes | Protocol lodged (IRCT2015012612494N3) No sample size power calculation Trial supported financially by the IRHRC affiliated to Shahid Beheshti Unvirsity of Medical Sciences Tehran No conflicts of interest | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "Of the 6 health centres, 3 were randomly allocated to provide the patients with tranexamic acid and the other 3 were assigned to provide them with mefenamic acid." | | Allocation concealment (selection bias) | Low risk | Different health centre received different drugs | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "Investigators were blinded of the intervention" | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "The questionnaire forms were filled out before the treatment as well as every month for 3 months" Subjective assessment, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "After the 3‐month treatment, 57 subjects in the tranexamic acid group and 37 subjects in the mefenamic acid group had completed the study and statistical analysis was done on all 94 cases" | | Selective reporting (reporting bias) | Low risk | Outcomes listed were reported | | Other bias | Low risk | Quote: "The number of women who referred to the first 3 health centres (tranexamic acid group) and were eligible to participate in the study was incidentally higher compared to the other 3 health centres" Comment: no statistically significant baseline differences | Sordal 2013. | Study characteristics | || | Methods | Double‐blind, 3‐arm, randomized placebo‐controlled, phase IV trial | | | Participants | 187 women aged 18‐45 years old Setting: 12 trial centres in Denmark, Ireland, and Norway Type of IUD: LNG IUD Trial duration: March‐December 2011 Inclusion criteria: healthy women aged 18–45 years requesting contraception and who had a history of regular, cyclic menstrual cycles (cycle length 21–35 days) without use of hormonal contraceptives, normal or clinically insignificant cervical smear not requiring further follow‐up Exclusion criteria: pregnant or breastfeeding, had not had at least 2 complete menstrual cycles after removal of a previous LNG IUD, had a vaginal or cesarean delivery or abortion within 6 weeks of initial screening, had an infected abortion or postpartum endometritis within 90 days of screening, had been indicated for treatment of idiopathic HMB or had a history of abnormal bleeding, had any pelvic, genital, or gynaecologic abnormalities, had any malignancy or severe hypertension, or had used long‐acting contraceptive methods within 90 days of screening, daily or frequent NSAID use for any condition or those unwilling to use non‐NSAIDs (e.g. paracetamol) for pain management | | | Interventions | Treatment arms:oral tranexamic acid (500 mg) mefenamic acid (500 mg), placebo (lactose and magnesium stearate) 1 capsule 3 times/day, on the first day of a bleeding or spotting episode until bleeding or spotting stopped Duration: 90 days | | | Outcomes | Number of bleeding/spotting days, satisfaction with drug/placebo, occurrence of pain, number of days pain medication used to alleviate pain, adverse effects Women recorded vaginal bleeding, study drug intake and use of pain medication on diary cards | | | Notes | Protocol published (NCT01295294) Sample size power calculation provided Funded by Bayer Healthcare, Berlin, Germany Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "..were randomised 1:1:1 to treatment.." "Randomization was performed in a sequential manner in blocks of six using a SAS‐generated randomisation list prepared by the study sponsor" | | Allocation concealment (selection bias) | Unclear risk | No details on how allocation was concealed | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quadruple blinding (participant, care provider, investigator, outcomes assessor) | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quadruple blinding (participant, care provider, investigator, outcomes assessor) however subjective assessment of pain by participants | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Those lost to follow‐up not analysed Intention to treat used for adverse effects | | Selective reporting (reporting bias) | Low risk | Outcomes listed were reported. Protocol published | | Other bias | Low risk | Appears free from other sources of bias | Warner 2010. | Study characteristics | || | Methods | Double‐blind, placebo‐controlled RCT | | | Participants | 136 women, aged 19‐49 years old Location/setting: family planning clinic in the UK Type of IUD: LNG IUD Inclusion criteria: those attending a large family planning clinic and initiating use of an LNG IUD for contraception, regular menstrual cycles lasting 17–42 days, menstrual periods lasting < 11 days, and no contraindications to LNG IUD insertion Exclusion criteria: breastfeeding, within 3 months of childbirth, or with a chronic medical or psychiatric condition, gynaecological disorders (including fibroids, ovarian cysts or unexplained irregular vaginal bleeding) or on long‐term medication | | | Interventions | Oral CDB‐2914 (50 mg/day) vs placebo, 3 consecutive days with separate treatments starting 21, 49 and 77 days after LNG IUD insertion | | | Outcomes | Amount of bleeding/spotting after treatment, removal of LNG IUD within 6 months; the longest run of amenorrhoea in the 64 days after third treatment, side effects Participants kept daily records and filled in questionnaires | | | Notes | Protocol published (ISRCTN Trial no. ISRCTN58283041) Sample size power calculation provided Trial funded by the National Institute of Child Health and Human Development. Drug provided by HRA Pharma, France Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "randomised (1:1 in blocks of 20), and numbered sequentially, so that randomisation was achieved by dispensing packs in numeric order" | | Allocation concealment (selection bias) | Low risk | Quote: "...were packaged to look identical by HRA Pharma," | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "The trial was randomised, double‐blind and placebo‐controlled.." No details on who was blinded | | Blinding of outcome assessment (detection bias) All outcomes | High risk | No details on blinding of outcome assessors Subjective outcome, self‐reported by participants in questionnaires | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Final analysis only excluded those lost to follow‐up/withdrew | | Selective reporting (reporting bias) | Low risk | Outcomes listed and published in protocol reported | | Other bias | Low risk | Trial appears free from other sources of bias | Yavarikia 2013. | Study characteristics | || | Methods | Double‐blinded RCT | | | Participants | 84 women aged 15‐40 years old Setting: Shohadaye Fardis Health Medical Center, Iran Type of IUD: unknown IUD type Inclusion criteria: lack of medicine sensitivity or allergy, within 3 months of placing the IUD, IUD‐induced bleeding, not having constraints for using mefenamic acid (peptic ulcer and allergy to this medicine), willingness to participate in the trial, having minimal literacy, being younger than 40, no genital tract infections, and gaining a minimum score of 100 in Higham chart | | | Interventions | Oral mefenamic acid 250 mg vs Vitex agnus, 3 times/day from the first day of menstruation until day 8 Duration: 4 months | | | Outcomes | Mean bleed score via PBAC Participants recorded PBAC score on charts | | | Notes | No protocol lodged Sample size power calculation provided Funded by Deputy of Tabriz University of Medical Sciences No conflicts of interest | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "The random allocation of individuals in groups was done by computer random number table with random blocks of 4 and 6." | | Allocation concealment (selection bias) | Low risk | Quote: "Each participant was given a sealed envelope (all the envelopes had similar appearance)" "the vitex agnus capsule was similar to the mefenamic acid in colour and size.." | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "The researcher and the patients were not aware of the medication allocation in any groups" | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Participants bleeding were assessed by the researcher" "The reason for giving them the same pads was for having the same assessment of the bleeding amount" | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Lost data not included in analysis | | Selective reporting (reporting bias) | Unclear risk | Outcome listed reported. No protocol lodged | | Other bias | Low risk | Trial appears free from other sources of bias | Ylikorkala 1978. | Study characteristics | || | Methods | RCT with blinding of participants and investigators | | | Participants | 160 women of unspecified ages requesting insertion of a Cu T200 IUD Location/setting: Finland Type of IUD: Cu IUD Inclusion criteria: normal history and physical examination | | | Interventions | Tolfenamic acid 600 mg/day starting at IUD insertion and continuing for 7 days; this was to be repeated during the next 3 menstruations. Placebo given in same regimen Duration: 3 cycles | | | Outcomes | Subjective reports of pain and bleeding patterns (more abundant, clots), number of pads used Women filled in questionnaires | | | Notes | No protocol published Sample size calculation not provided Trial funded by Yrjo Jahnson Foundation and drugs were courtesy of Medica Ltd, Finland Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Low risk | Quote: "Each women was given a code numbered package..." | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No details on who was blinded | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "The patient filled in the form and posted it to the investigators" Comment: subjective outcome, self‐reported by participants | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No details | | Selective reporting (reporting bias) | Unclear risk | Outcome listed reported. No protocol lodged | | Other bias | Low risk | Trial appears to be free from other sources of bias | Ylikorkala 1983. | Study characteristics | || | Methods | RCT with blinding and cross‐over | | | Participants | 19 women aged 25‐44 years (18 were using a Cu IUD and 1 a non‐medicated device) Location/setting: Finland Type of IUD: Cu IUD Inclusion criteria: measured mean MBL > 70 mL with normal pelvic and general physical examinations | | | Interventions | Tranexamic acid 4.5 g/day for 5 days vs sodium diclofenac 150 mg on day 1 then 75 mg/day on days 2 through 4 vs placebo Each participant received placebo for 1 month, 2 months of tranexamic acid, and 2 months of sodium diclofenac Duration: 5 months | | | Outcomes | MBL (alkaline hematin) and duration of bleeding Women collected sanitary pads/ tampons to be assessed via alkaline hematin method. | | | Notes | No protocol published No sample size calculation provided Pads were donated by Molnlycke Co and trial was supported by Medical Research Council, Finland Conflicts of interest not declared | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | Quote: "Because the tranexamic acid and diclofenac tablets were different in size and shape, the patients were always given the diclofenac, placebo together with the active tranexamic acid tablets and vice versa to achieve the double‐blind nature of the trial" | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "Because the tranexamic acid and diclofenac tablets were different in size and shape, the patients were always given the diclofenac, placebo together with the active tranexamic acid tablets and vice versa to achieve the double‐blind nature of the trial" No other details on who was blinded | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Quote: "recorded their symptoms and opinions on special questionnaires, which were filled in during pretreatment and each treated period" "Daily blood loss was measured as described by Hallberg & Nilsson (1964)" Comment: subjective outcome, self‐reported by participants. MBL assessed by alkaline hematin method. No details on blinding of outcome assessors | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "Thus, the final assessment was made in 19 women..." | | Selective reporting (reporting bias) | Unclear risk | Outcomes listed reported. No protocol published | | Other bias | Low risk | Cross‐over design but no carry‐over effect seen | Cu IUD: copper intrauterine device; DMPA: depot‐medroxyprogesterone acetate; HMB: heavy menstrual bleeding; IUD: intrauterine device; LNG IUD: levonorgestrel intrauterine device MBL: menstrual blood loss; NSAIDs: non‐steroidal anti‐inflammatory drugs; PBAC: pictorial blood loss assessment chart; RCT: randomized controlled trial Characteristics of excluded studies [ordered by study ID] | Study | Reason for exclusion | |---|---| | Abbas 2018 | Examined pain and bleeding 5 minutes after IUD insertion | | Baldwin 2016 | Examined effect of timing of IUD placement with greater use at 3 months post partum. Outcome reported was pain during insertion | | Batar 1978 | Not a RCT | | Dreher 1980 | Not a RCT | | Grunloh 2013 | Not a RCT | | Guillebaud 1978 | Before‐after trial | | Hidalgo 2002 | Not a RCT | | Lal 2010 | Not a RCT | | Tavakolian 2015 | Trial examined pain during insertion | | Toppozoda 1987 | Not a RCT | | Van der Heijden 2017 | Trial only reported outcome on pain during insertion | IUD: intrauterine device; RCT: randomized controlled trial Characteristics of studies awaiting classification [ordered by study ID] Bayer 2013. | Methods | Prospective, double‐blind, 3‐arm comparative, randomized, placebo‐controlled phase IV trial | | Participants | 204 women aged 18‐45 years old Location/setting: 6 recruiting trial centres in Denmark, 3 in Ireland, and 3 in Norway Inclusion criteria: fertile healthy women aged 18‐45 years inclusive, who planned to have insertion of the LNG IUD for contraception. Interval insertion (within 7 days of the onset of menstruation/withdrawal bleeding). Regular menstrual cycles (length of cycle 21‐35 days) Exclusion criteria: pregnancy or lactation, climacteric symptoms prior to the screening visit, known or suspected clinically significant ovarian cysts, endometrial polyps, fibroids, or other genital organ pathology, that, in the opinion of the investigator, may interfere with the assessment of the bleeding profile during the trial, undiagnosed abnormal genital bleeding, current or history of thromboembolic disease, or established risk factors for venous thromboembolism, current migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischaemia, or exceptionally severe headaches, hypersensitivity to any ingredient of the investigational medicinal products or the non‐investigational medicinal product, daily or frequent use of NSAIDs for any condition and not willing to use NSAIDs medication as pain medication during the double‐blind treatment period | | Interventions | Treatment arms:oral tranexamic acid 500 mg 3 times daily during bleeding/spotting episodes oral mefenamic acid 500 mg 3 times daily during bleeding/spotting episodes oral placebo 3 times daily during bleeding/spotting episodes Duration: 90 days treatment period, 30 days follow‐up period | | Outcomes | Primary outcome: cumulative number of bleeding/spotting days Secondary outcome: bleeding patterns, satisfaction, occurrence of pain, continuation rate with drugs, continuation rate with Mirena, adverse events, number of days of pain medication for pain | | Notes | Results of trial not published | Di Lieto 1987. | Methods | Double‐blind cross‐over trial | | Participants | 28 women using IUD who suffered from increased MBL and pelvic pain. | | Interventions | Suprofen 80 mg/day on day 1, then 60 mg/day vs placebo. Each regimen was started at the first sign of bleeding and continued up for the duration of symptoms or up to 7 days. Each participant had 1 pre‐treatment month, 1 month with suprofen or placebo followed by alternative for the third cycle. | | Outcomes | Reduction in pain and MBL. Methods of measurement not described | | Notes | No full text of publication found, unable to obtain information from investigator | Jensen 1998. | Methods | RCT with 4 treatment groups | | Participants | 55 women having insertion of either a Nova T or Gyne T 380 Slimline IUD Location/setting: a contraception clinic in Denmark Trial duration: May 1994‐May 1995 Inclusion criteria: all Danish‐speaking women in good health who requested an IUD in the investigators' clinic Exclusion criteria: age < 18 years, serious illness, allergy to NSAID or aspirin, and medication of any kind except for oral contraceptives | | Interventions | Ibuprofen 1800 mg in divided doses (before insertion, 4‐6 hours after insertion, and next morning) vs placebo The type of IUD to be inserted was randomly chosen | | Outcomes | Pain assessed by a 10‐point scale, administered during insertion, 4‐6 hours after insertion, and again during the first 3 days | | Notes | No full text of publication found, unable to obtain information from investigator | Massey 1974. | Methods | | | Participants | | | Interventions | | | Outcomes | | | Notes | No abstract or full text of publication found. Unable to obtain information from investigator | Toppozada 1982. | Methods | Single‐blind RCT with cross‐over | | Participants | 18 parous women, aged 20‐35 years using a Cu IUD Location/setting: Egypt Inclusion criteria: regular menstruation and haemoglobin > 12 g% Exclusion criteria: peptic ulcer disease, salpingitis, or "allergic" disease | | Interventions | Treatment arms:indomethacin 100 mg/day flufenamic acid 600 mg/day alclofenac 1500 mg/day placebo Treatment started on the first day of bleeding and was given for 3 days. In each treatment arm, half started on active drug and half on placebo; after 2 months, cross‐over to the alternative occurred. Thus, each participant had 2 months on the assigned NSAID and 2 months on placebo. Duration: 4 months | | Outcomes | MBL measured by alkaline hematin method | | Notes | No full text of publication found. Unable to obtain information from investigator | Wang 2013. | Methods | RCT, uncertain of blinding | | Participants | 2004, women of child‐bearing age requiring IUD for contraception Location/setting: outpatient departments of China‐Japan Friendship Hospital of Jilin University, Peking University First Hospital, Peking University Third Hospital, Jilin University Second Hospital and Affiliated Shengjing Hospital of China Medical University | | Interventions | MyCuIUD containing indomethacin vs TCu380A IUD Followed up at 1, 3, 6, 12, 24, 36, 48 and 60 months post‐insertion | | Outcomes | Cumulative pregnancy rate, expulsion rate, termination due to bleeding/pain, side effects | | Notes | No full text of publication found. Unable to obtain information from investigator | Wu 2000. | Methods | RCT, uncertain of blinding | | Participants | 180 parous women Location/setting: China Inclusion criteria: complaints of heavy or prolonged menstruation (> 7 days), good general health, Cu IUD for at least 6 months Exclusion criteria: haemorrhagic illness or leiomyomas, unwillingness to avoid other medicines, and unwillingness to maintain a menstrual diary | | Interventions | Indomethacin 50 mg daily in divided doses for 7 days, starting on the first day of menstruation vs baofuxin (a traditional Chinese medicine containing tangshen, radix astragali seu hedysari, ass‐hide asafetida, hairyvein agrimonia herb, Indian madder root and other ingredients in a granular compound). The 8 g bag was dissolved in hot water and drunk twice daily for 10 days, starting on the first day of menstruation. Duration: 3 cycles | | Outcomes | Menstrual patterns as determined by diaries. Menstrual diaries were maintained for 90 days before, 3 menstrual cycles of treatment, and 90 days after stopping treatment. | | Notes | No full text of publication found. Unable to obtain information from investigator | Yarkoni 1984. | Methods | RCT with blinding and cross‐over | | Participants | 9 women with Lippes Loop IUD Inclusion criteria: measured MBL of > 100 mL | | Interventions | Indomethacin vs placebo | | Outcomes | MBL, method of measurement not described | | Notes | No full text of publication found. Unable to obtain information from investigator. | Cu IUD: copper intrauterine device; IUD: intrauterine device; LNG IUD: levonorgestrel intrauterine device; MBL: menstrual blood loss; NSAIDs: non‐steroidal anti‐inflammatory drugs; Differences between protocol and review This review focuses on interventions to prevent or treat heavy menstrual bleeding or pain associated with intrauterine device use whereas the original protocol focused only on non‐steroidal anti‐inflammatory drugs. Intervention: included any intervention used for the treatment or prevention of heavy/painful menstruation associated with IUD use Outcomes: duration of menstruation was included in the primary outcome instead of secondary outcome as we felt that it was an important finding which correlated to the volume of bleeding. Contributions of authors Karen Christelle drafted the protocol, assisted with the literature search, performed an independent data extraction and wrote the review. Norhayati Mohd Noor registered the topic, edited the protocol, performed an independent data extraction and helped write the review. Sharifah Halimah Jaafar edited the protocol and helped write the review. Sources of support Internal sources - Universiti Sains Malaysia, Malaysia Provision of subscribed databases External sources National Institute of Child Health and Human Development, USA Declarations of interest Karen Christelle: none known Mohd N Norhayati: none known Sharifah Halimah Jaafar: none known New search for studies and content updated (conclusions changed)

References to studies included in this review Alanwar 2018 {published data only} - Alanwar A, Abbas AM, Hussain SH, Elhawwary G, Mansour DY, Faisal MM, et al. Oral micronised flavonoids versus tranexamic acid for treatment of heavy menstrual bleeding secondary to copper IUD use: a randomised double-blind clinical trial. European Journal of Contraception & Reproductive Health Care 2018;23(5):365-70. [PMID: ] [DOI] [PubMed] [Google Scholar] Buttram 1979 {published data only} - Buttram V, Izu A, Henzl MR. Naproxen sodium in uterine pain following intrauterine contraceptive device insertion. American Journal of Obstetrics and Gynecology 1979;134:575-8. [DOI] [PubMed] [Google Scholar] Davies 1981 {published data only} - Davies AJ, Anderson AB, Turnbull AC. Reduction by naproxen of excessive menstrual bleeding in women using intrauterine devices. Obstetrics and Gynecology 1981;57:74-8. 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