Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a very common condition in women of reproductive age, affecting 2 to 5 of every 10 women. Diverse treatments, either medical (hormonal or non-hormonal) or surgical, are currently available for HMB, with different effectiveness, acceptability, costs and side effects. The best treatment will depend on the woman's age, her intention to become pregnant, the presence of other symptoms, and her personal views and preferences. OBJECTIVES: To identify, systematically assess and summarise all evidence from studies included in Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), using reviews with comparable participants and outcomes; and to present a ranking of the first- and second-line treatments for HMB. METHODS: We searched for published Cochrane Reviews of HMB interventions in the Cochrane Database of Systematic Reviews. The primary outcomes were menstrual bleeding and satisfaction. Secondary outcomes included quality of life, adverse events and the requirement of further treatment. Two review authors independently selected the systematic reviews, extracted data and assessed quality, resolving disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool and evaluated the certainty of the evidence for each outcome using GRADE methods. We grouped the interventions into first- and second-line treatments, considering participant characteristics (desire for future pregnancy, failure of previous treatment, candidacy for surgery). First-line treatments included medical interventions, and second-line treatments included both the levonorgestrel-releasing intrauterine system (LNG-IUS) and surgical treatments; thus the LNG-IUS is included in both groups. We developed different networks for first- and second-line treatments. We performed network meta-analyses of all outcomes, except for quality of life, where we performed pairwise meta-analyses. We reported the mean rank, the network estimates for mean difference (MD) or odds ratio (OR), with 95% confidence intervals (CIs), and the certainty of evidence (moderate, low or very low certainty). We also analysed different endometrial ablation and resection techniques separately from the main network: transcervical endometrial resection (TCRE) with or without rollerball, other resectoscopic endometrial ablation (REA), microwave non-resectoscopic endometrial ablation (NREA), hydrothermal ablation NREA, bipolar NREA, balloon NREA and other NREA. MAIN RESULTS: We included nine systematic reviews published in the Cochrane Library up to July 2021. We updated the reviews that were over two years old. In July 2020, we started the overview with no new reviews about the topic. The included medical interventions were: non-steroidal anti-inflammatory drugs (NSAIDs), antifibrinolytics (tranexamic acid), combined oral contraceptives (COC), combined vaginal ring (CVR), long-cycle and luteal oral progestogens, LNG-IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecified endometrial ablation (EA) and LNG-IUS. We grouped the interventions as follows. First-line treatments Evidence from 26 studies with 1770 participants suggests that LNG-IUS results in a large reduction of menstrual blood loss (MBL; mean rank 2.4, MD -105.71 mL/cycle, 95% CI -201.10 to -10.33; low certainty evidence); antifibrinolytics probably reduce MBL (mean rank 3.7, MD -80.32 mL/cycle, 95% CI -127.67 to -32.98; moderate certainty evidence); long-cycle progestogen reduces MBL (mean rank 4.1, MD -76.93 mL/cycle, 95% CI -153.82 to -0.05; low certainty evidence), and NSAIDs slightly reduce MBL (mean rank 6.4, MD -40.67 mL/cycle, -84.61 to 3.27; low certainty evidence; reference comparator mean rank 8.9). We are uncertain of the true effect of the remaining interventions and the sensitivity analysis for reduction of MBL, as the evidence was rated as very low certainty. We are uncertain of the true effect of any intervention (very low certainty evidence) on the perception of improvement and satisfaction. Second-line treatments Bleeding reduction is related to the type of hysterectomy (total or supracervical/subtotal), not the route, so we combined all routes of hysterectomy for bleeding outcomes. We assessed the reduction of MBL without imputed data (11 trials, 1790 participants) and with imputed data (15 trials, 2241 participants). Evidence without imputed data suggests that hysterectomy (mean rank 1.2, OR 25.71, 95% CI 1.50 to 439.96; low certainty evidence) and REA (mean rank 2.8, OR 2.70, 95% CI 1.29 to 5.66; low certainty evidence) result in a large reduction of MBL, and NREA probably results in a large reduction of MBL (mean rank 2.0, OR 3.32, 95% CI 1.53 to 7.23; moderate certainty evidence). Evidence with imputed data suggests hysterectomy results in a large reduction of MBL (mean rank 1.0, OR 14.31, 95% CI 2.99 to 68.56; low certainty evidence), and NREA probably results in a large reduction of MBL (mean rank 2.2, OR 2.87, 95% CI 1.29 to 6.05; moderate certainty evidence). We are uncertain of the true effect for REA (very low certainty evidence). We are uncertain of the effect on amenorrhoea (very low certainty evidence). Evidence from 27 trials with 4284 participants suggests that minimally invasive hysterectomy results in a large increase in satisfaction (mean rank 1.3, OR 7.96, 95% CI 3.33 to 19.03; low certainty evidence), and NREA also increases satisfaction (mean rank 3.6, OR 1.59, 95% CI 1.09 to 2.33; low certainty evidence), but we are uncertain of the true effect of the remaining interventions (very low certainty evidence). AUTHORS' CONCLUSIONS: Evidence suggests LNG-IUS is the best first-line treatment for reducing menstrual blood loss (MBL); antifibrinolytics are probably the second best, and long-cycle progestogens are likely the third best. We cannot make conclusions about the effect of first-line treatments on perception of improvement and satisfaction, as evidence was rated as very low certainty. For second-line treatments, evidence suggests hysterectomy is the best treatment for reducing bleeding, followed by REA and NREA. We are uncertain of the effect on amenorrhoea, as evidence was rated as very low certainty. Minimally invasive hysterectomy may result in a large increase in satisfaction, and NREA also increases satisfaction, but we are uncertain of the true effect of the remaining second-line interventions, as evidence was rated as very low certainty.

Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is common in otherwise healthy women of reproductive age, and can affect physical health and quality of life. Surgery is usually a second-line treatment of HMB. Endometrial resection/ablation (EA/ER) to remove or ablate the endometrium is less invasive than hysterectomy. Hysterectomy is the definitive treatment and can be via open (laparotomy) approach, or via minimally invasive approaches (vaginally or laparoscopically). Each approach has its own advantages and risk profile. OBJECTIVES: To compare the effectiveness, acceptability and safety of endometrial resection or ablation versus different routes of hysterectomy (open, minimally invasive hysterectomy, or unspecified route) for the treatment of HMB. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility specialised register, CENTRAL, MEDLINE, Embase and PsycINFO (July 2020), and reference lists, grey literature and trial registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared techniques of endometrial resection/ablation with hysterectomy (by any technique) for the treatment of HMB in premenopausal women. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 10 RCTs (1966 participants) comparing EA/ER to hysterectomy (open (abdominal), minimally invasive (laparoscopic or vaginal), or unspecified (or at surgeon's discretion) route of hysterectomy). The results were rated as moderate-, low- and very low-certainty evidence. Endometrial resection/ablation versus open hysterectomy We found two trials. Women having EA/ER are probably less likely to perceive an improvement in HMB compared to women having open hysterectomy (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.84 to 0.95; 2 studies, 247 women; moderate-certainty evidence) and probably have a 13% risk of requiring further surgery for treatment failure (compared to 0 on the open hysterectomy group; 2 studies, 247 women; moderate-certainty evidence). Both treatments probably lead to similar quality of life at two years (mean difference (MD) -5.30, 95% CI -11.90 to 1.30; 1 study, 155 women; moderate-certainty evidence) and satisfaction rate at one year (RR 0.91, 95% CI 0.82 to 1.00; 1 study, 194 women; moderate-certainty evidence). There may be no difference in serious adverse events (RR 1.29, 95% CI 0.32 to 5.20; 2 studies, 247 women; low-certainty evidence). EA/ER probably reduces time to return to normal activity compared to open hysterectomy (MD -21.00 days, 95% CI -24.78 to -17.22; 1 study, 197 women; moderate-certainty evidence). Endometrial resection/ablation versus minimally invasive hysterectomy We found five trials. The proportion of women with perception of improvement in HMB at two years may be similar between groups (RR 0.97, 95% CI 0.90 to 1.04; 1 study, 79 women; low-certainty evidence). Blood loss may be higher in the EA/ER group when assessed using the Pictorial Blood Assessment Chart (MD 44.00, 95% CI 36.09 to 51.91; 1 study, 68 women; low-certainty evidence). Quality of life is probably lower in the EA/ER group compared to the minimally invasive hysterectomy group at two years according to the 36-item Short Form (SF-36) (MD -10.71, 95% CI -15.11 to -6.30; 2 studies, 145 women; moderate-certainty evidence) and Menorrhagia Multi-Attribute Scale (RR 0.82, 95% CI 0.70 to 0.95; 1 study, 616 women; moderate-certainty evidence). EA/ER probably increases the risk of further surgery for HMB compared to minimally invasive hysterectomy (RR 7.70, 95% CI 2.54 to 23.32; 4 studies, 922 women; moderate-certainty evidence) and treatments probably have similar rates of any serious adverse events (RR 0.75, 95% CI 0.35 to 1.59; 4 studies, 809 women; moderate-certainty evidence). Women with EA/ER are probably less likely to be satisfied with treatment at one year (RR 0.90, 95% CI 0.85 to 0.94; 1 study, 558 women; moderate-certainty evidence). We were unable to pool data for time to return to work or normal life because of extreme heterogeneity (99%); however, the three studies reporting this all had the same direction of effect favouring EA/ER. Endometrial resection/ablation versus unspecified route of hysterectomy We found three trials. EA/ER may lead to a lower perception of improvement in HMB compared to unspecified route of hysterectomy (RR 0.89, 95% CI 0.83 to 0.95; 2 studies, 403 women; low-certainty evidence). Although EA/ER may lead to similar quality of life using the SF-36 General Health Perception at two years' follow-up (MD -1.90, 95% CI -8.67 to 4.87; 1 study, 209 women; low-certainty evidence), the proportion of women with improvement in general health at one year may be lower (RR 0.85, 95% CI 0.77 to 0.95; 1 study, 185 women; low-certainty evidence). EA/ER probably has a risk of 5.4% of requiring further surgery for treatment failure (compared to 0 with total hysterectomy; 2 studies, 374 women; moderate-certainty evidence) and reduces the proportion of women with any serious adverse event (RR 0.21, 95% CI 0.06 to 0.80; 2 studies, 374 women; moderate-certainty evidence). Both treatments probably lead to a similar satisfaction rate at one year' follow-up (RR 0.96, 95% CI 0.88 to 1.04; 3 studies, 545 women; moderate-certainty evidence). EA/ER may lead to shorter time to return to normal activity (MD -18.90 days, 95% CI -24.63 to -13.17; 1 study, 172 women; low-certainty evidence). AUTHORS' CONCLUSIONS: Endometrial resection/ablation (EA/ER) offers an alternative to hysterectomy as a surgical treatment for HMB. Effectiveness varies with EA/ER compared to different hysterectomy approaches. The perception of improvement in HMB with EA/ER is probably lower compared to open and unspecified route of hysterectomy, but may be similar compared to minimally invasive. Quality of life with EA/ER is probably similar to open and unspecified route of hysterectomy, but lower compared to minimally invasive hysterectomy. Further surgery for treatment failure is probably more likely with EA/ER compared to all routes of hysterectomy. Satisfaction rates also vary. EA/ER probably has a similar rate of satisfaction compared to open and unspecified route of hysterectomy, but a lower rate of satisfaction compared to minimally invasive hysterectomy. The proportion having any serious adverse event appears similar in all groups, but specific adverse events did reported difference between EA/ER and different routes. We were unable to draw conclusions about the time to return to normal activity, but the direction of effect suggests it is likely to be shorter with EA/ER.

Interventions commonly available during pandemics for heavy menstrual bleeding: an overview of Cochrane Reviews.

BACKGROUND: Within the context of heavy menstrual bleeding, pandemics impact upon women's assessment and treatment by healthcare providers. OBJECTIVES: To summarise the evidence from Cochrane Reviews evaluating interventions for heavy menstrual bleeding that are commonly available during pandemics. METHODS: We sought published Cochrane Reviews, evaluating interventions that can continue during pandemics for women with heavy menstrual bleeding with no known underlying cause. We identified Cochrane Reviews by searching the Cochrane Database of Systematic Reviews in June 2020. The primary outcome was menstrual bleeding. Secondary outcomes included quality of life, patient satisfaction, side effects, and serious adverse events. We undertook the selection of systematic reviews, data extraction, and quality assessment in duplicate. We resolved any disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool, and the certainty of the evidence for each outcome using GRADE methods. MAIN RESULTS: We included four Cochrane Reviews, with 11 comparisons, data from 44 randomised controlled trials (RCTs), and 3196 women. We assessed all the reviews to be high quality. Non-steroidal anti-inflammatory drugs (NSAIDs) NSAIDs may be more effective in reducing heavy menstrual bleeding than placebo (mean difference (MD) -124 mL per cycle, 95% confidence interval (CI) -186 to -62 mL per cycle; 1 RCT, 11 women; low-certainty evidence). Mefenamic acid may be similar to naproxen (MD 21 mL per cycle, 95% CI -6 to 48 mL per cycle; 2 RCTs, 61 women; low-certainty evidence), and NSAIDs may be similar to combined hormonal contraceptives for heavy menstrual bleeding (MD 25 mL per cycle, 95% CI -22 to 73 mL per cycle; 1 RCT, 26 women; low-certainty evidence). NSAIDs may be be less effective in reducing menstrual bleeding than antifibrinolytics (relative risk (RR) 0.70, 95% CI 0.58 to 0.85; 2 RCTs, 161 women; low-certainty evidence). We are uncertain whether NSAIDs reduce menstrual blood loss more than short-cycle progestogens (RR 0.80, 95% CI 0.49 to 1.32; 1 RCT 32 women; very low-certainty evidence). Antifibrinolytics Antifibrinolytics appear to be more effective in reducing heavy menstrual bleeding than placebo (MD -53 mL per cycle, 95% CI -63 to -44 mL per cycle; 4 RCTs, 565 women; moderate-certainty evidence). Antifibrinolytics may be similar to placebo on the incidence of side effects (RR 1.05, 95% CI 0.93 to 1.18; 1 RCT, 297 women; low-certainty evidence), and they are probably similar on the incidence of serious adverse events (thrombotic events; RR 0.10, 95% CI 0.00 to 2.46; 2 RCT, 468 women; moderate-certainty evidence). Antifibrinolytics may be more effective in reducing heavy menstrual bleeding than short-cycle progestogen (MD -111 mL per cycle, 95% CI -178 mL to -44 mL per cycle; 1 RCT, 46 women; low-certainty evidence). We are uncertain whether antifibrinolytics are similar to short-cycle progestogens on quality of life (RR 1.67, 95% CI 0.76 to 3.64; 1 RCT, 44 women; very low-certainty evidence), patient satisfaction (RR 0.91, 95% CI 0.59 to 1.39; 1 RCT, 42 women; very low-certainty evidence), or side effects (RR 0.85, 95% CI 0.65 to 1.12; 3 RCTs, 211 women; very low-certainty evidence). We are uncertain whether antifibrinolytics are more effective in reducing heavy menstrual bleeding when compared with long-cycle progestogen (MD -9 points per cycle, 95% CI -30 to 12 points per cycle; 2 RCTs, 184 women; low-certainty evidence). Antifibrinolytics may increase self-reported improvement in menstrual bleeding when compared with long-cycle medroxyprogesterone acetate (RR 1.32, 95% CI 1.08 to 1.61; 1 RCT, 94 women; low-certainty evidence). Antifibrinolytics may be similar to long-cycle progestogens on quality of life (MD 5, 95% CI -2.49 to 12.49; 1 RCT, 90 women; low-certainty evidence). We are uncertain whether antifibrinolytics are similar to long-cycle progestogens on side effects (RR 0.58, 95% CI 0.33 to 1.00; 2 RCTs, 184 women; very low-certainty evidence). There were no trials comparing antifibrinolytics to combined hormonal contraceptives. Combined hormonal contraceptives Combined hormonal contraceptives appear to be more effective for heavy menstrual bleeding than placebo or no treatment (RR 13.25, 95% CI 2.94 to 59.64; 2 RCTs, 363 women; moderate-certainty evidence). Combined hormonal contraceptives are probably similar to placebo on the incidence of side effects (RR 1.53, 95% CI 0.90 to 2.60; 2 RCTs, 411 women; moderate-certainty evidence). Progestogens There were no trials comparing progestogens to placebo. Limitations in the evidence included risk of bias in the primary RCTs, inconsistency between the primary RCTs, and imprecision in effect estimates. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that antifibrinolytics and combined hormonal contraceptives reduce heavy menstrual bleeding compared with placebo. There is low-certainty evidence that NSAIDs reduce heavy menstrual bleeding compared with placebo. There is low-certainty evidence that antifibrinolytics are more effective in reducing heavy menstrual bleeding when compared with NSAIDs and short-cycle progestogens, but we are unable to draw conclusions about the effects of antifibrinolytics compared to long-cycle progestogens, on low-certainty evidence.

Progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) impacts the quality of life of otherwise healthy women. The perception of HMB is subjective and management depends upon, among other factors, the severity of the symptoms, a woman's age, her wish to get pregnant, and the presence of other pathologies. Heavy menstrual bleeding was classically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. Currently the definition is based on the woman's perception of excessive bleeding which is affecting her quality of life. The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss: users of the levonorgestrel-releasing intrauterine system (LNG-IUS) reported reductions of up to 90%. Insertion may, however, be regarded as invasive by some women, which affects its acceptability. OBJECTIVES: To determine the effectiveness, acceptability and safety of progestogen-releasing intrauterine devices in reducing heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL (from inception to June 2019); and we searched grey literature and for unpublished trials in trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in women of reproductive age treated with LNG-IUS devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the certainty of evidence. MAIN RESULTS: We included 25 RCTs (2511 women). Limitations in the evidence included risk of attrition bias and low numbers of participants. The studies compared the following interventions. LNG-IUS versus other medical therapy The other medical therapies were norethisterone acetate, medroxyprogesterone acetate, oral contraceptive pill, mefenamic acid, tranexamic acid or usual medical treatment (where participants could choose the oral treatment that was most suitable). The LNG-IUS may improve HMB, lowering menstrual blood loss according to the alkaline haematin method (mean difference (MD) 66.91 mL, 95% confidence interval (CI) 42.61 to 91.20; 2 studies, 170 women; low-certainty evidence); and the Pictorial Bleeding Assessment Chart (MD 55.05, 95% CI 27.83 to 82.28; 3 studies, 335 women; low-certainty evidence). We are uncertain whether the LNG-IUS may have any effect on women's satisfaction up to one year (RR 1.28, 95% CI 1.01 to 1.63; 3 studies, 141 women; I² = 0%, very low-certainty evidence). The LNG-IUS probably leads to slightly higher quality of life measured with the SF-36 compared with other medical therapy if (MD 2.90, 95% CI 0.06 to 5.74; 1 study: 571 women; moderate-certainty evidence) or with the Menorrhagia Multi-Attribute Scale (MD 13.40, 95% CI 9.89 to 16.91; 1 trial, 571 women; moderate-certainty evidence). The LNG-IUS and other medical therapies probably give rise to similar numbers of women with serious adverse events (RR 0.91, 95% CI 0.63 to 1.30; 1 study, 571 women; moderate-certainty evidence). Women using other medical therapy are probably more likely to withdraw from treatment for any reason (RR 0.49, 95% CI 0.39 to 0.60; 1 study, 571 women, moderate-certainty evidence) and to experience treatment failure than women with LNG-IUS (RR 0.34, 95% CI 0.26 to 0.44; 6 studies, 535 women; moderate-certainty evidence). LNG-IUS versus endometrial resection or ablation (EA) Bleeding outcome results are inconsistent. We are uncertain of the effect of the LNG-IUS compared to EA on rates of amenorrhoea (RR 1.21, 95% CI 0.85 to 1.72; 8 studies, 431 women; I² = 21%; low-certainty evidence) and hypomenorrhoea (RR 0.98, 95% CI 0.73 to 1.33; 4 studies, 200 women; low-certainty evidence) and eumenorrhoea (RR 0.55, 95% CI 0.30 to 1.00; 3 studies, 160 women; very low-certainty evidence). We are uncertain whether both treatments may have similar rates of satisfaction with treatment at 12 months (RR 0.95, 95% CI 0.85 to 1.07; 5 studies, 317 women; low-certainty evidence). We are uncertain if the LNG-IUS compared to EA has any effect on quality of life, measured with SF-36 (MD -14.40, 95% CI -22.63 to -6.17; 1 study, 33 women; very low-certainty evidence). Women with the LNG-IUS compared with EA are probably more likely to have any adverse event (RR 2.06, 95% CI 1.44 to 2.94; 3 studies, 201 women; moderate-certainty evidence). Women with the LNG-IUS may experience more treatment failure compared to EA at one year follow up (persistent HMB or requirement of additional treatment) (RR 1.78, 95% CI 1.09 to 2.90; 5 studies, 320 women; low-certainty evidence); or requirement of hysterectomy may be higher at one year follow up (RR 2.56, 95% CI 1.48 to 4.42; 3 studies, 400 women; low-certainty evidence). LNG-IUS versus hysterectomy We are uncertain whether the LNG-IUS has any effect on HMB compared with hysterectomy (RR for amenorrhoea 0.52, 95% CI 0.39 to 0.70; 1 study, 75 women; very low-certainty evidence). We are uncertain whether there is difference between LNG-IUS and hysterectomy in satisfaction at five years (RR 1.01, 95% CI 0.94 to 1.08; 1 study, 232 women; low-certainty evidence) and quality of life (SF-36 MD 2.20, 95% CI -2.93 to 7.33; 1 study, 221 women; low-certainty evidence). Women in the LNG-IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1-year follow-up compared to the hysterectomy group (RR 48.18, 95% CI 2.96 to 783.22; 1 study, 236 women; low-certainty evidence). None of the studies reported cost data suitable for meta-analysis. AUTHORS' CONCLUSIONS: The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA.

Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. OBJECTIVES: To determine the effectiveness, safety and tolerability of NSAIDs in achieving a reduction in menstrual blood loss (MBL) in women of reproductive years with HMB. SEARCH METHODS: We searched, in April 2019, the Cochrane Gynaecology and Fertility specialised register, Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, the clinical trial registries and reference lists of articles. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of individual NSAIDs or combined with other medical therapy with each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment-induced) causes for their HMB. DATA COLLECTION AND ANALYSIS: We identified 19 randomised controlled trials (RCTs) (759 women) that fulfilled the inclusion criteria for this review and two review authors independently extracted data. We estimated odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes from the data of nine trials. We described in data tables the results of the remaining seven cross-over trials with data unsuitable for pooling, one trial with skewed data, and one trial with missing variances. One trial had no data available for analysis. MAIN RESULTS: As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs, but this did not appear to affect the acceptability of treatment, based on trials from 1980 to 1990. However, currently danazol is not a usual or recommended treatment for HMB. There was no clear evidence of difference between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system and the oral contraceptive pill (OCP), but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. The evidence quality ranged from low to moderate, the main limitations being risk of bias and imprecision. AUTHORS' CONCLUSIONS: NSAIDs reduce HMB when compared with placebo, but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, there was no clear evidence of a difference in efficacy between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCP or the older progesterone-releasing intrauterine system.

Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women of reproductive age, causing them physical problems, social disruption and reducing their quality of life. Medical therapy has traditionally been first-line therapy. Surgical treatment of HMB often follows failed or ineffective medical therapy. The definitive treatment is hysterectomy, but this is a major surgical procedure with significant physical and emotional complications, as well as social and economic costs. Less invasive surgical techniques, such as endometrial resection and ablation, have been developed with the purpose of improving menstrual symptoms by removing or ablating the entire thickness of the endometrium. OBJECTIVES: To compare the effectiveness, acceptability and safety of techniques of endometrial destruction by any means versus hysterectomy by any means for the treatment of heavy menstrual bleeding. SEARCH METHODS: Electronic searches for relevant randomised controlled trials (RCTs) targeted-but were not limited to-the following: the Cochrane Gynaecology and Fertility Group's specialised register, CENTRAL via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, and the ongoing trial registries. We made attempts to identify trials by examining citation lists of review articles and guidelines and by performing handsearching. Searches were performed in 1999, 2007, 2008, 2013 and on 10 December 2018. SELECTION CRITERIA: Any RCTs that compared techniques of endometrial resection or ablation (by any means) with hysterectomy (by any technique) for the treatment of heavy menstrual bleeding in premenopausal women. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed trials for risk of bias. MAIN RESULTS: We identified nine RCTs that fulfilled our inclusion criteria for this review. For two trials, the review authors identified multiple publications that assessed different outcomes at different postoperative time points for the same women. No included trials used third generation techniques.Clinical measures of improved bleeding symptoms and satisfaction rates were observed in women who had undergone hysterectomy compared to endometrial ablation. A slightly lower proportion of women who underwent endometrial ablation perceived improvement in bleeding symptoms at one year (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.85 to 0.93; 4 studies, 650 women, I² = 31%; low-quality evidence), at two years (RR 0.92, 95% CI 0.86 to 0.99; 2 studies, 292 women, I² = 53%) and at four years (RR 0.93, 95% CI 0.88 to 0.99; 2 studies, 237 women, I² = 79%). Women in the endometrial ablation group also showed improvement in pictorial blood loss assessment chart compared to their baseline (PBAC) score at one year (MD 24.40, 95% CI 16.01 to 32.79; 1 study, 68 women; moderate-quality evidence) and at two years (MD 44.00, 95% CI 36.09 to 51.91; 1 study, 68 women). Repeat surgery resulting from failure of the initial treatment was more likely to be needed after endometrial ablation than after hysterectomy at one year (RR 16.17, 95% CI 5.53 to 47.24; 927 women; 7 studies; I2 = 0%), at two years (RR 34.06, 95% CI 9.86 to 117.65; 930 women; 6 studies; I2 = 0%), at three years (RR 22.90, 95% CI 1.42 to 370.26; 172 women; 1 study) and at four years (RR 36.32, 95% CI 5.09 to 259.21;197 women; 1 study). The satisfaction rate was lower amongst those who had endometrial ablation at two years after surgery (RR 0.87, 95% CI 0.80 to 0.95; 4 studies, 567 women, I² = 0%; moderate-quality evidence), and no evidence of clear difference was reported between post-treatment satisfaction rates in groups at other follow-up times (1 and 4 years).Most adverse events, both major and minor, were more likely after hysterectomy during hospital stay. Women who had an endometrial ablation were less likely to experience sepsis (RR 0.19, 95% CI 0.12 to 0.31; participants = 621; studies = 4; I2 = 62%), blood transfusion (RR 0.20, 95% CI 0.07 to 0.59; 791 women; 5 studies; I2 = 0%), pyrexia (RR 0.17, 95% CI 0.09 to 0.35; 605 women; 3 studies; I2 = 66%), vault haematoma (RR 0.11, 95% CI 0.04 to 0.34; 858 women; 5 studies; I2 = 0%) and wound haematoma (RR 0.03, 95% CI 0.00 to 0.53; 202 women; 1 study) before hospital discharge. After discharge from hospital, the only difference that was reported for this group was a higher rate of infection (RR 0.27, 95% CI 0.13 to 0.58; 172 women; 1 study).Recovery time was shorter in the endometrial ablation group, considering hospital stay, time to return to normal activities and time to return to work; we did not, however, pool these data owing to high heterogeneity. Some outcomes (such as a woman's perception of bleeding and proportion of women requiring further surgery for HMB), generated a low GRADE score, suggesting that further research in these areas is likely to change the estimates. AUTHORS' CONCLUSIONS: Endometrial resection and ablation offers an alternative to hysterectomy as a surgical treatment for heavy menstrual bleeding. Both procedures are effective, and satisfaction rates are high. Although hysterectomy offers permanent and immediate relief from heavy menstrual bleeding, it is associated with a longer operating time and recovery period. Hysterectomy also has higher rates of postoperative complications such as sepsis, blood transfusion and haematoma (vault and wound). The initial cost of endometrial destruction is lower than that of hysterectomy but, because retreatment is often necessary, the cost difference narrows over time.

Cyclical progestogens for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is a menstrual blood loss perceived by women as excessive that affects the health of women of reproductive age, interfering with their physical, emotional, social and material quality of life. Whilst abnormal menstrual bleeding may be associated with underlying pathology, in the present context, HMB is defined as excessive menstrual bleeding in the absence of other systemic or gynaecological disease. The first-line therapy is usually medical, avoiding possibly unnecessary surgery. Of the wide variety of medications used to reduce HMB, oral progestogens were originally the most commonly prescribed agents. This review assesses the effectiveness of two different types and regimens of oral progestogens in reducing ovulatory HMB.This is the update of a Cochrane review last updated in 2007, and originally named "Effectiveness of cyclical progestagen therapy in reducing heavy menstrual bleeding" (1998). OBJECTIVES: To determine the effectiveness, safety and tolerability of oral progestogen therapy taken either during the luteal phase (short cycle) or for a longer course of 21 days per cycle (long cycle), in achieving a reduction in menstrual blood loss in women of reproductive age with HMB. SEARCH METHODS: In January 2019 we searched Cochrane Gynaecology and Fertility's specialized register, CENTRAL, MEDLINE, Embase, CINAHL and PsycInfo. We also searched trials registers, other sources of unpublished or grey literature and reference lists of retrieved trials. We also checked citation lists of review articles to identify trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing different treatments for HMB that included cyclical oral progestogens were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias and extracted data. We contacted trial authors for clarification of methods or additional data when necessary. We only assessed adverse events if they were separately measured in the included trials. We compared cyclical oral progestogen in different regimens and placebo or other treatments. Our primary outcomes were menstrual blood loss and satisfaction with treatment; the secondary outcomes were number of days of bleeding, quality of life, compliance and acceptability of treatment, adverse events and costs. MAIN RESULTS: This review identified 15 randomized controlled trials (RCTs) with 1071 women in total. Most of the women knew which treatment they were receiving, which may have influenced their judgements about menstrual blood loss and satisfaction. Other aspects of trial quality varied among trials.We did not identify any RCTs comparing progestogen treatment with placebo. We assessed comparisons between oral progestogens and other medical therapies separately according to different regimens.Short-cycle progestogen therapy during the luteal phase (medroxyprogesterone acetate or norethisterone for 7 to 10 days, from day 15 to 19) was inferior to other medical therapy, including tranexamic acid, danazol and the progestogen-releasing intrauterine system (Pg-IUS (off of the market since 2001)), releasing 60 mcg of progesterone daily, with respect to reduction of menstrual blood loss (mean difference (MD) 37.29, 95% confidence interval (CI) 17.67 to 56.91; I2 = 50%; 6 trials, 145 women). The rate of satisfaction and the quality of life with treatment was similar in both groups. The number of bleeding days was greater on the short cycle progestogen group compared to other medical treatments. Adverse events (such as gastrointestinal symptoms and weight gain) were more likely with danazol when compared with progestogen treatment. We note that danazol is no longer in general use for treating HMB.Long-cycle progestogen therapy (medroxyprogesterone acetate or norethisterone), from day 5 to day 26 of the menstrual cycle, is also inferior to the levonorgestrel-releasing intrauterine system (LNG-IUS), releasing tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss (MD 16.88, 95% CI 10.93 to 22.84; I2 = 87%; 4 trials, 355 women). A higher proportion of women taking norethisterone found their treatment unacceptable compared to women having Pg-IUS (Peto odds ratio (OR) 0.12, 95% CI 0.03 to 0.40; 1 trial, 40 women). However, the adverse effects of breast tenderness and intermenstrual bleeding were more likely in women with the LNG-IUS. No trials reported on days of bleeding or quality of life for this comparison.The evidence supporting these findings was limited by low or very low gradings of quality; thus, we are uncertain about the findings and there is a potential that they may change if we identify other trials. AUTHORS' CONCLUSIONS: Low- or very low-quality evidence suggests that short-course progestogen was inferior to other medical therapy, including tranexamic acid, danazol and the Pg-IUS with respect to reduction of menstrual blood loss. Long cycle progestogen therapy (medroxyprogesterone acetate or norethisterone) was also inferior to the LNG-IUS, tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss.

Combined hormonal contraceptives for heavy menstrual bleeding.

BACKGROUND: Menorrhagia or heavy menstrual bleeding (HMB) is an excessive blood loss that impairs a woman's quality of life, either physical, emotional, social or material. It is benign and not associated with pregnancy or any other gynaecological or systemic disease. Medical treatments used to reduce excessive menstrual blood loss (MBL) include prostaglandin synthetase inhibitors, antifibrinolytics, oral contraceptive pills, and other hormones. The combined oral contraceptive pill (COCP) is claimed to have a variety of beneficial effects, inducing a regular shedding of a thinner endometrium and inhibiting ovulation, thus having the effect of both treating HMB and providing contraception. More recently, a contraceptive vaginal ring (CVR) has been trialled to investigate whether this treatment can provide similar benefits to COCP while lessening hormonal systemic exposure. This review is an update of a review which originally focused on COCP alone. The scope of the review has been widened to consider other types of delivery of combined hormonal contraceptives for reduction of MBL. OBJECTIVES: To determine the efficacy of combined hormonal contraceptives (pills, vaginal ring or patch) compared with other medical therapies, placebo, or no therapy in the treatment of HMB. A secondary objective was to compare the COCP with the CVR. SEARCH METHODS: We searched the Gynecology and Fertility Group trials register, MEDLINE, Embase, CENTRAL, CINAHL and PsycINFO (search dates: Oct 1996, May 2002, June 2004, April 2006, June 2009, July 2017 and September 2018) for all randomised controlled trials (RCTs) of COCP and CVR for the treatment of HMB. We also searched trial registers and the reference lists of retrieved studies for additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of the use of COCP or CVR compared with no treatment, placebo, or other medical therapies for women with HMB and regular menstrual cycles. DATA COLLECTION AND ANALYSIS: All assessments of trial quality and data extraction were performed unblinded by at least two review authors. Our primary review outcomes were treatment success, menstrual bleeding (assessed objectively, semi-objectively or subjectively), and participant satisfaction with treatment. Secondary outcomes were adverse events, quality of life, and haemoglobin level. MAIN RESULTS: We identified eight RCTs involving 805 participants. Two trials comparing COCP with placebo were considered to be moderate quality and the remaining studies were low to very low quality, mainly because of serious risk of bias from lack of blinding and concerns over precision.COCP versus placeboCOCP, with a step-down oestrogen and step-up progestogen regimen, improved response to treatment (return to menstrual 'normality') (OR 22.12, 95% CI 4.40 to 111.12; 2 trials; 363 participants; I2 = 50%; moderate-quality evidence), and lowered MBL (OR 5.15, 95% CI 3.16 to 8.40; 2 trials; 339 participants; I2 = 0%; moderate-quality evidence) when compared to placebo. The results suggested that, if the chance of 'successful' treatment was 3% in women taking placebo, then COCP increased this chance from 12% to 77% in women with unacceptable HMB. Minor adverse events, in particular breast pain, were more common with COCP. No study in this comparison reported semi-objectively assessed MBL or participant satisfaction with treatment.COCP versus other medical treatmentsNon-steroidal anti-inflammatory drugs (NSAIDs)There was insufficient evidence to determine whether the COCP reduced MBL when compared to NSAIDs (mefenamic acid and naproxen). No study in this comparison reported semi-objectively assessed MBL, subjectively assessed MBL, participant satisfaction with treatment or adverse events.Levonorgestrel-releasing intrauterine system (LNG IUS)The LNG IUS was more effective than COCP in reducing MBL (OR 0.21, 95% CI 0.09 to 0.48; 2 trials; 151 participants; I2 = 0%; low-quality evidence) but it was not clear whether satisfaction with treatment or adverse effects varied according to which treatment was used. No study in this comparison reported semi-objectively assessed MBL or subjectively assessed MBL.Contraceptive vaginal ring (CVR) versus other medical treatmentsCOCP COCP was compared with CVR in two trials. There were discrepancies between some of the findings and there was no evidence of a benefit for one treatment compared to the other for response to treatment, MBL or participant satisfaction with treatment. There was a greater likelihood of nausea with COCP. No study in this comparison reported objectively assessed MBL or subjectively assessed MBL.ProgestogensCVR was compared to long course progestogens in one trial. It is possible that CVR increased the odds of satisfaction; but we are uncertain whether CVR improved MBL. The evidence was based on small numbers of participants and was very low quality, so definitive conclusions could not be reached. No study in this comparison reported objectively assessed MBL, subjectively assessed MBL, or adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that the combined oral contraceptive pill over six months reduces HMB in women with unacceptable HMB from 12% to 77% (compared to 3% in women taking placebo). When compared with other medical options for HMB, COCP was less effective than the LNG IUS. Limited evidence suggested that COCP and CVR had similar effects. There was insufficient evidence to determine comparative efficacy of combined hormonal contraceptives with NSAIDs, or long course progestogens.

Antibiotics for treating urogenital Chlamydia trachomatis infection in men and non-pregnant women.

BACKGROUND: The genital infection caused by Chlamydia trachomatis (CT) is a common sexually transmitted infection (STI) globally. The infection is mainly asymptomatic in women, thus it can produce infertility and chronic pelvic pain. In men infection is mainly symptomatic, but can evolve to prostatitis. Clinical practice guidelines for CT urogenital infections do not give any specific recommendation about which antibiotic use as first option OBJECTIVES: To assess the efficacy and safety of antibiotic treatment for CT genital infection in men and non-pregnant women. SEARCH METHODS: The Cochrane Sexually Transmitted Infections' (STI) Information Specialist developed the electronic searches in electronic databases (CENTRAL, MEDLINE, Embase and LILACS), and trials registers. We searched studies published from inception to June 2018. SELECTION CRITERIA: We included parallel, randomised controlled trials (RCTs) of men, and sexually-active, non-pregnant women with CT infection (urethritis or uterine cervicitis or asymptomatic), diagnosed by cell culture for CT, nucleic acid amplification tests (NAAT) or antigen-based detection methods, who had been treated with any of the antibiotic regimens recommended by any of the updated to 2013 CT Guidelines. DATA COLLECTION AND ANALYSIS: Four review authors screened evidence according to selection criteria and independently extracted data and assessed risk of bias. Two authors developed the 'Summary of findings' tables. We used a fixed-effect meta-analysis model for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect. We estimated the pooled risk ratio in order to establish the effects of the comparisons. Our primary outcomes were microbiological failure and adverse events, and our secondary outcomes were clinical failure, antimicrobial resistance and reinfection. MAIN RESULTS: We selected 14 studies ( 2715 participants: 2147 (79.08%) men and 568 (20.92%) women). The studies were conducted mainly at STD clinics. Sample sizes ranged from 71 to 606 participants; follow-up was 29.7 days on average.For the comparison: azithromycin single dose versus doxycycline once or twice daily for 7 days, in men treated for CT, the risk of microbiological failure was higher in the azithromycin group (RR 2.45, 95% CI 1.36 to 4.41; participants = 821; studies = 9; moderate-quality evidence), but regarding clinical failure, the results showed that the effect is uncertain (RR 0.94, 95% CI 0.43 to 2,05; I² = 55%; participants = 525; studies = 3; low-quality evidence). Regarding adverse events (AE) in men there could be little or no difference between the antibiotics (RR 0.83, 95% CI 0.67 to 1.02; participants = 1424; studies = 6; low-quality evidence). About women treated for CT, the effect on microbiological failure was uncertain (RR = 1.71, 95% CI 0.48 to 6.16; participants = 338; studies = 5; very low-quality evidence). There were no studies assessing clinical failure or adverse events in women, however, we found that azithromycin probably has fewer adverse events in both genders (RR 0.83, 95% CI 0.71 to 0.98; I² = 0%; participants = 2261; studies = 9; moderate-quality evidence).For the second comparison: doxycycline compared to ofloxacin, for men treated for CT the effect on microbiological failure was uncertain (RR 8.53, 95% CI 0.43 to 167.38, I² not applicable; participants = 80; studies = 2; very low-quality evidence), as also it was on clinical failure (RR 0.85, 95% CI 0.28 to 2.62; participants = 36; studies = 1; very low-quality evidence). The effect of in women on clinical failure was uncertain (RR 0.94, 95% CI 0.39 to 2.25; I² = 39%; participants = 127; studies = 2; very low-quality evidence).Regarding adverse events, the effect in both men and women was uncertain (RR 1.02 95% CI 0.66 to 1.55; participants = 339 studies = 3; very low-quality evidence). The effect on microbiological failure in women and in men and women together, the effect on microbiological failure was not estimable. The most frequently AE reported were not serious and of gastrointestinal origin.No studies assessed antimicrobial resistance or reinfection in either comparison. AUTHORS' CONCLUSIONS: In men, regimens with azithromycin are probably less effective than doxycycline for microbiological failure, however, there might be little or no difference for clinical failure. For women, we are uncertain whether azithromycin compared to doxycycline increases the risk of microbiological failure. Azithromycin probably slightly reduces adverse events compared to doxycycline in men and women together but may have little difference in men alone. We are uncertain whether doxycycline compared to ofloxacin reduces microbiological failure in men or women alone, or men and women together, nor if it reduces clinical failure or adverse events in men or women.Based on the fact that women suffer mainly asymptomatic infections, and in order to test the effectiveness and safety of the current recommendations (azithromycin, doxycycline and ofloxacin), for CT infection, especially in low and middle income countries, future RCTs should be designed and conducted to include a large enough sample size of women, and with low risk of bias. It is also important that future RCTs include adherence, CT resistance to antibiotic regimens, and risk of reinfection as outcomes to be measured. In addition, it is important to conduct a network meta-analysis in order to evaluate all those studies that included in one arm only the current antibiotic treatments for CT infection that are recommended by the updated clinical practice guidelines.

Endometrial resection and ablation techniques for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is a significant health problem in premenopausal women; it can reduce their quality of life and can cause social disruption and physical problems such as iron deficiency anaemia. First-line treatment has traditionally consisted of medical therapy (hormonal and non-hormonal), but this is not always successful in reducing menstrual bleeding to acceptable levels. Hysterectomy is a definitive treatment, but it is more costly and carries some risk. Endometrial ablation may be an alternative to hysterectomy that preserves the uterus. Many techniques have been developed to 'ablate' (remove) the lining of the endometrium. First-generation techniques require visualisation of the uterus with a hysteroscope during the procedure; although it is safe, this procedure requires specific technical skills. Newer techniques for endometrial ablation (second- and third-generation techniques) have been developed that are quicker than previous approaches because they do not require hysteroscopic visualisation during the procedure. OBJECTIVES: To compare the efficacy, safety, and acceptability of endometrial destruction techniques to reduce heavy menstrual bleeding (HMB) in premenopausal women. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, CINAHL, and PsycInfo (from inception to May 2018). We also searched trials registers, other sources of unpublished or grey literature, and reference lists of retrieved studies, and we made contact with experts in the field and with pharmaceutical companies that manufacture ablation devices. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different endometrial ablation or resection techniques for women reporting HMB without known uterine pathology, other than fibroids outside the uterine cavity and smaller than 3 centimetres, were eligible. Outcomes included improvement in HMB and in quality of life, patient satisfaction, operative outcomes, complications, and the need for further surgery, including hysterectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias, and extracted data. We contacted study authors for clarification of methods or for additional data. We assessed adverse events only if they were separately measured in the included trials. We undertook comparisons with individual techniques as well as an overall comparison of first- and second-generation ablation methods. MAIN RESULTS: We included in this update 28 studies (4287 women) with sample sizes ranging from 20 to 372. Most studies had low risk of bias for randomisation, attrition, and selective reporting. Less than half of these studies had adequate allocation concealment, and most were unblinded. Using GRADE, we determined that the quality of evidence ranged from moderate to very low. We downgraded evidence for risk of bias, imprecision, and inconsistency.Overall comparison of second-generation versus first-generation (i.e. gold standard hysteroscopic ablative) techniques revealed no evidence of differences in amenorrhoea at 1 year and 2 to 5 years' follow-up (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.78 to 1.27; 12 studies; 2145 women; I² = 77%; and RR 1.16, 95% CI 0.78 to 1.72; 672 women; 4 studies; I² = 80%; very low-quality evidence) and showed subjective improvement at 1 year follow-up based on a Pictorial Blood Assessment Chart (PBAC) (< 75 or acceptable improvement) (RR 1.03, 95% CI 0.98 to 1.09; 5 studies; 1282 women; I² = 0%; and RR 1.12, 95% CI 0.97 to 1.28; 236 women; 1 study; low-quality evidence). Study results showed no difference in patient satisfaction between second- and first-generation techniques at 1 year follow-up (RR 1.01, 95% CI 0.98 to 1.04; 11 studies; 1750 women; I² = 36%; low-quality evidence) nor at 2 to 5 years' follow-up (RR 1.02, 95% CI 0.93 to 1.13; 672 women; 4 studies; I² = 81%).Compared with first-generation techniques, second-generation endometrial ablation techniques were associated with shorter operating times (mean difference (MD) -13.52 minutes, 95% CI -16.90 to -10.13; 9 studies; 1822 women; low-quality evidence) and more often were performed under local rather than general anaesthesia (RR 2.8, 95% CI 1.8 to 4.4; 6 studies; 1434 women; low-quality evidence).We are uncertain whether perforation rates differed between second- and first-generation techniques (RR 0.32, 95% CI 0.10 to 1.01; 1885 women; 8 studies; I² = 0%).Trials reported little or no difference between second- and first-generation techniques in requirement for additional surgery (ablation or hysterectomy) at 1 year follow-up (RR 0.72, 95% CI 0.41 to 1.26; 6 studies: 935 women; low-quality evidence). At 5 years, results showed probably little or no difference between groups in the requirement for hysterectomy (RR 0.85, 95% CI 0.59 to 1.22; 4 studies; 758 women; moderate-quality evidence). AUTHORS' CONCLUSIONS: Approaches to endometrial ablation have evolved from first-generation techniques to newer second- and third-generation approaches. Current evidence suggests that compared to first-generation techniques (endometrial laser ablation, transcervical resection of the endometrium, rollerball endometrial ablation), second-generation approaches (thermal balloon endometrial ablation, microwave endometrial ablation, hydrothermal ablation, bipolar radiofrequency endometrial ablation, endometrial cryotherapy) are of equivalent efficacy for heavy menstrual bleeding, with comparable rates of amenorrhoea and improvement on the PBAC. Second-generation techniques are associated with shorter operating times and are performed more often under local rather than general anaesthesia. It is uncertain whether perforation rates differed between second- and first-generation techniques. Evidence was insufficient to show which second-generation approaches were superior to others and to reveal the efficacy and safety of third-generation approaches versus first- and second-generation techniques.

Antifibrinolytics for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important physical and social problem for women. Oral treatment for HMB includes antifibrinolytic drugs, which are designed to reduce bleeding by inhibiting clot-dissolving enzymes in the endometrium.Historically, there has been some concern that using the antifibrinolytic tranexamic acid (TXA) for HMB may increase the risk of venous thromboembolic disease. This is an umbrella term for deep venous thrombosis (blood clots in the blood vessels in the legs) and pulmonary emboli (blood clots in the blood vessels in the lungs). OBJECTIVES: To determine the effectiveness and safety of antifibrinolytic medications as a treatment for heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and two trials registers in November 2017, together with reference checking and contact with study authors and experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing antifibrinolytic agents versus placebo, no treatment or other medical treatment in women of reproductive age with HMB. Twelve studies utilised TXA and one utilised a prodrug of TXA (Kabi). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary review outcomes were menstrual blood loss (MBL), improvement in HMB, and thromboembolic events. MAIN RESULTS: We included 13 RCTs (1312 participants analysed). The evidence was very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding, and poor reporting of study methods), imprecision and inconsistency.Antifibrinolytics (TXA or Kabi) versus no treatment or placeboWhen compared with a placebo, antifibrinolytics were associated with reduced mean blood loss (MD -53.20 mL per cycle, 95% CI -62.70 to -43.70; I² = 8%; 4 RCTs, participants = 565; moderate-quality evidence) and higher rates of improvement (RR 3.34, 95% CI 1.84 to 6.09; 3 RCTS, participants = 271; moderate-quality evidence). This suggests that if 11% of women improve without treatment, 43% to 63% of women taking antifibrinolytics will do so. There was no clear evidence of a difference between the groups in adverse events (RR 1.05, 95% CI 0.93 to 1.18; 1 RCT, participants = 297; low-quality evidence). Only one thromboembolic event occurred in the two studies that reported this outcome.TXA versus progestogensThere was no clear evidence of a difference between the groups in mean blood loss measured using the Pictorial Blood Assessment Chart (PBAC) (MD -12.22 points per cycle, 95% CI -30.8 to 6.36; I² = 0%; 3 RCTs, participants = 312; very low quality evidence), but TXA was associated with a higher likelihood of improvement (RR 1.54, 95% CI 1.31 to 1.80; I² = 32%; 5 RCTs, participants = 422; low-quality evidence). This suggests that if 46% of women improve with progestogens, 61% to 83% of women will do so with TXA.Adverse events were less common in the TXA group (RR 0.66, 95% CI 0.46 to 0.94; I² = 28%; 4 RCTs, participants = 349; low-quality evidence). No thromboembolic events were reported in any group.TXA versus non-steroidal anti-inflammatory drugs (NSAIDs)TXA was associated with reduced mean blood loss (MD -73.00 mL per cycle, 95% CI -123.35 to -22.65; 1 RCT, participants = 49; low-quality evidence) and higher likelihood of improvement (RR 1.43, 95% CI 1.18 to 1.74; 12 = 0%; 2 RCTs, participants = 161; low-quality evidence). This suggests that if 61% of women improve with NSAIDs, 71% to 100% of women will do so with TXA. Adverse events were uncommon and no comparative data were available. No thromboembolic events were reported.TXA versus ethamsylateTXA was associated with reduced mean blood loss (MD 100 mL per cycle, 95% CI -141.82 to -58.18; 1 RCT, participants = 53; low-quality evidence), but there was insufficient evidence to determine whether the groups differed in rates of improvement (RR 1.56, 95% CI 0.95 to 2.55; 1 RCT, participants = 53; very low quality evidence) or withdrawal due to adverse events (RR 0.78, 95% CI 0.19 to 3.15; 1 RCT, participants = 53; very low quality evidence).TXA versus herbal medicines (Safoof Habis and Punica granatum)TXA was associated with a reduced mean PBAC score after three months' treatment (MD -23.90 pts per cycle, 95% CI -31.92 to -15.88; I² = 0%; 2 RCTs, participants = 121; low-quality evidence). No data were available for rates of improvement. TXA was associated with a reduced mean PBAC score three months after the end of the treatment phase (MD -10.40 points per cycle, 95% CI -19.20 to -1.60; I² not applicable; 1 RCT, participants = 84; very low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 2.25, 95% CI 0.74 to 6.80; 1 RCT, participants = 94; very low quality evidence). No thromboembolic events were reported.TXA versus levonorgestrel intrauterine system (LIUS)TXA was associated with a higher median PBAC score than TXA (median difference 125.5 points; 1 RCT, participants = 42; very low quality evidence) and a lower likelihood of improvement (RR 0.43, 95% CI 0.24 to 0.77; 1 RCT, participants = 42; very low quality evidence). This suggests that if 85% of women improve with LIUS, 20% to 65% of women will do so with TXA. There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 0.83, 95% CI 0.25 to 2.80; 1 RCT, participants = 42; very low quality evidence). No thromboembolic events were reported. AUTHORS' CONCLUSIONS: Antifibrinolytic treatment (such as TXA) appears effective for treating HMB compared to placebo, NSAIDs, oral luteal progestogens, ethamsylate, or herbal remedies, but may be less effective than LIUS. There were too few data for most comparisons to determine whether antifibrinolytics were associated with increased risk of adverse events, and most studies did not specifically include thromboembolism as an outcome.

Preoperative medical therapy before surgery for uterine fibroids.

BACKGROUND: Uterine fibroids occur in up to 40% of women aged over 35 years. Some are asymptomatic, but up to 50% cause symptoms that warrant therapy. Symptoms include anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and low quality of life. Surgery is the first choice of treatment. In recent years, medical therapies have been used before surgery to improve intraoperative and postoperative outcomes. However, such therapies tend to be expensive.Fibroid growth is stimulated by oestrogen. Gonadotropin-hormone releasing analogues (GnRHa) induce a state of hypo-oestrogenism that shrinks fibroids , but has unacceptable side effects if used long-term. Other potential hormonal treatments, include progestins and selective progesterone-receptor modulators (SPRMs).This is an update of a Cochrane Review published in 2000 and 2001; the scope has been broadened to include all preoperative medical treatments. OBJECTIVES: To assess the effectiveness and safety of medical treatments prior to surgery for uterine fibroids. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL in June 2017. We also searched trials registers (ClinicalTrials.com; WHO ICTRP), theses and dissertations and the grey literature, handsearched reference lists of retrieved articles and contacted pharmaceutical companies for additional trials. SELECTION CRITERIA: We included randomised comparisons of medical therapy versus placebo, no treatment, or other medical therapy before surgery, myomectomy, hysterectomy or endometrial resection, for uterine fibroids. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included a total of 38 RCTs (3623 women); 19 studies compared GnRHa to no pretreatment (n = 19), placebo (n = 8), other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (n = 7), and four compared SPRMs with placebo. Most results provided low-quality evidence due to limitations in study design (poor reporting of randomisation procedures, lack of blinding), imprecision and inconsistency. GnRHa versus no treatment or placebo GnRHa treatments were associated with reductions in both uterine (MD -175 mL, 95% CI -219.0 to -131.7; 13 studies; 858 participants; I² = 67%; low-quality evidence) and fibroid volume (heterogeneous studies, MD 5.7 mL to 155.4 mL), and increased preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.7 to 1.1; 10 studies; 834 participants; I² = 0%; moderate-quality evidence), at the expense of a greater likelihood of adverse events, particularly hot flushes (OR 7.68, 95% CI 4.6 to 13.0; 6 studies; 877 participants; I² = 46%; moderate-quality evidence).Duration of hysterectomy surgery was reduced among women who received GnRHa treatment (-9.59 minutes, 95% CI 15.9 to -3.28; 6 studies; 617 participants; I² = 57%; low-quality evidence) and there was less blood loss (heterogeneous studies, MD 25 mL to 148 mL), fewer blood transfusions (OR 0.54, 95% CI 0.3 to 1.0; 6 studies; 601 participants; I² = 0%; moderate-quality evidence), and fewer postoperative complications (OR 0.54, 95% CI 0.3 to 0.9; 7 studies; 772 participants; I² = 28%; low-quality evidence).GnRHa appeared to reduce intraoperative blood loss during myomectomy (MD 22 mL to 157 mL). There was no clear evidence of a difference among groups for other primary outcomes after myomectomy: duration of surgery (studies too heterogeneous for pooling), blood transfusions (OR 0.85, 95% CI 0.3 to 2.8; 4 studies; 121 participants; I² = 0%; low-quality evidence) or postoperative complications (OR 1.07, 95% CI 0.43 to 2.64; I² = 0%; 5 studies; 190 participants; low-quality evidence). No suitable data were available for analysis of preoperative bleeding. GnRHa versus other medical therapies GnRHa was associated with a greater reduction in uterine volume (-47% with GnRHa compared to -20% and -22% with 5 mg and 10 mg ulipristal acetate) but was more likely to cause hot flushes (OR 12.3, 95% CI 4.04 to 37.48; 5 studies; 183 participants; I² = 61%; low-quality evidence) compared with ulipristal acetate. There was no clear evidence of a difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.3 to 1.7; 1 study; 199 participants; moderate-quality evidence; ulipristal acetate 10 mg: OR 0.39, 95% CI 0.1 to 1.1; 1 study; 203 participants; moderate-quality evidence) or haemoglobin levels (MD -0.2, 95% CI -0.6 to 0.2; 188 participants; moderate-quality evidence).There was no clear evidence of a difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI -5.9 to 31.3; 2 studies; 110 participants; I² = 0%; low-quality evidence).The included studies did not report usable data for any other primary outcomes. SPRMs versus placebo SPRMs (mifepristone, CDB-2914, ulipristal acetate and asoprisnil) were associated with greater reductions in uterine or fibroid volume than placebo (studies too heterogeneous to pool) and increased preoperative haemoglobin levels (MD 0.93 g/dL, 0.5 to 1.4; 2 studies; 173 participants; I² = 0%; high-quality evidence). Ulipristal acetate and asoprisnil were also associated with greater reductions in bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.3 to 112.4; 1 study; 143 participants; low-quality evidence; ulipristal acetate 10 mg: OR 78.83, 95% CI 24.0 to 258.7; 1 study; 146 participants; low-quality evidence; asoprisnil: MD -166.9 mL; 95% CI -277.6 to -56.2; 1 study; 22 participants; low-quality evidence). There was no evidence of differences in preoperative complications. No other primary outcomes were measured. AUTHORS' CONCLUSIONS: A rationale for the use of preoperative medical therapy before surgery for fibroids is to make surgery easier. There is clear evidence that preoperative GnRHa reduces uterine and fibroid volume, and increases preoperative haemoglobin levels, although GnRHa increases the incidence of hot flushes. During hysterectomy, blood loss, operation time and complication rates were also reduced. Evidence suggests that ulipristal acetate may offer similar advantages (reduced fibroid volume and fibroid-related bleeding and increased haemoglobin levels) although replication of these studies is advised before firm conclusions can be made. Future research should focus on cost-effectiveness and distinguish between groups of women with fibroids who would most benefit.

Management of ovarian stimulation for IVF: narrative review of evidence provided for World Health Organization guidance.

In this paper, a review of evidence provided to the World Health Organization (WHO) guideline development, who prepare global guidance on the management of ovarian stimulation for women undergoing IVF, is presented. The purpose of ovarian stimulation is to facilitate retrieval of multiple oocytes during a single IVF cycle. Availability of multiple oocytes compensates for inefficiencies in subsequent stages of the cycle, which include oocyte maturation, IVF, embryo culture, embryo transfer, and implantation. Multiple embryos can be transferred in most women, and spare embryos can be frozen to allow for future chances of pregnancy without the need for repeated ovarian stimulation and oocyte retrieval. Our evidence synthesis team addressed 10 clinical questions on management of ovarian stimulation for IVF, prepared a narrative review of the evidence and drafted recommendations to be considered through WHO guideline development processes. Our main outcome measures were live birth, clinical pregnancy, and ovarian hyperstimulation syndrome.

Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques.

BACKGROUND: Among subfertile women undergoing assisted reproductive technology (ART), hormone pills given before ovarian stimulation may improve outcomes. OBJECTIVES: To determine whether pretreatment with the combined oral contraceptive pill (COCP) or with a progestogen or oestrogen alone in ovarian stimulation protocols affects outcomes in subfertile couples undergoing ART. SEARCH METHODS: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, The Cochrane Central Register Studies Online, MEDLINE, Embase, CINAHL and PsycINFO. We also searched the reference lists of relevant articles and registers of ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of hormonal pretreatment in women undergoing ART. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth or ongoing pregnancy and pregnancy loss. MAIN RESULTS: We included 29 RCTs (4701 women) of pretreatment with COCPs, progestogens or oestrogens versus no pretreatment or alternative pretreatments, in gonadotrophin-releasing hormone (GnRH) agonist or antagonist cycles. Overall, evidence quality ranged from very low to moderate. The main limitations were risk of bias and imprecision. Most studies did not describe their methods in adequate detail. Combined oral contraceptive pill versus no pretreatmentWith antagonist cycles in both groups the rate of live birth or ongoing pregnancy was lower in the pretreatment group (OR 0.74, 95% CI 0.58 to 0.95; 6 RCTs; 1335 women; I2 = 0%; moderate quality evidence). There was insufficient evidence to determine whether the groups differed in rates of pregnancy loss (OR 1.36, 95% CI 0.82 to 2.26; 5 RCTs; 868 women; I2 = 0%; moderate quality evidence), multiple pregnancy (OR 2.21, 95% CI 0.53 to 9.26; 2 RCTs; 125 women; I2 = 0%; low quality evidence), ovarian hyperstimulation syndrome (OHSS; OR 0.98, 95% CI 0.28 to 3.40; 2 RCTs; 642 women; I2 = 0%, low quality evidence), or ovarian cyst formation (OR 0.47, 95% CI 0.08 to 2.75; 1 RCT; 64 women; very low quality evidence).In COCP plus antagonist cycles versus no pretreatment in agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (OR 0.89, 95% CI 0.64 to 1.25; 4 RCTs; 724 women; I2 = 0%; moderate quality evidence), multiple pregnancy (OR 1.36, 95% CI 0.85 to 2.19; 4 RCTs; 546 women; I2 = 0%; moderate quality evidence), or OHSS (OR 0.63, 95% CI 0.20 to 1.96; 2 RCTs; 290 women, I2 = 0%), but there were fewer pregnancy losses in the pretreatment group (OR 0.40, 95% CI 0.22 to 0.72; 5 RCTs; 780 women; I2 = 0%; moderate quality evidence). There were no data suitable for analysis on ovarian cyst formation.One small study comparing COCP versus no pretreatment in agonist cycles showed no clear difference between the groups for any of the reported outcomes. Progestogen versus no pretreatmentAll studies used the same protocol (antagonist, agonist or gonadotrophins) in both groups. There was insufficient evidence to determine any differences in rates of live birth or ongoing pregnancy (agonist: OR 1.35, 95% CI 0.69 to 2.65; 2 RCTs; 222 women; I2 = 24%; low quality evidence; antagonist: OR 0.67, 95% CI 0.18 to 2.54; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 0.63, 95% CI 0.09 to 4.23; 1 RCT; 42 women; very low quality evidence), pregnancy loss (agonist: OR 2.26, 95% CI 0.67 to 7.55; 2 RCTs; 222 women; I2 = 0%; low quality evidence; antagonist: OR 0.36, 95% CI 0.06 to 2.09; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 1.00, 95% CI 0.06 to 17.12; 1 RCT; 42 women; very low quality evidence) or multiple pregnancy (agonist: no data available; antagonist: OR 1.05, 95% CI 0.06 to 17.76; 1 RCT; 47 women; low quality evidence; gonadotrophins: no data available). Three studies, all using agonist cycles, reported ovarian cyst formation: rates were lower in the pretreatment group (OR 0.16, 95% CI 0.08 to 0.32; 374 women; I2 = 1%; moderate quality evidence). There were no data on OHSS. Oestrogen versus no pretreatmentIn antagonist or agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (antagonist versus antagonist: OR 0.79, 95% CI 0.53 to 1.17; 2 RCTs; 502 women; I2 = 0%; low quality evidence; antagonist versus agonist: OR 0.88, 95% CI 0.51 to 1.50; 2 RCTs; 242 women; I2 = 0%; very low quality evidence), pregnancy loss (antagonist versus antagonist: OR 0.16, 95% CI 0.02 to 1.47; 1 RCT; 49 women; very low quality evidence; antagonist versus agonist: OR 1.59, 95% CI 0.62 to 4.06; 1 RCT; 220 women; very low quality evidence), multiple pregnancy (antagonist versus antagonist: no data available; antagonist versus agonist: OR 2.24, 95% CI 0.09 to 53.59; 1 RCT; 22 women; very low quality evidence) or OHSS (antagonist versus antagonist: no data available; antagonist versus agonist: OR 1.54, 95% CI 0.25 to 9.42; 1 RCT; 220 women). Ovarian cyst formation was not reported. Head-to-head comparisonsCOCP was compared with progestogen (1 RCT, 44 women), and with oestrogen (2 RCTs, 146 women), and progestogen was compared with oestrogen (1 RCT, 48 women), with an antagonist cycle in both groups. COCP in an agonist cycle was compared with oestrogen in an antagonist cycle (1 RCT, 25 women). Data were scant but there was no clear evidence that any of the groups differed in rates of live birth or ongoing pregnancy, pregnancy loss or other adverse events. AUTHORS' CONCLUSIONS: Among women undergoing ovarian stimulation in antagonist protocols, COCP pretreatment was associated with a lower rate of live birth or ongoing pregnancy than no pretreatment. There was insufficient evidence to determine whether rates of live birth or ongoing pregnancy were influenced by pretreatment with progestogens or oestrogens, or by COCP pretreatment using other stimulation protocols. Findings on adverse events were inconclusive, except that progesterone pretreatment may reduce the risk of ovarian cysts in agonist cycles, and COCP in antagonist cycles may reduce the risk of pregnancy loss compared with no pretreatment in agonist cycles.

Long-term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. OBJECTIVES: To assess effects of long-term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment. SEARCH METHODS: We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews. SELECTION CRITERIA: We included randomised double-blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods. MAIN RESULTS: We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow-up: from 5 per 1000 to between 6 and 13 per 1000).Oestrogen-only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow-up time.Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long-term use.Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen-only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer.One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen-only HT versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause.For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms. AUTHORS' CONCLUSIONS: Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented.HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long-term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age.

Local oestrogen for vaginal atrophy in postmenopausal women.

BACKGROUND: Vaginal atrophy is a frequent complaint of postmenopausal women; symptoms include vaginal dryness, itching, discomfort and painful intercourse. Systemic treatment for these symptoms in the form of oral hormone replacement therapy is not always necessary. An alternative choice is oestrogenic preparations administered vaginally (in the form of creams, pessaries, tablets and the oestradiol-releasing ring). This is an update of a Chochrane systematic review; the original version was first published in October 2006. OBJECTIVES: The objective of this review was to compare the efficacy and safety of intra-vaginal oestrogenic preparations in relieving the symptoms of vaginal atrophy in postmenopausal women. SEARCH METHODS: We searched the following databases and trials registers to April 2016: Cochrane Gynaecology and Fertility Group Register of trials, The Cochrane Central Register of Controlled Trials (CENTRAL; 2016 issue 4), MEDLINE, Embase, PsycINFO, DARE, the Web of Knowledge, OpenGrey, LILACS, PubMed and reference lists of articles. We also contacted experts and researchers in the field. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of oestrogenic preparations administered intravaginally in postmenopausal women for at least 12 weeks for the treatment of symptoms resulting from vaginal atrophy or vaginitis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and extracted the data. The primary review outcomes were improvement in symptoms (participant-assessed), and the adverse event endometrial thickness. Secondary outcomes were improvement in symptoms (clinician-assessed), other adverse events (breast disorders e.g. breast pain, enlargement or engorgement, total adverse events, excluding breast disorders) and adherence to treatment. We combined data to calculate pooled risk ratios (RRs) (dichotomous outcomes) and mean differences (MDs) (continuous outcomes) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: We included 30 RCTs (6235 women) comparing different intra-vaginal oestrogenic preparations with each other and with placebo. The evidence was low to moderate quality; limitations were poor reporting of study methods and serious imprecision (effect estimates with wide confidence intervals)1. Oestrogen ring versus other regimensOther regimens included oestrogen cream, oestrogen tablets and placebo. There was no evidence of a difference in improvement in symptoms (participant assessment) either between oestrogen ring and oestrogen cream (odds ratio (OR) 1.33, 95% CI 0.80 to 2.19, two RCTs, n = 341, I(2) = 0%, low-quality evidence) or between oestrogen ring and oestrogen tablets (OR 0.78, 95% CI 0.53 to 1.15, three RCTs, n = 567, I(2) = 0%, low-quality evidence). However, a higher proportion of women reported improvement in symptoms following treatment with oestrogen ring compared with placebo (OR 12.67, 95% CI 3.23 to 49.66, one RCT, n = 67). With respect to endometrial thickness, a higher proportion of women who received oestrogen cream showed evidence of increase in endometrial thickness compared to those who were treated with oestrogen ring (OR 0.36, 95% CI 0.14 to 0.94, two RCTs, n = 273; I(2) = 0%, low-quality evidence). This may have been due to the higher doses of cream used. 2. Oestrogen tablets versus other regimensOther regimens in this comparison included oestrogen cream, and placebo. There was no evidence of a difference in the proportions of women who reported improvement in symptoms between oestrogen tablets and oestrogen cream (OR 1.06, 95% CI 0.55 to 2.01, two RCTs, n = 208, I(2) = 0% low-quality evidence). A higher proportion of women who were treated with oestrogen tablets reported improvement in symptoms compared to those who received placebo using a fixed-effect model (OR 12.47, 95% CI 9.81 to 15.84, two RCTs, n = 1638, I(2) = 83%, low-quality evidence); however, using a random-effect model did not demonstrate any evidence of a difference in the proportions of women who reported improvement between the two treatment groups (OR 5.80, 95% CI 0.88 to 38.29). There was no evidence of a difference in the proportions of women with increase in endometrial thickness between oestrogen tablets and oestrogen cream (OR 0.31, 95% CI 0.06 to 1.60, two RCTs, n = 151, I(2) = 0%, low-quality evidence).3. Oestrogen cream versus other regimensOther regimens identified in this comparison included isoflavone gel and placebo. There was no evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and isoflavone gel (OR 2.08, 95% CI 0.08 to 53.76, one RCT, n = 50, low-quality evidence). However, there was evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and placebo with more women who received oestrogen cream reporting improvement in symptoms compared to those who were treated with placebo (OR 4.10, 95% CI 1.88 to 8.93, two RCTs, n = 198, I(2) = 50%, low-quality evidence). None of the included studies in this comparison reported data on endometrial thickness. AUTHORS' CONCLUSIONS: There was no evidence of a difference in efficacy between the various intravaginal oestrogenic preparations when compared with each other. However, there was low-quality evidence that intra-vaginal oestrogenic preparations improve the symptoms of vaginal atrophy in postmenopausal women when compared to placebo. There was low-quality evidence that oestrogen cream may be associated with an increase in endometrial thickness compared to oestrogen ring; this may have been due to the higher doses of cream used. However there was no evidence of a difference in the overall body of evidence in adverse events between the various oestrogenic preparations compared with each other or with placebo.

High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer.

BACKGROUND: Overall survival rates are disappointing for women with early poor prognosis breast cancer. Autologous transplantation of bone marrow or peripheral stem cells (in which the woman is both donor and recipient) has been considered a promising technique because it permits use of much higher doses of chemotherapy. OBJECTIVES: To compare the effectiveness and safety of high-dose chemotherapy and autograft (either autologous bone marrow or stem cell transplantation) with conventional chemotherapy for women with early poor prognosis breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE (1966 to October 2015), EMBASE (1980 to October 2015), the World Health Organization's International Clinical Trials Registry Search Platform, and ClinicalTrials.gov on the 21 October 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. DATA COLLECTION AND ANALYSIS: Two review authors selected RCTs, independently extracted data and assessed risks of bias. We combined data using a Mantel-Haenszel fixed-effect model to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed the quality of the evidence using GRADE methods. Outcomes were survival rates, toxicity and quality of life. MAIN RESULTS: We included 14 RCTs of 5600 women randomised to receive high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. The studies were at low risk of bias in most areas.There is high-quality evidence that high-dose chemotherapy does not increase the likelihood of overall survival at any stage of follow-up (at three years: RR 1.02, 95% CI 0.95 to 1.10, 3 RCTs, 795 women, I² = 56%; at five years: RR 1.00, 95% CI 0.96 to 1.04, 9 RCTs, 3948 women, I² = 0%; at six years: RR 0.94, 95% CI 0.81 to 1.08, 1 RCT, 511 women; at eight years: RR1.17, 95% CI 0.95 to 1.43, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.99 to 1.42, 1 RCT, 382 women).There is high-quality evidence that high-dose chemotherapy improves the likelihood of event-free survival at three years (RR 1.19, 95% CI 1.06 to 1.34, 3 RCTs, 795 women, I² = 56%) but this effect was no longer apparent at longer duration of follow-up (at five years: RR 1.04, 95% CI 0.99 to 1.09, 9 RCTs, 3948 women, I² = 14%; at six years RR 1.04, 95% CI 0.87 to 1.24, 1 RCT, 511 women; at eight years: RR 1.27, 95% CI 0.99 to 1.64, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.95 to 1.45, 1 RCT, 382 women).Treatment-related deaths were much more frequent in the high-dose arm (RR 7.97, 95% CI 3.99 to 15.92, 14 RCTs, 5600 women, I² = 12%, high-quality evidence) and non-fatal morbidity was also more common and more severe in the high-dose group. There was little or no difference between the groups in the incidence of second cancers at four to nine years' median follow-up (RR 1.25, 95% CI 0.90 to 1.73, 7 RCTs, 3423 women, I² = 0%, high-quality evidence). Women in the high-dose group reported significantly worse quality-of-life scores immediately after treatment, but there were few statistically significant differences between the groups by one year.The primary studies were at low risk of bias in most areas, and the evidence was assessed using GRADE methods and rated as high quality for all comparisons. AUTHORS' CONCLUSIONS: There is high-quality evidence of increased treatment-related mortality and little or no increase in survival by using high-dose chemotherapy with autograft for women with early poor prognosis breast cancer.

Surgery versus medical therapy for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding significantly impairs the quality of life of many otherwise healthy women. Perception of heavy menstrual bleeding is subjective and management usually depends upon what symptoms are acceptable to the individual. Surgical options include conservative surgery (uterine resection or ablation) and hysterectomy. Medical treatment options include oral medication and a hormone-releasing intrauterine device (LNG-IUS). OBJECTIVES: To compare the effectiveness, safety and acceptability of surgery versus medical therapy for heavy menstrual bleeding. SEARCH METHODS: We searched the following databases from inception to January 2016: Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and clinical trials registers (clinical trials.gov and ICTRP). We also searched the reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing conservative surgery or hysterectomy versus medical therapy (oral or intrauterine) for heavy menstrual bleeding. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies, assessed their risk of bias and extracted the data. Our primary outcomes were menstrual bleeding, satisfaction rate and adverse events. Where appropriate we pooled the data to calculate pooled risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs), using a fixed-effect model. We assessed heterogeneity with the I(2) statistic and evaluated the quality of the evidence using GRADE methods. MAIN RESULTS: We included 15 parallel-group RCTs (1289 women). Surgical interventions included hysterectomy and endometrial resection or ablation. Medical interventions included oral medication and the levonorgestrel-releasing intrauterine device (LNG-IUS). The overall quality of the evidence for different comparisons ranged from very low to moderate. The main limitations were lack of blinding, attrition and imprecision. Moreover, it was difficult to interpret long-term study findings as many women randomised to medical interventions subsequently underwent surgery. Surgery versus oral medicationSurgery (endometrial resection) was more effective in controlling bleeding at four months (RR 2.66, 95% CI 1.94 to 3.64, one RCT, 186 women, moderate quality evidence) and also at two years (RR 1.29, 95% CI 1.06 to 1.57, one RCT, 173 women, low quality evidence). There was no evidence of a difference between the groups at five years (RR 1.14, 95% CI 0.97 to 1.34, one RCT, 140 women, very low quality evidence).Satisfaction with treatment was higher in the surgical group at two years (RR 1.40, 95% CI 1.13 to 1.74, one RCT, 173 women, moderate quality evidence), but there was no evidence of a difference between the groups at five years (RR 1.13, 95% CI 0.94 to 1.37, one RCT, 114 women, very low quality evidence). There were fewer adverse events in the surgical group at four months (RR 0.26, 95 CI 0.15 to 0.46, one RCT, 186 women). These findings require cautious interpretation, as 59% of women randomised to the oral medication group had had surgery within two years and 77% within five years. Surgery versus LNG-IUSWhen hysterectomy was compared with LNG-IUS, the hysterectomy group were more likely to have objective control of bleeding at one year (RR 1.11, 95% CI 1.05 to 1.19, one RCT, 223 women, moderate quality evidence). There was no evidence of a difference in quality of life between the groups at five or 10 years, but by 10 years 46% of women originally assigned to LNG-IUS had undergone hysterectomy. Adverse effects associated with hysterectomy included surgical complications such as bladder or bowel perforation and vesicovaginal fistula. Adverse effects associated with LNG-IUS were ongoing bleeding and hormonal symptoms.When conservative surgery was compared with LNG-IUS, at one year the surgical group were more likely to have subjective control of bleeding (RR 1.19, 95% CI 1.07 to 1.32, five RCTs, 281 women, low quality evidence, I(2) = 15%). Satisfaction rates were higher in the surgical group at one year (RR 1.16, 95% CI 1.04, to 1.28, six RCTs, 442 women, I(2) = 27%), but this finding was sensitive to the choice of statistical model and use of a random-effects model showed no conclusive evidence of a difference between the groups. There was no evidence of a difference between the groups in satisfaction rates at two years (RR 0.93, 95% CI 0.81 to 1.08, two RCTs, 117 women, I(2) = 1%).At one year there were fewer adverse events (such as bleeding and spotting) in the surgical group (RR 0.36, 95% CI 0.15 to 0.82, three RCTs, moderate quality evidence). It was unclear what proportion of women assigned to LNG-IUS underwent surgery over long-term follow-up, as there were few data beyond one year. AUTHORS' CONCLUSIONS: Surgery, especially hysterectomy, reduces menstrual bleeding more than medical treatment at one year. There is no conclusive evidence of a difference in satisfaction rates between surgery and LNG-IUS, though adverse effects such as bleeding and spotting are more likely to occur with LNG-IUS. Oral medication suits a minority of women in the long term, and the LNG-IUS device provides a better alternative to surgery in most cases. Although hysterectomy is a definitive treatment for heavy menstrual bleeding, it can cause serious complications for a minority of women. Most women may be well advised to try a less radical treatment as first-line therapy. Both LNG-IUS and conservative surgery appear to be safe, acceptable and effective.

Fibroids (uterine myomatosis, leiomyomas).

INTRODUCTION: Between 50% and 77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, mass and pressure effects, infertility, or recurrent pregnancy loss. Risk factors for fibroids include obesity, having no children, and no long-term use of the oral contraceptive pill. Fibroids tend to shrink or fibrose after the menopause. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of surgical/interventional radiological treatments in women with fibroids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: Five studies were included. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: magnetic resonance-guided focused ultrasound surgery versus no/sham treatment; magnetic resonance-guided focused ultrasound surgery versus other interventions (hysterectomy, myomectomy, hysteroscopic resection, rollerball endometrial ablation, thermal balloon ablation, thermal myolysis with laser); uterine artery embolisation versus no/sham treatment; uterine artery embolisation versus hysterectomy; uterine artery embolisation versus myomectomy; uterine artery embolisation versus other interventions (magnetic resonance-guided focused ultrasound surgery, hysteroscopic resection, rollerball endometrial ablation, thermal balloon ablation, thermal myolysis with laser).