Abstract
Introduction
Menorrhagia limits normal activities, and causes anaemia in two-thirds of women with objective menorrhagia (loss of 80 mL blood per cycle). Prostaglandin disorders may be associated with idiopathic menorrhagia, and with heavy bleeding due to fibroids, adenomyosis, or use of intrauterine devices (IUDs). Fibroids have been found in 10% of women with menorrhagia overall, and in 40% of women with severe menorrhagia; but half of women having a hysterectomy for menorrhagia are found to have a normal uterus.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments for menorrhagia? What are the effects of surgical treatments for menorrhagia? What are the effects of endometrial thinning before endometrial destruction in treating menorrhagia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2011 (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
We found 39 systematic reviews, RCTs, or observational studies that met our inclusion criteria. 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 medical interventions: combined pill, danazol, etamsylate, gonadorelin analogues, intrauterine progesterone, non-steroidal anti-inflammatory drugs (NSAIDs), progestogens, and the following surgical interventions: dilatation and curettage, endometrial destruction, and hysterectomy.
Key Points
Menorrhagia limits normal activities, and causes anaemia in two-thirds of women with objective menorrhagia (blood loss of 80 mL or more per cycle).
Prostaglandin disorders may be associated with idiopathic menorrhagia, and with heavy bleeding caused by fibroids, adenomyosis, or use of IUDs.
Fibroids have been found in 10% of women with menorrhagia overall, and in 40% of women with severe menorrhagia; but half of women having a hysterectomy for menorrhagia are found to have a normal uterus.
NSAIDs, tranexamic acid, and danazol all reduce blood loss compared with placebo.
Tranexamic acid and danazol may be more effective than NSAIDs, etamsylate, and oral progestogens at reducing blood loss, but any benefits of danazol must be weighed against the high risk of adverse effects.
NSAIDs reduce dysmenorrhoea, and may be as effective at reducing menstrual blood loss as oral progestogens given in the luteal phase, but we don't know how they compare with etamsylate, combined oral contraceptives, intrauterine progestogens, or gonadorelin analogues.
We don't know whether combined oral contraceptives, levonorgestrel-releasing intrauterine devices, or gonadorelin analogues are effective at reducing menorrhagia, as few trials were found.
Hysterectomy reduces blood loss and the need for further surgery compared with medical treatments or endometrial destruction, but can lead to complications in up to a third of women. Fewer women reported overall treatment dissatisfaction with hysterectomy.
Endometrial destruction is more effective at reducing menorrhagia compared with medical treatment, but complications can include infection, haemorrhage, and uterine perforation.
We don't know whether any one type of endometrial destruction is superior, or whether dilatation and curettage has any effect on menstrual blood loss.
Preoperative gonadorelin analogues reduce long-term postoperative moderate or heavy blood loss, and increase amenorrhoea compared with placebo, but we don't know whether oral progestogens or danazol are also beneficial when used preoperatively.
About this condition
Definition
Menorrhagia is defined as heavy, but regular, menstrual bleeding. Idiopathic ovulatory menorrhagia is regular heavy bleeding in the absence of recognisable pelvic pathology, or a general bleeding disorder. Objective menorrhagia is taken to be a total menstrual blood loss of 80 mL or more in each menstruation. Subjectively, menorrhagia may be defined as a complaint of regular excessive menstrual blood loss occurring over several consecutive cycles in a woman of reproductive age.
Incidence/ Prevalence
In the UK, 5% of women aged 30 to 49 years consult their general practitioners each year with menorrhagia. In New Zealand, 2% to 4% of primary-care consultations by premenopausal women are for menstrual problems.
Aetiology/ Risk factors
Idiopathic ovulatory menorrhagia is thought to be caused by disordered prostaglandin production within the endometrium. Prostaglandins may also be implicated in menorrhagia associated with uterine fibroids, adenomyosis, or the presence of an IUD. Fibroids have been reported in 10% of women with menorrhagia (80–100 mL/cycle), and in 40% of women with severe menorrhagia (at least 200 mL/cycle).
Prognosis
Menorrhagia limits normal activities and causes iron-deficiency anaemia in two-thirds of women shown to have objective menorrhagia. One in five women in the UK, and one in three in the USA, have a hysterectomy before the age of 60 years; menorrhagia is the main presenting problem in at least half of these women. About half of women who have a hysterectomy for menorrhagia are found to have an anatomically normal uterus.
Aims of intervention
To reduce menstrual bleeding; improve quality of life; and prevent or correct iron-deficiency anaemia with minimum adverse effects.
Outcomes
Anaemia, primarily measured by haemoglobin concentration; intraoperative and postoperative complications; menstrual blood loss (assessed objectively [mL/cycle] or subjectively), including rates of amenorrhoea; patient satisfaction; postoperative recovery; quality of life; and adverse drug effects. Whether a particular percentage reduction in menstrual blood loss is considered clinically important will depend on pretreatment menstrual loss and on individual women's perceptions of acceptable menstrual loss. Women may regard amenorrhoea as a benefit or a harm of treatment, depending on their perspective.
Methods
Clinical Evidence search and appraisal June 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2011, Embase 1980 to June 2011, and The Cochrane Database of Systematic Reviews, May 2011 [online] (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, where possible, because blinding is difficult when comparing different modalities such as IUDs versus tablets or medical versus surgical. Therefore, open studies were included in these scenarios. Studies contained >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Menorrhagia.
| Important outcomes | Anaemia, Intraoperative and postoperative complications, Menstrual blood loss, Need for re-treatment, Patient satisfaction, Postoperative recovery, Quality of life | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of medical treatments for menorrhagia? | |||||||||
| 12 (313) | Menstrual blood loss | NSAIDs versus placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for differences in regimens between trials |
| 2 (61) | Menstrual blood loss | NSAIDs versus each other | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for small number of comparisons |
| 3 (79) | Menstrual blood loss | NSAIDs versus danazol | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (48) | Menstrual blood loss | NSAIDs versus oral progestogens (luteal phase) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (at least 340) | Menstrual blood loss | Tranexamic acid versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete presentation of results |
| 1 (187) | Quality of life | Tranexamic acid versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 4 (164) | Menstrual blood loss | Tranexamic acid versus NSAIDs | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and other methodological flaws |
| 1 (81) | Menstrual blood loss | Tranexamic acid versus etamsylate | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and other methodological flaws |
| 2 (146) | Menstrual blood loss | Tranexamic acid versus oral progestogens (luteal phase) | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and methodological flaws |
| 1 (81) | Menstrual blood loss | Etamsylate versus NSAIDs | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and other methodological flaws |
| 4 (193) | Menstrual blood loss | Danazol versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete presentation of results. Directness point deducted for indirect comparisons |
| 1 (38) | Menstrual blood loss | Combined oral contraceptives versus NSAIDs | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (38) | Menstrual blood loss | Combined oral contraceptives versus danazol | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (151) | Menstrual blood loss | Combined oral contraceptives versus intrauterine progestogens | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for sparse data. Consistency point deducted for conflicting results. Directness point deducted for different doses of contraceptive |
| 2 (151) | Quality of life | Combined oral contraceptives versus intrauterine progestogens | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (39) | Anaemia | Combined oral contraceptives versus intrauterine progestogens | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (51) | Menstrual blood loss | Progestogens (oral) in the luteal phase versus danazol | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (162) | Menstrual blood loss | Intrauterine progestogens versus oral progestogen (luteal phase) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (<74) | Menstrual blood loss | Intrauterine progestogens versus oral progestogen (long cycle) | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and baseline differences in severity of menorrhagia. Directness point deducted for analysis of indirect comparisons |
| 1 (44) | Patient satisfaction | Intrauterine progestogens versus oral progestogen (long cycle) | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for unclear clinical importance of outcome measure |
| 2 (<81) | Menstrual blood loss | Intrauterine progestogens versus NSAIDs | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and baseline differences in severity of menorrhagia. Directness points deducted for multiple drugs in comparison and analysis of indirect comparisons |
| 1 (30) | Menstrual blood loss | Intrauterine progestogens versus danazol | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and baseline differences in severity of menorrhagia. Directness points deducted for multiple drugs in comparison and analysis of indirect comparisons |
| at least 5 (at least 317) | Menstrual blood loss | Intrauterine progestogens versus endometrial destruction (ablation) | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for study involving mainly women <40 years |
| 3 at least (310 at most) | Need for re-treatment | Intrauterine progestogens versus endometrial destruction (ablation) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 4 at most (at least 274) | Patient satisfaction | Intrauterine progestogens versus endometrial destruction (ablation) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (210 at most) | Quality of life | Intrauterine progestogens versus endometrial destruction (ablation) | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 1 (33) | Anaemia | Intrauterine progestogens versus endometrial destruction (ablation) | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for for sparse data and incomplete reporting of results |
| 1 (232) | Patient satisfaction | Intrauterine progestogens versus hysterectomy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting. Directness point deducted for high switch rates to surgery |
| 1 (232) | Quality of life | Intrauterine progestogens versus hysterectomy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting. Directness point deducted for high switch rates to surgery |
| 1 (228) | Anaemia | Intrauterine progestogens versus hysterectomy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for high switch rates to surgery |
| What are the effects of surgical treatments for menorrhagia? | |||||||||
| 3 (440) | Menstrual blood loss | Hysterectomy versus endometrial destruction | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (708) | Need for re-treatment | Hysterectomy versus endometrial destruction | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for wide confidence intervals in largest RCT contributing results regarding this outcome |
| at least 5 (at least 836) | Patient satisfaction | Hysterectomy versus endometrial destruction | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (394) | Quality of life | Hysterectomy versus endometrial destruction | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting. Directness point deducted for no direct comparison between groups |
| at least 7 (at least 1066) | Postoperative recovery | Hysterectomy versus endometrial destruction | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 2 (at least 708) | Intraoperative and postoperative complications | Hysterectomy versus endometrial destruction | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for contradictory results |
| 3 (733) | Menstrual blood loss | Subtotal hysterectomy versus total hysterectomy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for analysis not limited to women with menorrhagia |
| 2 (411) | Intraoperative and postoperative complications | Subtotal hysterectomy versus total hysterectomy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for analysis not limited to women with menorrhagia |
| 23 (1728) | Postoperative recovery | Abdominal hysterectomy versus vaginal or laparoscopic hysterectomy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for analysis not limited to women with menorrhagia |
| 1 (187) | Menstrual blood loss | Endometrial destruction (resection or ablation) versus oral drugs | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for range of drugs in comparison |
| 4 (2085) | Menstrual blood loss | First-generation versus second-generation techniques | 4 | 0 | 0 | 0 | 0 | High | |
| 7 (1028) | Need for re-treatment | First-generation versus second-generation techniques | 4 | 0 | 0 | 0 | 0 | High | |
| 11 (1690) | Patient satisfaction | First-generation versus second-generation techniques | 4 | 0 | 0 | 0 | 0 | High | |
| 8 (1885) | Intraoperative and postoperative complications | First-generation versus second-generation techniques | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results |
| 4 (391) | Menstrual blood loss | First-generation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (438) | Need for re-treatment | First-generation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (462) | Patient satisfaction | First-generation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting |
| 2 (486) | Intraoperative and postoperative complications | First-generation techniques versus each other | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results |
| 4 (517) | Menstrual blood loss | Second-generation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (241) | Need for re-treatment | Second-generation techniques versus each other | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 2 (286) | Patient satisfaction | Second-generation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (81) | Quality of life | Second-generation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (367) | Intraoperative and postoperative complications | Second-generation techniques versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| What are the effects of endometrial thinning before endometrial destruction in treating menorrhagia? | |||||||||
| 8 (618) | Menstrual blood loss | Gonadorelin analogues (GnRHa) versus placebo or no treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for no objective measure of menorrhagia |
| 3 (340) | Menstrual blood loss | GnRHa versus danazol | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (202) | Menstrual blood loss | Danazol versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (70) | Menstrual blood loss | Oral progestogens versus no treatment | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Laser ablation
A hysteroscopic procedure in which endometrium is destroyed under direct vision by a laser beam.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Transcervical endometrial resection
A hysteroscopic procedure in which endometrium is removed under direct vision by using an electrosurgical loop.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Fibroids (uterine myomatosis, leiomyomas)
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Kirsten Duckitt, Obstetrician and Gynaecologist, Campbell River and District General Hospital, Campbell River, Canada.
Sally Collins, John Radcliffe Hospital, Oxford, UK.
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