Abstract
Introduction
Between 5-77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, 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 questions: What are the effects of: medical treatment alone; preoperative medical treatments for women scheduled for surgery; and surgical treatments in women with fibroids? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (BMJ 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 41 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 interventions: gonadorelin analogues (with progestogen, raloxifene, tibolone, or combined oestrogen-progestogen); hysterectomy (plus oophorectomy); hysteroscopic resonance-focused ultrasound; laparoscopic myomectomy; laparoscopically assisted vaginal hysterectomy; rollerball endometrial ablation; thermal balloon ablation; thermal myolysis with laser; total abdominal hysterectomy; total abdominal myomectomy; total laparoscopic hysterectomy; total vaginal hysterectomy.
Key Points
Between 5-77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, 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.
Gonadorelin analogues reduce bleeding compared with placebo, but can cause menopausal symptoms and bone loss, which may limit their long-term use.
Adding progesterone, tibolone, or raloxifene to gonadorelin analogues may prevent these adverse effects, but their addition doesn't produce any greater effect on fibroid symptoms than gonadorelin analogues alone.
We don't know whether NSAIDs or the levonorgestrel intrauterine system improve symptoms of fibroids.
Gonadorelin analogues given before fibroid surgery reduce bleeding, and increase the likelihood of having a vaginal rather than abdominal hysterectomy, but increase anti-oestrogenic adverse effects (such as hot flushes, change in breast size, vaginal symptoms).
Total abdominal hysterectomy is considered to be beneficial in reducing fibroid-related symptoms, but total vaginal hysterectomy and total laparoscopic hysterectomy may have lower risks of complications, and shorter recovery times.
Laparoscopically assisted vaginal hysterectomy may increase operative times and blood loss compared with total vaginal hysterectomy.
Myomectomy maintains fertility, but we don't know whether it is better at reducing fibroid symptoms compared with hysterectomy.
Laparoscopic myomectomy reduces complications and recovery time compared with abdominal myomectomy.
We don't know whether thermal myolysis with laser, hysteroscopic resection, thermal balloon ablation, or rollerball ablation, or magnetic resonance-guided focused ultrasound surgery are beneficial in women with fibroids compared with hysterectomy, as we found no studies.
About this condition
Definition
Fibroids (uterine leiomyomas) are benign tumours of the smooth muscle cells of the uterus. Women with fibroids can be asymptomatic, or may present with menorrhagia (30%), pelvic pain with or without dysmenorrhoea or pressure symptoms (34%), infertility (27%), and recurrent pregnancy loss (3%). Much of the data describing the relationship between the presence of fibroids and symptoms are based on uncontrolled studies that have assessed the effect of myomectomy on the presenting symptoms. One observational study (142 women) undertaken in the USA suggested that the prevalence of fibroids in infertile women can be as high as 13%, but no direct causal relationship between fibroids and infertility has been established.
Incidence/ Prevalence
The reported incidence of fibroids varies from 5.4-77.0%, depending on the method of diagnosis used (the gold standard is histological evidence). It is not possible to state the actual incidence of fibroids, because some women with fibroids will not have symptoms, and will therefore not be tested for fibroids. Observational evidence suggests that, in premenopausal women, the incidence of fibroids increases with age, reducing during menopause. Based on postmortem examination, 50% of women were found to have these tumours. Gross serial sectioning at 2 mm intervals of 100 consecutive hysterectomy specimens revealed the presence of fibroids in 50/68 (73%) premenopausal women and 27/32 (84%) postmenopausal women. These women were having hysterectomies for reasons other than fibroids. The incidence of fibroids in black women is three times greater than that in white women, based on ultrasound or hysterectomy diagnosis. Submucosal fibroids have been diagnosed in 6-34% of women having a hysteroscopy for abnormal bleeding, and in 2-7% of women having infertility investigations.
Aetiology/ Risk factors
The cause of fibroids is unknown. Each fibroid is of monoclonal origin and arises independently. Factors thought to be involved include the sex steroid hormones oestrogen and progesterone, as well as the insulin-like growth factors, epidermal growth factor, and transforming growth factor. Risk factors for fibroid growth include nulliparity, and obesity. Risk also reduces consistently with increasing number of term pregnancies; women with five term pregnancies have a quarter of the risk of nulliparous women (P less than 0.001). Obesity increases the risk of fibroid development by 21% with each 10 kg weight gain (P = 0.008). The combined oral contraceptive pill also reduces the risk of fibroids with increasing duration of use (women who have taken oral contraceptives for 4-6 years compared with women who have never taken oral contraceptives: OR 0.8, 95% CI 0.5 to 1.2; women who have taken oral contraceptives for at least 7 years compared with women who have never taken oral contraceptives: OR 0.5, 95% CI 0.3 to 0.9). Women who have had injections containing 150 mg depot medroxyprogesterone acetate also have a reduced incidence compared with women who have never had injections of this drug (OR 0.44, 95% CI 0.36 to 0.55).
Prognosis
There are few data on the long-term untreated prognosis of these tumours, particularly in women asymptomatic at diagnosis. One small case control study reported that, in a group of 106 women treated with observation alone over 1 year, there was no significant change in symptoms and quality of life over that time. Fibroids tend to shrink or fibrose after the menopause.
Aims of intervention
To reduce menstrual bleeding; reduce pressure symptoms; reduce pelvic pain; and induce a change in fertility status, with minimal adverse effects.
Outcomes
Menstrual blood flow (assessed objectively [mL/cycle] or subjectively); haemoglobin concentration and haematocrit; pelvic pain, pressure, or both (measured by a validated scale or subjective report); reduction in fibroid and uterine volume; pregnancy rate; quality of life; adverse effects. Some of the outcomes relate to surgery: ease of surgery as assessed by the surgeon; complication rates during and after surgery; blood loss during surgery; duration of surgery; length of hospital stay; rate of blood transfusions; probability of transverse versus vertical incisions during surgery; probability of vaginal versus abdominal hysterectomy; recurrence rate; patient satisfaction rate.
Methods
BMJ Clinical Evidence search and appraisal November 2006. The following databases were used to identify studies for this review: Medline 1966 to November 2006, Embase 1980 to November 2006, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow up required to evaluate studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We also did a search for cohort studies on specific harms of named interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the chapter as required. We compared all listed medical interventions versus all listed surgical interventions and included all RCTs of sufficient quality. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for fibroids.
| Important outcomes | Menstrual blood flow; Reduction in fibroid/uterine volume; Pregnancy rate; Pelvic pain/pressure; Postoperative recovery times; Adverse effects/complications | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of medical treatment alone in women with fibroids? | |||||||||
| 1 (41) | Heavy bleeding | Gonadorelin analogues plus progestogen v gonadorelin analogues alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and subjective outcome assessment |
| 2 (40) | Vasomotor adverse effects | Gonadorelin analogues plus progestogen v gonadorelin analogues alone | 4 | –2 | 0 | 0 | 1 | Moderate | Quality points deducted for sparse data and incomplete reporting of results. Effect size point added for RR less than 0.2 |
| 1 (100) | Fibroid/uterus size | Gonadorelin analogues plus raloxifene v gonadorelin analogues alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete presentation of results |
| 1 (100) | Fibroid -related symptoms (menorrhagia, pelvic pain) | Gonadorelin analogues plus raloxifene v gonadorelin analogues alone | 4 | –2 | 0 | 0 | 0 | Low | Quality point s deducted for sparse data and incomplete presentation of results |
| 2 (70) | Fibroid/uterine size | Gonadorelin analogues plus tibolone v gonadorelin analogues alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (50) | Fibroid-related symptoms (menorrhagia, pelvic pain) | Gonadorelin analogues plus tibolone v gonadorelin analogues alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (70) | Gonadorelin analogue adverse effects | Gonadorelin analogues plus tibolone v gonadorelin analogues alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 6 (562) | Menstrual blood loss (amenorrhoea) | Gonadorelin analogues v placebo | 4 | –2 | +1 | 0 | 0 | Low | Quality points deducted for poor follow-up and other methodological flaws. Consistency point added for dose response (1 additional RCT, 257 women) |
| 3 (96) | Fibroid size | Intranasal gonadorelin analogues v subcutaneous gonadorelin analogues | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, subjective assessment of outcomes |
| 3 (96) | Menorrhagia | Intranasal gonadorelin analogues v subcutaneous gonadorelin analogues | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, subjective assessment of outcomes |
| 1 (51) | Uterus size | Gonadorelin analogue plus combined oestrogen-progesterone v gonadorelin analogue plus progesterone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (51) | Menorrhagia | Gonadorelin analogue plus combined oestrogen-progesterone v gonadorelin analogue plus progesterone | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for no direct comparison between groups |
| In women scheduled for fibroid surgery, what are the effects of preoperative medical treatments? | |||||||||
| 3 (372) | Improvement in pelvic symptoms | Gonadorelin analogue pre-treatment plus surgery v surgery | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted as only preoperative symptoms assessed |
| 1 (60) | Pregnancy rate | Myomectomy plus gonadorelin analogue pretreatment v myomectomy alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted as not all women had infertility problems |
| 3 (142) | Recurrence of fibroids | Myomectomy plus gonadorelin analogue pretreatment v myomectomy alone | 4 | –1 | –1 | 0 | 1 | Moderate | Quality point deducted for sparse data. Consistency point deducted for conflicting results. Effect size point added for OR less than 5 |
| 1 (25) | Need for further treatment | Gonadorelin analogue plus surgery v gonadorelin analogue alone | 4 | –2 | 0 | 0 | 1 | Moderate | Quality points deducted for sparse data and no blinding of surgical treatment. Effect size point added for RR less than 5 |
| What are the effects of surgical treatments in women with fibroids? | |||||||||
| 2 (171) | Postoperative recovery (and duration of hospital stay) | Laparoscopic myomectomy v abdominal myomectomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (148) | Postoperative recovery | Laparoscopic myomectomy v minilaparotomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (131) | Pregnancy rate | Laparoscopic myomectomy v abdominal myomectomy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (87) | Recurrence of fibroids | Laparoscopic myomectomy v abdominal myomectomy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (152) | Postoperative recovery | Laparoscopically assisted vaginal hysterectomy v total abdominal hysterectomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (239) | Postoperative recovery | Total abdominal hysterectomy v total vaginal hysterectomy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for range of outcomes included |
| 1 (90) | Postoperative recovery | Laparoscopically assisted vaginal hysterectomy v total vaginal hysterectomy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (122) | Postoperative recovery | Total laparoscopic hysterectomy v total abdominal hysterectomy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion criteria reducing generalisability |
| 1 (96) | Menstrual bleeding (amenorrhoea) | Thermal balloon ablation v rollerball endometrial ablation | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted as all women had pre-treatment with gonadorelin analogues |
| 1 (96) | Need for subsequent treatment (hysterectomy) | Thermal balloon ablation v rollerball endometrial ablation | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted as all women had pre-treatment with gonadorelin analogues |
| 1 (96) | Intraoperative complications | Thermal balloon ablation v rollerball endometrial ablation | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted as all women had pre-treatment with gonadorelin analogues |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.
Glossary
- Endometrial resection
Destruction of the endometrium using a cutting tool.
- 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.
- Myomectomy
Removal of fibroids from the uterus. The mode of removal may be abdominal, laparoscopic, or hysteroscopic.
- Pelvic symptom score scale
An ordinal scale that adds the results of pelvic pain and pelvic pressure. Each symptom is evaluated on a scale ranging from 0–3, where 0 means absence of pain, and increasing numbers represent mild, moderate, and severe pain. Because both results are added, the absence of symptoms is represented by 0 and severe pain and pelvic pressure by 6. We found no data on validation of the scale. However, it is commonly used in studies evaluating pelvic pain.
- Pictorial bleeding assessment chart
Used to measure menstrual bleeding. Validation studies indicate that a pictorial bleeding assessment chart score of 100–185 is suggestive of menorrhagia (heavy menstrual bleeding), which is objectively defined by the alkaline haematin test as a menstrual blood loss greater than 80 mL. The chart score used as an end point varies between studies.
- Rollerball endometrial ablation
Destruction of the endometrium using electrical coagulation with a rollerball electrode applied through the cervical os.
- Thermal balloon ablation
Destruction of the endometrium using pressure from a balloon catheter inserted through the cervical os and then filled with fluid to a pressure of 160–180 mm Hg and heated to about 87 °C.
- Total hysterectomy
Removal of the uterus. The mode of removal may be through the abdominal wall (total abdominal hysterectomy), through the vagina (total vaginal hysterectomy), partially through the vagina and partially morcellated and removed by laparoscopic incision (laparoscopically assisted vaginal hysterectomy), or entirely by laparoscopic excision (total laparoscopic hysterectomy). In some situations, total abdominal hysterectomy is performed in conjunction with a bilateral salpingo-oophorectomy — the removal of both ovaries and fallopian tubes.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Menorrhagia (many women with fibroids experience symptoms of heavy menstrual bleeding). See menorrhagia.
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
Anne Elizabeth Lethaby, Cochrane Menstrual Disorders and Subfertility Group, Auckland, New Zealand.
Dr Beverley Janine Vollenhoven, Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
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