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Clinical presentation of fibroids
Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 22, No. 4, pp. 615–626, 2008 doi:10.1016/j.bpobgyn.2008.01.008 available online at http://www.sciencedirect.com
4 Clinical presentation of fibroids Sahana Gupta
MRCOG
Specialist Registrar
Jude Jose
MRCOG
Specialist Registrar Obstetrics & Gynaecology, Queen’s Hospital, Romford, UK
Isaac Manyonda *
BSc, PhD, MRCOG
Consultant Gynaecologist St George’s Hospital, Blackshaw Road, London SW17 0QT, UK
Uterine fibroids, the most common tumours in women of reproductive age, are asymptomatic in at least 50% of afflicted women. However, in other women, they cause significant morbidity and affect quality of life. Clinically, they present with a variety of symptoms: menstrual disturbances including menorrhagia, dysmenorrhoea and intermenstrual bleeding; pelvic pain unrelated to menstruation; and pressure symptoms such as a sensation of bloatedness, increased urinary frequency and bowel disturbance. In addition, they may compromise reproductive function, possibly contributing to subfertility, early pregnancy loss and later pregnancy complications such as pain, preterm labour, malpresentations, increased need for caesarean section, and postpartum haemorrhage. Large fibroids may distend the abdomen, which may be aesthetically displeasing to many women. Abnormal bleeding occurs in 30% of symptomatic women, and abnormal bleeding, bloating and pelvic discomfort due to mass effect constitute the most common symptoms. The incidence of fibroids is highest in Black women, who tend to have multiple and larger fibroids, and more symptomatic fibroids at the time of diagnosis. The prevalence of clinically significant myomas peaks in the perimenopausal years and declines after the menopause. It is not known why some fibroids are symptomatic while others are quiescent. The size, number and location of fibroids undoubtedly determine their clinical behaviour, but research has yet to correlate these parameters with clinical presentation of the fibroids. Key words: fibroids; myoma; leiomyomas; menorrhagia; dysmenorrhoea; intramural fibroid; subserosal fibroid; submucosal fibroid; pelvic pain; subfertility; miscarriage; pregnancy.
* Corresponding author. Tel.: þ44 (0)20 8725 3663; Fax: þ44 (0)20 8725 0078. E-mail address: [email protected] (I. Manyonda). 1521-6934/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
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Fibroids (myomas or leiomyomas) are essentially benign tumours which are rarely associated with mortality, but which cause significant morbidity and have an adverse effect on quality of life.1 Due to their high prevalence, it might be anticipated that the incidence of leiomyoma-associated symptoms would be high, but in fact, the majority of fibroids (estimated to be in excess of 50%) are asymptomatic.2–5 When women with fibroids present with symptoms, it is not always possible to be certain that it is the fibroids that are causing the symptoms. The symptoms that are associated with fibroids are very variable, but often begin as an insidious feeling of discomfort and may include pelvic pressure, congestion, bloating, heaviness, dyspareunia, urinary frequency, constipation, reproductive dysfunction and abnormal bleeding. Abnormal bleeding occurs in 30% of patients.4 Abnormal uterine bleeding, abdominal bloating and pelvic discomfort due to mass effect are the most common symptoms.6 Approximately 62% of women with symptomatic myomas present with multiple symptoms.7 Black women tend to have more symptomatic tumours at the time of diagnosis, and usually present with multiple and larger fibroids.8–10 The incidence and severity of symptoms associated with leiomyomas vary with size, number and location, as well as concomitant degenerative changes.2,11,12 The prevalence of clinically significant myomas peaks in the perimenopausal years and declines following the menopause.13 There is controversy about the impact of fibroids on reproductive function, especially with regard to whether they cause subfertility or miscarriage. In later pregnancy, they may enlarge and can be associated with various adverse outcomes such as abruption, intra-uterine growth restriction (IUGR) and increased need for operative delivery.11 ABNORMAL VAGINAL BLEEDING Excessive menstrual bleeding is often the sole symptom reported by women with leiomyomas.6 The bleeding pattern most characteristic of myomas is menorrhagia, i.e. an increase in the amount of blood loss per month, and prolonged vaginal bleeding.14 Neither of these patterns is diagnostic nor is one bleeding pattern more common, with many women experiencing both patterns. The bleeding can be sufficiently severe to cause iron-deficiency anaemia. It may lead to social isolation and loss of productive time because of the need to change sanitary towels frequently.2,6 The quoted incidence of abnormal bleeding of 30% belies the fact that few data verify this, just as the exact mechanism by which fibroids cause abnormal bleeding is unknown. In a recent study that evaluated premenopausal women with and without abnormal vaginal bleeding, women with abnormal bleeding were significantly more likely to have either an intramural (58% vs 13%) or submucous leiomyoma (21% vs 1%) when compared with asymptomatic women.15 Although this study did not directly assess the proportion of women with leiomyomas who had abnormal bleeding, it demonstrated that women who present with abnormal uterine bleeding are more likely to have a leiomyoma, and that women with either intramural or submucous leiomyomas could be asymptomatic. In other words, the mere presence of myomas does not necessarily lead to menorrhagia. Therefore, other possible aetiologies should be considered, including coagulopathies such as Von Willebrand’s disease.16 When a population-based, non-care-seeking cohort of women was evaluated with abdominal and transvaginal sonography, myomas were detected in 73 women (21.4%). After adjustment of covariates, the presence of any myoma was not significantly related to the length of menstrual cycle (P ¼ 40) or heaviness of flow [odds ratio (OR) 1.3, 95% confidence interval (CI) 0.7–2.5%]. Neither the number, volume or
Clinical presentation of fibroids 617
location (subserosal or intramural, anterior or posterior position) of myomas were related to menstrual cycle characteristics. The sample was too small to analyse the impact of submucosal tumours.17 A random sample of women aged 35–49 years was evaluated by self-reported bleeding patterns and by abdominal and transvaginal sonography to determine the presence, size and location of myomas. Of the 878 women screened, 64% had myomas and 36% did not. Of the women with myomas, 46% reported gushing of blood during their menstrual cycle compared with 28% of women without myomas. Gushing of blood and length of periods were related to the size of myomas (large myomas, relative risk 1.9, 95%CI 1.5–2.5), but not to the location or number of myomas. The same study showed that women with myomas larger than 5 cm had slightly more gushing of blood, and used an additional three or more pads or tampons on the heaviest day of bleeding than women with smaller myomas.18 As alluded to above, the pathophysiology of abnormal uterine bleeding associated with uterine leiomyomas is unknown. Some theories have been advanced as follows:2 increased endometrial surface area;19 increased vascularity of the uterus; interference with normal uterine contractility; endometrial ulceration over submucous leiomyomas, which could also cause intermenstrual bleeding; and compression of venous plexus within the myometrium, leading to endometrial venule ectasia which results in the congestion of myometrium and endometrium leading to profuse menstrual bleeding.20,21
Women presenting with metrorrhagia should be investigated fully to exclude other endometrial pathologies, since this symptom is not characteristic of myomas.6 Submucous myomas deserve a special mention as they cause abnormal vaginal bleeding in a number of ways. Hypermenorrhoea may be enhanced by the presence of an endometritis which is a frequent histological finding within the endometrium overlying submucous myomas.6,22 They may also lead to intermenstrual bleeding by ulcerating through the endometrial lining, or causing distortion and congestion of the surrounding vessels.3 Although a rare occurrence, a submucous myoma may prolapse through the cervix resulting in profuse bleeding.2,6 Recent basic science investigations into leiomyomas have indicated dysregulation of several growth factors or their receptors that have direct effects on vascular function and angiogenesis.23 These changes may be responsible for vascular abnormalities leading to dysregulation of the vascular structures in the uterus and subsequent menorrhagia. Myomas commonly regress after the menopause, which is accompanied by atrophy of the endometrium and cessation of uterine bleeding. It has been reported that postmenopausal women with submucous myomas using hormone therapy have a two-fold increased risk of experiencing abnormal bleeding compared with women without submucous myomas.24 PELVIC PAIN Pelvic pain or pressure is a fairly common symptom in women with leiomyomas, although women with myomas are only slightly more likely to experience pain than women without myomas.1 Transvaginal sonography was performed on a population-based cohort of
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635 non-care-seeking women with an intact uterus to determine the presence of uterine myomas. Concurrent symptoms of dyspareunia, dysmenorrhoea or non-cyclic pelvic pain were measured by visual analogue scale. The 96 women with myomas were only slightly more likely to report moderate or severe dyspareunia (OR 2.8, 95%CI 0.9– 8.3) or non-cyclic pelvic pain (OR 2.6, 95%CI 0.9–7.6), and had no higher incidence of moderate or severe dysmenorrhoea (OR 1.1, 95%CI 0.59–2.6) compared with women without myomas. Neither the number nor the total volume of myomas was related to pain.25 It should, however, be appreciated that increased menstrual flow in itself may be associated with dysmenorrhoea, especially if it is associated with the passage of blood clots, which is, of course, more likely if the flow is heavy in the first place. The pelvic and abdominal discomfort that women experience with myomas is often referred to as a sensation of pressure, and could be similar to the discomfort that women experience during pregnancy caused by uterine growth.2 The location of the pain/pressure is related to the location of the fibroids; thus, fibroids located posteriorly may cause lower back pain, while anterior tumours may cause bladder discomfort and increased urinary frequency. Leiomyomas that fill the pelvis may cause difficulty with urination, defaecation and dyspareunia.2 Acute pain is usually associated with torsion of the pedicle of a pedunculated myoma, cervical dilatation by a submucous myoma protruding through the lower uterine segment, or so-called ‘red degeneration’ associated with pregnancy where haemorrhage occurs within the leiomyoma, causing an acute onset of pain.26 Pain can also occur when the uterus with the fibroid becomes incarcerated within the pelvis.4,27 Rarely, myomas in the broad ligament may cause unilateral lower abdominal pain or sciatic nerve pain.2,6 Uterine myomas as large as 100 lbs have been reported. These large myomas may outgrow their blood supply, leading to ischaemia and necrosis within the tumour. This degeneration is usually associated with severe acute pain which may necessitate surgical exploration.6 Such large myomas can also be expected to cause respiratory compromise.2 It is important to emphasize, however, that pain is not a common presenting feature of fibroids, and it would constitute a clinical error to readily attribute pelvic pain to fibroids. Other pathologies such as ectopic pregnancy, rupture/torsion of an ovarian cyst or acute pelvic inflammatory disease must be considered in any woman with identifiable myomas who experiences acute abdominal pain. While myomas are frequently associated with adenomyosis, which can cause pain, such pain is usually associated with menstruation (dysmenorrhoea). At the best of times, adenomyosis is a difficult condition to diagnose, and this becomes especially true in a uterus distorted by myomas. Magnetic resonance imaging may be helpful,26 but the definitive diagnosis is based on tissue histology, usually following hysterectomy or from biopsies obtained at myomectomy. PELVIC MASS SYMPTOMS The diagnosis of myomas is often suspected on the basis of palpation of an enlarged uterine contour on pelvic examination. By convention, the size of the myomatous uterus is described in menstrual weeks (as with the pregnant uterus), and a uterus of more than 12 weeks in size may be palpated on abdominal examination.14 In a study of 2623 healthy asymptomatic volunteers (mean age 51 years, range 25–92 years) who underwent pelvic examination as part of an ovarian screening programme, a bulky or fibroid uterus was detected in 12.9% of women.28
Clinical presentation of fibroids 619
Pelvic pressure arises with increasing uterine size, and pressure and increased abdominal girth are more commonly encountered than pain. These symptoms develop insidiously and are often vaguely described. Women presenting with masses as large as 28 weeks often say that they thought they were simply putting on weight, especially if the fibroids had caused no change in menstrual pattern and if they had experienced no pain. As the tumours grow, pressure is exerted on adjacent organs, especially the urinary tract and recto-sigmoid.6 The dynamics of the bladder and its capacity may change; the capacity at first desire to void as well as maximum bladder capacity can be reduced, causing increased urinary frequency. Urinary incontinence can also be associated with uterine leiomyomas, but such women should be evaluated fully for detrusor over-activity and genuine stress incontinence as these disorders may co-exist with uterine leiomyomas.2 Some women may experience voiding difficulties as a result of changes in the urethrovesical junction. They may complain of difficulty initiating micturition, or incomplete bladder emptying. Unilateral or bilateral ureteral compression has been reported, and it may cause hydronephrosis and compromise renal function. Ureteral compression is more likely to occur when the myoma is located in the broad ligament or the lateral aspect of the uterine fundus.2 It is remarkable that although it seems evident that a large pelvic mass such as a myoma might be expected to cause urinary dysfunction, research on this issue is scant. Fourteen women with large myomas and urinary symptoms were given a total of six injections of a gonadotrophin-releasing hormone (GnRH) agonist, administered monthly, which resulted in a 55% decrease in uterine volume. Associated with this was a decrease in urinary frequency, nocturia and urgency, but urge and stress incontinence remained unchanged as measured by symptoms or urodynamic studies. It is unclear whether these findings are related to a decrease in uterine volume, or reflect other effects of the GnRH treatment.29 In another study where women underwent uterine artery embolization and experienced a 35% reduction in mean uterine volume, frequency and urgency were greatly improved in 53% of women (n ¼ 306), moderately improved in 15%, slightly improved in 18%, and unchanged or worse in 14%.30 These findings suggest that it is the increased uterine volume associated with myomas that is likely to be responsible for the urinary symptoms. A posterior wall fibroid exerting pressure on the recto-sigmoid could cause constipation or tenesmus. Rectal pressure may occur because of the incarceration of the myomatous uterus in the cul-de-sac, or due to the presence of a large posterior uterine myoma.6 However, it is imperative that women presenting with altered bowel habit and fibroids should be evaluated fully to exclude other bowel pathology. REPRODUCTIVE DYSFUNCTION The impact of fibroids on reproductive function is dealt with extensively in another chapter in this issue (see Khaund and Lumsden). However, since reproductive dysfunction could be a mode of fibroid presentation, the issue will be dealt with here briefly for completeness. If, at a conservative estimate, 30% of women have a fibroid(s) by the age of 30 years, and since in industrialized countries, women are embarking on their first pregnancy in their 30s or later, fibroids will be found frequently in association with pregnancy.6 As the vast majority of women have successful pregnancies, it is reasonable to suppose that the vast majority of fibroids do not have an adverse effect on pregnancy. While this is likely to be the case, depending on their size, number and location, fibroids
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may distort uterine anatomy, and thereby interfere with normal uterine physiology. It then becomes teleologically sound to suppose that in some cases, fibroids could indeed have an adverse effect on reproductive function. It has been suggested that this could include subfertility, miscarriage and later pregnancy complications, including pain (red degeneration), premature rupture of membranes, preterm labour, placental abruption, malpresentations, unstable lie, IUGR, increased operative deliveries, postpartum haemorrhage, retained placenta and puerperal sepsis. Is there evidence for this, and how robust is this evidence? Subfertility The American Society of Reproductive Medicine has reported that uterine myomas are associated with infertility in 5–10% of cases,31 but when all other causes of infertility are excluded, it is generally thought that myomas may be responsible for only 2–3% of infertility cases.32 There are fundamental problems with research in this area; both fibroids and infertility increase with age, and so does the risk of aneuploidy and subsequent pregnancy loss. In addition, normal reproductive function involves numerous factors such as ovulation, fallopian tube function, fertilization and nidation; all confounding variables that may be difficult to control for when assessing the impact of a single factor such as fibroids on fertility.2 Although it is thought that 27% of infertile women have myomas, there are no data to assess whether the proportion of infertile women with myomas is greater than the proportion of normally fertile women with myomas.2 As a result, the natural history of fibroids and their association with reproductive dysfunction remains unclear. The definitive study, which has yet to be undertaken, will recruit women who are planning a pregnancy, establish whether or not they have fibroids, and then assess their rate of conception; such a study would go a long way towards establishing whether or not fibroids cause subfertility. Provided it is appropriately powered, the same study would also give important data on the impact of fibroids on early pregnancy loss, as well as later pregnancy complications. Data from studies on patients undergoing assisted reproduction technology (ART) suggest that submucosal fibroids and intramural fibroids distorting the uterine cavity compromise success with ART; therefore, such fibroids should be removed. Evidence points to improved outcomes after such intervention.33 It remains unclear whether purely intramural fibroids compromise ART, but the overall impression is that subserosal fibroids do not. In non-ART situations, myomectomy, whether by the conventional abdominal route or laparoscopically, appears to be associated with improved pregnancy rates.34 Again, studies are fraught with confounding variables such as myoma diagnostic methods, type of evaluation of the uterine cavity, size and number of myomas, patient age and type of fertility treatment. Most studies lack the statistical power to reach valid conclusions. Miscarriage Several reports have suggested that first- and second-trimester miscarriage rates are higher in women with fibroids, and fibroids have been implicated in recurrent pregnancy loss.22,35 In a review of 1941 cases of myomectomy that included pre- and postoperative abortion rates, the rate of miscarriage in the next pregnancy was found to be reduced from 41% to 19%.36 In reality, however, the literature reports highly
Clinical presentation of fibroids 621
variable rates of miscarriage in association with fibroids, and the impact of myomectomy. From a practical point of view, it seems reasonable to offer a hysteroscopic resection to a woman presenting with recurrent pregnancy loss and submucosal fibroid(s); it is an easy operation that would also cure the woman of other symptoms associated with submucosal fibroids.37 Myomectomy in a similar woman with an intramural fibroid significantly distorting the uterine cavity would also seem to be reasonable. However, there are insufficient data to aid in decision making when purely intramural or subserosal fibroids are found in women presenting with miscarriage. Later pregnancy complications Red degeneration, presenting with acute pain in pregnancy, is probably the classically recognized complication specifically associated with fibroids in pregnancy. Its incidence in terms of symptoms and sonographic evidence is about 5%.38,39 It is unknown precisely why some women develop this complication while others do not. Pregnancy appears to have variable and unpredictable effects on myoma growth; there is controversy regarding whether they increase, decrease or remain the same size. However, it appears that most myomas do not increase in size during pregnancy. Any increase in size occurs in early pregnancy, after which they remain stable or decrease in size. Larger myomas often reduce in size late in pregnancy.38 It is probably the case that the presence of myoma(s) during pregnancy very seldom leads to an unfavourable outcome. Current literature regarding the effect of myomas in pregnancy is ridden with problems, the most significant of which is probably selection bias.1 However, three studies have reported on large populations of pregnant women examined with routine second-trimester sonography with follow-up and delivery at the same institution. In one study, 12 600 women were evaluated and the outcomes of 167 women with myomas were compared with women without myomas. There were no significant differences in the incidence of preterm delivery, premature rupture of membranes, IUGR, placenta praevia, abruption, postpartum haemorrhage or retained placenta. Only caesarean section was more common among women with myomas (23% vs 12%, P < 0.001).39 In another study, 15 104 pregnancies were reviewed and the 401 women found to have myomas were compared with controls. There was increased risk of preterm delivery (19.2% vs 12.7%), placenta praevia (3.5% vs 1.8%), postpartum haemorrhage (8.3% vs. 2.9%) and caesarean section (49.1% vs 21.4%) in the myoma group. No increase was detected in the incidence of premature rupture of membranes, operative vaginal delivery, chorioamnionitis or endomyometritis.40 In the third population-based study, the authors evaluated a large sample of women located in one state and included a control group. Pregnant women with myomas were more likely to be above 35 years of age, nulliparous and Black, and were at an increased risk for first-trimester bleeding, premature rupture of membranes, placental abruption, breech presentation, prolonged labour, low APGAR scores and low birth weight. The study controlled for confounding factors such as maternal age, race, previous caesarean section, maternal weight gain, diabetes and hypertension.41 Rupture of myomectomy scar If myomectomy improves pregnancy rates in selected cases, it is reasonable to consider whether the scarring of the uterus from the myomectomy might predispose
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to scar rupture during pregnancy or labour. Only one out of 76 cases of uterine rupture in the third trimester in a group of 98 872 deliveries had a previous myomectomy.42 Similarly, a review of 137 582 pregnancies found 133 cases of uterine rupture after the 28th week of pregnancy, of which three followed abdominal myomectomy.43 Neither of these studies recorded the number of women with previous myomectomy, and therefore the true incidence of scar rupture cannot be calculated. Eleven reports of uterine rupture following laparoscopic myomectomy have been published.44–53 Concerns have been raised about scar integrity following laparoscopic myomectomy, but in expert laparoscopic hands, this should not pose a major problem.54 The bottom line is that in modern-day surgical practice, scar rupture in pregnancy following myomectomy is a rare event. MALIGNANCY Malignant transformation of myomas is extremely rare and the general consensus is that leiomyosarcomas arise de novo and are unrelated to benign leiomyomata.55,56 Two earlier studies quoted rates of 0.13 and 0.29%,57,58 while a more recent study quoted 0.23.59 Given the fact that only a small percentage of women with myomas are symptomatic and may require surgery, a more realistic figure for malignancy with presumed uterine myomas is probably much smaller than the rates cited above.26 RARE ASSOCIATIONS Myomas may be parasitic, being attached to the omentum from which they derive their blood supply. Floating myomas may lead to obstruction of these vessels, resulting in transudation and development of ascitis. Rarely, secondary polycythaemia may occur in association with myomas due to raised erythropoietin, and this resolves following hysterectomy.6 There are several reports of familial clustering of uterine myomas, and it is suggested that myomas are four to five times more common in first-degree relatives of women with myomas.60,61 Some inherited disorders have been defined; e.g. Reed syndrome, in which multiple myomas are present in both the skin and the uterus.62 Recently, there have been reports of various families in England and Finland with uterine and cutaneous myomas and papillary renal cell carcinoma, which were linked to mutations in the fumarate hydratase gene.63 The finding of cutaneous myomas in a woman should prompt screening of the patient and her family, not only for renal cell carcinoma but also for uterine sarcomas which are more common in these patients and their immediate families. Benign metastasizing myomas are characterized by myoma-like lesions, usually in the lungs, in women with myomas. Intravenous leiomyomatosis is a hormonally responsive disease that manifests as vermiform extensions arising in the uterus and extending as far as the heart.64 SUMMARY Uterine myomas are the most common solid pelvic tumours in women of reproductive age, and more than 50% are asymptomatic. When they are symptomatic, they often present with abnormal vaginal bleeding and pelvic discomfort. Myomas may also cause pain and urinary/bladder symptoms due to pressure effects. When their location
Clinical presentation of fibroids 623
is submucosal and/or intramural causing distortion of the uterine cavity, they appear to cause significant reproductive dysfunction, with their removal resulting in improved fertility and reduced risk of miscarriage. It is unlikely that myomas interfere with fertility and cause miscarriage when located purely intramurally, or when they are subserosal. Red degeneration, presenting as acute pain during pregnancy, is a classic association, but it is reasonable to suppose that fibroids cause other later pregnancy complications, in part by their mass effect, and such complications could include preterm labour, malpresentations, IUGR and placental abruption. If they are located in the lower uterine segment, they may interfere with engagement of the fetal head and/or cause malpositioning, and in this way they will increase the risk of operative delivery. Through their mass effect, they can interfere with uterine contraction following delivery, and predispose to postpartum haemorrhage and possibly pelvic sepsis. Malignant transformation is a rare event and may be suspected in postmenopausal women with rapidly growing tumours. It is more likely that leiomyosarcoma arises de novo rather than reflecting transformation of a previously benign myoma. A great deal of research is required to elucidate many aspects of fibroid disease.
Practice points approximately 50% of fibroids are asymptomatic most symptomatic fibroids present with abnormal bleeding and pressure symptoms although fibroids may present with pelvic pain, other causes must be ruled out because pain is not a common clinical presentation while women with fibroids may present with constipation and tenesmus, other more sinister causes must be ruled out because fibroids do not commonly cause these symptoms data from studies in ART suggest that submucosal and intramural fibroids distorting the uterine cavity compromise fertility, and their removal improves fertility treatment outcomes purely intramural and subserosal fibroids do not appear to compromise reproductive function although fibroids may cause or be associated with a range of complications in later pregnancy and labour, these complications are rare relative to the incidence of fibroids when a leiomyosarcoma occurs in a woman with fibroids, it is more likely that the malignancy has arisen de novo rather than being a malignant transformation of a previously benign tumour
Research agenda symptomatic versus quiescent fibroids: what renders some fibroids symptomatic and others quiescent? definitive population-based studies of the extent of the contribution of fibroids to subfertility and early pregnancy loss
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8. 9. 10. *11. 12. 13. *14. 15. 16. 17. 18. *19. 20. 21. *22. 23. 24. 25. *26. 27. 28.
Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007; 87: 725–736. Stovall DW. Clinical symptomatology of uterine leiomyomas. Clin Obstet Gynaecol 2001; 44: 364–371. Christiansen JK. The facts about fibroids. Postgrad Med 1993; 9: 129–137. Lacey CG. Benign disorders of the uterine corpus. In Pernoll ML (ed.). Current Obstetric and Gynaecologic Diagnosis and Treatment. 7th edn. Norwalk, CT: Appleton & Lange, 1991, pp. 732–738. Friedman AJ, Hoffman DI, Comite F et al. Treatment of leiomyomata uteri with leuprolide acetate depot: a double blind placebo controlled multicentre study. Obstet Gynaecol 1991; 77: 720–725. Bukulmez O & Doody KJ. Clinical features of myomas. Obstet Gynaecol Clin N Am 2006; 33: 69–84. Olufowobi O, Sharif K, Papaionnou S et al. Are the anticipated benefits of myomectomy achieved in women of reproductive age? A five year review of the results at a tertiary hospital. J Obstet Gynecol 2004; 24: 434–440. Day Baird D, Dunson DB, Hill MC et al. High cumulative incidence of leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003; 188: 100–107. Kjerulff KH, Langenberg P, Seidman JD et al. Uterine leiomyomas: racial differences in severity, symptoms and age at diagnosis. J Reprod Med 1996; 41: 483–490. Marshall LM, Spiegelman D, Barbieri RL et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 1997; 90: 967–973. Lumsden MA & Wallace EM. Clinical presentation of uterine fibroids. Baillieres Clin Obstet Gynaecol 1998; 12: 177–195. Ozumba BC, Megafu UC & Igwegbe AO. Uterine fibroids: clinical presentation and management in a Nigerian teaching hospital. Ir Med J 1992; 85: 158–159. Flake GP, Andersen J & Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 2003; 111: 1037–1054. Stewart EA. Uterine fibroids. Lancet 2001; 357: 293–298. Clevenger-Hoeft M, Syrop CH, Stovall DW et al. Sonohysterography in premenopausal women with and without abnormal bleeding. Obstet Gynecol 1999; 2: 295–306. Munro MG & Lukes AS. Abnormal uterine bleeding and underlying haemostatic disorders: report of a consensus process. Fertil Steril 2005; 84: 1335–1337. Marino JL, Eskenazi B, Warner M et al. Uterine leiomyomata and menstrual cycle characteristics in a population-based cohort study. Hum Reprod 2004; 19: 2350–2355. Wegienka G, Baird DD, Hertz-Picciotto I et al. Self-reported heavy bleeding associated with uterine leiomyomata. Obstet Gynecol 2003; 101: 431–437. Sehgal N & Haskins AL. The mechanism of uterine bleeding in the presence of fibromyomas. Am Surg 1960; 26: 21–23. Farrer-Brown G, Beilby JO & Tarbit MH. The vascular pattern in myomatous uteri. J Obstet Gynaecol Br Commonw 1970; 77: 967–975. Farrer-Brown G, Beilby JO & Tarbit MH. Venous changes in endometrium of myomatous uteri. Obstet Gynecol 1971; 38: 743–751. Propst AM & Hill 3rd JA. Anatomic factors associated with recurrent pregnancy loss. Semin Reprod Med 2000; 18: 341–350. Stewart EA & Nowak RA. Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era. Hum Reprod Update 1996; 2: 295–306. Akkad AA, Habiba MA, Ismail N et al. Abnormal uterine bleeding on hormone replacement: the importance of intrauterine structural abnormalities. Obstet Gynecol 1995; 86: 354–357. Lippman SA, Warner M, Samuels S et al. Uterine fibroids and gynaecologic pain symptoms in a population based study. Fertil Steril 2003; 80: 1488–1494. Wallach EE & Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 2004; 104: 393–406. Moore JG. Benign diseases of the uterus. In Hacker NF & Moore JG (eds.). Essentials of Obstetrics and Gynaecology. 1st ed. Philadelphia: Saunders, 1986, pp. 272–276. Grover SR & Quinn MA. Is there any value in bimanual pelvic examination as a screening test. Med J Aust 1995; 162: 408–410.
Clinical presentation of fibroids 625 29. Langer R, Golan A, Neuman M et al. The effect of large uterine fibroids on urinary bladder function and symptoms. Am J Obstet Gynecol 1990; 163: 1139–1141. 30. Pron G, Bennet J, Common A et al. The Ontario Uterine Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids. Fertil Steril 2003; 79: 120–127. 31. Practice Committee of the American Society for Reproductive Medicine. Myomas and reproductive function. Fertil Steril 2004; 82(Suppl. 1): S111–S116. 32. Buttram Jr. VC & Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1982; 36: 433–445. 33. Fernandez H, Sefrioui O, Virelizier C et al. Hysteroscopic resection of submucosal myomas in patients with infertility. Hum Reprod 2001; 16: 1489–1492. 34. Bulletti C, Ziegler D, Levi Setti P et al. Myomas, pregnancy outcome, and in vitro fertilization. Ann NY Acad Sci 2004; 1034: 84–92. 35. Benson CB, Chow JS, Chang-Lee W et al. Outcome of pregnancies in women with uterine leiomyomas identified by sonography in the first trimester. J Clin Ultrasound 2001; 29: 261–264. 36. Buttram Jr. VC & Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1981; 36: 433–445. 37. Manyonda I, Sinthamoney E & Belli AM. Controversies and challenges in the modern management of uterine fibroids. BJOG 2004; 111: 95–102. 38. Lev-Toaff AS, Coleman BG, Arger PH et al. Leiomyomas in pregnancy: sonographic study. Radiology 1987; 164: 375–380. 39. Vergani P, Ghidini A, Strobelt N et al. Do uterine leiomyomas influence pregnancy outcome? Am J Perinatol 1994; 11: 356–358. 40. Qidwai GI, Caughey AB & Jacoby AF. Obstetric outcome in women with sonographically detected uterine leiomyomata. Obstet Gynecol 2006; 107: 376–382. *41. Coronado GD, Marshall LM & Schwartz SM. Complications in pregnancy, labor and delivery with uterine leiomyomas: a population based study. Obstet Gynecol 2000; 95: 764–769. 42. Palerme GR & Friedman EA. Rupture of the gravid uterus in the third trimester. Am J Obstet Gynecol 1966; 94: 571–576. 43. Garnet JD. Uterine rupture during pregnancy. An analysis of 133 patients. Obstet Gynecol 1964; 23: 898– 905. 44. Pelosi 3rd MA & Pelosi MA. Spontaneous uterine rupture at thirty three weeks subsequent to previous superficial myomectomy. Am J Obstet Gynecol 1997; 177: 1547–1549. 45. Hasbergen U, Summerer-Moustaki M, Hillemanns P et al. Uterine dehiscence in a nullipara, diagnosed by MRI, following use of unipolar electrocautery during laparoscopic myomectomy: a case report. Hum Reprod 2002; 17: 2180–2182. 46. Lieng M, Istre O & Langebrekke A. Uterine rupture after laparoscopic myomectomy. J Am Assoc Gynecol Laparosc 2004; 11: 92–93. 47. Dubuisson JB, Chavet X, Chapron C et al. Uterine rupture during pregnancy after laparoscopic myomectomy. Hum Reprod 1995; 10: 1475–1477. 48. Harris WJ. Uterine dehiscence following laparoscopic myomectomy. Obstet Gynecol 1992; 80: 545–546. 49. Hockstein S. Spontaneous uterine rupture in the early third trimester after laparoscopically assisted myomectomy. A case report. J Reprod Med 2000; 45: 139–141. 50. Oktem O, Gokaslan H & Durmusoglu F. Spontaneous uterine rupture in pregnancy 8 years after laparoscopic myomectomy. J Am Assoc Gynecol Laparosc 2001; 8: 618–621. 51. Asakura H, Oda T, Tsunoda Y et al. A case report: change in fetal heart rate pattern on spontaneous uterine rupture at 35 weeks gestation after laparoscopically assisted myomectomy. J Nippon Med Sch 2004; 71: 69–72. 52. Banas T, Klimek M, Fugiel A et al. Spontaneous uterine rupture at 35 weeks’ gestation, 3 years after laparoscopic myomectomy, without signs of fetal distress. J Obstet Gynaecol Res 2005; 31: 527–530. 53. Grande N, Catalano GF, Ferrari L et al. Spontaneous uterine rupture in the third trimester of gestation after laparoscopic myomectomy. A case report. Minerva Ginecol 2004; 56: 479–480 [in Italian]. 54. Seracchioli R, Manuzzi L, Vianello F et al. Obstetric and delivery outcome of pregnancies achieved after laparoscopic myomectomy. Fertil Steril 2006; 86(1): 159–165. 55. Rein MS, Freidman AJ, Barbieri RL et al. Cytogenetic abnormalities in uterine leiomyomata. Obstet Gynecol 1991; 77: 923–926.
626 S. Gupta et al 56. Levy B, Mukherjee T & Hirschhorn K. Molecular cytogenetic analysis of uterine leiomyoma and leiomyosarcoma by comparative genomic hybridization. Cancer Genet Cytogenet 2000; 121: 1–8. 57. Montague AC, Swartz DP & Woodruff JD. Sarcoma arising in a leiomyoma of the uterus: factors influencing prognosis. Am J Obstet Gynecol 1965; 92: 421–427. 58. Corscaden JA & Singh BP. Leiomyosarcoma of the uterus. Am J Obstet Gynecol 1958; 75: 149–153 (discussion:153-5). 59. Parker WH, Fu YS & Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol 1994; 83: 414–418. 60. Vikhlyaeva EM, Khodzhaeva ZS & Fantschenko ND. Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet 1995; 51: 127–131. 61. Schwartz SM, Marshall LM & Baird DD. Epidemiologic contributions to understanding the etiology of uterine leiomyomata. Environ Health Perspect 2000; 108(Suppl. 5): 821–827. 62. Reed WB, Walker R & Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venerol 1973; 53: 409–416. 63. Tomlinson IP, Alam NA, Rowan AJ et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30: 406–410. 64. Walker CL & Stewart EA. Uterine fibroids: the elephant in the room. Science 2005; 308: 1589–1592.
4 Clinical presentation of fibroids Sahana Gupta
MRCOG
Specialist Registrar
Jude Jose
MRCOG
Specialist Registrar Obstetrics & Gynaecology, Queen’s Hospital, Romford, UK
Isaac Manyonda *
BSc, PhD, MRCOG
Consultant Gynaecologist St George’s Hospital, Blackshaw Road, London SW17 0QT, UK
Uterine fibroids, the most common tumours in women of reproductive age, are asymptomatic in at least 50% of afflicted women. However, in other women, they cause significant morbidity and affect quality of life. Clinically, they present with a variety of symptoms: menstrual disturbances including menorrhagia, dysmenorrhoea and intermenstrual bleeding; pelvic pain unrelated to menstruation; and pressure symptoms such as a sensation of bloatedness, increased urinary frequency and bowel disturbance. In addition, they may compromise reproductive function, possibly contributing to subfertility, early pregnancy loss and later pregnancy complications such as pain, preterm labour, malpresentations, increased need for caesarean section, and postpartum haemorrhage. Large fibroids may distend the abdomen, which may be aesthetically displeasing to many women. Abnormal bleeding occurs in 30% of symptomatic women, and abnormal bleeding, bloating and pelvic discomfort due to mass effect constitute the most common symptoms. The incidence of fibroids is highest in Black women, who tend to have multiple and larger fibroids, and more symptomatic fibroids at the time of diagnosis. The prevalence of clinically significant myomas peaks in the perimenopausal years and declines after the menopause. It is not known why some fibroids are symptomatic while others are quiescent. The size, number and location of fibroids undoubtedly determine their clinical behaviour, but research has yet to correlate these parameters with clinical presentation of the fibroids. Key words: fibroids; myoma; leiomyomas; menorrhagia; dysmenorrhoea; intramural fibroid; subserosal fibroid; submucosal fibroid; pelvic pain; subfertility; miscarriage; pregnancy.
* Corresponding author. Tel.: þ44 (0)20 8725 3663; Fax: þ44 (0)20 8725 0078. E-mail address: [email protected] (I. Manyonda). 1521-6934/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
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Fibroids (myomas or leiomyomas) are essentially benign tumours which are rarely associated with mortality, but which cause significant morbidity and have an adverse effect on quality of life.1 Due to their high prevalence, it might be anticipated that the incidence of leiomyoma-associated symptoms would be high, but in fact, the majority of fibroids (estimated to be in excess of 50%) are asymptomatic.2–5 When women with fibroids present with symptoms, it is not always possible to be certain that it is the fibroids that are causing the symptoms. The symptoms that are associated with fibroids are very variable, but often begin as an insidious feeling of discomfort and may include pelvic pressure, congestion, bloating, heaviness, dyspareunia, urinary frequency, constipation, reproductive dysfunction and abnormal bleeding. Abnormal bleeding occurs in 30% of patients.4 Abnormal uterine bleeding, abdominal bloating and pelvic discomfort due to mass effect are the most common symptoms.6 Approximately 62% of women with symptomatic myomas present with multiple symptoms.7 Black women tend to have more symptomatic tumours at the time of diagnosis, and usually present with multiple and larger fibroids.8–10 The incidence and severity of symptoms associated with leiomyomas vary with size, number and location, as well as concomitant degenerative changes.2,11,12 The prevalence of clinically significant myomas peaks in the perimenopausal years and declines following the menopause.13 There is controversy about the impact of fibroids on reproductive function, especially with regard to whether they cause subfertility or miscarriage. In later pregnancy, they may enlarge and can be associated with various adverse outcomes such as abruption, intra-uterine growth restriction (IUGR) and increased need for operative delivery.11 ABNORMAL VAGINAL BLEEDING Excessive menstrual bleeding is often the sole symptom reported by women with leiomyomas.6 The bleeding pattern most characteristic of myomas is menorrhagia, i.e. an increase in the amount of blood loss per month, and prolonged vaginal bleeding.14 Neither of these patterns is diagnostic nor is one bleeding pattern more common, with many women experiencing both patterns. The bleeding can be sufficiently severe to cause iron-deficiency anaemia. It may lead to social isolation and loss of productive time because of the need to change sanitary towels frequently.2,6 The quoted incidence of abnormal bleeding of 30% belies the fact that few data verify this, just as the exact mechanism by which fibroids cause abnormal bleeding is unknown. In a recent study that evaluated premenopausal women with and without abnormal vaginal bleeding, women with abnormal bleeding were significantly more likely to have either an intramural (58% vs 13%) or submucous leiomyoma (21% vs 1%) when compared with asymptomatic women.15 Although this study did not directly assess the proportion of women with leiomyomas who had abnormal bleeding, it demonstrated that women who present with abnormal uterine bleeding are more likely to have a leiomyoma, and that women with either intramural or submucous leiomyomas could be asymptomatic. In other words, the mere presence of myomas does not necessarily lead to menorrhagia. Therefore, other possible aetiologies should be considered, including coagulopathies such as Von Willebrand’s disease.16 When a population-based, non-care-seeking cohort of women was evaluated with abdominal and transvaginal sonography, myomas were detected in 73 women (21.4%). After adjustment of covariates, the presence of any myoma was not significantly related to the length of menstrual cycle (P ¼ 40) or heaviness of flow [odds ratio (OR) 1.3, 95% confidence interval (CI) 0.7–2.5%]. Neither the number, volume or
Clinical presentation of fibroids 617
location (subserosal or intramural, anterior or posterior position) of myomas were related to menstrual cycle characteristics. The sample was too small to analyse the impact of submucosal tumours.17 A random sample of women aged 35–49 years was evaluated by self-reported bleeding patterns and by abdominal and transvaginal sonography to determine the presence, size and location of myomas. Of the 878 women screened, 64% had myomas and 36% did not. Of the women with myomas, 46% reported gushing of blood during their menstrual cycle compared with 28% of women without myomas. Gushing of blood and length of periods were related to the size of myomas (large myomas, relative risk 1.9, 95%CI 1.5–2.5), but not to the location or number of myomas. The same study showed that women with myomas larger than 5 cm had slightly more gushing of blood, and used an additional three or more pads or tampons on the heaviest day of bleeding than women with smaller myomas.18 As alluded to above, the pathophysiology of abnormal uterine bleeding associated with uterine leiomyomas is unknown. Some theories have been advanced as follows:2 increased endometrial surface area;19 increased vascularity of the uterus; interference with normal uterine contractility; endometrial ulceration over submucous leiomyomas, which could also cause intermenstrual bleeding; and compression of venous plexus within the myometrium, leading to endometrial venule ectasia which results in the congestion of myometrium and endometrium leading to profuse menstrual bleeding.20,21
Women presenting with metrorrhagia should be investigated fully to exclude other endometrial pathologies, since this symptom is not characteristic of myomas.6 Submucous myomas deserve a special mention as they cause abnormal vaginal bleeding in a number of ways. Hypermenorrhoea may be enhanced by the presence of an endometritis which is a frequent histological finding within the endometrium overlying submucous myomas.6,22 They may also lead to intermenstrual bleeding by ulcerating through the endometrial lining, or causing distortion and congestion of the surrounding vessels.3 Although a rare occurrence, a submucous myoma may prolapse through the cervix resulting in profuse bleeding.2,6 Recent basic science investigations into leiomyomas have indicated dysregulation of several growth factors or their receptors that have direct effects on vascular function and angiogenesis.23 These changes may be responsible for vascular abnormalities leading to dysregulation of the vascular structures in the uterus and subsequent menorrhagia. Myomas commonly regress after the menopause, which is accompanied by atrophy of the endometrium and cessation of uterine bleeding. It has been reported that postmenopausal women with submucous myomas using hormone therapy have a two-fold increased risk of experiencing abnormal bleeding compared with women without submucous myomas.24 PELVIC PAIN Pelvic pain or pressure is a fairly common symptom in women with leiomyomas, although women with myomas are only slightly more likely to experience pain than women without myomas.1 Transvaginal sonography was performed on a population-based cohort of
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635 non-care-seeking women with an intact uterus to determine the presence of uterine myomas. Concurrent symptoms of dyspareunia, dysmenorrhoea or non-cyclic pelvic pain were measured by visual analogue scale. The 96 women with myomas were only slightly more likely to report moderate or severe dyspareunia (OR 2.8, 95%CI 0.9– 8.3) or non-cyclic pelvic pain (OR 2.6, 95%CI 0.9–7.6), and had no higher incidence of moderate or severe dysmenorrhoea (OR 1.1, 95%CI 0.59–2.6) compared with women without myomas. Neither the number nor the total volume of myomas was related to pain.25 It should, however, be appreciated that increased menstrual flow in itself may be associated with dysmenorrhoea, especially if it is associated with the passage of blood clots, which is, of course, more likely if the flow is heavy in the first place. The pelvic and abdominal discomfort that women experience with myomas is often referred to as a sensation of pressure, and could be similar to the discomfort that women experience during pregnancy caused by uterine growth.2 The location of the pain/pressure is related to the location of the fibroids; thus, fibroids located posteriorly may cause lower back pain, while anterior tumours may cause bladder discomfort and increased urinary frequency. Leiomyomas that fill the pelvis may cause difficulty with urination, defaecation and dyspareunia.2 Acute pain is usually associated with torsion of the pedicle of a pedunculated myoma, cervical dilatation by a submucous myoma protruding through the lower uterine segment, or so-called ‘red degeneration’ associated with pregnancy where haemorrhage occurs within the leiomyoma, causing an acute onset of pain.26 Pain can also occur when the uterus with the fibroid becomes incarcerated within the pelvis.4,27 Rarely, myomas in the broad ligament may cause unilateral lower abdominal pain or sciatic nerve pain.2,6 Uterine myomas as large as 100 lbs have been reported. These large myomas may outgrow their blood supply, leading to ischaemia and necrosis within the tumour. This degeneration is usually associated with severe acute pain which may necessitate surgical exploration.6 Such large myomas can also be expected to cause respiratory compromise.2 It is important to emphasize, however, that pain is not a common presenting feature of fibroids, and it would constitute a clinical error to readily attribute pelvic pain to fibroids. Other pathologies such as ectopic pregnancy, rupture/torsion of an ovarian cyst or acute pelvic inflammatory disease must be considered in any woman with identifiable myomas who experiences acute abdominal pain. While myomas are frequently associated with adenomyosis, which can cause pain, such pain is usually associated with menstruation (dysmenorrhoea). At the best of times, adenomyosis is a difficult condition to diagnose, and this becomes especially true in a uterus distorted by myomas. Magnetic resonance imaging may be helpful,26 but the definitive diagnosis is based on tissue histology, usually following hysterectomy or from biopsies obtained at myomectomy. PELVIC MASS SYMPTOMS The diagnosis of myomas is often suspected on the basis of palpation of an enlarged uterine contour on pelvic examination. By convention, the size of the myomatous uterus is described in menstrual weeks (as with the pregnant uterus), and a uterus of more than 12 weeks in size may be palpated on abdominal examination.14 In a study of 2623 healthy asymptomatic volunteers (mean age 51 years, range 25–92 years) who underwent pelvic examination as part of an ovarian screening programme, a bulky or fibroid uterus was detected in 12.9% of women.28
Clinical presentation of fibroids 619
Pelvic pressure arises with increasing uterine size, and pressure and increased abdominal girth are more commonly encountered than pain. These symptoms develop insidiously and are often vaguely described. Women presenting with masses as large as 28 weeks often say that they thought they were simply putting on weight, especially if the fibroids had caused no change in menstrual pattern and if they had experienced no pain. As the tumours grow, pressure is exerted on adjacent organs, especially the urinary tract and recto-sigmoid.6 The dynamics of the bladder and its capacity may change; the capacity at first desire to void as well as maximum bladder capacity can be reduced, causing increased urinary frequency. Urinary incontinence can also be associated with uterine leiomyomas, but such women should be evaluated fully for detrusor over-activity and genuine stress incontinence as these disorders may co-exist with uterine leiomyomas.2 Some women may experience voiding difficulties as a result of changes in the urethrovesical junction. They may complain of difficulty initiating micturition, or incomplete bladder emptying. Unilateral or bilateral ureteral compression has been reported, and it may cause hydronephrosis and compromise renal function. Ureteral compression is more likely to occur when the myoma is located in the broad ligament or the lateral aspect of the uterine fundus.2 It is remarkable that although it seems evident that a large pelvic mass such as a myoma might be expected to cause urinary dysfunction, research on this issue is scant. Fourteen women with large myomas and urinary symptoms were given a total of six injections of a gonadotrophin-releasing hormone (GnRH) agonist, administered monthly, which resulted in a 55% decrease in uterine volume. Associated with this was a decrease in urinary frequency, nocturia and urgency, but urge and stress incontinence remained unchanged as measured by symptoms or urodynamic studies. It is unclear whether these findings are related to a decrease in uterine volume, or reflect other effects of the GnRH treatment.29 In another study where women underwent uterine artery embolization and experienced a 35% reduction in mean uterine volume, frequency and urgency were greatly improved in 53% of women (n ¼ 306), moderately improved in 15%, slightly improved in 18%, and unchanged or worse in 14%.30 These findings suggest that it is the increased uterine volume associated with myomas that is likely to be responsible for the urinary symptoms. A posterior wall fibroid exerting pressure on the recto-sigmoid could cause constipation or tenesmus. Rectal pressure may occur because of the incarceration of the myomatous uterus in the cul-de-sac, or due to the presence of a large posterior uterine myoma.6 However, it is imperative that women presenting with altered bowel habit and fibroids should be evaluated fully to exclude other bowel pathology. REPRODUCTIVE DYSFUNCTION The impact of fibroids on reproductive function is dealt with extensively in another chapter in this issue (see Khaund and Lumsden). However, since reproductive dysfunction could be a mode of fibroid presentation, the issue will be dealt with here briefly for completeness. If, at a conservative estimate, 30% of women have a fibroid(s) by the age of 30 years, and since in industrialized countries, women are embarking on their first pregnancy in their 30s or later, fibroids will be found frequently in association with pregnancy.6 As the vast majority of women have successful pregnancies, it is reasonable to suppose that the vast majority of fibroids do not have an adverse effect on pregnancy. While this is likely to be the case, depending on their size, number and location, fibroids
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may distort uterine anatomy, and thereby interfere with normal uterine physiology. It then becomes teleologically sound to suppose that in some cases, fibroids could indeed have an adverse effect on reproductive function. It has been suggested that this could include subfertility, miscarriage and later pregnancy complications, including pain (red degeneration), premature rupture of membranes, preterm labour, placental abruption, malpresentations, unstable lie, IUGR, increased operative deliveries, postpartum haemorrhage, retained placenta and puerperal sepsis. Is there evidence for this, and how robust is this evidence? Subfertility The American Society of Reproductive Medicine has reported that uterine myomas are associated with infertility in 5–10% of cases,31 but when all other causes of infertility are excluded, it is generally thought that myomas may be responsible for only 2–3% of infertility cases.32 There are fundamental problems with research in this area; both fibroids and infertility increase with age, and so does the risk of aneuploidy and subsequent pregnancy loss. In addition, normal reproductive function involves numerous factors such as ovulation, fallopian tube function, fertilization and nidation; all confounding variables that may be difficult to control for when assessing the impact of a single factor such as fibroids on fertility.2 Although it is thought that 27% of infertile women have myomas, there are no data to assess whether the proportion of infertile women with myomas is greater than the proportion of normally fertile women with myomas.2 As a result, the natural history of fibroids and their association with reproductive dysfunction remains unclear. The definitive study, which has yet to be undertaken, will recruit women who are planning a pregnancy, establish whether or not they have fibroids, and then assess their rate of conception; such a study would go a long way towards establishing whether or not fibroids cause subfertility. Provided it is appropriately powered, the same study would also give important data on the impact of fibroids on early pregnancy loss, as well as later pregnancy complications. Data from studies on patients undergoing assisted reproduction technology (ART) suggest that submucosal fibroids and intramural fibroids distorting the uterine cavity compromise success with ART; therefore, such fibroids should be removed. Evidence points to improved outcomes after such intervention.33 It remains unclear whether purely intramural fibroids compromise ART, but the overall impression is that subserosal fibroids do not. In non-ART situations, myomectomy, whether by the conventional abdominal route or laparoscopically, appears to be associated with improved pregnancy rates.34 Again, studies are fraught with confounding variables such as myoma diagnostic methods, type of evaluation of the uterine cavity, size and number of myomas, patient age and type of fertility treatment. Most studies lack the statistical power to reach valid conclusions. Miscarriage Several reports have suggested that first- and second-trimester miscarriage rates are higher in women with fibroids, and fibroids have been implicated in recurrent pregnancy loss.22,35 In a review of 1941 cases of myomectomy that included pre- and postoperative abortion rates, the rate of miscarriage in the next pregnancy was found to be reduced from 41% to 19%.36 In reality, however, the literature reports highly
Clinical presentation of fibroids 621
variable rates of miscarriage in association with fibroids, and the impact of myomectomy. From a practical point of view, it seems reasonable to offer a hysteroscopic resection to a woman presenting with recurrent pregnancy loss and submucosal fibroid(s); it is an easy operation that would also cure the woman of other symptoms associated with submucosal fibroids.37 Myomectomy in a similar woman with an intramural fibroid significantly distorting the uterine cavity would also seem to be reasonable. However, there are insufficient data to aid in decision making when purely intramural or subserosal fibroids are found in women presenting with miscarriage. Later pregnancy complications Red degeneration, presenting with acute pain in pregnancy, is probably the classically recognized complication specifically associated with fibroids in pregnancy. Its incidence in terms of symptoms and sonographic evidence is about 5%.38,39 It is unknown precisely why some women develop this complication while others do not. Pregnancy appears to have variable and unpredictable effects on myoma growth; there is controversy regarding whether they increase, decrease or remain the same size. However, it appears that most myomas do not increase in size during pregnancy. Any increase in size occurs in early pregnancy, after which they remain stable or decrease in size. Larger myomas often reduce in size late in pregnancy.38 It is probably the case that the presence of myoma(s) during pregnancy very seldom leads to an unfavourable outcome. Current literature regarding the effect of myomas in pregnancy is ridden with problems, the most significant of which is probably selection bias.1 However, three studies have reported on large populations of pregnant women examined with routine second-trimester sonography with follow-up and delivery at the same institution. In one study, 12 600 women were evaluated and the outcomes of 167 women with myomas were compared with women without myomas. There were no significant differences in the incidence of preterm delivery, premature rupture of membranes, IUGR, placenta praevia, abruption, postpartum haemorrhage or retained placenta. Only caesarean section was more common among women with myomas (23% vs 12%, P < 0.001).39 In another study, 15 104 pregnancies were reviewed and the 401 women found to have myomas were compared with controls. There was increased risk of preterm delivery (19.2% vs 12.7%), placenta praevia (3.5% vs 1.8%), postpartum haemorrhage (8.3% vs. 2.9%) and caesarean section (49.1% vs 21.4%) in the myoma group. No increase was detected in the incidence of premature rupture of membranes, operative vaginal delivery, chorioamnionitis or endomyometritis.40 In the third population-based study, the authors evaluated a large sample of women located in one state and included a control group. Pregnant women with myomas were more likely to be above 35 years of age, nulliparous and Black, and were at an increased risk for first-trimester bleeding, premature rupture of membranes, placental abruption, breech presentation, prolonged labour, low APGAR scores and low birth weight. The study controlled for confounding factors such as maternal age, race, previous caesarean section, maternal weight gain, diabetes and hypertension.41 Rupture of myomectomy scar If myomectomy improves pregnancy rates in selected cases, it is reasonable to consider whether the scarring of the uterus from the myomectomy might predispose
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to scar rupture during pregnancy or labour. Only one out of 76 cases of uterine rupture in the third trimester in a group of 98 872 deliveries had a previous myomectomy.42 Similarly, a review of 137 582 pregnancies found 133 cases of uterine rupture after the 28th week of pregnancy, of which three followed abdominal myomectomy.43 Neither of these studies recorded the number of women with previous myomectomy, and therefore the true incidence of scar rupture cannot be calculated. Eleven reports of uterine rupture following laparoscopic myomectomy have been published.44–53 Concerns have been raised about scar integrity following laparoscopic myomectomy, but in expert laparoscopic hands, this should not pose a major problem.54 The bottom line is that in modern-day surgical practice, scar rupture in pregnancy following myomectomy is a rare event. MALIGNANCY Malignant transformation of myomas is extremely rare and the general consensus is that leiomyosarcomas arise de novo and are unrelated to benign leiomyomata.55,56 Two earlier studies quoted rates of 0.13 and 0.29%,57,58 while a more recent study quoted 0.23.59 Given the fact that only a small percentage of women with myomas are symptomatic and may require surgery, a more realistic figure for malignancy with presumed uterine myomas is probably much smaller than the rates cited above.26 RARE ASSOCIATIONS Myomas may be parasitic, being attached to the omentum from which they derive their blood supply. Floating myomas may lead to obstruction of these vessels, resulting in transudation and development of ascitis. Rarely, secondary polycythaemia may occur in association with myomas due to raised erythropoietin, and this resolves following hysterectomy.6 There are several reports of familial clustering of uterine myomas, and it is suggested that myomas are four to five times more common in first-degree relatives of women with myomas.60,61 Some inherited disorders have been defined; e.g. Reed syndrome, in which multiple myomas are present in both the skin and the uterus.62 Recently, there have been reports of various families in England and Finland with uterine and cutaneous myomas and papillary renal cell carcinoma, which were linked to mutations in the fumarate hydratase gene.63 The finding of cutaneous myomas in a woman should prompt screening of the patient and her family, not only for renal cell carcinoma but also for uterine sarcomas which are more common in these patients and their immediate families. Benign metastasizing myomas are characterized by myoma-like lesions, usually in the lungs, in women with myomas. Intravenous leiomyomatosis is a hormonally responsive disease that manifests as vermiform extensions arising in the uterus and extending as far as the heart.64 SUMMARY Uterine myomas are the most common solid pelvic tumours in women of reproductive age, and more than 50% are asymptomatic. When they are symptomatic, they often present with abnormal vaginal bleeding and pelvic discomfort. Myomas may also cause pain and urinary/bladder symptoms due to pressure effects. When their location
Clinical presentation of fibroids 623
is submucosal and/or intramural causing distortion of the uterine cavity, they appear to cause significant reproductive dysfunction, with their removal resulting in improved fertility and reduced risk of miscarriage. It is unlikely that myomas interfere with fertility and cause miscarriage when located purely intramurally, or when they are subserosal. Red degeneration, presenting as acute pain during pregnancy, is a classic association, but it is reasonable to suppose that fibroids cause other later pregnancy complications, in part by their mass effect, and such complications could include preterm labour, malpresentations, IUGR and placental abruption. If they are located in the lower uterine segment, they may interfere with engagement of the fetal head and/or cause malpositioning, and in this way they will increase the risk of operative delivery. Through their mass effect, they can interfere with uterine contraction following delivery, and predispose to postpartum haemorrhage and possibly pelvic sepsis. Malignant transformation is a rare event and may be suspected in postmenopausal women with rapidly growing tumours. It is more likely that leiomyosarcoma arises de novo rather than reflecting transformation of a previously benign myoma. A great deal of research is required to elucidate many aspects of fibroid disease.
Practice points approximately 50% of fibroids are asymptomatic most symptomatic fibroids present with abnormal bleeding and pressure symptoms although fibroids may present with pelvic pain, other causes must be ruled out because pain is not a common clinical presentation while women with fibroids may present with constipation and tenesmus, other more sinister causes must be ruled out because fibroids do not commonly cause these symptoms data from studies in ART suggest that submucosal and intramural fibroids distorting the uterine cavity compromise fertility, and their removal improves fertility treatment outcomes purely intramural and subserosal fibroids do not appear to compromise reproductive function although fibroids may cause or be associated with a range of complications in later pregnancy and labour, these complications are rare relative to the incidence of fibroids when a leiomyosarcoma occurs in a woman with fibroids, it is more likely that the malignancy has arisen de novo rather than being a malignant transformation of a previously benign tumour
Research agenda symptomatic versus quiescent fibroids: what renders some fibroids symptomatic and others quiescent? definitive population-based studies of the extent of the contribution of fibroids to subfertility and early pregnancy loss
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