Philipp, Claire S. MD; Faiz, Ambarina MD, MPH; Dowling, Nicole PhD; Dilley, Anne PhD*; Michaels, Lisa A. MD; Ayers, Charletta MD, MPH; Miller, Connie H. PhD; Bachmann, Gloria MD; Evatt, Bruce MD; Saidi, Parvin MD
Menorrhagia is a common problem among women of reproductive age.1 Approximately 30% of women complain of heavy menses,1,2 and annually approximately 5% of women seek medical care for excessive menstrual bleeding.3,4 In approximately 50% of cases, no organic pathology is determined, and dysfunctional uterine bleeding is diagnosed.1,5,6 Recently, underlying bleeding disorders, particularly von Willebrand’s disease and platelet function disorders, have been found to be prevalent in women with menorrhagia.3,7–10 Von Willebrand’s disease is a hereditary disorder due to decreases in the quantity of von Willebrand’s factor, categorized as Type I (mild) and Type III (severe) von Willebrand’s disease, or qualitative defects of von Willebrand’s factor (Type II).11 In hereditary platelet function disorders, the bleeding tendency is associated with abnormalities in platelet function rather than decreases in platelet count.12
Von Willebrand’s disease is reported to have a prevalence in the general population of approximately 1%.13 However, studies in women with menorrhagia report a prevalence ranging from 10 to 20% in white women, with a lower (1–2%) prevalence in black women.3,9,10,14 The prevalence of platelet function disorders in the general population is unknown and may have been underappreciated in studies of menorrhagia that did not systematically evaluate platelet function. With comprehensive evaluation, platelet dysfunction has been found to be common in women with otherwise unexplained menorrhagia9,15 compared with control women without menorrhagia.9 Single coagulation factor deficiencies, particularly factors XI, VII, and V, have also been identified in studies of women with menorrhagia, although at lower frequencies than von Willebrand’s disease and platelet function defects.3,7,9,15
Menorrhagia occurring during adolescence and perimenopause is presumed to be associated with anovulation or, during perimenopause, also anatomic causes, such as submucosal uterine myoma.1 The frequency of bleeding disorders in women diagnosed with menorrhagia at the extremes of menstruating age, ie, adolescence and perimenopause, are not known. The present study was conducted to determine the frequency and types of hemostatic disorders in adolescent, perimenopausal, and postadolescent reproductive age women presenting with unexplained menorrhagia.
MATERIALS AND METHODS
The study population consisted of women between the ages of 13 and 55 with a physician diagnosis of menorrhagia seen by the faculty primary care gynecology practice of UMDNJ-Robert Wood Johnson Medical School or collaborating community gynecology and pediatric practices. Women were excluded from participation before consent and study entry if they had other known causes of heavy menstrual bleeding, ie, previously diagnosed bleeding disorders, endocrine disorders including thyroid disease, submucous uterine myoma, uterine polyps, gynecologic malignancy, use of an intrauterine device, or treatment with anticoagulants within the past 2 months. In addition, use of oral contraceptives within 1 cycle of participation, or use of nonsteroidal anti-inflammatory agents, aspirin, other platelet-impairing medications or herbal agents within 14 days of participation were excluded to avoid potential interference with hemostatic testing. A pelvic examination by a gynecologist was required for all women 19 years or older.
Informed consent, approved by the Institutional Review Boards of UMDNJ-Robert Wood Johnson Medical School and the Centers for Disease Control and Prevention, was obtained from study participants or their parent or legal guardian for subjects younger than 18 years old. Assent was also obtained from study participants less than 18 years old. All eligible women who consented were entered into the study. After obtaining informed consent, an in-person questionnaire was administered that elicited information on menstrual history, medical history, nongynecologic bleeding history, and family history. A blood sample and bleeding time were obtained in participants between days 3–9 of their menstrual cycle. Women were enrolled between November 1999 and March 2004.
Testing for von Willebrand’s disease, platelet function defects, and coagulation factor deficiencies was performed as previously described on citrated blood (3.2% sodium citrate).9 Briefly, von Willebrand’s factor antigen was measured by enzyme-linked immunosorbent assay (Asserachrom VWF, Diagnostica Stago, Parsippany, NJ). Von Willebrand’s ristocetin cofactor was measured by aggregation of lyophilized normal platelets. Factor VIII was measured by 1-stage assay on an automated analyzer (STAR, Diagnostica Stago). Platelet aggregation and adenosine triphosphate (ATP) release were performed using platelet-rich plasma on an optical Chrono-log Platelet Lumi-Aggregometer (Chrono-log Corp, Havertown, PA) using ristocetin, adenosine diphosphate (ADP), arachidonic acid, epinephrine, and collagen as agonists for platelet aggregation and thrombin, ADP, arachidonic acid, and collagen as agonists for ATP release. Coagulation factors II, VII, V, IX, X, XI, and XII were performed using factor deficient plasmas. All samples were tested in duplicate. Bleeding time was performed by 1 of 2 experienced personnel using a Simplate device (Organon-Technica, Durham, NC).
At the time of their study visit, women were provided a pictorial chart to complete with their next menses and an explanation of how it should be completed as previously described.9,16,17 Using the pictorial charts, lightly, moderately, and heavily soiled pads and tampons were recorded for the entire menstrual flow. Clots were also recorded in comparison with coins9,17 as previously described.
The data were analyzed using SAS 8.2 statistical package (SAS Institute, Cary, NC). Frequencies of bleeding disorders were calculated in the overall study population and in 3 age groups. The 3 age groups were defined as adolescents 19 years of age or younger, women 20 to 44 years of age, and perimenopausal-age women 45 years old or older, based on a reported median perimenopausal age of 45.5 years.18 Ages of participants are reported in full years. Reference ranges for the hemostatic tests were calculated as 2 standard deviations about the mean for control subjects. The differences in means for age at menarche, duration of menses, length of cycle, hemoglobin (gm/dL), platelet count (per microliter), and pictorial blood assessment chart scores among the 3 age groups were tested using analysis of variance. The distribution of race, blood group, anemia, and pictorial blood assessment chart scores greater than 100 or greater than 185 in the 3 age groups were evaluated by χ2 test. The Cochran-Armitage trend test was performed to test the trend for past and family history of bleeding and hemostatic abnormalities in the 3 age groups.19 Adjusted odds ratios were derived through logistic regression analysis in relation to age, controlling for race, anemia, and pictorial blood assessment chart score more than 100. P < .05 was considered statistically significant.
One hundred fifteen women with a physician diagnosis of menorrhagia and a mean age of 35.4 ± 11.9 years (range 13–53 years) were studied. Participants included 25 adolescent women 19 years or younger, 65 women between 20 and 44 years, and 25 perimenopausal-age women 45 years or older.
Of the entire cohort, 58% of women reported a past history of anemia, and 89% of these women reported receiving treatment for anemia. Four percent of women had received blood transfusions. Forty-one percent (47/115) of women were anemic at the time of testing, with hemoglobin less than 12 gg/dL. There were no significant differences among the 3 age groups in mean hemoglobin, percentage of women anemic, age at menarche, duration of menses, length of cycle, or race (Table 1). Among adolescent participants, time since onset of menarche varied between 0 and 6 years (mean 3.2 ± 1.8). There were no significant differences in mean scores measured by the pictorial blood assessment tool or percentage of women with scores greater than 100 or 185 among the 3 age groups (Table 2).
Personal past history of bleeding after surgery, tooth extraction, delivery or miscarriage and family history of nonuterine bleeding symptoms were frequently reported among women with menorrhagia (Table 3). A family history of a diagnosed bleeding disorder was significantly more common among adolescents (27%) than among women 20 to 44 years old (15%) or more than 45 years old (4%) (P < .05). There were no statistically significant differences among the groups of women with regard to history of menorrhagia in mothers and sisters, family history of other bleeding symptoms, or personal history of bleeding after surgery or tooth extraction.
On laboratory testing, almost half of the participants (54/115, 47%, 95% confidence interval [CI] 38–57) were found to have 1 or more hemostatic abnormalities, including platelet aggregation abnormalities, von Willebrand’s factor, and single factor deficiencies (Table 4). When women found on testing to have a hemoglobin less than 12 were compared using χ2 with women found to have a hemoglobin 12 or more, there was no significant difference in the prevalence of bleeding disorders (P = .4). Study entry was based on a physician diagnosis of menorrhagia. When reanalyzed using only study participants who also had a pictorial blood assessment chart score more than 100, there was no significant difference in the prevalence of bleeding disorders between the entire study population (physician diagnosis of menorrhagia) and the study population who also had pictorial blood assessment chart scores more than 100 (46% compared with 38%, P = .6). Forty-eight percent of adolescents (95% CI 28–69), 54% women aged 20–44 years (95% CI 41–66), and 32% of perimenopausal-age women (95% CI 15–53) were found to have hemostatic abnormalities (Table 4). Adolescents and perimenopausal-age women were just as likely to have hemostatic defects as were women aged 20 to 44 years (Table 4). Additionally, age was not predictive of having a bleeding disorder when age was used as a continuous variable in a logistic regression model, even when adjusted for race, anemia, and pictorial blood assessment chart score more than 100.
Platelet dysfunction was the most commonly observed hemostatic defect. Platelet aggregation abnormalities were found in 44% (50/115, 95% CI 34–53) of women including 44% (11/25, 95% CI 24–65) of adolescents, 48% (31/65, 95% CI 35–60) women aged 20 to 44 years and 32% (8/25, 95% CI 15–53) women 45 years or older (Table 4). There were no significant differences in the prevalence of platelet dysfunction among the 3 age groups. The type of platelet aggregation defects observed were similar among the 3 age groups with the exception of ADP-induced platelet aggregation defects, which were seen significantly more often in adolescents compared with older women (Table 5, P < .01). The most common platelet aggregation defects in women 20 years and older were with ristocetin and epinephrine. However, among adolescents, ADP platelet aggregation defects were the most common. Platelet ATP-release abnormalities are also reported in Table 5. Decreases in von Willebrand’s factor were found in 7% of the participants, and there were also no significant differences in prevalence among the 3 age groups. Various single-factor deficiencies were found in 5% (6/115) of the women, including decreased factor XI (2/115), factor VIII (1/115), factor V (1/114), factor VII (1/115), and combined factor XI and VII (1/115).
These results demonstrate that underlying bleeding disorders are frequent in women from adolescent to perimenopausal age and that the diagnosis of anovulatory bleeding or uterine pathology such as intramural or subserosal myoma may not fully account for the heavy menses. Platelet dysfunction and von Willebrand’s disease were the most common hemostatic defects found in adolescent, reproductive age, and perimenopausal-age women.
Prior studies of adolescents have been retrospective and limited to adolescents with acute menorrhagia resulting in hospitalization or presenting to an emergency room or urgent care facility.20–22 Claessens20 reported 19% “coagulation” disorders among 59 adolescents with acute menorrhagia, including 3 adolescents with von Willebrand’s disease, 2 adolescents with platelet dysfunction, and 6 with thrombocytopenic disorders. More recently, Bevans et al21 reported finding, in a retrospective review of records, bleeding disorders in 8 of 14 adolescents presenting with menorrhagia without thrombocytopenia who underwent comprehensive testing for a bleeding disorder. Platelet dysfunction was found in 42% (6/14), and von Willebrand’s disease was found in 14% (2/14). The findings in our prospective study in a primary, nonacute setting are similar.
The higher frequency of a family history of bleeding disorders found among our adolescent group compared with older women suggests the possibility of variability in the diagnosis of menorrhagia by physicians evaluating adolescents compared with physicians evaluating older women. In this study, women with a physician diagnosis of menorrhagia were recruited from the primary care setting. Because there are no objective tests used in clinical practice for the diagnosis of menorrhagia, we also collected pictorial blood assessment chart information on study participants. The pictorial blood assessment chart has been suggested as a possible “objective” measure of menorrhagia,16,17 although it is not used in clinical practice, and some investigators have suggested that it offers no significant improvement in the quality of the objective diagnosis of menorrhagia.23 This study, which was not designed to evaluate the physician diagnosis of menorrhagia but rather to incorporate conditions similar to what physicians in the primary care setting evaluating women with menorrhagia would encounter in daily practice, did not demonstrate significant differences in the pictorial blood assessment chart scores between adolescents and older women with a physician diagnosis of menorrhagia. Furthermore, we found no significant difference in the prevalence of bleeding disorders with the additional criteria of a pictorial blood assessment chart score more than 100 added to the study entry requirement of a physician diagnosis of menorrhagia. The American College of Obstetricians and Gynecologists24 recommends screening adolescents presenting with severe menorrhagia based on Claessens study.20 Our results, which demonstrate a high prevalence of bleeding disorders in adolescents with menorrhagia, support the American College of Obstetricians and Gynecologists screening recommendations.
Prior studies examining bleeding disorders in adult women with menorrhagia have not specifically examined the frequency in older, perimenopausal-age women presenting with menorrhagia. Our results, although the statistical power in this subgroup of the study population was limited, suggest that perimenopausal-age women presenting with menorrhagia late in their reproductive years may also warrant screening for underlying bleeding disorders, even if fibroids are present.
Because complaints of menorrhagia are so common in the general population and bleeding disorders are prevalent in women presenting with menorrhagia regardless of age, these data suggest that women with menorrhagia should be considered for further hemostatic evaluation. However, additional age-specific studies evaluating treatment benefits, outcomes, and cost-benefit analysis in women with menorrhagia diagnosed with bleeding disorders and the development of screening tools to better target those women needing hemostatic evaluation seem warranted before broad public health recommendations to test all women with menorrhagia are adopted.
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