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Abstract

Aim: Excessive blood loss during menstruation is a major problem for women of reproductive age. Women who experience heavy menstrual bleeding (HMB) often present to physicians because of the subsequent negative impact HMB has on their daily lives and activities. The objective of this post-hoc analysis is to evaluate daily menstrual blood loss (MBL) in women with HMB and assess the relationship between daily MBL and women's perceptions of MBL, limitations in physical activities and limitations in social/leisure activities as measured by the Menorrhagia Impact Questionnaire. Materials & methods: Data from two randomized, placebo-controlled studies of an oral tranexamic acid formulation in women with HMB were assessed. Daily MBLs and Menorrhagia Impact Questionnaire scores were evaluated for two pretreatment cycles and the first three tranexamic acid treatment cycles of each study. Effect-size analyses were not conducted. Results & conclusion: Highest daily MBLs occurred on days 2 and 3 of menstrual cycles. Women's perceptions of daily MBL were consistent with objective measures of MBL. Higher daily MBL was related to increased limitations in physical activities and limitations in social/leisure activities. Daily MBL values were consistent with women's perceptions of MBL. Reduced daily MBL was associated with improvements in health-related quality of life.

Keywords

Heavy menstrual bleeding (HMB) is defined as excessive blood loss (>80 ml/cycle) during regular intervals of menstruation [1]. Excessive blood loss during menstruation is estimated to affect up to one-third of women of reproductive age [2]. Women who experience HMB will often present to a physician because of the subsequent negative impact on their daily lives and activities [3,4]. HMB has been shown to adversely affect mood, energy/vitality, work productivity, social interactions, family life and sexual functioning [5 –7]. The effect HMB has on a woman's health-related quality of life (HRQL) derives from both the effort associated with managing menstrual bleeding and the consequences of excessive blood loss, such as fatigue and iron deficiency anemia [7].

Tranexamic acid has been shown to diminish the increased fibrinolytic activity observed in the endometrial tissues of women with HMB [8]. Immediate-release (IR) tranexamic acid is a nonhormonal, competitive plasmin inhibitor that is administered only during HMB. IR tranexamic acid has a well-established safety profile and does not appear to affect fertility [9,10]. A modified-release oral formulation of tranexamic acid (TA; Lysteda®, Ferring Pharmaceuticals, Inc., NJ, USA) was approved in November 2009 by the US FDA for the treatment of cyclic HMB in patients. In Phase I studies, TA was shown to be bioequivalent to IR tranexamic acid and was well tolerated [11]. Two pivotal Phase III studies have shown TA to be an effective nonhormonal treatment for HMB [12,13], and long-term data have demonstrated the tolerability of TA [14,15].

Numerous clinical trials investigating HMB have shown a reduction in menstrual blood loss (MBL) as the key efficacy end point, without measuring the effects of treatment on patient-reported outcomes. Some studies involving oral contraceptives, progestins and other pharmacologic therapies for HMB have demonstrated some improvement in patient HRQL; however, these improvements in HRQL were less than those noted with other treatments for HMB (i.e., ablation or hysterectomy) [7]. Another study indicated that HRQL improved in women with menorrhagia and abnormal laboratory hemostasis when they were treated with either tranexamic acid or intranasal desmopressin; tranexamic acid proved to be more effective [16]. Recent studies have shown that TA, in addition to reducing mean MBL per cycle, also has a positive impact on HRQL [12 –14] as measured by the validated Menorrhagia Impact Questionnaire (MIQ) [17].

Using data from two pivotal Phase III TA studies [12,13], the objectives of this post-hoc analysis were to evaluate daily MBL in women with HMB and assess the relationship between individual daily MBL values and MIQ scores for patient perception of MBL, limitations in physical activity, and limitations in social/leisure activity during pretreatment and TA-treatment menstrual cycles.

Materials & methods

Patients

Women aged 18–49 years were enrolled in one of two Phase III studies if they had a mean baseline MBL of ≥80 ml (average MBL over two pretreatment menstrual cycles with the first MBL having a minimum of ≥60 ml) as measured by a validated alkaline hematin method. Women were required to have regular menstrual cycles (21–35 days apart) with each menstruation not lasting >10 days in at least four of the last 6 months prior to screening. In addition, women also had to have normal findings on pelvic examinations, cervical cytology screenings and transvaginal ultrasonograms. Although it is noted that fibroids are not considered a normal finding during pelvic examinations or on transvaginal ultrasonograms, for these studies, women with fibroids were not excluded unless, based on investigators' opinions, the fibroids required surgical management.

Women were excluded from the studies based on history or presence of anovulatory dysfunctional uterine bleeding, metrorrhagia, menometrorrhagia, polymenorrhea, endometrial polyps, endometrial hyperplasia, endometrial carcinoma, cervical carcinoma or any other clinically significant comorbid disease. Additional exclusion criteria consisted of clinically significant abnormalities that could confound the study or be detrimental to the patient as noted at physical examination. Women with a history of bilateral oophorectomy or hysterectomy, or women who were pregnant, breastfeeding, planning to become pregnant or became pregnant during either of the studies were also excluded.

Study design

Both randomized, double-blind, placebo-controlled, parallel-group Phase III studies were conducted at multiple sites within the USA [12,13]. In both studies, patients were randomized after two pretreatment menstrual cycles. In the first pivotal Phase III study, women were randomized (2:2:1) to receive 1.95 or 3.9 g/day TA or placebo for up to 5 days per menstrual cycle for three cycles [12]. In the second pivotal Phase III study, women were randomized to receive either 3.9 g/day TA or placebo for up to 5 days per menstrual cycle for six cycles [13].

Each study was approved by the institutional review board at the study sites. Both studies were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical practice and the applicable regulatory requirements. Patients were required to provide written informed consent.

Patient assessments

In both Phase III studies, MBL was measured via the alkaline hematin method and HRQL was measured using the validated MIQ [17]. Patient perception of MBL was assessed by the question on the MIQ: ‘During your most recent menstrual period, your blood loss was …?’ Categorical responses consisted of ‘light’, ‘moderate’, ‘heavy’ or ‘very heavy’. Limitations in physical activity were assessed by the question on the MIQ: ‘During your most recent menstrual period, how much did your bleeding limit you in your physical activities?’ Categorical responses consisted of ‘not at all’, ‘slightly’, ‘moderately’, ‘quite a bit’ and ‘extremely’. Limitations in social/leisure activity were assessed by the question on the MIQ: ‘During your most recent menstrual period, how much did your bleeding limit you in your social or leisure activities?’ Categorical responses consisted of ‘not at all’, ‘slightly’, ‘moderately’, ‘quite a bit’ and ‘extremely’. Safety was assessed in each study primarily by adverse event (AE) monitoring.

Statistical methods

Assessments of MBL and MIQ scores were conducted using the combined intent-to-treat (ITT) populations from the 3.9 g/day TA treatment groups from each study. This post-hoc analysis examined MBL and MIQ scores obtained for two pretreatment menstrual cycles and the first three TA-treatment menstrual cycles. The ITT populations included all randomized patients who received at least one dose of study drug. Descriptive statistics were calculated for overall daily MBL and for daily MBL according to categorical MIQ scores. Safety data were reported for the ITT population from each study. Frequency counts were compiled for classification of AEs.

Results

Patients

Patient disposition and demographics for each study have been presented separately in previous publications [12,13]. Demographics and baseline characteristics are briefly summarized for this post-hoc analysis in Table 1. The majority (≥95%) of patients receiving 3.9 g/day TA were included in the pooled ITT population. More than 75% of patients receiving 3.9 g/day TA completed the trials. Failure to return was the predominant reason for study withdrawal. Patients who received 3.9 g/day TA were approximately 39-years-old and had been coping with HMB for approximately 10 years. More than two-thirds of patients who received 3.9 g/day TA were of white race (70%). The mean number of dosing days per menstrual cycle was 3.4 days with a mean daily dose of 3.74 g/day.

Table 1.

Patient demographics and baseline characteristics.

Variable	Pooled ITT population; 3.9 g/day TA (n = 232)

Age (years), mean (SD)	38.97 (8.9)

Duration of HMB (years), mean (SD)	11.01 (12.9)

Race, n (%)

White	163 (70.26)
Black	57 (24.57)
Asian	1 (0.43)
Native American	1 (0.43)
Pacific Islander	0
Other	10 (4.31)

Alcohol use, n (%)

Yes	122 (52.59)
No	110 (47.41)

Tobacco use, n (%)

Yes	90 (38.79)
No	142 (61.21)

HMB: Heavy menstrual bleeding; ITT: Intent-to-treat; TA: Tranexamic acid; SD: Standard deviation.

Daily MBL

The mean daily MBL for the two pretreatment and first three TA-treatment menstrual cycles are presented in Figure 1. Mean daily MBL was highest on day 2 and lowest on day 6 of each pretreatment as well as TA-treatment menstrual cycle. The mean MBL on all cycle days was markedly reduced during the TA-treatment menstrual cycles compared with the pretreatment cycles, with the largest reduction occurring on day 2 when MBL was highest.

Figure 1.

Overall daily menstrual blood loss for pretreatment and 3.9 g/day tranexamic acid treatment menstrual cycles.

Relationship between daily MBL & MIQ scores

Perception of MBL

Values for daily MBL by perception of menstrual blood flow for the second pretreatment and the first and third TA-treatment menstrual cycles are presented in Figures 2A–C. In general, mean daily MBL values corresponded to patients' perceptions of their menstrual blood flow. Across the second pretreatment cycle and the first and third TA-treatment menstrual cycles, patients who perceived their menstrual blood flow as ‘heavy’ or ‘very heavy’ had the highest mean MBL per day of each cycle. During these cycles, patients identified days 2 and 3 of menses as the heaviest menstrual blood flow days. During the second pretreatment menstrual cycle, the majority (70–73%) of patients perceived their menstrual blood flow as ‘heavy’ or ‘very heavy’ across all days of menses ( Figure 2D ). By contrast, during the first and third TA-treatment menstrual cycles, at least one-quarter (25–38%) of patients treated with 3.9 g/day TA perceived their menstrual blood flow as ‘heavy’ or ‘very heavy’. During the first and third TA-treatment menstrual cycles, the majority (62–75%) of patients perceived their menstrual blood flow as ‘moderate’ or ‘light’ across all days of menses.

Figure 2.

Patient assessment of menstrual blood loss versus actual mean menstrual blood loss by menstrual cycle day.

Limitations in physical activity

Values for the degree of limitations in physical activity by mean daily MBL for the second pretreatment and the first and third TA-treatment menstrual cycles is presented in Figures 3A–C. Across these pretreatment and TA-treatment menstrual cycles and on any given menstrual cycle day, patients who had the highest mean daily MBL responded that their physical activities were either ‘extremely’ limited or limited ‘quite a bit’. During the second pretreatment and first and third TA-treatment menstrual cycles, limitations in physical activity were most bothersome for patients on days 2 and 3 of menses, which corresponds to the days of highest MBL. More than half of the patients (64–91%) reported some degree of limitation on these days. During the second pretreatment menstrual cycle, the majority (68–69%) of patients believed that their physical activities were ‘extremely’, ‘quite a bit’ or ‘moderately’ limited across all days of menses ( Figure 3D ). However, during the first and third TA-treatment menstrual cycles, 28–38% of patients believed that their physical activities were ‘extremely’, ‘quite a bit’ or ‘moderately’ limited. During the first and third TA-treatment menstrual cycles, a majority (62–72%) of patients believed that their physical activities were ‘slightly’ or ‘not at all’ limited across all days of menses.

Figure 3.

Relationship between daily menstrual blood loss and limitations in physical activity. Patient assessment of limitations in physical activity by menstrual cycle day for the (A) second pretreatment, (B) first 3.9 g/day tranexamic acid (TA)-treatment and (C) third 3.9 g/day TA-treatment menstrual cycles. (D) The percentage of patients reporting limitations in physical activity as ‘extremely’ limited, limited ‘quite a bit’ or ‘moderately’ limited for the pretreatment cycle 2 and TA-treatment cycles 1 and 3. The pattern of patient assessment of limitations in physical activity by actual mean MBL across menstrual cycle days was similar between the second and third TA-treatment menstrual cycles.

Limitations in social/leisure activity

The degree of limitations in social/leisure activity by mean daily MBL for the second pretreatment and the first and third TA-treatment menstrual cycles is presented in Figures 4A–C. Across these pretreatment and TA-treatment menstrual cycles and on any given menstrual cycle day, patients who had the highest mean daily MBL responded that their social/leisure activities were either ‘extremely’ limited, limited ‘quite a bit’ or ‘moderately’ limited. During the second pretreatment and first and third TA-treatment menstrual cycles, limitations in social/leisure activity were most bothersome for patients on days 2 and 3 of menses. More than half of the patients (57–88%) reported some degree of limitation on these days. During the second pretreatment menstrual cycle, approximately three-quarters (63–64%) of patients believed that their social/leisure activities were ‘extremely’, ‘quite a bit’, or ‘moderately’ limited across all days of menses ( Figure 4D ). However, during the first and third TA-treatment menstrual cycles, 20–34% of patients believed that their social/leisure activities were ‘extremely’ limited, limited ‘quite a bit’, or ‘moderately’ limited. During the first and third TA-treatment menstrual cycles, a majority (66–80%) of patients believed that their social/leisure activities were ‘slightly’ or ‘not at all’ limited across all days of menses.

Figure 4.

Relationship between daily menstrual blood loss and limitations in social/leisure activity. Patient assessment of limitations in social/leisure activity by menstrual cycle day for the (A) second pretreatment, (B) first 3.9 g/day tranexamic acid (TA)-treatment and (C) third 3.9 g/day TA-treatment menstrual cycles. (D) The percentage of patients reporting social/leisure activities as ‘extremely’ limited, limited ‘quite a bit’ or ‘moderately’ limited for the pretreatment cycle 2 and TA-treatment cycles 1 and 3. The pattern of patient assessment of limitations in social/leisure activity by actual mean MBL across menstrual cycle days was similar between the second and third TA-treatment menstrual cycles.

Safety

Primary safety data from both Phase III pivotal studies have been reported previously [12,13]. Taken together, the majority of AEs across both studies were mild-to-moderate in intensity. The most commonly reported AEs in women treated with 3.9 g/day TA in the first Phase III pivotal study (occurring in ≥5% of TA-treated women and at twice the percentage of placebo-treated women) included viral upper respiratory tract infection (7%), musculoskeletal pain (5%) and myalgia (5%) [12]. The most commonly reported AEs in women treated with 3.9 g/day TA in the second Phase III pivotal study (occurring in ≥10 patients, irrespective of causality) included menstrual discomfort (61.5%), headache (56%), back pain (24%), nausea (15%) and anemia (10%) [13]. A total of six serious treatment-emergent AEs were reported by four women treated with 3.9 g/day TA; none were considered to be related to treatment [12,13]. In the first pivotal Phase III study, one woman treated with 3.9 g/day TA withdrew from the study due to treatment-emergent AEs; all events had resolved by the follow-up study visit [12]. In the second Phase III study, three patients treated with TA withdrew from the study due to AEs [13]. No deaths occurred among randomized women during the study periods in either pivotal study [12,13].

Discussion

Overall, mean MBL was highest on days 2 and 3 then lowest on day 6 for both pretreatment and TA-treatment menstrual cycles. These heavy- and light-flow days are also consistent with those days reported previously by women complaining of HMB [18]. As illustrated in Figure 1 , the pattern of MBL in women across all days of their menstrual cycles did not change with TA treatment. This is important to note as it may not be the case with other medications, devices or procedures used to treat HMB.

To the authors' knowledge, this study is the first to evaluate daily MBL in women with HMB and to establish relationships between patients' perceptions of daily MBL and identify how MBL is perceived to limit physical and social/leisure activities. Among women enrolled in the study, patient perception of menstrual blood flow generally coincided with mean daily MBL. However, anecdotal observations in practice often suggest that women perceive a greater MBL than can be objectively documented. The degree of limitations in physical activity was reflective of the mean daily MBL experienced during both pretreatment and TA-treatment menstrual cycles. However, TA treatment reduced the number of patients reporting ‘extremely’, ‘quite a bit’ or ‘moderately’ limited physical activities. In general, limitations in social/leisure activity were consistent with increased mean daily MBL experienced during both pretreatment and TA-treatment menstrual cycles. However, TA treatment reduced the number of patients reporting ‘extremely’, ‘quite a bit’ or ‘moderately’ limited social activities. For both limitations in physical and social/leisure activity, reducing MBL via TA treatment resulted in positive effects on these measures of HRQL.

Taken together, the relationships between daily mean MBL, patient perception of MBL, limitations in physical activity and limitations in social/leisure activity may influence the clinical management of HMB. The results of this study show that patient perceptions of daily MBL coincide with objective measurements of daily MBL, indicating that patient concerns regarding HMB should be assessed seriously. In addition, daily MBL is related to HRQL measures in that higher daily MBLs are associated with worse ratings of HRQL. Therefore, efforts to diagnose and decrease MBL should be a high priority for clinicians to improve the daily lives of women with HMB.

Limitations

Women with HMB in each of these studies were treated with TA, thus results may not be generalized to other women with HMB treated with other medications, devices or procedures. Furthermore, this was an exploratory post-hoc analysis to assess daily MBL in women with HMB and examine any relationships between objective measures of daily MBL and subjective measures regarding patient perceptions of MBL and its subsequent impact on HRQL. Future studies specifically designed to assess the statistical significance of these relationships would be beneficial.

Conclusion

This post-hoc analysis based on data from two pivotal Phase III studies of TA revealed that mean daily MBL values coincided with patients' perceptions of MBL, and that mean daily MBL was related to the degree of limitation in both physical and social/leisure activities. TA was well tolerated in women in both Phase III pivotal studies.

Future perspective

These results point to the importance of assessing HRQL when evaluating women with HMB as the two are closely linked. Treatment of HMB should include not only reducing MBL, but also improving the patient's overall quality of life during menses. We also look forward to future studies regarding the impact of TA on HRQL and other functional outcomes.

Executive summary

The objective of this post-hoc analysis of data from two Phase III studies was to evaluate daily menstrual blood loss (MBL) in women with heavy menstrual bleeding and assess the relationship between individual daily MBL values and Menorrhagia Impact Questionnaire (MIQ) scores for patient perception of MBL, limitations in physical activity, and limitations in social/leisure activity during pretreatment and tranexamic acid (TA)-treatment menstrual cycles.

MBL was measured via the alkaline hematin method and health-related quality of life was measured using the validated MIQ.

Effect-size analyses for daily MBL and MIQ scores were not conducted.

Safety was assessed primarily by the incidence of spontaneously reported adverse events (AEs).

Mean daily MBL was highest on day 2 and lowest on day 6 of each pretreatment as well as TA-treatment menstrual cycle. The mean MBL on all cycle days was markedly reduced during the TA-treatment menstrual cycles compared with the pretreatment cycles, with the largest reduction occurring on day 2 when MBL was highest.

Mean daily MBL values corresponded to patients' perceptions of their menstrual blood flow.

Across pretreatment and TA-treatment menstrual cycles and on any given menstrual cycle day, patients who had the highest mean daily MBL responded that their physical activities were either ‘extremely’ limited or limited ‘quite a bit’.

Across pretreatment and TA-treatment menstrual cycles and on any given menstrual cycle day, patients who had the highest mean daily MBL responded that their social/leisure activities were either ‘extremely’ limited, limited ‘quite a bit’ or ‘moderately’ limited.

The majority of AEs across both studies were mild-to-moderate in intensity.

Across studies, the most commonly reported AEs in women treated with 3.9 g/day TA were menstrual discomfort, headache, back pain, nausea, anemia, viral upper respiratory tract infection, musculoskeletal pain and myalgia.

Footnotes

Financial support for data analysis and manuscript development was provided by Ferring Pharmaceuticals, Inc. Authors were not compensated for their work on this manuscript. AS Lukes has received funding from Abbott Pharmaceuticals, American Medical Systems, Bayer, CDC and Prevention/Association for Prevention Teaching and Research, Duramed, Endoceutics, Ethicon, Hologic, Interlace Medical, Luitpold, Merck, National Improvements for Women's Healthcare, NIH, Smith and Nephew, Trent Foundation and Xanodyne Pharmaceuticals. She has also been a consultant and/or has served as a speaker for Abbott Pharmaceuticals, AMAG (4 years ago), American Medical Systems, Bayer, Boehringer-Ingelheim, Daichii, Ethicon, Ferring Pharmaceuticals, Inc., Hologic, Interlace Medical, Microsulis (5 years ago), Myriad, Watson Pharmaceuticals and Xanodyne Pharmaceuticals. J Baker has received research support from Ferring Pharmaceuticals, Inc. S Eder has received research support from Bayer, Boehringer-Ingleheim, Church and Dwight, Graceway Pharmaceuticals, Teva, Warner-Chilcott and X anodyne Pharmaceuticals. He has also served as a consultant for Everett Laboratories and as a speaker for Ferring Pharmaceuticals, Inc. and Merck. TL Adomako is an employee of Ferring Pharmaceuticals, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was funded by Ferring Pharmaceuticals, Inc. (NJ, USA). Professional writing assistance was provided by L Miesle of The JB Ashtin Group Inc. (MI, USA).

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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Daily Menstrual Blood Loss and Quality of Life in Women with Heavy Menstrual Bleeding

Abstract

Keywords

Materials & methods

Patients

Study design

Patient assessments

Statistical methods

Results

Patients

Daily MBL

Relationship between daily MBL & MIQ scores

Perception of MBL

Limitations in physical activity

Limitations in social/leisure activity

Safety

Discussion

Limitations

Conclusion

Future perspective

Footnotes

References