Impact of diagnosis and treatment of uterine fibroids on quality of life and labor productivity: The Japanese online survey for uterine fibroids and quality of life (JOYFUL survey)

To investigate the impact of uterine fibroid diagnosis/treatment status on quality of life (QOL) and work productivity in women living in Japan.


INTRODUCTION
Uterine fibroids are common benign tumors that develop from uterine smooth muscle in women of reproductive age.Their prevalence has been reported as 4.5%-68.6%depending on race and age. 1 Many women with uterine fibroids are asymptomatic; approximately 30% of women have symptoms. 2It has been estimated that only approximately 550 000 women have been treated for uterine fibroids in Japan. 3However, considering the prevalence rate and proportion of symptomatic women, it is speculated that many women have symptoms but do not receive any treatment.
Women with symptomatic uterine fibroids experience heavy menstrual bleeding, abnormal uterine bleeding, iron deficiency anemia, lower abdominal pain, and infertility.Of these, heavy menstrual bleeding is the most common symptom, and significantly affects quality of life (QOL). 4In previous online fibroid surveys in Canada and the United States, reduced QOL was identified in women who had uterine fibroid-like symptoms but were undiagnosed. 5,6t has therefore been suggested that undiagnosed and/or untreated uterine fibroids may affect QOL in women.
However, previous studies in Canada and the United States have mainly focused on Caucasian, Black, and Hispanic women, 5,6 and there are well-known racial differences in the incidence, size, and number of uterine fibroids. 7,8To our knowledge, no studies have been performed to compare QOL in diagnosed and undiagnosed women in Asian populations.In the present study, an online uterine fibroid survey was therefore conducted in women living in Japan to investigate the impact of uterine fibroid diagnosis and treatment status on QOL and work productivity.
Furthermore, although previous online surveys have reported the impact of uterine fibroids and treatments on QOL, 5,6,9 the impact of uterine fibroids on QOL in relation to treatment type has not yet been investigated.We therefore assessed the relationship between QOL and treatment type.

Participants and data collection
The online survey was conducted in women aged 20-49 years old who had anonymously registered on the web panel of the Japanese online research company, Macromill, Inc. (Tokyo, Japan).Macromill was used because it included many women of the target age range with areas of residence over the entire country.To recruit respondents, e-mails from Macromill were sent to 239 976 panelists, of whom 20 000 were selected by probability sampling based on the population composition.Participants provided consent through the opt-in consent method.The survey consisted of 34 questions and took approximately 20 min to complete.Respondents were divided into five groups based on the diagnosis and treatment status of uterine fibroids: women with unknown status of uterine fibroids (unknown), women diagnosed with no uterine fibroids (no uterine fibroids), and women diagnosed with uterine fibroids that were not treated (untreated), were currently undergoing treatment (ongoing treatment), or had been treated in the past (past treatment).The recruitment continued on a first-come, first-served basis until the number of women reached the target sample size in each group.

Survey questionnaires
Demographic characteristics and obstetrics and gynecology-related questionnaires were used to collect the following information: age, work status (full-or part-time), number of pregnancies and deliveries, menstrual status (presence or absence of menstruation, menstrual cycle, menstrual period, and regularity [regular or irregular]), monthly spend on menstrual hygiene products, concomitant disease (endometriosis, adenomyosis, premenstrual syndrome/premenstrual dysphoric disorder, heavy dysmenorrhea, anemia, hypertension, diabetes, and dyslipidemia), diagnosis of uterine fibroids (by obstetrics/gynecological examination, prenatal examination, cervical cancer screening, endometrial cancer screening, medical examinations, other, or unknown), and treatment for uterine fibroids (hysterectomy, other surgeries [myomectomy, uterine artery embolization, or focused ultrasound surgery], hormone therapy [gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonist, progestin, estrogen-progestin combinations], and other drugs [iron preparations, tranexamic acid, analgesics, or herbal medicines]).If multiple treatments were selected, the treatment type was determined in the following order: hysterectomy, other surgeries, hormone therapy, and other drugs.
Health-related QOL (HRQOL) was assessed using the validated Japanese version of the 36-Item Short-Form Health Survey v2.0 (SF-36), [10][11][12][13] which consists of eight subscales (physical functioning, role physical, bodily pain, general health perception, vitality, social functioning, role emotional, and mental health) and three-component summary scores (physical component summary, mental component summary, and role/social component summary), each subscale and summary score based on 36 questions.Subscale and summary scores were calculated using a norm-based method in which scores were adjusted relative to the mean score of 50 in the Japanese population, with 1 standard deviation equal to a score of 10.Uterine fibroid-related severity of symptoms and HRQOL were assessed using the uterine fibroid symptom and HRQOL (UFS-QOL) questionnaire, 14 which consists of a HRQOL score (ranging from 0 to 100, with a higher score indicating a better HRQOL) and a symptom severity score (ranging from 0 to 100, with a higher score indicating more severe symptoms).The UFS-QOL was not administered to women who had no menstruation.
Based on previous clinical studies of Japanese women with uterine fibroids, 4,15 a UFS-QOL symptom severity score ≥40 points was defined as moderate to severe symptoms.This cut-off value for the symptom severity score was determined in reference to a previous Canadian study. 5The QOL scores were therefore compared between women with symptom severity scores ≥40 and <40 points.To determine the impact of treatment types in women with ongoing or past treatment, QOL scores were analyzed based on treatment types (hysterectomy, other surgeries, and hormone therapy).
Work productivity was evaluated using the World Health Organization Health and Work Performance Questionnaire (short form) Japanese edition, which is a self-reported instrument by which absenteeism and presenteeism can be assessed. 16,17The absenteeism-and presenteeism-based monthly economic loss was evaluated in women with full-and part-time jobs.Wages were calculated based on the results of the Basic Survey on Wage Structure 2020. 18

Sample size
Assuming that the frequency of women with ongoing treatment was 1.5%-the lowest among women in other groupsand that its incidence rate followed a Poisson distribution, 200 women were estimated to be required for the ongoing treatment group.In Japan, there were approximately 21.8 million women aged 20-49 years in 2021 according to population projections; of these, 6.55 million are likely to have uterine fibroids (based on a prevalence of uterine fibroids of 30%). 2 However, based on a report by the Japan Society of Obstetrics and Gynecology, just 0.55 million women were diagnosed with uterine fibroids (equivalent to 3% of Japanese women aged 20-49 years). 3Assuming that 10% of women with uterine fibroids are currently undergoing treatment, 2000 women with diagnosed uterine fibroids would need to participate in the survey to ensure a sample of 200 women with ongoing treatment.Accordingly, the target sample size was determined to be 4000, comprising 1000 respondents with unknown status, 1000 with no uterine fibroids, and 2000 with ongoing treatment, untreated, or past treatment.

Statistical analysis methods
Between-group differences for the evaluation of QOL (SF-36 and UFS-QOL), work productivity (the World Health Organization Health and Work Performance Questionnaire [short form] Japanese edition), and work productivity-based economic loss were assessed using the t-test.Between-group differences of concomitant diseases were evaluated using the Z test based on normal approximation.A generalized linear model with age as a covariate was used to adjust for age.Bonferroni adjustment was used for multiplicity adjustments.The level of significance was set at 0.05.To identify predictor variables associated with lowered QOL in women with ongoing treatment, and to explore predictor variables associated with lowered QOL in women with hormone therapy compared with those who underwent surgery in the past treatment group, classification and regression tree (CART) analysis was used with the one standard error rule.Statistical analyses were conducted using R3.6.3 and SAS version 9.4 (SAS Institute, Cary, NC).

Respondent characteristics
In total, 239 976 women were contacted and 20 000 women were selected by probability sampling based on the population composition.Of these, 4120 women provided responses to the survey questionnaires from July 12, 2021 to July 14, 2021, on a first-come, first-served basis until the number of women in each group had reached the target sample size (Figure 1).Based on their responses to the survey, 2060 women had diagnosed uterine fibroids (1362 untreated, 249 ongoing treatment, and 449 with past treatment), 1030 had no uterine fibroids, and 1030 had unknown status for the presence or absence of uterine fibroids.
Respondent characteristics are given in Table 1.There were significant differences in age between all groups ( p < 0.05 in all cases) except between the untreated and ongoing treatment groups ( p > 0.1).Women with diagnosed uterine fibroids (mean age: 41.5 years in the untreated group, 40.6 years in the ongoing treatment group, and 43.2 in the past treatment group) were significantly older than those with unknown status (34.2 years) and no uterine fibroids (36.8 years).Because of the significant age differences among the groups, all between-group comparisons were adjusted for age (see Table S1 for age-unadjusted SF-36 and UFS-QOL scores).
There were notable differences in characteristics other than age between women with ongoing treatment and those in the other groups.The mean numbers of pregnancies and deliveries in the ongoing treatment group were lower than those in the no uterine fibroids, untreated, and past treatment groups (p < 0.05 in all cases).Furthermore, a significantly lower proportion of women had menstruation in the ongoing and past treatment groups compared with those in the unknown, no uterine fibroids, and untreated groups (p < 0.05).A higher proportion of women in the ongoing treatment group had menstruation than those in the past treatment group (p < 0.05).Mean menstrual period duration in the ongoing treatment group was significantly longer than that in all other groups (p < 0.05, ongoing treatment vs. other groups) except the no uterine fibroid group; however, there were no differences in the mean number of days between consecutive menstrual periods between any groups.Compared with the other groups, a higher proportion of women in the ongoing treatment group tended to have irregular menstruation.There was also a tendency of higher mean monthly spend on menstrual hygiene products in the ongoing treatment group than in the other groups.
Of the women who were diagnosed with uterine fibroids, the proportion of women diagnosed by obstetric/ gynecological examinations was lower in the untreated group than in the ongoing and past treatment groups.
Regarding concomitant disease, higher proportions of women in the ongoing treatment group had endometriosis, adenomyosis, heavy dysmenorrhea, and anemia than in the other groups (untreated vs. other groups, p < 0.05 for each disease).Moreover, a higher proportion of patients had hypertension (p < 0.05), diabetes (p < 0.05), and dyslipidemia (p < 0.05) in the ongoing treatment group than in the unknown and no uterine fibroid groups.Regarding ongoing and past treatment types, approximately 90% of women in the ongoing treatment group were being treated with hormonal or other drugs, whereas 51.0% and 21.2% of women in the past treatment group had had other surgeries and hysterectomy, respectively.

QOL as assessed by the SF-36 and UFS-QOL
The three-component summary scores of the SF-36 (the physical component summary, mental component summary, and role/social component summary) in women with ongoing treatment were significantly lower than those in other groups ( p < 0.05 vs. each group; Table 2).
In particular, the role/social component summary score was almost 5 points lower than that in other groups.Furthermore, the scores of all eight subscales in women with ongoing treatment were significantly lower than those in other groups ( p < 0.05); the scores in the role physical, general health perception, and social functioning subscales in women with ongoing treatment were almost 5 points lower than those in other groups.
Analysis of the UFS-QOL scores revealed that both HRQOL and symptom severity scores in the untreated, ongoing treatment, and past treatment groups were significantly worse than those in the unknown and no uterine fibroid groups (Table 2, p < 0.05).Of the women with diagnosed uterine fibroids, those with ongoing treatment had significantly lower HRQOL and higher symptom severity scores than the other two groups (p < 0.05).To identify the predictor variables associated with lowered QOL in women with ongoing treatment (the UFS-QOL HRQOL or symptom severity score), CART analyses were performed.Anemia was identified at the first split for both reduced UFS-QOL HRQOL and symptom severity scores with a complexity parameter of 0.032 and 0.024, respectively (Figure S1).
The proportion of women with symptom severity scores ≥40 points in the ongoing treatment group was 49.8%, which was the highest among the five groups (Table 3).Overall, the proportion of women with symptom severity scores ≥40 points was approximately 20%, irrespective of the presence/absence of uterine fibroids and treatment status.When UFS-QOL HRQOL scores were stratified by symptom severity scores (<40 vs. ≥40 points), women with symptom severity scores ≥40 had significantly lower HRQOL scores in all groups ( p < 0.05).The same trend was identified in the scores of two or more of the three-component summary scores of SF-36 (Table 3).The SF-36 and UFS-QOL scores were also evaluated by treatment types in women in both the ongoing and past treatment groups (Table 4).The most notable difference was identified in the ongoing treatment group; the mean SF-36 role/social component summary score in women who underwent hysterectomy was ≥15 points lower than that of women treated with hormonal therapy or other surgeries (p < 0.05).In the ongoing treatment group, women treated with hormonal therapy also had significantly lower UFS-QOL HRQOL scores (by 13 points, on average) than those who underwent other surgeries (p < 0.05).In the past treatment group, women treated with hormonal therapy had significantly lower mean SF-36 physical component summary scores than those who underwent hysterectomy (p < 0.05) and other surgeries (p < 0.05), and lower HRQOL scores than those with other surgeries (p < 0.05).However, they had higher UFS-QOL symptom severity scores than those who underwent other surgeries (p < 0.05).The CART analyses were performed to identify the predictor variables associated with lowered QOL in women with hormone therapy compared with those who underwent surgery in the past treatment group.The analyses identified cervical cancer screening at the first split for reduced UFS-QOL HRQOL with a complexity parameter of 0.18, and GnRH antagonists for reduced symptom severity scores with a complexity parameter of 0.15 (Figure S2).

Work productivity and economic loss
There were no significant differences in absolute absenteeism between any groups (Table 5).However, relative absenteeism was higher in women with unknown status than in untreated women ( p < 0.05).Among women who worked, relative absenteeism was higher in those with unknown status and no uterine fibroids than in those with ongoing treatment.Of the women with part-time jobs, relative absenteeism was higher in women with unknown status, no uterine fibroids, and who were untreated than in women with ongoing treatment.Regarding presenteeism, mean absolute presenteeism in women with no uterine fibroids was higher than that in women in the other groups.However, there were no significant differences in mean relative presenteeism between any groups.Mean economic loss as a result of absenteeism in women with full-time jobs was significantly higher in those with ongoing treatment than in those with past treatment.There were no significant differences in mean economic loss as a result of presenteeism between any groups.

DISCUSSION
An online survey of women living in Japan was conducted to evaluate QOL and work productivity in women with unknown uterine fibroid status, no uterine fibroids, untreated uterine fibroids, uterine fibroids with ongoing treatment, and uterine fibroids with past treatment.
The two main findings of the current study can be summarized as follows.First, uterine fibroids had a significant impact on the physical and psychosocial aspects of women in the ongoing treatment group compared with those in the other groups.The uterine fibroid-specific QOL score in women with diagnosed uterine fibroids (untreated, ongoing treatment, or past treatment) was lower than in those with unknown status or no uterine fibroids.Furthermore, in women with diagnosed uterine fibroids, those with ongoing treatment had lower UFS-QOL HRQOL and SF-36 scores.Because approximately 50% of women in the ongoing treatment group had symptom severity scores ≥40, it is likely that these women sought medical treatment because of their severe symptoms.The lower QOL scores in the ongoing treatment group may therefore be the result of symptom severity rather than the treatment itself.
In the present study, we identified anemia as a plausible predictor variable for reduced QOL in the ongoing treatment group based on CART analysis (Figure S1).This result is supported by the finding that women in this group had relatively long menstrual durations and spent the most on menstrual hygiene products.It has been demonstrated that anemia-associated with heavy menstrual bleeding-is one  of the major symptoms of uterine fibroids, 2 and negatively affects QOL. 19,20Together with previous results, our findings therefore suggest that QOL may be improved by appropriately treating anemia in women who are currently undergoing treatment. 20egarding the impact of uterine fibroids and treatment status on psychosocial aspects, the SF-36 role/social component summary scores in the ongoing treatment group were lower than those of the other groups by almost the minimum important difference of 5 points.Similarly, the subscales of role physical, general health perception, and social functioning were almost 5 points lower than those in other groups.As previously reported, uterine fibroids affect not only physical health, but also psychosocial health 21,22 ; psychosocial care is therefore needed in patients with severe uterine fibroids who seek treatment.
The second major finding of the present study was that approximately of women-even in groups other than the ongoing treatment group-experienced moderate to severe uterine fibroid-like symptoms, as indicated by UFS-QOL symptom severity scores ≥40.Notably, QOL was lower in these women than in those with scores <40.The present results were consistent with those of a previous Canadian study. 5Similarly, in a previous US study (in which women were not diagnosed with uterine fibroids), women with uterine fibroid-like symptoms had lowered QOL scores. 6These findings indicate that a substantial number of women are undiagnosed and/or untreated despite experiencing uterine fibroid-like symptoms, and that the QOL of these women is affected.In contrast, women with past treatment had similar SF-36 scores to women with no uterine fibroids and those with unknown status.Although UFS-QOL scores were significantly lower in women with past treatment than in those with no uterine fibroids or unknown status, HRQOL and symptom severity scores were better than those in the ongoing treatment group.Together, these results indicate that it is important to complete treatment to improve QOL.This means that it is essential that women who experience uterine fibroid-like symptoms are examined and treated to improve their QOL; those with untreated uterine fibroids should receive treatment, those with past treatment should be followed up and start treatment again if necessary, and those with no uterine fibroids or unknown status should be examined for uterine fibroids.
In addition to the main findings, the current study revealed that treatment types affect QOL differently in women with uterine fibroids.In women in the ongoing treatment group who had undergone hysterectomy (probably relatively recently), the SF-36 and social role functioning scores were reduced.A previous study has reported that the incidences of depression and anxiety increase in patients who undergo hysterectomy. 23urthermore, patients are often treated with GnRH analogs prior to hysterectomy.It is therefore possible that QOL was reduced because of GnRH analog-induced ovarian deficiency symptoms immediately after hysterectomy.
The reduced QOL in women in the ongoing treatment group who had undergone hysterectomy might also have been caused by the burden of surgery and/or loss from hysterectomy.In contrast, QOL was not significantly different between women who had undergone hysterectomy (probably a relatively long time ago) and women who had undergone other treatments in the past treatment group.The previous US study reported higher QOL scores in women with hysterectomy than in those with uterine fibroids or uterine fibroid-like symptoms. 6Hysterectomy remains the only definitive surgical treatment for symptomatic fibroids. 2Together, the present and previous results suggest that although QOL is temporarily lowered after hysterectomy, in the long term it both eliminates symptoms and improves patient QOL.
We also identified an impact of hormone therapy on QOL in women with uterine fibroids.Of women with past treatment, those who had received hormone therapy had reduced SF-36 physical functioning and UFS-QOL HRQOL scores compared with those who had undergone hysterectomy and/or other surgeries.GnRH agonists and antagonists are the first-line drugs for uterine fibroids therapy; however, they cannot be administered long term because of a risk of bone density loss. 24Because there is an increased risk of regrowth and recurrence of uterine fibroids after treatment withdrawal, 25 women who prefer not to undergo surgery are recommended to take a longterm medical treatment such as hormonal add-back therapy to improve their QOL. 25n the present evaluation of work productivity and economic loss in relation to uterine fibroids and treatment status, the diagnosis or treatment status of uterine fibroids had no clear impact.Previous studies have demonstrated lower work productivity and greater economic loss in women who had pain, such as dysmenorrhea, as their main symptoms. 26,27However, because pain is not the main symptom of uterine fibroids, the impact of uterine fibroids on work productivity may be less than that of dysmenorrhea.
The current study had the following limitations.First, because the study was performed in women who registered for the online panel, the results may not be generalized to represent all women living in Japan aged 20-49 years.Second, because uterine fibroids show racedependent pathological features, our findings of the impact of uterine fibroids on QOL may be similar to those of Asian women living outside of Japan.However, our results regarding the impact of treatment types on QOL may not be applicable to Asian women outside of Japan because available treatments vary by region.Third, we relied on self-reported information that was not verified for accuracy; this means that recall bias, such as inaccurate information about diagnosis and treatment status, might have been included in the analyses.Fourth, we did not investigate how participants' infertility status or income level affected their QOL because such items were not included in the questionnaire; no related information was therefore collected in this study.The present results need to be interpreted in consideration of these limitations.This is the first study to investigate QOL in Japanese women in relation to uterine fibroid diagnosis and treatment status.The present results revealed that a high proportion of women with ongoing treatment had moderate to severe uterine fibroid-like symptoms accompanied by reduced QOL.In contrast, QOL in women with past treatment was similar to that in women with unknown uterine fibroid status or no uterine fibroids.Treating menorrhagia, which causes anemia, may improve QOL because anemia was associated with reduced QOL in women with ongoing treatment.Furthermore, it has been estimated that approximately 550 000 women have been treated for uterine fibroids in Japan; this accounts for only 1.5% of women aged 20 to 49 years (the target age range in this study).Notably, approximately 20% of women with unknown, untreated, and past treatment status had moderate to severe uterine fibroid-like symptoms in the present study, and also tended to have reduced QOL.These women are likely unaware that menorrhagia can be caused by uterine fibroids; disease awareness of fibroids and their symptoms is therefore important.Moreover, because reductions in uterine fibroid-related QOL can be improved by appropriate treatment, women with uterine fibroid-like symptoms, such as menorrhagia, are recommended to undergo examination and seek appropriate treatment.

T A B L E 5
Work productivity and economic loss.
Summary of SF-36 and UFS-QOL scores stratified by uterine fibroid and treatment status.
T A B L E 2Note: Values are shown as the mean (standard error)." A-E" between-group differences (p < 0.05).Abbreviations: HRQOL, health-related quality of life; MCS, mental component summary; PCS, physical component summary; RCS, role/social component summary; SF-36, 36-Item Short-Form Survey; SSS, symptom severity score, UFS-QOL, Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire.
Quality of life stratified by treatment in women with ongoing and past treatment.
T A B L E 3 QOL stratified by SSS (≥40 and <40).Note: Values are shown as the mean (standard error) unless otherwise specified.Abbreviations: HRQOL, health-related quality of life; MCS, mental component summary; PCS, physical component summary; RCS, role/social component summary; SF-36, 36-Item Short-Form Survey; SSS, symptom severity score, UFS-QOL, Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire.*p<0.05.T A B L E 4 BNote: Values are shown as the mean (standard error)." A-C " between-group differences (p < 0.05).Abbreviations: HRQOL, health-related quality of life; MCS, mental component summary; PCS, physical component summary; RCS, role/social component summary; SF-36, 36-Item Short-Form Survey; SSS, symptom severity score, UFS-QOL, Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire.