Use of Chinese Medicine and Subsequent Surgery in Women with Uterine Fibroid: A Retrospective Cohort Study

Abstract

Background. Chinese medicine (CM) has been used to relieve symptoms relevant to uterine fibroids. Objective. This study investigated the association between the use of CM and the incidence of uterine surgery in women with uterine fibroids. Subjects and Methods. This retrospective cohort study extracted records for 16,690 subjects diagnosed with a uterine fibroid between 2000 and 2003 from the National Health Insurance reimbursement database. The risk factors for surgery were examined via Cox proportional hazard analysis, and the difference in incidence of surgery between CM users and nonusers was compared using incidence rate ratios (IRRs) derived from Poisson's models. Results. After an average follow-up period of 4.5 years, the cumulative incidence of uterine surgery was significantly lower in CM users than CM nonusers (P < 0.0001). Compared to CM nonusers, CM users were more unlikely to undergo uterine surgery (adjusted hazard ratio = 0.18, 95% confidence interval (CI) = 0.17, 0.19). The incidence of surgery in CM users was dramatically different from that for CM nonusers (IRR = 0.17, 95% CI = 0.16, 0.18). Conclusion. The risk of uterine surgery among fibroid patients who used CM was significantly decreased, implying an effective treatment of fibroid-related symptoms provided by CM.

Full text

Title: Use of Chinese medicine and subsequent surgery in women with uterine
fibroid: a retrospective cohort study
Shan-Yu Su, DMS1,2, Chih-Hsin Muo, MS3,4 , and Donald E. Morisky, ScD, MSPH, ScM5
1Department of Chinese Medicine, China Medical University Hospital, Taichung 40447,
Taiwan
2School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China
Medical University, Taichung 40402, Taiwan
3Department of Public Health, China Medical University Hospital, Taichung, 40402,
Taiwan
4Management Office for Health Data, China Medical University Hospital, Taichung
40402, Taiwan
5Department of Community Health Sciences, UCLA Fielding School of Public Health,
Los Angeles, California 90095-1772, U.S.A.
Correspondence to: Shan-Yu Su. Department of Chinese Medicine, China Medical
University Hospital. No. 2 Yuh-Der Road, Taichung, Taiwan 40447. Tel: 886-4-
22052121ext.1675; Fax: 886-4-22365141; E-mail address: shanyusu@yahoo.com.tw
1

Abbreviations:
CI, confidence interval; CM, Chinese medicine; ICD-9-CM, International Classification
of Diseases, 9th Revision, Clinical Modification; HR, hazard ratio; IR, incidence rate;
IRR, incidence rate ratio; LHID, Longitudinal Health Insurance Database; NHI, National
Health Insurance.
2

Abstract
Background: Chinese medicine (CM) has been used to relieve symptoms relevant to
uterine fibroids.
Objective: This study investigated the association between the use of CM and the
incidence of uterine surgery in women with uterine fibroids.
Subjects and Methods: This retrospective cohort study extracted records for 16,690
subjects diagnosed with a uterine fibroid between 2000 and 2003 from the National
Health Insurance reimbursement database. The risk factors for surgery were examined via
Cox proportional hazard analysis, and the difference in incidence of surgery between CM
users and nonusers were compared using incidence rate ratios (IRRs) derived from
Poisson models.
Results: After an average follow-up period of 4.5 years, the cumulative incidence of
uterine surgery was significantly lower in CM users than CM nonusers (P < 0.0001).
Compared to CM nonusers, CM users were more unlikely to undergo uterine surgery
(adjusted hazard ratio = 0.18, 95% confidence interval (CI) = 0.17, 0.19). The incidence
of surgery in CM users was dramatically different from that for CM nonusers (IRR =
0.17, 95% CI = 0.16, 0.18).
Conclusion: The risk of uterine surgery among fibroid patients who used CM was
significantly decreased, implying an effective treatment of fibroid-related symptoms
provided by CM.
Keywords: uterine fibroid, Chinese medicine, uterine surgery
3

1. Introduction
Uterine fibroids, also known as leiomyoma, are the most commonly occurring
benign tumors of the female reproductive system, with a cumulative incidence of more
than 60% in women over the age of 45 years . They are the leading indication for
hysterectomy all over the world and are associated with a substantial economic impact on
health care systems, including associated costs of $4-9 billion per year in the United
States alone . These tumors grow frequently in women of reproductive age, regressing
after menopause , and can cause various symptoms including infertility, pregnancy
complications , pelvic pain , and abnormal or heavy bleeding that can lead to anemia .
Surgery has traditionally been the gold standard for the treatment of symptomatic
uterine fibroids. Hysterectomy is indicated in women who have completed childbearing,
particularly in those who are expected to go into menopause soon, while myomectomy is
indicated in women who wish to preserve their fertility . For asymptomatic patients, on
the other hand, serial follow-ups (without surgery) to monitor the size of the tumor and
check for related symptoms are advisable . Surgery is an invasive treatment that can
cause even more severe complications than a fibroid itself. Potential short-term
complications of surgery include febrile morbidity, blood loss, and organ injuries, while
possible long-term complications, such as fistula formation, adhesion, and sexual
4

dysfunctions, can last for many years, even beyond menopause, when a uterine
leiomyoma is no longer a threat to health . Consequently, alternative treatments to
surgery for the management of fibroid-related symptoms have been sought and evaluated
for years to minimize surgery in patients .
In Asian countries, Chinese medicine (CM) is one of the most commonly used
complementary alternative medicines and has been reported to be used more by females
than by males around the world . In Taiwan, CM has been covered by the National Health
Insurance (NHI) system since 1995 . According to the NHI database, diseases of the
female reproductive system, including menstruation disorders, abnormal bleeding, and
non-inflammatory disorders of female genital organs, are on the list of the top twenty
most common diseases for which patients utilize CM . The high utilization rate of CM for
these symptoms, all of which are potentially related to uterine fibroids, implies the
possibility that CM might treat those symptoms and, in turn, reduce surgery among
patients with uterine fibroids.
This population-based retrospective cohort study used a national insurance
reimbursement database to investigate the association between the use of CM and the
incidence of uterine surgery in women with uterine fibroids. The results provide
population-based evidence for the benefit of CM in women with uterine fibroids.
5

2. Materials and Methods
2.1. Study subjects
This study used the Longitudinal Health Insurance Database 2000 (LHID2000),
which is a part of the National Health Insurance Research Database set up by Taiwan’s
National Health Research Institutes. This database contains chronological information on
one million randomly selected individuals who were beneficiaries from 1996 to 2000.
There are no differences in gender and age between the beneficiaries in the LHID2000
and the beneficiaries in the entire NHI database. The beneficiary information includes
gender, birth date, income, occupation status, area of registration, all medical claims for
inpatient and outpatient care, the dates of visits, and up to three diagnostic codes in the
International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM)
of these beneficiaries from 1996 to 2009.
A total of 16,848 women were diagnosed with uterine fibroid (ICD-9-CM 218)
from 2000 to 2003 in outpatient visits. The diagnosis date was used as the entry date and
surgery was defined as the outcome. There were 158 women who were excluded because
they had undergone uterine surgery before the entry date. The remaining 16,690 women
were selected as research subjects and divided into CM users and CM nonusers according
to their use (or non-use) of orally administered CM between the entry date and endpoint
6

date. The endpoint date was defined as the date of surgery, death, withdrawal from the
insurance program, or December 31, 2009.
The examined variables were socio-demographic factors, including age (< 20, 20-
29, 30-39, 40-49, and ≥ 50 years), income level (< 564.3, 564.3-656.5, 656.6-779.6, and
≥ 779.7 US$ per month based on quartile), occupation status (white collar, blue collar,
and others), and registered location (northern, central, southern, and eastern, and island),
and fibroid-related co-morbidities, including excessive menstruation (ICD-9-CM 626.2),
iron-deficiency anemia (ICD-9-CM 280), dysmenorrhea (ICD-9-CM 625.3), and
infertility (ICD-9-CM 628 and 628.3).
2.2. Statistical analysis
The chi-square test and t-test were used to assess differences for categorical and
continuous variables between CM users and CM nonusers, respectively. Cox proportional
regression was used to estimate the hazard ratio (HR) and its 95% confidence intervals
(CIs) for undergoing surgery. The Kaplan-Meier method was used to plot the cumulative
incidence, and the log-rank test was used to test the difference in cumulative rates
between CM users and nonusers. Adjusted models were controlled for age, occupation,
area, excessive menstruation, iron-deficiency anemia, and dysmenorrhea. The incidence
rate (IR) for surgery (per 1000 person-years) was also calculated. The association
7

between the use of CM and uterine surgery was estimated by using the incidence rate
ratio (IRR) and the corresponding 95% CI by Poisson distribution model. All statistical
analyses were performed using SAS software, version 9.1 (SAS Institute Inc., Carey,
NC), and the significance level was set at a two-tailed P value of less than 0.05.
8

3. Results
3.1. Characteristics of CM users and CM nonusers in fibroid patients
Among the 16,690 females with a uterine fibroid diagnosis from 2000 to 2003,
12,238 (73.3%) used CM between the diagnosis and endpoint date. The mean age of CM
users (41.6 years) was lower than that of CM nonusers (42.9 years). Significantly, the
proportion of patients among CM users who were young (under 40), white collar, and
registered their insurance in Central Taiwan was higher than that among CM nonusers. In
terms of co-morbidity, CM users were more likely to have fibroid-related co-morbidities,
including excessive menstruation, anemia, and dysmenorrhea (Table 1).
3.2. Risk factors for uterine surgery among fibroid patients
At the end of the observation, 22% of the patients (n = 3681) received surgery of the
uterus, including myomectomy and hysterectomy. Compared to nonusers, CM users were
significantly more unlikely to undergo surgery after adjustment for socio-demographic
factors (age, occupation, and area) and co-morbid covariates (excessive menstruation,
iron-deficiency anemia, and dysmenorrhea), with an HR of 0.18 (Table 2). The adjusted
HRs for surgery were more than double among patients between 30 to 50 years old
compared to those who were under 30 years old. Adjusted HRs were also higher among
patients who were blue collar, registered in Central and Southern Taiwan, and whose
9

diseases were co-morbid with excessive menstruation, iron-deficiency anemia, and
dysmenorrhea. The mean observation time in this cohort was 4.5 years.
3.3. Incidence of surgery among CM users and CM nonusers
At the end of observation, 8.7% of CM users and 46.6% of CM nonusers have
undergone surgery. Kaplan-Meier analysis showed a significant difference in cumulative
incidence of surgery between CM users and nonusers (P < 0.0001, Figure 1). This
difference developed rapidly in the first several months after the diagnosis of a uterine
fibroid.
The overall IR for surgery among CM users was 17.7 per 1,000 fibroid patients,
while that among CM nonusers was 103.7 per 1,000. Poisson regression modeling
revealed that the IRs for surgery were lower among CM users in all demographic
subgroups except for those younger than 20 years of ag e. In terms of fibroid-related co-
morbidity, the IRs were also lower for CM users than for CM nonusers whether patients
had excessive menstruation, anemia, and dysmenorrhea or not, while the IRs were similar
between CM users and nonusers among patients with infertility (Table 3).
In light of the rapid development of the difference in the cumulative incidence of
surgery between the two groups, time lag stratification was performed to rule out the
possibility that rapid decisions in favor of surgery biased the results (Table 4). Adjusted
10

HRs for surgery remained lower in CM users than in CM nonusers even after the deletion
of subjects with a diagnosis-to-surgery period of less than three months to five years, but
the adjusted HR for surgery in CM users increased from 0.33 to 0.79 compared to
nonusers.
11

4. Discussion
This retrospective cohort study investigated the relationship between the use of CM
and the incidence of uterine surgery in women with uterine fibroids using an NHI
database documenting medical claims from 1996 to 2009. After an average follow-up
time of 4.5 years, the data shows that patients who received CM had a significantly lower
risk of uterine surgery compared to patients who did not receive CM treatment.
Moreover, the incidence of surgery in CM nonusers was more than five times higher than
in CM users. The low surgery incidence in CM users was not affected by age, income,
occupational status, area of insurance registration, or co-morbidities including excessive
menstruation, iron-deficiency anemia, and dysmenorrhea.
The strength of the present study is that the database we used was from the NHI,
which is a government-run, single-payer national health insurance program that insures
over 97% of citizens and over 99% of health-care institutes ; this rendered the present
study representative of the general population, thereby offering a comprehensive picture
of the risks of surgery in fibroid patients. The data revealed a lower surgery incidence in
fibroid patients who used CM compared to those who did not use CM, implying that
Taiwanese women with uterine fibroids benefited sufficiently from CM to avoid surgery.
12

This study further suggested that CM might provide an effective alternative therapy to
surgery for uterine fibroids.
Several studies have reported socio-demographic trends regarding the use of CM in
women. CM users have been reported to be younger than CM nonusers when it comes to
women with constipation , insomnia , and breast cancer , although the primary age group
varies from disease to disease. The present study supported such findings by showing that
patients under 40 with uterine fibroids were more likely to use CM. In terms of income,
education, and occupational status, studies that have investigated female-specific
diseases, including breast cancer and gynecological malignancies, have reported that
users of CM and complementary medicines tend to be highly educated, have high
incomes, and are more likely to be employed by the government, schools, enterprises,
and institutions . The data of the present study, meanwhile, showed that while CM users
tended to be white collar instead of blue collar workers, there were no differences in
income between CM users and nonusers. The present study also found that there was a
higher proportion of patients who registered their insurance in Central Taiwan among
CM users than among CM nonusers, a finding being attributed to the high density of
Chinese medical institutes per person in Central Taiwan . When taking into account co-
morbidities, it appeared that fibroid patients with relevant co-morbidities tended to use
13

CM. Since suffering from disease is one of the factors that has been reported to positively
and directly influence the purchasing behavior of CM outpatients , the existence of
symptoms related to uterine fibroids might be one of the factors that drove patients to
utilize CM.
Analysis of the risk factors for surgery revealed that patients who are more than 30
years of age, blue collar, and registered in the Central and Southern regions were more
likely to undergo surgery. Moreover, fibroid-related symptoms, including excessive
menstruation, anemia, and dysmenorrhea, were also risk factors for surgery (although
infertility was not related to surgery). These risk factors had HRs ranging from 1.24 to
2.54. On the other hand, the adjusted HR for surgery in CM users was 0.18 compared to
nonusers, indicating that CM nonusers were 5.5 times more at risk of surgery than CM
users. Moreover, the overall IR of surgery for CM users was 0.17 times that of CM
nonusers. Both results imply that the use of CM was a protective factor against surgery in
fibroid patients. In the stratified analysis, the IRRs of surgery in CM users for all the
subgroups of socio-demographic status and for almost all the subgroups of co-morbidities
were lower than 0.25, implying that the protective effect of CM was strong enough to
protect almost all the subgroups for socio-demographic and co-morbid status. Only in
patients with infertility did the difference in IR between CM users and nonusers not exist.
14

The reason was speculated to be that hysterectomy is contraindicated for women who
want to preserve their fertility, and therefore patients with infertility did not tend to
receive surgery regardless of whether they utilized CM or not.
Although there was a big difference in the cumulative incidence of surgery between
CM users and nonusers, Kaplan-Meier analysis indicated that the difference increased
rapidly in the first few months after diagnosis. Results for a time lag stratification
revealed that even after the deletion of subjects with a diagnosis-to-surgery period of less
than three months to five years, the differences in IR between the two groups still existed,
indicating that there were still protective effects from CM in patients who had been
diagnosed for five years. However, the adjusted HR for surgery increased from 0.33 to
0.79 with time lag periods from three months to five years, indicating that the protective
effects were weakened in patients who had a long diagnosis-to-surgery duration. We
speculate that the increased proportion of asymptomatic patients in groups of long
diagnosis-to-surgery duration caused the weakening of CM protection. Surgery is not
indicated in asymptomatic patients, therefore those who were asymptomatic would not
undergo surgery whether they took CM treatment or not.
Clinical trials regarding the effects of CM on the outcome of uterine fibroids are
very limited. A small randomized controlled trial with 25 women in total, using strict
15

randomization methods and data management, showed that fibroids shrank after
treatment with a medicinal formulation of Nona Roguy for six months; the shrinkage of
fibroids for the CM group was comparable to that in a mifepristone group . Another trial
with 25 subjects published in Japan showed that one CM formula, Toki-shakuyaku-san,
improved symptoms of hypermenorrhea, dysmenorrhea, and anemia . The same group of
researchers has also reported that CM elevates hemoglobin levels in patients with iron-
deficiency anemia . Other studies that show the effectiveness of CM on uterine fibroids
are either of low quality or contain methodological flaws, such as a lack of
randomization, not being blind, or using improper data management . The present study
provided epidemiological evidence showing different outcomes between CM users and
nonusers among fibroid patients. This study elucidated the possible effect of CM on
uterine fibroids from the point of view of public health, expressing the same idea with the
above-mentioned clinical studies.
As the database used by this study was produced primarily for administrative and
insurance claim purposes and not for research, the first limitation of this study included
the possibility of errors in register information. Secondly, it is also possible that there
might have been slight differences in the principle of treatment between hospitals. This
might account for the difference in the risk of surgery and CM usage among different
16

areas. Thirdly, the NHI does not cover infertility, meaning that most infertility patients
were not registered in the NHI database, leading to possible bias in our data related to
infertility. Lastly, the most important disadvantage of studies which extract data from
NHI database is that the causal relationship cannot be clarified. The negative correlation
between surgery and the use of CM could come from the effect of CM or the original
rejection of surgery by CM users. Therefore, further rigorous, randomized, multi-
centered, double-blinded placebo-controlled clinical trial should be carried out to study
the efficacy of CM.
5. Conclusion
The present study revealed that the risk and the incidence of uterine surgery were
lower in CM users than CM nonusers among patients with uterine fibroids, implying an
effective treatment of fibroid-related symptoms provided by CM. The low incidence of
surgery in CM users existed in almost all investigated socio-demographic and co-morbid
subgroups. Further large clinical trials are obviously required to evaluate the dimension
of benefits that CM could provide. If the protective effect described herein is confirmed,
CM is worthy of adoption by women with uterine fibroids not only in Asian but also in
Western countries.
17

Acknowledgements
This study was supported in part by the National Science Council (Grant No. NSC
99-2621-M-039-001), the Department of Health (Grant Nos. DOH101-TD-B-111-004
and DOH101-TD-C-111-005), and the China Medical University Hospital (Grant No.
1MS1 and DMR-101-016). We thank the National Health Research Institutes for
providing us with the insurance data.
18

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Legend of Figure 1
Figure 1. Kaplan-Meier analysis for cumulative incidence of uterine surgery between CM
users and CM nonusers
24

Table 1. Comparison of socio-demographic factors and co-morbidities between
Chinese medicine (CM) users and nonusers in patients with uterine fibroids
CM
nonusers
N=4452
users
N=12238
Total
N= 16690 P-valuea
n % n % n %
Age, years <0.0001
<20 18 0.40 110 0.90 128 0.77
20-29 268 6.02 1151 9.41 1419 8.50
30-39 112
0
25.2 3603 29.4 4723 28.3
40-49 239
4
53.8 5643 46.1 8037 48.2
≥ 50 652 14.7 1731 14.1 2383 14.3
Mean ± SD 42.9 ± 8.20 41.6 ± 8.84 41.9 ± 8.69 <0.0001
Income, US$ per month 0.86
< 564.3 117
8
26.5 3276 26.8 4454 26.7
564.3-656.5 868 19.5 2438 19.9 3306 19.8
656.6-779.6 129
3
29.0 3514 28.7 4807 28.8
≥ 779.7 111
3
25.0 3010 24.6 4123 24.7
Occupational status 0.009
White collar 245
4
55.1 7015 57.3 9469 56.8
Blue collar 150
0
33.7 4016 32.8 5516 33.1
Others 498 11.2 1202 9.83 1700 10.2
25

Area <0.0001
Northern Taiwan 228
8
51.4 5505 45.0 7793 46.7
Central Taiwan 604 13.6 2353 19.2 2957 17.7
Southern Taiwan 136
4
30.6 3852 31.5 5216 31.3
Eastern Taiwan and
offshore islands
196 4.40 523 4.28 719 4.31
Co-morbidity
Excessive
menstruation
782 17.6 2718 22.2 3500 21.0 <0.0001
Iron-deficiency
anemia
473 10.6 1549 12.7 2022 12.1 0.0004
Dysmenorrhea 555 12.5 2571 21.0 3126 18.7 <0.0001
Infertility 9 0.20 94 0.77 103 0.62 <0.0001
aChi-square test and t-test.
26

Table 2. Crude / adjusted hazard ratios and 95% confidence intervals for undergoing
surgery
Crude Adjusteda
HR (95% CI) HR (95% CI)
CM
No 1.00 (reference) 1.00 (reference)
Yes 0.20 (0.18-
0.21)***
0.18 (0.17-0.19)***
Age, years
< 30 1.00 (reference) 1.00 (reference)
30-39 2.65 (2.24-
3.14)***
2.36 (1.99-2.80)***
40-49 3.00 (2.54-
3.54)***
2.54 (2.15-3.00)***
≥ 50 1.35 (1.11-
1.64)**
1.24 (1.02-1.51)*
Occupational status
White collar 1.00 (reference) 1.00 (reference)
Blue collar 1.18 (1.11-
1.27)***
1.15 (1.07-1.23)***
Others 0.99 (0.89-1.11) 0.90 (0.81-1.01)
Area
Northern Taiwan 1.00 (reference) 1.00 ()
Central Taiwan 1.25 (1.15-
1.37)***
1.51 (1.38-1.65)***
Southern Taiwan 1.20 (1.12-
1.30)***
1.26 (1.17-1.36)***
Eastern Taiwan and offshore
islands
1.09 (0.93-1.29) 1.03 (0.87-1.22)
Co-morbidity (vs. no)
Excessive menstruation 1.34 (1.25- 1.26 (1.17-1.36)***
27

1.44)***
Iron-deficiency anemia 1.61 (1.48-
1.75)***
1.56 (1.43-1.70)***
Dysmenorrhea 1.23 (1.14-
1.32)***
1.35 (1.25-1.47)***
Infertility 0.68 (0.12-1.09) --
aAdjusted for age, occupation, area, excessive menstruation, iron-deficiency anemia,
and dysmenorrhea.
** P < 0.01 and *** P < 0.0001.
28

Table 3. Incidence and relative incidence of surgery for CM users and nonusers
CM nonusers CM users
Patients with
surgery
Person-
years
IRaPatients with
surgery
Person-
years
IR IRRb(95% CI)
Overall 2074 19994 103.7
3
1607 90744 17.71 0.17 (0.16-0.18)***
Age, years
< 20 0 144 0.00 0 843 0.00 --
20-29 66 1578 41.83 84 8849 9.49 0.23 (0.16-0.31)***
30-39 509 5390 94.43 636 26484 24.01 0.25 (0.23-0.29)***
40-49 1281 9488 135.0
1
807 41316 19.53 0.14 (0.13-0.16)***
≥ 50 218 3394 64.23 80 13252 6.04 0.09 (0.07-0.12)***
Income, US$ per month
< 564.3 516 5401 95.54 406 24169 16.80 0.18 (0.15-0.20)***
564.3-656.5 415 3854 107.6
8
334 18075 18.48 0.17 (0.15-0.20)***
656.6-779.6 671 5268 127.3
7
469 26095 17.97 0.14 (0.13-0.16)***
≥ 779.7 472 5470 86.29 398 22406 17.76 0.21 (0.18-0.24)***
29

Occupational status
White collar 1094 11524 94.93 899 52095 17.26 0.18 (0.17-0.20)***
Blue collar 779 6078 128.1
7
559 29825 18.74 0.15 (0.13-0.16)***
Others 201 2392 84.03 149 8824 16.89 0.20 (0.16-0.25)***
Area
Northern Taiwan 946 11161 84.76 618 41349 14.95 0.18 (0.16-0.20)***
Central Taiwan 361 2137 168.9
3
368 17166 21.44 0.13 (0.11-0.15)***
Southern Taiwan 682 5759 118.4
2
549 28345 19.37 0.16 (0.15-0.18)***
Eastern Taiwan and offshore
islands
85 935 90.91 72 3884 18.54 0.20 (0.15-0.28)***
Comorbidity
Excessive menstruation
No 1653 16616 99.48 1056 71005 14.87 0.15 (0.14-0.16)***
Yes 421 3378 124.6
3
551 19739 27.91 0.22 (0.20-0.25)***
Iron-deficiency anemia
No 1800 18054 99.70 1225 79864 15.34 0.15 (0.14-0.17)***
Yes 274 1940 141.2 382 10880 35.11 0.25 (0.21-0.29)***
30

4
Dysmenorrhea
No 1776 17481 101.6
0
1072 72183 14.85 0.15 (0.14-0.16)***
Yes 298 2512 118.6
3
535 18562 28.82 0.24 (0.21-0.28)***
Infertility
No 2072 19929 103.9
7
1592 90011 17.69 0.17 (0.16-0.18)***
Yes 2 65 30.77 15 733 20.46 0.67 (0.15-2.91)
aIR, incidence rate per 1,000 people.
bIRR, incidence rate ratio, compared to CM nonusers.
*** P < 0.0001.
31

Table 4. Incidence for women who received myomectomy among time lag
Diagnosis-
to-surgery
period
(year)
CM nonusers CM users
Patients
with
surgery
Person-
years
IR Patients with
surgery
Person-
years
IR cHRa(95% CI) aHRb(95% CI)
Overall 2074 19994 103.7
3
1607 90744 17.71 0.20 (0.18-0.21)*** 0.18 (0.17-
0.19)***
>0.25 882 19922 44.27 1483 90732 16.34 0.38 (0.35-0.41)*** 0.33 (0.30-
0.36)***
>0.5 731 19863 36.80 1416 90705 15.61 0.43 (0.39-0.47)*** 0.37 (0.34-
0.41)***
>1 562 19730 28.48 1285 90601 14.18 0.50 (0.45-0.55)*** 0.42 (0.38-
0.47)***
>3 253 19060 13.27 871 89670 9.71 0.72 (0.63-0.83)*** 0.59 (0.51-
0.68)***
≥5 91 18346 4.96 455 87840 5.18 1.01 (0.80-1.26) 0.79 (0.63-0.99)*
acHR, crude HR.
b aHR, HR adjusted for age, occupation, area, excessive menstruation, iron-deficiency anemia, and dysmenorrhea.
32

* <0.05, and *** p<0.0001.
33

Figure 1
34