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World Endometriosis Research Foundation Global Study of Women’s Health

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  • Cwm Taf Morgannwg University Health Board
  • World Endometriosis Research Foundation (WERF)

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Impact of endometriosis on quality of life and work
productivity: a multicenter study across ten countries
Kelechi E. Nnoaham, M.D.,
a,b
Lone Hummelshoj,
c
Premila Webster, M.D.,
a
Thomas d’Hooghe, M.D.,
d
Fiorenzo de Cicco Nardone, M.D.,
e
Carlo de Cicco Nardone, M.D.,
e
Crispin Jenkinson, D.Phil.,
f
Stephen H. Kennedy, M.R.C.O.G.,
b
and Krina T. Zondervan, D.Phil.,
b,g
on behalf of the World Endometriosis
Research Foundation Global Study of Women’s Health consortium
a
Department of Public Health, University of Oxford, Oxford, UK;
b
Nuffield Department of Obstetrics & Gynaecology,
University of Oxford, Oxford, UK;
c
World Endometriosis Research Foundation (WERF), London, UK;
d
Department of
Obstetrics & Gynaecology, Leuven University Fertility Center, Leuven, Belgium;
e
Department of Obstetrics and Gynecology,
Universit!
a Cattolica del Sacro Cuore, Rome, Italy;
f
Health Services Research Unit, University of Oxford, Oxford, UK; and
g
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
Objective: To assess the impact of endometriosis on health-related quality of life (HRQoL) and work productivity.
Design: Multicenter cross-sectional study with prospective recruitment.
Setting: Sixteen clinical centers in ten countries.
Patient(s): A total of 1,418 premenopausal women, aged 18–45 years, without a previous surgical diagnosis of
endometriosis, having laparoscopy to investigate symptoms or to be sterilized.
Intervention(s): None.
Main Outcome Measure(s): Diagnostic delay, HRQoL, and work productivity.
Result(s): There was a delay of 6.7 years, principally in primary care, between onset of symptoms and a surgical
diagnosis of endometriosis, which was longer in centers where women received predominantly state-funded health
care (8.3 vs. 5.5 years). Delay was positively associated with the number of pelvic symptoms (chronic pelvic pain,
dysmenorrhoea, dyspareunia, and heavy periods) and a higher body mass index. Physical HRQoL was significantly
reduced in affected women compared with those with similar symptoms and no endometriosis. Each affected
woman lost on average 10.8 hours (SD 12.2) of work weekly, mainly owing to reduced effectiveness while
working. Loss of work productivity translated into significant costs per woman/week, from US$4 in Nigeria to
US$456 in Italy.
Conclusion(s): Endometriosis impairs HRQoL and work productivity across countries and ethnicities, yet women
continue to experience diagnostic delays in primary care. A higher index of suspicion is needed to expedite specialist
assessment of symptomatic women. Future research should seek to clarify pain mechanisms in relation to endome-
triosis severity. (Fertil Steril
!
2011;96:366–73. "2011 by American Society for Reproductive Medicine.)
Key Words: Endometriosis, quality of life, work productivity
Endometriosis (the presence of endometrial-like tissue outside the
uterus) is a chronic disease associated with pelvic pain and subfer-
tility (1). Prevalence rates in the general population are unknown,
because a definitive diagnosis is established only at laparoscopy.
However, based on community prevalence estimates of symptoms
(2–4), endometriosis probably affects 10% of all and 30%–50% of
symptomatic premenopausal women (5). This represents !176
million affected women worldwide (6).
The diagnosis may be overlooked in primary care, and patients
think that this causes unnecessary suffering and reduced quality of
life (7). However, the impact of endometriosis has been poorly re-
searched (8), focusing on highly selected, mainly Western populations
with small sample sizes, poorly selected control subjects, and inade-
quately validated instruments (9–12). Therefore, the influence on
quality of life of factors such as disease stage, symptom severity,
and care seeking remains unclear (13). In one U.S. study, the direct
costs of endometriosis were estimated at US$2,801 per woman (14),
but indirect costs were not provided. Few studies have quantified
reported absence from work (15, 16); however, these are
geographically limited and focused on women who knew their
disease status, with potential for recall bias. Furthermore, work
absenteeism does not describe the full spectrum of disease-related
work productivity loss. To generate meaningful estimates, both pre-
senteeism (reduced productivity while at work) and absenteeism
(time lost from work) must be considered (17).
The lack of robust information about the impact of endometriosis
world-wide led us to initiate the Global Study of Women’s Health
(GSWH) to investigate the care-seeking experience of affected
women and to examine in detail the impact of endometriosis on
health-related quality of life (HRQoL) and work productivity on
a global scale.
Received February 7, 2011; revised May 6, 2011; accepted May 25, 2011;
published online June 30, 2011.
Bayer Schering Pharma (BSP) provided a grant to the World Endometri-
osis Research Foundation (WERF), from which L.H. was paid an hono-
rarium for project management, K.T.Z., F.d.C.N., C.d.C.N., T.d’H., and
S.H.K. received institutional grants from WERF as well as the European
Union Public Health Programme, K.E.N., K.T.Z., L.H. received support
for travel to meetings related the study, K.T.Z. received payment for
translation of study questionnaire into Dutch, and C.d.C.N. received
payment for translation into Italian. K.T.Z., L.H., S.H.K., and T.d’H.
have been consultants for BSP. P.W. has nothing to disclose. C.J. has
nothing to disclose.
Reprint requests: Kelechi E. Nnoaham, M.D., Directorate of Public Health,
NHS Berkshire West, 57–59 Bath Road, Reading RG30 2BA, United
Kingdom (E-mail: nnoaham.kelechi@berkshire.nhs.uk).
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Vol. 96, No. 2, August 2011 0015-0282/$36.00
Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2011.05.090
366
METHODS
The methods, reported in detail elsewhere (18), are summarized here.
Recruitment and Study Population
The GSWH is a cross-sectional study in 16 hospitals in 10 countries. Between
August 2008 and January 2010, we prospectively recruited consecutive
premenopausal women, aged 18–45 years, scheduled for a laparoscopy:
1) to investigate endometriosis-associated pelvic pain (i.e., chronic pelvic
pain (CPP), dysmenorrhoea, pain during or after intercourse), and/or subfer-
tility, with or without pelvicmass; or 2) to be sterilized. Women with previous
surgical diagnosis of endometriosis were excluded. The Mid and South
Buckinghamshire Research Ethics Committee and local Ethics Committees
approved the study.
Data Collection
In the week before surgery, women completed a 67-item questionnaire in their
own language about presenting complaints and their effect on HRQoL and
ability to function, medical history, reproductive factors, and health care re-
source use (http://www.endometriosisfoundation.org/GSWH-questionnaire-
English.pdf). Experienced gynecologists recorded laparoscopic findings in
a standard manner (http://www.endometriosisfoundation.org/GSWH-
surgical-sheet.pdf). Following European Society of Human Reproduction
and Embryology (ESHRE) guidelines, endometriosis was diagnosed on
visual evidence alone (1). Disease severity was staged using the revised
American Fertility Society (rAFS) classification: I (minimal), II (mild), III
(moderate), or IV (severe) (19). Stages I/II and III/IV were amalgamated in
analyses, as in earlier studies (20, 21).
Health-Related Quality of Life and Work Impairment
Validated language versions of the Short Form–36 version 2 (SF36v2) ques-
tionnaire were used to measure HRQoL (22). A general health version of the
Work Productivity and Activity Impairment (WPAI:GH) questionnaire (23)
was incorporated to: 1) assess absenteeism and presenteeism in symptomatic
employed women; and 2) assess the impact of symptoms on activities. We, as
others have (24), used a 4-week assessment period instead of the original 7
days, because the week before surgery may not reflect true work patterns
and endometriosis-associated symptoms fluctuate cyclically. Work produc-
tivity and other activities were measured on a 0 (‘‘symptoms had no effect
on work’’) to 10 (‘‘symptoms completely prevented working’’) scale.
Analyses
Comparison groups There were three outcome groups: 1) Women with
endometriosis (including disease found at sterilisation); 2) symptomatic
control women without endometriosis; and 3) sterilization control women
without endometriosis. Comparisons were also made across sites (centers),
with those that recruited %25 women combined into an ‘‘other’’ center.
See Supplemental Material 1 (available online at www.fertstert.org) for
methods regarding characteristics of the study population at recruitment
and the care-seeking experience.
Endometriosis and HRQoL For each SF36v2 dimension, item scores
were coded, summed, and transformed on a 0–100 (worst to best possible
health state) scale; missing data were not substituted. The physical health
(PCS) and mental health (MCS) component summaries were calculated,
standardized to normative data from the Third Oxford Health and Lifestyles
Survey (25) (Supplemental Material 2, available online at www.fertstert.org).
Endometriosis and work productivity The WPAI:GH dimensions were
calculated by recruitment centre and outcome group using standard methods
(23) (Supplemental Material 3, available online at www.fertstert.org). Lost
hours multiplied by 2007 hourly labour cost (26) produced estimates of the
cost of work productivity loss for countries.
Statistical Methods
We used chi-square analyses and Fisher’exact tests to study categoric
variables in the Stata program (v.11). We investigated continuous variables
using independent-sample ttest or nonparametric Mann-Whitney Utest as
appropriate. Multiple logistic and linear regression analyses were used to
study associations between variables and outcomes, adjusting for potential
confounders independently associated with exposure and outcome of interest
in univariate analysis. Pvalues of <.05 were considered nominally
significant.
RESULTS
Study Population and Diagnostic Incidence of
Endometriosis
In total, 1,486 (89%) of 1,669 eligible women agreed to participate.
Fifty-two had not undergone surgery by the close of recruitment, and
16 did not meet inclusion criteria, leaving complete data for 1,418
women (Supplemental Fig. 1, available online at www.fertstert.org).
Endometriosis was found in 745/1,418 (cumulative diagnostic
incidence 52.5%, 95% confidence interval [CI] 49.9%–55.1%),
ranging from 34.8% (95% CI 28.3–41.2%) in Oxford to 100% in
Siena. Diagnostic incidence was 54.3% (699/1,287, 95% CI 51.6%–
57%) among women undergoing laparoscopy for symptoms and
35.1% (46/131, 95% CI 26.9–43.3%) inthose being sterilized. Among
affected women, 60.5% (95% CI 57%–64%) had moderate/severe
disease. Of the 46 affected women undergoing sterilization, 25
(54.3%, 95% CI 40.0%–68.7%) had moderate/severe disease
(Supplemental Fig. 2, available online at www.fertstert.org).
Demographic and Clinical Characteristics
Compared with symptomatic control wom en (Tabl e 1), affected women
had higher educational achievement (P¼.004) and lower body mass
index (BMI; P<.001) and were less likely to be married or cohabiting
(P¼.002) (Tab le 1;Supplemental Material 4;Supplemental Table 1).
Endometriosis: Care-Seeking Experience
Diagnostic delay was 6.7 years (SD 6.3) in affected women and 5.9
years (SD 6.0) in symptomatic control women (P¼.017). This was
mainly due to delays in referral from primary care physician to
gynecologist, with women reporting an average of seven visits be-
fore specialist referral. After adjusting for demographic factors,
type of presenting symptoms, severity of pelvic pain, and comorbid-
ity, delay was longer in women with higher BMI (P¼.040) and more
‘pelvic’’ symptoms (P<.001; Supplemental Table 2, available
online at www.fertstert.org).
Diagnostic delay varied across centers: 3.3 years (SD 3.6) in
Guangzhou to 10.7 years (SD 9.3) in Siena (Fig. 1). After adjustment
for potential confounders (site, demographic differences, BMI,
symptom type and severity, and comorbidity), it was significantly
longer in centers with predominantly state-funded (8.3 years, 95%
CI 7.5–9.0) compared with self- or insurance-funded (5.5 years,
95% CI 5.1–5.9) health care (P¼.001; Fig. 1).
Endometriosis and Health-Related Quality of Life
Compared with both symptomatic and sterilization control women,
mean HRQoL scores in affected women were poorest in all SF36v2
dimensions except physical functioning. After adjusting for relevant
covariates (demographic factors, pelvic pain severity, type and num-
ber of presenting symptoms, and comorbidity), affected women had
significantly reduced HRQoL compared with symptomatic control
women in physical functioning (P¼.02), physical (P¼.013) and
mental (P¼.022) role limitation, and bodily pain (P¼.039; Fig. 2).
Compared with sterilization control women, affected women had
significantly poorer HRQoL only in bodily pain (P¼.024). Symp-
tomatic control women and affected women had lower PCS scores,
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TABLE 1
Characteristics of the women at recruitment.
Characteristic
Endometriosis
(n [745)
No endometriosis (n [673)
Symptomatic
(n [587) Pvalue
a
Laparoscopic
sterilization (n [86) Pvalue
b
Demographic/personal
Age (y) [Mean (SD)] 32.5 (6.2) 33.1 (6.4) .10 37.2 (5.0) <.001
Postsecondary
education [% (n)]
69.9 (521) 61.7 (362) .004 45.3 (39) <.001
In employment [% (n)] 78.5 (585) 73.6 (432) .054 70.9 (61) .067
Ethnicity [% (n)] .005 <.001
White 50.1 (373) 45.3 (266) 48.8 (42)
Asian/Oriental 32.0 (238) 35.4 (208) 8.1 (7)
Black 7.0 (52) 10.6 (62) 8.1 (7)
Other/mixed 9.7 (72) 6.1 (36) 33.7 (29)
Married or living with
partner [% (n)]
73.3 (546) 80.2 (471) .002 84.9 (73) .017
Body mass index (kg/m
2
)
[mean (SD)]
22.5 (4.1) 23.4 (4.8) <.001 25.2 (4.4) <.001
Smoked >100 cigarettes
in lifetime [% (n)]
27.2 (203) 25.6 (150) .53 39.5 (34) .012
Regular vigorous
exercise in past
3 months [% (n)]
27.0 (201) 25.2 (148) .86 20.9 (18) .54
Clinical
Hormonal contraception
in past 3 months
[% (n)]
23.4 (174) 16.9 (99) .004 45.3 (39) <.001
Reasons for hormonal contraception [% (n)] .42 <.001
Contraception/other 58.6 (102) 63.6 (63) 97.4 (38)
Pelvic pain, irregular or
heavy periods
40.2 (70) 35.4 (35) 2.6 (1)
Menstrual cycle length [% (n)] .041 .23
%24 days 16.2 (121) 13.8 (81) 20.9 (18)
25–32 days 63.2 (471) 60.3 (354) 58.1 (50)
R33 days 5.4 (40) 8.5 (50) 2.3 (2)
Menstrual duration
(days) [mean (SD)]
4.9 (2.8) 4.9 (2.3) .99 4.7 (2.4) .63
Parity [mean (SD)] 0.2 (0.5) 0.5 (1.0) <.001 1.8 (1.4) <.001
Gravidity [mean (SD)] 0.5 (0.9) 1.0 (1.4) <.001 2.3 (1.6) <.001
Subfertility [% (n)] 39.6 (295) 51.8 (304) <.001 18.6 (16) <.001
Type of symptoms reported [% (n)]
Pelvic pain, no
subfertility
42.7 (318) 29.3 (172) <.001 8.1 (7) <.001
Pelvic pain and
subfertility
17.7 (132) 15.2 (89) .21 2.3 (2) <.001
Subfertility, no
pelvic pain
13.4 (100) 28.6 (168) <.001 4.7 (4) .02
No pelvic pain,
no subfertility
26.2 (195) 27.1 (159) .72 84.7 (73) <.001
No. of symptoms [mean (SD)]
‘‘Pelvic’’ symptoms 1.5 (1.5) 1.0 (1.3) <.001 0.3 (0.9) <.001
‘‘Bowel’’ symptoms 0.5 (0.9) 0.3 (0.6) <.001 0.1 (0.4) <.001
‘‘Urinary’’ symptoms 0.2 (0.5) 0.1 (0.4) .015 0.0 (0.1) .005
‘‘Pelvic mass’
symptoms
1.3 (0.8) 0.9 (0.8) <.001 1.0 (0.4) .004
Pelvic pain severity NRS
0–10 [mean (SD)]
5.6 (2.2) 4.7 (2.2) <.001 5.0 (2.5) .048
Other pathologies at laparoscopy [% (n)]
Nonendometriotic
adhesions
11.0 (82) 34.2 (201) <.001 10.5 (9) .89
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
368 Nnoaham et al. Endometriosis, quality of life and work Vol. 96, No. 2, August 2011
and all three outcome groups had lower MCS scores, than the nor-
mative population; compared with symptomatic controls, affected
women had significantly reduced PCS but not MCS scores (Fig. 2;
Supplemental Fig. 3, available online at www.fertstert.org).
HRQoL was higher in women who werein paid or self-employment
(P<.001) and who did not report any pelvic pain (P¼.017), but lower
in those who had more severe pelvic pain (P<.001). After adjusting
for site (center), health care funding, pelvic pain, subfertility, severity
of pelvic pain, and number of ‘‘pelvic’’ and ‘‘bowel’ symptoms
reported, longer diagnostic delays were associated with reduced
physical HRQoL in affected women (P¼.047; Supplemental
Material 5, available online at www.fertstert.org).
Endometriosis and Work Productivity
See Supplemental Material 6 (available online at www.fertstert.org)
for more. Affected women reported greater absenteeism and presen-
teeism compared with symptomatic control women (Table 2): Over-
all work productivity loss was 10.8 h/wk (SD 12.2) versus 8.4 h/wk
(SD 10.2), respectively (P<.001; Table 2).
FIGURE 1
Diagnostic delay by center of recruitment. Others comprises Buenos Aires, Washington, DC, San Francisco, and Palo Alto.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
TABLE 1
Continued.
Characteristic
Endometriosis
(n [745)
No endometriosis (n [673)
Symptomatic
(n [587) Pvalue
a
Laparoscopic
sterilization (n [86) Pvalue
b
Nonendometriotic
cysts
10.6 (79) 25.7 (151) .018 4.7 (4) .81
Fibroids 16.1 (120) 21.5 (126) .015 3.5 (3) .54
Other
c
2.8 (21) 8.2 (48) <.001 1.2 (1) .37
Comorbidity [% (n)]
d
Cancer 1.5 (11) 1.9 (11) .58 2.3 (2) .55
Autoimmune/atopic
conditions
19.7 (147) 20.1 (118) .64 14.0 (12) .20
Other 76.9 (573) 60.3 (354) <.001 47.8 (41) <.001
Any 82.4 (614) 66.3 (389) <.001 53.5 (46) <.001
a
Endometriosis vs. symptomatic control subjects.
b
Endometriosis vs. laparoscopic sterilization control subjects.
c
Other pathologies were mainly teratoma and bilateral tubal blockage.
d
Cancer included breast and ovarian cancer, melanoma and Hodgkin/non-Hodgkin lymphoma; autoimmune/atopic conditions included asthma, eczema,
Hashimoto disease, multiple sclerosis, rheumatoid arthritis, Sjogren syndrome, thyroid disease, and systematic lupus erythematosus; Other included
chronic fatigue syndrome, deafness, fibromyalgia, depression, diabetes, fibroids, gland ular fever, imperforate hymen, migraines, ovarian cysts, polycystic
ovarian syndrome, pyloric stenosis, scoliosis, and mitral valve prolapse.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
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369
In multivariate analyses, overall work productivity loss in em-
ployed women was greater in those with pelvic pain without subfer-
tility (P¼.030) and more severe pelvic pain (P<.001) and less in
those who had higher educational attainment (P¼.032). After ad-
justing for educational attainment, marital status, type and number
of symptoms, pelvic pain severity, and comorbidity, we found that
absenteeism (P¼.019), presenteeism (P¼.033) and overall work
productivity loss (P¼.014) increased with increasing disease sever-
ity (Supplemental Fig. 4, available online at www.fertstert.org).
Absenteeism-related costs ranged from US$1/wk in Nigeria to
US$231/wk in Italy; presenteeism costs ranged from US$3/wk in
Nigeria to US$250/wk in the USA (Supplemental Fig. 5, available
online at www.fertstert.org).
DISCUSSION
Patient groups have advocated that endometriosis is associated with
diagnostic delay, reduced quality of life, and loss of work productiv-
ity. However, past studies, mainly in Western countries, are limited
by small sample sizes (9, 12), suboptimal control selection (10), lack
of geographic spread (11), and potential recall bias. Using robust
quantitative methods, the GSWH is the first to demonstrate the
substantial impact of endometriosis on women and society across
different countries and ethnicities. These data have never been
available in most of the participating countries.
We found an average diagnostic delay of 6.7 years (consistent
with earlier U.K. and U.S. reports (27–29). Delay was longer in
women with more ‘‘pelvic’’ symptoms (e.g., CPP, dysmenorrhoea,
and dyspareunia) and a higher BMI, and at centers delivering
predominantly state-funded health care. We showed that delays
are strongly associated with care-seeking experiences in primary
care, as previously suggested (30, 31), but we do not exclude
other reasons. For example, women may delay seeking help
because of the ‘‘discrediting’’ nature of menstrual irregularities
and risk of stigmatization (27, 32).
An association between higher BMI and diagnostic delay is rec-
ognized in other diseases (33, 34); in endometriosis it may arise
because of difficulty detecting pathology on pelvic examination.
The association between diagnostic delay and health care funding
in endometriosis is novel, although similar findings are reported in
cancer patients (35). Rationing of health care and differences in
readiness of clinicians to suggest surgery in private- versus public-
funded health care settings are possible explanations but other influ-
ences, such as negative experiences of primary care consultations,
cannot be excluded (31).
The effect of endometriosis on physical (but not mental) HRQoL
of women was substantial, with SF36v2 PCS scores similar to those
reported in women with cancer (36). The effect was less if women
were employed and free of pelvic pain, and worse with severe pelvic
pain and advanced disease. Notably, even after adjusting for covari-
ates, such as pain severity and comorbidity, bodily pain, health per-
ception, and PCS scores were significantly reduced in those with
moderate/severe compared with minimal/mild disease.
We demonstrated that pelvic pain and disease severity are the major
drivers of work productivity loss in endometriosis. Although reduced
effectiveness at work is less frequently assessed and recorded than
work absence, it accounted for nearly 60% of total work productivity
loss. The annual costs (per employed woman) of endometriosis-
associated work productivity loss (varying from US$208 in Nigeria
to US$23,712 in Italy), is markedly higher than earlier estimates (di-
rect costs US$2,801 and indirect costs US$1,023 in the U.S.) (14, 15),
but those studies only considered absenteeism.
The greater impairment in HRQoL (particularly bodily pain) and
work productivity in moderate/severe versus minimal/mild disease,
FIGURE 2
Health-related quality of life in women with endometriosis (n ¼745), symptomatic control women (n ¼587), and laparoscopic sterilization
control women (n ¼86): SF-36v2 dimension scores with adjusted Pvalues
b
and 95% confidence intervals. A lower score means lower health-
related quality of life. Pvalues are presented as (P¼x; P¼y), x being the Pvalue for comparison of endometriosis and laparoscopic sterilization
control subjects and y being the Pvalue for comparison of endometriosis and symptomatic control subjects. Pvalues are adjusted for
education, maritalstatus, employment status, pelvic pain severity, type and number of presenting symptoms, and comorbidity.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
370 Nnoaham et al. Endometriosis, quality of life and work Vol. 96, No. 2, August 2011
after accounting for pelvic pain severity and comorbid conditions, is
intriguing and could have a number of causes. Despite careful
adjustment, there might still be residual differences in symptom
severity or differential reporting of comorbid conditions in case sub-
jects and symptomatic control subjects, but we would expect these to
affect mental as well as physical dimensions, which was not the
case. An alternative explanation is the role of central sensitization.
This theory, supported by experiments in animals and humans
(37–39), suggests that persistent pain stimuli, generated by
endometriotic tissue as disease advances, results over time in
heightened pain awareness even from regions removed from the
tissue itself. If true, such heightened awareness could explain the
impact of worsening endometriosis on HRQoL and work
productivity.
Although the GSWH was designed to avoid many of the
methodologic limitations of earlier studies, it had important poten-
tial limitations itself. First, HRQoL and work productivity in the
weeks leading up to scheduled surgery may be affected by both
the impending surgery and the symptoms themselves. This is per-
haps reflected in the reduced SF36v2 summary scores in sterilization
control subjects compared with general population standards.
However, because women in all groups were undergoing surgery,
its effect on comparing results between case and control groups
should be negligible. Second, work loss data were self-reported.
Although an independent measure of employment would be more
reliable, self-reported data compare favorably with more objective
data (e.g., employment records) and are an efficient and accurate
way to collect data on illness-related work productivity loss (40).
Third, we altered the standard 7-day recall period of the WPAI to
4 weeks for the reasons given above. A study that similarly extended
the recall period to 4 weeks found that the construct validity of the
modified questionnaire was similar to that of the original, though es-
timates of work productivity impairment were higher (24). Fourth,
endometriosis was diagnosed visually, without histologic confirma-
tion, following ESHRE guidelines (1), based on the premise that
negative histology does not exclude the presence of disease. Al-
though the hospitals were experienced in diagnosing endometriosis,
disease stage might have been inadequately classified. However,
combining minimal with mild and moderate with severe stages in
analyses minimizes such potential bias. Furthermore, in a post-
GSWH validation study, 29 surgeons from 12 of the 16 participating
centers viewed nine standardized videos to identify/eliminate and
stage endometriosis. Preliminary analysis suggested substantial in-
terrater agreement in disease identification and staging (both Fleiss
k>0.60; unpublished data, by courtesy of Drs C. Becker and K.
May, Oxford, U.K.).
The observation that 35.1% of women undergoing sterilization
had endometriosis is not surprising, because rates of 3%–45% are
reported in such women (41, 42). More surprising is that >50% of
them had moderate/severe endometriosis, which may indicate that
a relatively large proportion were not asymptomatic. Finally, the
variability in both the range of endometriosis prevalence (34.8%
in Oxford to 100% in Siena) and the proportion of moderate/
severe disease (30%–40% in most centers but nearly 90% in some
countries) may relate to a minority of participating centers
routinely assessing women with presurgical ultrasound scans and
prioritizing surgery in those with evidence of ovarian
(endometriotic) cysts, but they may also reflect reality, because
the proportion of moderate/severe endometriosis was reported as
63% in Iceland over a 20-year period (43). Although such
differences in routine clinical protocols should be borne in mind
when interpreting the results, additional adjustment of combined
HRQoL and work productivity results according to center showed
that key results were unaffected by any such differences.
A key strength of our study was that, to limit information bias, we
restricted our study to women undergoing a first laparoscopy for
TABLE 2
Work productivity in symptomatic women with and without endometriosis.
Work and productivity loss variables
Endometriosis
(n [745)
Symptomatic
control (n [587)
Unadjusted
Pvalue
Adjusted
Pvalue
a
General
Weekly hours paid to work, mean (SD) 39.2 (14.0) 38.6 (12.1) .44 .047
Weekly hours actually worked, mean (SD) 24.9 (16.1) 28.5 (25.0) .01 .32
Work Productivity and Activity Impairment dimensions
Absenteeism
b
%, mean (SD) 11.2 (21.6) 8.5 (20.0) .069 .58
h/wk, mean (SD) 4.4 (8.0) 3.3 (8.4) .24 .82
Presenteeism
c
%, mean (SD) 25.8 (26.8) 17.9 (22.1) <.001 .26
h/wk, mean (SD) 6.4 (7.9) 5.1 (6.7) .001 .36
Overall work productivity loss
d
%, mean (SD) 32.3 (29.8) 22.0 (25.1) <.001 .045
h/wk, mean (SD) 10.8 (12.2) 8.4 (10.2) <.001 .032
Activity impairment
e
%, mean (SD) 28.5 (26.9) 19.6 (23.4) <.001 .48
a
Variables adjusted for included educational attainment, marital status, type and number of symptoms, severity of pelvic pain, and comorbidity.
b
Time absent from work owing to symptoms.
c
Reduced effectiveness while on the job owing to symptoms.
d
Combination of absenteeism and presenteeism.
e
Reduced effectiveness while doing non–work-related activities, e.g., child care, exercise, housekeeping, etc.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
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symptoms suggestive of endometriosis or sterilization and collected
relevant data before diagnosis. Our results are therefore generaliz-
able to this incident patient group but may underestimate HRQoL
and work productivity figures among women who have suffered
from the condition for longer.
In conclusion, endometriosis significantly affects women and
societies world-wide, but substantial delays in diagnosis exist.
Heightened awareness of the disease in primary care should lead
to earlier diagnosis, less suffering, and improved work productivity.
Future research should address the underlying pain mechanisms in
endometriosis and identify symptom control strategies that target
those pathways to improve the outlook for affected women.
Acknowledgments: The authors thank all of the women who participated in
the GSWH for their valuable contributions. The authors are also grateful to
all of the clinical and research assistants at the collaborating centers and
thank Andrew Prentice for his contribution to the study protocol and
questionnaire design.
Members of the GSWH consortium: Mauricio Abr~
ao (University of S~
ao
Paulo, S~
ao Paulo, Brazil); David Adamson (Fertility Physicians of Northern
California, Palo Alto, California, USA); Francisco Carmona (University of
Barcelona, Barcelona, Spain); Thomas d’Hooghe (University of Leuven,
Leuven, Belgium); Carlo de Cicco Nardone (Universit!
a Cattolica del Sacro
Cuore, Rome, Italy); Fiorenzo de Cicco Nardone (Universit!
a Cattolica del
Sacro Cuore, Rome, Italy); Bukola Fawole (University of Ibadan, Ibadan,
Nigeria); Linda Giudice (University of California, San Francisco, Califor-
nia, USA); Mark Hornstein (Brigham and Women’s Hospital, Boston, Mas-
sachusetts, USA); Stephen Kennedy (University of Oxford, Oxford, U.K.);
Xishi Liu (Shanghai Obstetrics and Gynaecology Hospital, Shanghai,
China); Xu Min (Guangdong Provincial Hospital of Traditional Chinese
Medicine, Guangzhou, China); Stacey Missmer (Brigham and Women’s
Hospital, Boston, Massachusetts, USA); Felice Petraglia (University of
Siena, Siena, Italy); Carlos Petta (State University of Campinas, Campinas,
Brazil); Pamela Stratton (National Institutes of Health, Washington, DC,
USA); Carlos Sueldo (Center for Gynecology and Reproduction, Buenos
Aires, Argentina); and Mary Wingfield (National Maternity Hospital,
Dublin, Ireland).
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SUPPLEMENTAL MATERIAL 1
Characteristics of Study Population at Recruitment
We evaluated the type and number of symptoms for which women
underwent laparoscopy, and pelvic pain severity. Symptom types
were: 1) pelvic pain without subfertility; 2) pelvic pain with subfer-
tility; 3) subfertility without pelvic pain; and 4) no pelvic pain or
subfertility. Because some symptoms (e.g., pelvic pain and dysme-
norrhoea) are strongly correlated, principal-component analysis was
used to identify underlying patterns. Using the principal axis method
(1) with prior communality estimates of ‘‘1’’ and orthogonal rota-
tion, we extracted factors (symptom patterns) and retained those
with eigenvalues >1. A symptom was deemed to load onto a factor
if its component loading was >0.40 for that pattern and %0.40 for
the others. The mean number of individual symptoms within each
factor was then compared across outcome groups. Pelvic pain
severity was assigned by women as a numeric rating scale score
(on a 1–10 scale).
The Care-Seeking Experience
Diagnostic delay (interval between symptom onset and laparos-
copy) was compared across outcome groups. The age of a woman
at symptom onset was derived as the average of her reported ages
at onset of all the symptoms she reported. The influence of health
care funding, type and number of symptoms, and pelvic pain
severity was explored in multivariate analyses.
SUPPLEMENTAL MATERIAL 2
Mean dimension scores in case and sterilization/symptomatic
control subjects were compared, with adjustment for relevant
covariates.
SUPPLEMENTAL MATERIAL 3
Absenteeism and presenteeism were calculated as [hours missed due
to symptoms/(hours missed due to symptoms þhours actually
worked)] and reduced productivity while working, respectively,
both expressed as percentages. Overall productivity loss was
calculated as ([(hours missed due to symptoms þ(percent reduced
productivity while working $hours actually worked)]/[hours
missed due to symptoms þhours actually worked]) $100.
SUPPLEMENTAL MATERIAL 4
Principal-component analysis resulted in four categories of present-
ing complaints: ‘‘pelvic,’’ ‘‘bowel,’’ ‘‘urinary,’’ and ‘‘pelvic mass’
(Supplemental Table 1). Affected women reported more individual
symptoms in all categories (P<.001) (Table 1).
SUPPLEMENTAL MATERIAL 5
Notably, even after adjusting for site, education, marital status, em-
ployment status, pelvic pain severity, type and number of presenting
symptoms, and comorbidity, health-related quality of life in the do-
mains of bodily pain (P¼.026) and health perception (P<.001) and
the PCS score (P¼.009) fell as rAFS disease severity increased.
SUPPLEMENTAL MATERIAL 6
Most women were in paid or self-employment (77.2%, 95% CI
74.8–79.7%); those not working were mostly housewives or care
givers. One in seven symptomatic unemployed women (14.5%,
95% CI 10.5–18.6%) were not working because of their original
complaints.
REFERENCE
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373.e1 Nnoaham et al. Endometriosis, quality of life and work Vol. 96, No. 2, August 2011
SUPPLEMENTAL FIGURE 1
Participating centers and numbers of women recruited in the Global Study of Women’s Health (n ¼1,418).
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
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SUPPLEMENTAL FIGURE 2
Proportions of diagnostic endometriosis incidence and stage by center of recruitment. Others comprises Buenos Aires, Washington, DC, San
Francisco, and Palo Alto.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
373.e3 Nnoaham et al. Endometriosis, quality of life and work Vol. 96, No. 2, August 2011
SUPPLEMENTAL FIGURE 3
Health-related quality of life in women with endometriosis (n ¼745), symptomatic control women (n ¼587), and laparoscopic sterilization
control women (n ¼86): SF36v2 component summary scores with adjusted Pvalues and 95% confidence intervals. A lower score means
lower health-related quality of life. Pvalues are presented as (P¼x; P¼y), x being the Pvalue for comparison of endometriosis and
laparoscopic sterilization control subjects and y being the Pvalue for comparison of endometriosis and symptomatic control subjects.
Dashed line represents mean component summary score (50) for normative population. All Pvalues are adjusted for site, education, marital
status, employment status, pelvic pain severity, type and number of presenting symptoms, and comorbidity.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
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SUPPLEMENTAL FIGURE 4
Absenteeism, presenteeism, and overall work productivity loss by endometriosis severity (Revised American Fertility Society classification
[rAFS]). Adjusted Pvalues for the association between each work productivity dimension and rAFS disease stage (trend test) are given.
Variables adjusted for included educational attainment, marital status, type and number of symptoms, severity of pelvic pain, and
comorbidity.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
373.e5 Nnoaham et al. Endometriosis, quality of life and work Vol. 96, No. 2, August 2011
SUPPLEMENTAL FIGURE 5
Monetary loss from endometriosis-associated work absenteeism and presenteeism.
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
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SUPPLEMENTAL TABLE 1
Factors (symptom patterns) and loading symptom variables.
‘‘Pelvic’ symptoms ‘‘Bowel’’ symptoms ‘‘Urinary’’ symptoms ‘‘Pelvic mass’’ symptoms
Chronic pelvic pain Painful bowel opening Pain on passing urine Pelvic mass
Painful periods Bloody bowel opening Blood in urine Ovarian cyst
Painful intercourse Bowel upset Other urinary problems Not subfertile
Heavy periods
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
373.e7 Nnoaham et al. Endometriosis, quality of life and work Vol. 96, No. 2, August 2011
SUPPLEMENTAL TABLE 2
Care-seeking for symptoms, mean (SD).
Variables
Endometriosis
(n [745)
Symptomatic
control (n [587)
Unadjusted
Pvalue
Age at symptom onset (y) 25.9 (7.6) 27.2 (7.3) .0063
Age at first contact with general
physician for symptoms (y)
26.2 (7.9) 27.6 (7.4) .0016
No. of visits to general physician before
referral to specialist
6.5 (10.2) 6.8 (10.6) .59
Age at diagnosis (y) 32.6 (6.2) 33.1 (6.4) .10
Diagnostic delay (y) 6.7 (6.3) 5.9 (6.0) .017
Nnoaham. Endometriosis, quality of life and work. Fertil Steril 2011.
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Endometriosis is a heritable, complex chronic inflammatory disease, for which much of the causal pathogenic mechanism remains unknown. Genome-wide association studies (GWAS) to date have identified 12 single nucleotide polymorphisms at 10 independent genetic loci associated with endometriosis. Most of these were more strongly associated with revised American Fertility Society stage III/IV, rather than stage I/II. The loci are almost all located in intergenic regions that are known to play a role in the regulation of expression of target genes yet to be identified. To identify the target genes and pathways perturbed by the implicated variants, studies are required involving functional genomic annotation of the surrounding chromosomal regions, in terms of transcription factor binding, epigenetic modification (e.g., DNA methylation and histone modification) sites, as well as their correlation with RNA transcription. These studies need to be conducted in tissue types relevant to endometriosis-in particular, endometrium. In addition, to allow biologically and clinically relevant interpretation of molecular profiling data, they need to be combined and correlated with detailed, systematically collected phenotypic information (surgical and clinical). The WERF Endometriosis Phenome and Biobanking Harmonisation Project is a global standardization initiative that has produced consensus data and sample collection protocols for endometriosis research. These now pave the way for collaborative studies integrating phenomic with genomic data, to identify informative subtypes of endometriosis that will enhance understanding of the pathogenic mechanisms of the disease and discovery of novel, targeted treatments. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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Objective: To describe the anatomic variety of congenital cervical atresia and to explore the relationship between this disorder and pelvic endometriosis. Methods: In a retrospective study, records were reviewed for 96 patients with a confirmed diagnosis of congenital cervical atresia treated at a center in Beijing, China, between January 1984 and October 2014. Data on demographic parameters, symptoms, anatomic features, and endometriosis were obtained and analyzed. Results: Of the 96 patients, 54 (56%) had pelvic endometriosis, 23 (24%) had a uterine malformation, 75 (78%) had a vaginal malformation, and 12 (13%) had a urinary malformation. The patients with a delay from first symptoms to surgery of more than 1year had a higher incidence of endometriosis than did those with a delay of 1year or less (45/71 [63%] vs 7/23 [30%]; P=0.006), and this trend was not related to the severity of endometriosis (P=0.658). Among the 31 patients with unilateral endometrial cysts, 20 (65%) had left-sided cysts and 11 (35%) had right-sided cysts (P=0.005). Conclusion: More than half of patients with congenital cervical atresia had pelvic endometriosis. Early diagnosis and surgery seem to be necessary to prevent endometriosis among patients with congenital cervical atresia.
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Objective: To investigate serum microRNAs (miRNAs) in women with endometriosis. Design: Case-control study. Setting: University hospital. Patient(s): Women with (n = 24) and without (n = 24) endometriosis. Intervention(s): Serum samples were obtained from surgically diagnosed subjects. Main outcome measure(s): miRNA from women with without endometriosis were used for microarray profiling and confirmed by means of quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was performed on differentially expressed miRNAs. Result(s): miR-3613-5p, miR-6755-3p were down-regulated and miR-125b-5p, miR-150-5p, miR-342-3p, miR-143-3p, miR-145-5p, miR-500a-3p, miR-451a, miR-18a-5p were up-regulated more than 10-fold in the microarray. These results were confirmed with the use of qRT-PCR. Among the differentially expressed miRNAs, miR-125b-5p expression levels had the highest area under the ROC curve (AUC). The maximum AUC score of 1.000 was achieved when combining miR-125b-5p, miR-451a, and miR-3613-5p with the use of a logistic regression model. Conclusion(s): We identified several miRNAs in serum that distinguished subjects with endometriosis from those without. miR-125b-5p had the greatest potential as a single diagnostic biomarker. A combination of that miRNA with miR-451a and miR-3613-5p further improved diagnostic performance.
Chapter
Endometriosis is a gynecologic disease that affects more than 150 million women around the world. The disease is usually found in the pelvic cavity, affecting the ovaries, the fallopian tubes, the peritoneum, and the rectovaginal septum; it is less commonly found in the abdominal cavity affecting the small bowel, the large bowel, and other abdominal organs. It has been established that the best examination to evaluate endometriosis is transvaginal ultrasonography with bowel preparation. The laparoscopic ablation or excision of endometriotic lesions has as its objectives pain relief or fertility improvement and increasing the patient’s quality of life. It is essential to remove all visible lesions and to biopsy the doubtful ones in order to reduce the chances of recurrences and repeat surgery.
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Endometriosis affects an estimated 176 million women worldwide during the prime years of their lives. Yet many clinical questions remain unanswered, treatment failures are common, and there is little investment in investigating disease mechanisms. The World Endometriosis Research Foundation (WERF) has been created to provide a global platform where resources and intelligence are pooled to enable international collaboration in order to find answers so that treatments for endometriosis can be improved and prevention can become reality in future generations of women. WERF is now working with 30 centres in 19 countries conducting prospective studies investigating the impact of endometriosis, disease predictability, and personal and societal cost. (Journal of Endometriosis 2010; 2: 3-6).
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The combined investigation of environmental and genetic risk-factors in complex traits will refocus attention on the case-control study. Endometriosis is an example of a complex trait for which most case-control studies have not followed the basic criteria of epidemiological study design. Appropriate control selection has been a particular problem. This article reviews the principles underlying the design of case-control studies, and their application to the study of endometriosis. Only if it is designed well is the case-control study a suitable alternative to the prospective cohort study. Use of newly diagnosed over prevalent cases is preferable, as the latter may alter risk estimates and complicate the interpretation of findings. Controls should be selected from the source population from which cases arose. Potential confounding should be addressed both in studies of environmental and genetic factors. For endometriosis, a possible design would be to: (i) use newly diagnosed cases with 'endometriotic' disease; (ii) collect information predating symptom onset; and (iii) use at least one population-based female control group matched on unadjustable confounders and screened for pelvic symptoms. In conclusion, future studies of complex traits such as endometriosis will have to incorporate both environmental and genetic factors. Only adequately designed studies will allow reliable results to be obtained and any true aetiologic heterogeneity expected to underlie a complex trait to be detected.
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Chronic pelvic pain has often been described as a major women's health issue, but no information exists on the extent of the problem in the United Kingdom. To investigate the community prevalence of chronic pelvic pain and its effect on the lives of consulting and non-consulting women. Postal questionnaire survey. Women aged 18 to 49 (n = 3916) randomly selected from the Oxfordshire Health Authority Register. The questionnaire response rate (adjusted for non-deliveries) was 74% (2304/3106). Chronic pelvic pain was defined as recurrent or constant pelvic pain of at least six months' duration, unrelated to periods, intercourse, or pregnancy. Case subgroups comprised recent consulters, past consulters, and non-consulters. Women who reported dysmenorrhoea alone formed a comparison group. The three-month prevalence of chronic pelvic pain was 24.0% (95% CI = 22.1% to 25.8%). One-third of women reported pain that started more than five years ago. Recent consulters (32% of cases) were most affected by their symptoms in terms of pain severity, use of health care, physical and mental health scores, sleep quality, and pain-related absence from work. Non-consulters (41% of cases) did not differ from women with dysmenorrhoea in terms of symptom-related impairment. Irrespective of consulting behaviour, a high rate of symptom-related anxiety was found in women with chronic pelvic pain (31%) compared with women with dysmenorrhoea (7%). This study showed a high community prevalence of chronic pelvic pain in women of reproductive age. Cases varied substantially in the degree to which they were affected by their symptoms. The high symptom-related anxiety in these women emphasises the need for more information about chronic pelvic pain and its possible causes.
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Introduction: Endometriosis can be difficult to diagnose clinically and models that use symptoms to predict whether the disease is present or not are based on limited patient populations. Endometriosis also influences health-related quality of life, but little is known about its impact across the world. We therefore initiated two integrated multicentre studies to collect prospective, standardised, epidemiological data, to 1) examine the global impact of endometriosis and relative effect of risk-factors, and 2) develop a symptom-based diagnostic tool. Methods: The Global Study of Women's Health (GSWH) and the Women's Health Symptom Survey (WHSS) prospectively recruit 18-45 year old women having a laparoscopy across 23 and 19 centres, respectively, worldwide. Women with a previous surgical diagnosis of endometriosis are excluded. Multi-lingual patient questionnaires and a surgical questionnaire, incorporating validated instruments, are used to collect the data. The GSWH aims to recruit >2,000 women by December 2009; the WHSS to recruit 1,000 women in each of the two model-generating and validation stages. Results: A six-week pilot study in Oxford, UK, established the feasibility of the study protocols. Of 32 eligible women, 27 participated (response rate - 84.4%); 26% completed the questionnaire online. Endometriosis was found in 47.4%. Extrapolating the recruitment rates from the pilot study, the target sample sizes for the GWSH and WHSS were deemed feasible. Conclusions: Using standardised data collection, the GSWH and WHSS will provide insight into the global impact of endometriosis and develop a validated, symptom-based, diagnostic tool. They have the potential to provide the basis for future, longitudinal, follow-up studies and a collaborative Endometriosis Biobank implementing standardised collection of DNA and tissue samples.
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Endometriosis is an estrogen-dependent disorder where endometrial tissue forms lesions outside the uterus. Endometriosis affects an estimated 10% of women in the reproductive-age group, rising to 30% to 50% in patients with infertility and/or pain, with significant impact on their physical, mental, and social well-being. There is no known cure, and most current medical treatments are not suitable long term due to their side-effect profiles. Endometriosis has an estimated annual cost in the United States of $18.8 to $22 billion (2002 figures). Although endometriosis was first described more than 100 years ago, current knowledge of its pathogenesis, spontaneous evolution, and the pathophysiology of the related infertility and pelvic pain, remain unclear. A consensus workshop was convened following the 10th World Congress on Endometriosis to establish recommendations for priorities in endometriosis research. One major issue identified as impacting on the capacity to undertake endometriosis research is the
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