YGYNO-977835; No.

of pages: 7; 4C:
Gynecologic Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Review Article

Association between pelvic inflammatory disease and risk of ovarian

cancer: An updated meta-analysis
Jinlan Piao a, Eun Ji Lee b, Maria Lee a,b,⁎
a
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
b
Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Republic of Korea

H I G H L I G H T S

• Patients with pelvic inflammatory disease more likely to develop into ovarian cancer
• Positive association between PID and ovarian cancer was found among Asian patients.
• PID is associated with an increased risk of invasive and borderline ovarian cancer, non-serous ovarian cancer.
• Large and well-designed studies are still needed to further confirm this result.

a r t i c l e i n f o a b s t r a c t

Article history: Background. Because of conflicting reports regarding the relationship between pelvic inflammatory disease
Received 16 December 2019 (PID) and ovarian cancer, we performed an updated meta-analysis to investigate the association between PID
Received in revised form 28 January 2020 and the risk of this malignancy.
Accepted 1 February 2020
Methods. Embase, PubMed, and Web of Science were searched up until November 1, 2019. Hazard ratios
Available online xxxx
(HRs), along with 95% confidence intervals (CIs), were calculated to analyse outcomes.
Keywords:
Results. We included 16 studies in this meta-analysis. PID was associated with an increased risk of ovarian
Ovarian neoplasms cancer (HR 1.18, 95% CI 1.13 to 1.22; I2 = 41%). In subgroup analyses according to ethnicity, study design, tumour
Pelvic inflammatory disease invasiveness, and type of ovarian cancer, PID was significantly associated with ovarian cancer in all subgroups.
Meta-analysis The lowest heterogeneity (I2 = 0% to 38%) was observed for associations between PID and ovarian cancer in
Inflammation Asian patients (HR 1.25, 95% CI 1.10 to 1.42), ovarian cancer in case-control studies (HR 1.15, 95% CI 1.08 to
Risk factor 1.23), invasive ovarian cancer (HR 1.25, 95% CI 1.20 to 1.30), borderline ovarian cancer (HR 1.28, 95% CI 1.19
to 1.37), and non-serous ovarian cancer (HR 1.15, 95% CI 1.07 to 1.24).
Conclusions. This updated meta-analysis demonstrated that PID is associated with an increased risk of ovarian
cancer. Future large, well-designed studies are necessary to corroborate our findings.
© 2020 Elsevier Inc. All rights reserved.

Contents

1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2. Eligibility criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4. Study quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Search results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3. Association between PID and ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author at: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul 03080, Republic of Korea.
E-mail address: marialee@snu.ac.kr (M. Lee).

https://doi.org/10.1016/j.ygyno.2020.02.002
0090-8258/© 2020 Elsevier Inc. All rights reserved.

Please cite this article as: J. Piao, E.J. Lee and M. Lee, Association between pelvic inflammatory disease and risk of ovarian cancer: An updated
meta-analysis, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.002
2 J. Piao et al. / Gynecologic Oncology xxx (xxxx) xxx

3.4. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Ethics approval and consent to participate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Consent for publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Data availability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Authors' contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

A Society of Gynecologic Oncology Evidence-based Review (and 2.2. Eligibility criteria

Recommendations)
1. Background
As the seventh most frequent cancer in women worldwide,
ovarian cancer is responsible for about 239,000 new cancer diagno-
ses and approximately 152,000 deaths in the world each year [1,2].
The lifetime risk of ovarian cancer is approximately 1 in 75, and the
likelihood of dying from this malignancy is 1 in 100. Ovarian cancer
is usually diagnosed at an advanced stage, at which time the 5-year
relative survival rate is 29% [2]. Epithelial ovarian cancer accounts
for up to 90% of all histologic types [1]. Although the aetiology of
ovarian cancer remains unclear, numerous risk factors have been
identified, such as exposure to talc [3], use of hormone-
replacement therapy [4], presence of endometriosis [5], or a family
member with breast or ovarian cancer [4]. Chronic inflammation
has been hypothesized as a potential biologic mechanism for the
development of this malignancy [6–8]. Several authors have sug-
gested a potential association between pelvic inflammatory dis-
ease (PID) and an increased risk of ovarian cancer [9,10].
PID refers to an infection of the female upper reproductive tract,
which includes salpingitis, endometritis, tubo-ovarian abscess, and pel-
vic peritonitis. As such, PID has a varying array of clinical manifestations
[11]. PID results from microorganisms traveling from the vagina or cer-
vix to the upper reproductive organs, with endometritis occurring as an
intermediate stage in disease pathogenesis [12]. It is the most frequent
gynaecologic cause of emergency room visits, approaching 350,000
visits per year in the United States [13,14]. Although many studies
have evaluated the association between PID and ovarian cancer
[15–17], the mechanism whereby PID leads to this malignancy remains
unclear. It has been suggested that chronic inflammation promotes the
malignant transformation of ovarian epithelial cells [18]. Meta-analyses
of PID and ovarian cancer risk published in 2011 and 2017 included 4
and 13 studies, respectively [10,19]. Since 2017, 3 additional studies
have been reported. In the 2017 meta-analysis, heterogeneity was still
high (I2 = 58.8%). Thus, we conducted an updated meta-analysis to ex-
amine the relationship between PID and ovarian cancer risk and analyse
possible sources of heterogeneity.
2. Methods
2.1. Search strategy
Two authors (JP and ML) independently conducted literature
searches using Embase, PubMed, Web of Science, and other
sources. The final searches were conducted on November 1, 2019.
We restricted the searches to ‘human’ species and used the
following keywords: ‘pelvic inflammatory disease’ or ‘salpingitis’
or ‘endometriosis’ or ‘pelvic inflammation’ and ‘ovarian’ or ‘ovary’
and ‘cancer’ or ‘malignancy’ or ‘neoplasm’ or ‘carcinoma’. The ref-
erence sections of retrieved articles were screened for other appli-
cable studies.
Studies were included in this meta-analysis if they fulfilled all of
these criteria: focused on PID and ovarian cancer, involved patients
with histologically confirmed ovarian cancer, examined the potential
association between PID and ovarian cancer, and published in English.
We excluded studies not meeting the inclusion criteria, as well as arti-
cles that were not full-length original research papers (i.e., case reports,
conference abstracts, review articles, and letters to the editor). Two au-
thors (JP, ML) independently decided which studies to include, and dis-
agreements were discussed with a third author (EJL) to achieve
consensus.
2.3. Data extraction
Two authors (JP, ML) independently collected and recorded this in-
formation from each study: first author, year of publication, study time
period, ethnicity and age of the patients, number of cases and controls,
study design, exposure, outcomes, adjusted variants, and p value. The
outcome measures extracted from each study were the association be-
tween PID and ovarian cancer risk, including adjusted hazard ratios
(HRs), as well as 95% confidence intervals (CIs).
2.4. Study quality assessment
Two authors (JP, ML) independently examined the quality of each
study. They used the Newcastle-Ottawa Quality Assessment Scale
(NOS) to assess the quality of studies in meta-analysis, which evaluates
quality with its design, content and ease of use directed the task of in-
corporating the qualify assessment in the interpretation of meta-
analysis results. The NOS score considering 3 categories: comparability
(0 to 2 points), selection (0 to 4 points), and outcome (0 to 3 points).
The maximum possible NOS was 9 points; a score above 5 points was
considered ‘high quality.’
2.5. Statistical analysis
We evaluated the relationship between PID and risk of ovarian can-
cer using pooled HRs and 95% CIs. Heterogeneity across studies was
evaluated using the I2 metric and chi-square test. The I2 metric is used
to quantify the degree of heterogeneity in a meta-analysis and measure
the extent of true heterogeneity. The I2 index can be interpreted as the
percentage of total variation in study estimates that is due to heteroge-
neity. When substantial heterogeneity (I2 N 50%) was detected, we used
a random-effects model; when I2 was 50% or lower, we used a fixed-
effects model. To identify the origin of the heterogeneity, we performed
subgroup analyses based on ethnicity, study design, tumour invasive-
ness, and type of ovarian cancer. To assess potential publication bias,
we used Egger's linear regression test, as well as Begg's funnel plot.
STATA 15.0 and Review Manager 5.3 were used for all statistical testing.
p values below 0.05 were considered to represent statistical
significance.

Please cite this article as: J. Piao, E.J. Lee and M. Lee, Association between pelvic inflammatory disease and risk of ovarian cancer: An updated
meta-analysis, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.002
 J. Piao et al. / Gynecologic Oncology xxx (xxxx) xxx
3. Results
3.1. Search results
A total of 412 potentially applicable articles were retrieved through
our search strategies. After reviewing the titles and abstracts, 354
were excluded because they were not original full-length papers
(i.e., they were case reports, letters, review articles, or conference ab-
stracts) or not relevant to PID or ovarian cancer. Nine other articles
were excluded because they were duplicates. After reviewing the full-
text articles, another 33 were excluded because they did not evaluate
the relationship between PID and risk of ovarian cancer. Thus, the final
meta-analysis included 16 studies. Fig. 1 illustrates the process for
selecting the included studies.
3.2. Study characteristics
Table 1 summarizes the features of each included study. All NOS
scores were above 5; thus, all studies were considered to be ‘high qual-
ity’ (Table 2). Seven cohort studies and 9 case-control studies were in-
cluded. Three studies involved Asian populations, and the remaining
13 studies evaluated non-Asians. The studies analysed the association
between PID and various types of ovarian cancer, including serous,
non-serous, germ cell, and sex cord stromal cancers. Patients with PID
were identified in the studies by reviewing hospital records or by
obtaining a self-reported history of PID during interviews or question-
naires. The ovarian cancer diagnosis was confirmed in all studies by
reviewing hospital records.
3.3. Association between PID and ovarian cancer
In this meta-analysis, we pooled the data with a fixed-effects model
because the heterogeneity across studies was b50% (I2 = 41%, p = 0.05).
We observed a significant association between PID and an increased risk
of ovarian cancer, with moderate heterogeneity (HR 1.18, 95% CI 1.13 to
1.22; I2 = 41%, p b 0.001) (Fig. 2).
Because of the overall moderate heterogeneity, we proceeded with
subgroup analyses (Table 3). We observed a significant association be-
tween PID and ovarian cancer in Asian patients, with no heterogeneity
Fig. 1. Study selection flow chart.
Please cite this article as: J. Piao, E.J. Lee and M. Lee, Association between pelvic inflammatory disease and risk of ovarian cancer: An updated
meta-analysis, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.002
3
(HR 1.25, 95% CI 1.10 to 1.42; I2 = 0%, p b 0.001) [20–22]. PID was
also significantly associated with ovarian cancer in non-Asian patients,
but with moderate heterogeneity (HR 1.17, 95% CI 1.12 to 1.22; I2 =
48%, p b 0.001) [15–17,23–29]. Likewise, there was a significant associ-
ation between PID and ovarian cancer in case-control studies (HR 1.15,
95% CI 1.08 to 1.23; I2 = 17%, p b 0.001). PID was also associated with
ovarian cancer in cohort studies, but with high heterogeneity (HR
1.19, 95% CI 1.13 to 1.25; I2 = 60%, p b 0.001). We also observed a signif-
icant association between PID and invasive ovarian cancer (14 studies)
(HR 1.25, 95% CI 1.20 to 1.30; I2 = 38%, p b 0.001)
[15,17,20,25,26,28–31], as well as borderline ovarian cancer (2 studies)
(HR 1.28, 95% CI 1.19 to 1.37; I2 = 13%, p b 0.001) [16,24]. Regarding the
histologic type of cancer, 9 studies involved patients with non-serous
ovarian cancer [15,17,20,25,26,28–31], 4 studies enrolled patients
with serous ovarian cancer [16,27,32,33], and 1 study each evaluated
patients with clear cell ovarian cancer [27], sex cord stromal tumour
[20], and germ cell tumour [20]. Subgroup analysis revealed that there
was a significant association between PID and non-serous ovarian can-
cer (HR 1.15, 95% CI 1.07 to 1.24; I2 = 27%, p = 0.001). PID was also as-
sociated with serous ovarian cancer, but with higher heterogeneity (HR
1.19, 95% CI 1.15 to 1.23; I2 = 55%, p b 0.001).
3.4. Publication bias
As shown in Fig. 3a, Begg's funnel plot exhibited no asymmetry (p =
0.096). Similarly, the results of Egger's linear regression asymmetry test
demonstrated no evidence of publication bias (p = 0.013) (Fig. 3b).
4. Discussion
To the best of our knowledge, this study is the most recently updated
meta-analysis examining the relationship between PID and ovarian can-
cer. Our findings indicated that PID is associated with an increased ovar-
ian cancer risk.
Different study populations have differing characteristics, including
parity, use of fertility medications, use of hormone-replacement ther-
apy, age at menarche or menopause, breast feeding practices, and use
of oral contraceptives. We therefore performed subgroup analysis
based on ethnicity. Although PID was associated with ovarian cancer
 4
meta-analysis, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.002
Please cite this article as: J. Piao, E.J. Lee and M. Lee, Association between pelvic inflammatory disease and risk of ovarian cancer: An updated

Table 1
Characteristics of included studies.

Authors Country Study Age Study Baseline Prevalence Cases Prevalence Controls Exposure Type of ovarian cancer Adjusted variants Adjusted 95% CI p
(year) period (years) design prevalence of PID in of PID in HR
of cases controls
PID in
cohort
studies

Shu et al. China 1984–1986 NS Case-control 11% 229 1.3% 229 PID Epithelial, germ cell, sex Education, number of live 1.60 0.8–3.2 b0.01
(1989) cord, others births, ovarian cyst, age at
menarche
Risch et al. USA 1989–1992 NS Case-control 23% 450 18% 564 PID Epithelial Age, parity, OC use 1.53 1.10–2.13 0.001
(1995)
Parazzini USA 1983–1991 23–74 Case-control 1.4% 971 2.6% 2758 PID Epithelial Age, education, parity, family 0.70 0.40–1.30 0.001
et al. history, OC use
(1996)
Ness et al. USA 1994–1998 20–69 Case-control 1.8% 766 2% 1362 PID Epithelial Age, race, OC use, number of 1.30 0.60–2.50 0.001
(2000) pregnancies
Merritt Australia 2002–2005 18–79 Case-control 6.5% 1576 5.6% 1509 PID Epithelial Age, education, parity, OC use 1.18 0.81–1.70 0.001

J. Piao et al. / Gynecologic Oncology xxx (xxxx) xxx

et al.
(2008)
Wu et al. USA 1998–2002 18–74 Case-control 4% 609 3% 688 PID Epithelial Age, race, education, tubal 1.48 0.78–2.82 0.001
(2009) ligation, OC use, parity,
menopausal status
Lin et al. Taiwan 2004–2005 13–65 Cohort 33% 67,936 135,872 PID Not specified Age, race, income, other 1.92 1.27–2.92 0.001
(2011) diseases
Rasmussen Denmark 1995–1999 35–79 Case-control 35% 202 8% 1564 PID Borderline Age, pregnancy, OC use, 1.50 1.08–2.08 0.001
et al. history of ovarian cancer
(2013)
Stewart Australia 1982–2002 20–44 Cohort 18% 3890 17,756 PID Epithelial Age, start of follow-up 2.33 1.02–5.35 b0.001
et al.
(2013)
McAlpine Canada 1981–2012 20–52 Cohort 61.7% 888 552 PID Clear cell, endometrioid, Age, parity, smoking, 5.56 0.52–59.40 0.001
et al. epithelial, high-grade amenorrhea, endometriosis
(2014) serous, others
Shen et al. Taiwan 2000–2002 27–42 Cohort 50% 32,268 32,268 PID Ovarian cancer Age, race, income, follow-up 1.33 0.78–2.27 0.001
(2016) years
Rasmussen Denmark 1978–2012 30.51± Cohort 6.1% 81,263 1,237,662 PID Serous borderline Parity status 1.85 1.52–2.24 0.001
et al. 9.05a
(2016)
Rasmussen Denmark 1978–2012 30.51± Cohort 6.1% 81,281 1,237,648 PID Serous Age, follow-up, parity status, 1.19 1.00–1.41 0.047
et al. 9.05a endometriosis, hysterectomy,
(2017) tubal ligation
Stewart Australia 1980–2014 Born Cohort 7.5% 33,335 408,047 PID High-grade serous Age, hysterectomy, 1.47 1.04–2.07 0.01
et al. 1945–1975 salpingectomy,
(2018) oophorectomy, delivery,
parity
Park et al. USA 2010–2015 20–79 Case-control 8% 600 4.4% 752 PID Epithelial Age, BMI, marital status, 1.33 0.82–2.16 0.006
(2018) education, menstrual status,
medical history
Fortner Germany 1989–2011 30–55 Case-control 19% 337 12% 337 PID (C. Epithelial Age, parity, OC use, tubal 2.07 1.25–3.43 0.001
et al. trachomatis) ligation, marital status
(2019)

BMI, body mass index; CI, confidence interval; HR, hazard ratio; NS, not stated; OC, oral contraceptive; PID, pelvic inflammatory disease.
a
Mean ± standard deviation.
 J. Piao et al. / Gynecologic Oncology xxx (xxxx) xxx 5

Table 2 and ovarian cancer invasiveness, heterogeneity also varied by study de-
Quality assessment of the included studies based on the Newcastle-Ottawa Scale. sign and type of ovarian cancer in our study.
Authors Year Selection Comparability Exposure/outcome Total Chronic infection and inflammation have been estimated to contrib-
score ute to approximately 25% cases of cancer, overall [34]. Inflammation re-
Shu et al 1989 3 1 2 6 leases tumour-promoting mediators, such as growth factors, cytokines
Risch et al 1995 4 1 2 7 (especially interleukin 6 [35] and interleukin 8 [36]), chemokines, free
Parazzini et al 1996 4 1 2 7 radicals, reactive oxygen species, and prostaglandins, which can pro-
Ness et al. 2000 3 1 2 6
duce a number of genetic and epigenetic alterations, including point
Merritt et al 2008 4 1 2 7
Wu et al. 2009 3 1 2 6 mutations within tumour suppressor genes, alterations in DNA methyl-
Lin et al. 2011 4 1 2 7 ation patterns, and modifications at the post-translational level. These
Rasmussen et al 2013 4 1 2 7 alterations may lead to the development and progression of cancer by
Stewart et al 2013 3 2 3 8 affecting pathways necessary for cellular homeostasis [34,37,38]. A
McAlpine et al. 2014 3 1 3 7
Rasmussen et al 2016 4 1 3 8
number of epidemiological studies have also shown associations be-
Shen et al. 2016 4 1 3 8 tween ovarian cancer and infection with potentially carcinogenic vi-
Rasmussen 2017 4 1 3 8 ruses, such as human papillomavirus, cytomegalovirus, Epstein Barr
et al. virus, polymyoma virus, and hepatitis C virus [39,40]. Syahn et al.
Park et al. 2018 4 1 2 7
found Asian may have a higher prevalence of HPV and a stronger asso-
Stewart et al. 2018 4 1 2 7
Fortner et al 2019 3 1 3 7 ciation between PID and ovarian cancer risk [40]. Moreover, several
studies have reported associations between ovarian cancer and certain
bacterial sexually transmitted infections: Chlamydia trachomatis, Myco-
plasma genitalium, and Neisseria gonorrhoeae [39]. Chronic infections are
risk in both Asian and non-Asian populations, the association was more also associated with an increased number of cell divisions, which in-
consistent in Asians, as reflected by the lack of heterogeneity in Asian creases the risk of mutations by increasing the potential for DNA repli-
populations. We also demonstrated that PID was associated with ovar- cation errors during DNA repair, especially at key regulatory sites of
ian cancer risk in case-control studies and in patients with non-serous DNA [41]. Recently, personal habits such as douching and talc use
ovarian cancer, both with lower heterogeneity. Subgroup analysis ac- have been found associated with greater PID risk and possibly greater
cording to tumour invasiveness indicated that PID was associated with ovarian cancer risk [42].
an increased risk of both invasive and borderline ovarian cancer. How- Previously, it was hypothesized that every histologic type of ovarian
ever, the latter result should be considered preliminary because only 2 cancer originated from epithelial cells at the mesodermal surface, with
studies evaluated patients with borderline cancer; large prospective epithelial inflammation acting as the initiator of malignant transforma-
studies are required to confirm our findings. tion [6]. More recently, serous ovarian tumours have been suggested to
Although there was moderate heterogeneity (I2 = 41%) across stud- begin in fallopian tube epithelium, with inflammation of the tube con-
ies in the initial analysis, the heterogeneity declined considerably dur- tributing to their development [43]. In our histologic subtype analysis,
ing most subgroup analyses. In the 2017 meta-analysis of 13 studies, we observed a positive association between PID and both serous and
Zhou et al. found that PID was associated with an increased risk of ovar- non-serous ovarian cancers. Previous reports have shown associations
ian cancer, but the heterogeneity was high (I2 = 58.8%) and varied by between PID and type 1 tumours, including low-grade serous [10,23]
race during subgroup analysis [10]. Zhou et al. also reported that PID and clear cell subtypes [28]. These results support the theory suggesting
was associated with borderline ovarian cancer but not with invasive a stepwise transition from serous borderline ovarian tumours to low-
ovarian cancer, which differs from our results. In addition to ethnicity grade serous ovarian cancers. Potential differences in the associations

Fig. 2. Forest plot representing the association between pelvic inflammatory disease and risk of ovarian cancer. CI, confidence interval; IV, instrumental variables; SE, standard error.

Please cite this article as: J. Piao, E.J. Lee and M. Lee, Association between pelvic inflammatory disease and risk of ovarian cancer: An updated
meta-analysis, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.002
6 J. Piao et al. / Gynecologic Oncology xxx (xxxx) xxx

Table 3
Subgroup analysis of the association between pelvic inflammatory disease and ovarian cancer.

Number of studies Relative HR Pooled hazard ratios

HR (95% CI) p I2

Race
Asian 3 1 1.25 (1.10–1.42) b0.001 0%
Non-Asian 13 1 1.17 (1.12–1.22) b0.001 48%
Study design
Cohort 7 1 1.19 (1.13–1.25) b0.001 60%
Case-control 9 1 1.15 (1.08–1.23) b0.001 17%
Tumour invasiveness
Invasive 14 1 1.25 (1.20–1.30) b0.001 38%
Borderline 2 1 1.28 (1.19–1.37) b0.001 13%
Type of ovarian cancer
Non-serous 9 1 1.15 (1.07–1.24) 0.001 27%
Serous 4 1 1.19 (1.15–1.23) b0.001 55%

CI, confidence interval; HR, hazard ratio.

between various ovarian cancer subtypes and PID require further re-
search at both the epidemiologic and biologic level.
Because of the putative role of inflammation in the pathogenesis of
ovarian cancer, anti-inflammatory medications have been suggested
as a possible strategy for reducing the risk of this malignancy. In a
case-control study of over-the-counter analgesic use, Cramer et al.
found that non-steroidal anti-inflammatory drugs (aspirin and ibupro-
fen) were not associated with the development of ovarian cancer [44].
Conversely, Tzonou et al. reported that analgesics (primarily salicylates)
were associated with a decreased risk of epithelial ovarian cancer [45].
The potential preventative effects of anti-inflammatory drugs for ovar-
ian malignancies warrant further investigation.
Our meta-analysis has some limitations. Firstly, PID is a diffuse group
of inflammatory conditions, which may have differing roles in the path-
ogenesis of ovarian cancer and differing ovarian tumour risks. Secondly,
most studies did not indicate the cause of PID or report information
about PID exposure, such as age at initial infection, duration since first
infection, or number of PID episodes. Thirdly, the 7 cohort studies
used medical records to document the presence of PID, while the 9
case-control studies relied solely on self-reported PID histories. As recall
bias may have been an issue in the case-control studies, large cohort
studies, as well as accurate methods for documenting PID and adjusting
for confounding variables, will be necessary to more definitely confirm
the relationship between PID and ovarian cancer and determine the
magnitude of this association.
In summary, the results of this updated meta-analysis revealed
a positive association between PID and risk of ovarian cancer. This
association was more consistent in Asians and in case-control stud-
ies, based on the low heterogeneity of these subgroup analyses. PID
was associated with both borderline and invasive ovarian cancers,
in contrast to the results of the 2017 meta-analysis. PID was also
associated with both serous and non-serous ovarian cancers,
although less heterogeneity was observed for the non-serous
type. However, the number of studies evaluating borderline or se-
rous ovarian cancer was small, reducing the certainty of the results
for these subgroups. Large, well-designed studies with accurate as-
sessment of both PID and ovarian cancer are required to confirm
our results.
Ethics approval and consent to participate
In this meta-analysis, we used only previously published data. Be-
cause no unpublished data were used, we did not seek ethics committee
approval. The study is in accordance with the tenets of the Declaration
of Helsinki.

Fig. 3. Funnel plot (a) and Egger's graph (b) assessing publication bias. CI, confidence interval; SE, standard error; SND, standardized.

Please cite this article as: J. Piao, E.J. Lee and M. Lee, Association between pelvic inflammatory disease and risk of ovarian cancer: An updated
meta-analysis, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.002
 J. Piao et al. / Gynecologic Oncology xxx (xxxx) xxx
Consent for publication
Not applicable.
Data availability
Not applicable.
Authors' contributions
JP, EJL, and ML conceptualized this study, developed the protocol,
and wrote the manuscript. JP and ML selected articles for full-text re-
view, extracted data from the included studies, and performed all statis-
tical analyses.
Declaration of competing interest
None.
Acknowledgements
This work was supported by a grant from the Seoul National Univer-
sity Hospital Research Fund (Grant No. 0320190260).
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