Is pelvic inflammatory disease a risk factor for …cebp.aacrjournals.org/content/cebp/early/2016/09/24/1055-9965.EPI... · 1 Is pelvic inflammatory disease a risk factor for ovarian

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Is pelvic inflammatory disease a risk factor for ovarian cancer?

Christina B. Rasmussen1, Allan Jensen1, Vanna Albieri2, Klaus K. Andersen2, Susanne K.

Kjaer1, 3

Affiliations

1 Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark

2 Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center,

Copenhagen, Denmark

3 Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen,

Denmark

Running title: Pelvic inflammatory disease and ovarian cancer risk

Key words: gynecological cancer: ovarian; epidemiology; infections and the etiology of

cancer; pelvic inflammatory disease; inflammation

Financial support: This work was supported by the Mermaid project (MERMAID III)

Corresponding author

Susanne Krüger Kjaer

Virus, Lifestyle and Genes, Danish Cancer Society Research Center

Strandboulevarden 49, DK-2100 Copenhagen, Denmark

E-mail: [email protected]

Phone: +45 35257663; fax +45 352718111

on August 4, 2018. © 2016 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 26, 2016; DOI: 10.1158/1055-9965.EPI-16-0459

http://cebp.aacrjournals.org/

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Conflict of interest: all authors declare no conflicts of interest

Word count: 3,070

Number of tables and figures: 3




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Abstract

Background: Pelvic inflammatory disease (PID) has been proposed as a risk factor for ovarian

cancer. However, the existing literature on the association between PID and ovarian cancer

risk is inconclusive and only few cohort studies have been conducted.

Methods: Using nationwide Danish registries, we conducted a population-based cohort study

including all women from the birth cohorts 1940–1970 in Denmark during 1978-2012

(n=1,318,929) to investigate the association between PID and subsequent risk of epithelial

ovarian cancer. Among women in the cohort, 81,281 women were diagnosed with PID and

5,356 women developed ovarian cancer during follow-up through 2012. Cox regression

models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the

association between PID and ovarian cancer, both overall and according to histotype.

Results: For ovarian cancer overall, we observed no association with PID (HR=1.05; 95% CI:

0.92–1.20). However, in histotype-specific analyses, we found a statistically significantly

increased risk of serous ovarian cancer among women with PID (HR=1.19; 1.00–1.41;

p=0.047). Conversely, PID was not convincingly associated with risk of any of the other

histotypes of ovarian cancer.

Conclusion: PID was associated with a modestly increased risk of serous ovarian cancer, but

not other histotypes.

Impact: Our results indicate that PID is not a strong risk factor for ovarian cancer. Whether

PID is slightly associated with risk of serous ovarian cancer has to be confirmed in other

studies.




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Introduction

Infections and inflammation are well-established etiological factors for several types of cancer

and are estimated to contribute to the development of up to 25% of all cancer cases worldwide

(1). In 1999, Ness and Cottreau (2) suggested that a number of potential risk factors for

ovarian cancer, including endometriosis, talc use and pelvic inflammatory disease (PID), may

act through a common inflammatory mechanism. In addition, studies have shown that tubal

ligation and hysterectomy protects against ovarian cancer (3) and this protective effect may

also be related to inflammation as these surgical procedures potentially prevents inflammatory

reagents from reaching the fallopian tubes and the ovaries (2). Previously, all histotypes of

ovarian cancer were believed to originate from the ovarian surface epithelium, and

inflammation hereof was initially suggested to cause malignant transformation (2). However,

recent studies suggests that serous ovarian cancer originates in the fallopian tube and only

involves the ovary secondarily (4). Thus, inflammation of the tubes may also be important for

the development of this tumor type (5).

PID is an infection-induced inflammation of the upper genital tract, including the uterus,

fallopian tubes, ovaries and pelvic peritoneum, caused by ascending pathogens from the lower

genital tract (6). Knowledge on the true lifetime risk of PID among women in the Western

world is rather sparse and the few published results show great variation with cumulative

incidence rates ranging from 4% to 20% (7-10).

The existing literature on the association between PID and risk of ovarian cancer is

conflicting; some studies find an increased risk associated with PID (11-14), while others do

not find an association (15-19). In addition, many of the previous studies had methodological




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constraints. For example, the majority used a case-control design where information about

PID was based on self-reporting, thereby introducing a potential risk of recall bias and

misclassification. To date, only two cohort studies have been performed, both including

clinically verified diagnoses of PID (11, 12). However, these cohort studies had other

methodological limitations such as the inclusion of lower genital tract infections in the

definition of PID, a short follow-up period and a low number of ovarian cancers. Furthermore,

ovarian cancer is a heterogeneous disease with proposed differences in risk factors, origin and

genetic mutations among histotypes (4, 20), but few previous studies have investigated the

association between PID and ovarian cancer risk according to histotype (15, 18). Using data

from the Ovarian Cancer Association Consortium (OCAC), we have recently conducted a

pooled analysis, representing the largest study on PID and risk of ovarian cancer, and no

association between PID and risk of ovarian cancer overall was observed; however,

indications of differences across histotypes of ovarian cancer were noted (21). Nevertheless,

that study relied on self-reported information on PID and therefore has some of the same

limitations as most previous studies.

The conflicting evidence regarding the possible role of PID in ovarian carcinogenesis and the

methodological limitations of previous studies prompted us to conduct a large nationwide

cohort study using data from the Danish health registries to investigate the association

between PID and risk of epithelial ovarian cancer. The present register-based cohort study

will be the largest on this research topic to date. We expect that the large number of study

subjects included and the long follow-up period with up to 35 years of follow-up will enable

us to evaluate risk patterns with high statistical precision and to assess histotype-specific risks

as well as the effect of timing of PID and number of PID episodes.




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Materials and Methods

Study population

The Danish Civil Registration System was established in 1968 and since then, all citizens

have been registered with a unique personal identification number encoding date of birth and

sex (22). The personal identification number is used universally in the Danish society,

including in all Danish health registries ensuring accurate record linkage of information

between registries. The Civil Registration System also holds information about place of birth,

continuously updated information on vital status (date of death and data on migration), and

identifiable information about parents and live born offspring. From this registry, we

extracted data (personal identification number and information on vital status) for all women

born between January 1, 1940 and December 31, 1970, who were alive and living in Denmark

during the study period from January 1, 1978–December 31, 2012 (n = 1,319,155).

Ascertainment of exposure status

The Danish National Patient Registry was established in 1977 and contains information on all

diagnoses and surgical procedures performed at Danish hospitals (23). Initially, it covered

only inpatient contacts, but after 1994, outpatient and emergency room contacts were also

included. In the present study, PID was defined as an upper genital tract infection, including

endometritis, salpingitis, oophoritis, pelvic peritonitis and tubo-ovarian abscess and coded

according to the 8th revision of the International Classification of Diseases (ICD-8) during

1977–1993 and the 10th revision of the International Classification of Diseases (ICD-10)

during 1994–2011 (Supplementary Table 1). Using the personal identification numbers, the

study cohort was linked to the National Patient Registry to identify all women with a

diagnosis of PID from January 1, 1978 to December 31, 2011.




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Additional covariate information

From the National Patient Registry, we also obtained information on bilateral oophorectomy,

which was used as a censoring variable in the analyses. Potential confounders were selected a

priori based on the current knowledge of ovarian cancer etiology and availability in the

registries and included hysterectomy, tubal ligation, endometriosis, parity status and use of

oral contraceptives. Information on endometriosis, hysterectomy and tubal ligation was

obtained from the National Patient Registry. The surgical procedures were coded using the

Danish Classification of Surgical Procedures and Therapies from 1977-1995 and from 1996

and onwards, the Nordic Classification of Surgical Procedures. Information on parity status

was obtained from the Fertility Database, which was established in 1980, and contains

information on number of live born children for all women born from 1930 and onwards and

is considered complete for women born in 1945 or later (24). Finally, data on use of oral

contraceptives were retrieved from the National Prescription Registry, which contains data on

all prescriptions drugs dispensed at Danish pharmacies since 1995, including data on the

Anatomical Therapeutic Chemical (ATC) classification codes (Supplementary Table S1) (25).

Follow-up for ovarian cancer

All incident cases of epithelial ovarian cancer in the study cohort were identified by linkage to

the Danish Cancer Registry. Since 1943, this registry has collected information on all cases of

incident cancer in Denmark (26) and the registration of gynecological cancers is considered

virtually complete (27). Until 2003, the registry was based on notification forms from the

diagnosing physicians, supplemented by linkage to the Registry of Causes of Death and the

National Patient Registry to ensure completeness of data. Since 2004, the registry is based

entirely on recordings from several Danish health registries, mainly the Danish National




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Patient Registry. In the Cancer Registry, ovarian cancers were coded according to the

International Classification of Diseases, 7th edition (ICD-7) from 1943 to 1977 and according

to the International Classification of Diseases, 10th edition (ICD-10) and the International

Classification of Diseases for Oncology, 3rd edition (ICD-O-3) from 1978 and onwards. All

ovarian cancer cases included during the study period were identified using the ICD-10 code

C56 and an ICD-O-3 morphology code for epithelial ovarian cancer. The ICD-O-3

morphology codes were further used to classify the specific histotypes of epithelial ovarian

cancer (Supplementary Table 1). For all histotypes, only invasive cancers (i.e. with ‘3’ as the

last digit in the morphology code) were included.

All women in the study cohort were followed for development of histologically verified

epithelial ovarian cancer from January 1, 1978 until date of bilateral oophorectomy, date of

death, date of emigration or December 31, 2012, whichever came first. We excluded women

with a diagnosis of ovarian cancer (n = 220) or bilateral oophorectomy (n = 6) before start of

follow-up, leaving 1,318,929 women in the final study population (Figure 1).

Statistical analyses

The association between PID and risk of ovarian cancer was explored using Cox regression

models to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs).

We conducted analyses for overall ovarian cancer and for the following histotypes: serous,

mucinous, endometrioid, clear cell and other epithelial ovarian cancers (Supplementary Table

1). Age was used as the underlying time scale to ensure comparison of women of the same

age. We included a lag-phase of one year from diagnosis of PID to reduce the possibility of

reverse causation or early cancer symptoms being misinterpreted as an episode of PID.

Therefore, time at risk as exposed started one year after the first diagnosis of PID. Analyses




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were adjusted for parity (0, 1, 2 and ≥3), tubal ligation (yes/no), hysterectomy (yes/no) and

endometriosis (yes/no).

In addition to PID status (ever vs. never PID) we also investigated the risk of ovarian cancer

according to number of PID episodes, age at first PID and time since first PID. To count as a

new episode of PID, a PID diagnosis had to be at least two months after the previous

diagnosis. Number of PID episodes was categorized as 1, 2 or ≥3. Age at first PID was

categorized as <25, 25–29, 30–34 and ≥35 years, whereas time since first PID was

categorized as 1–4, 5–9, 10–19 and ≥20 years. For these categorical PID variables, tests for

trend were conducted. Both the PID exposure variables and the selected confounders were

included as time-dependent variables (i.e. all women in the cohort accrued person-time in the

unexposed group until a diagnosis of PID and thereafter contributed person-time in the

exposed group). In a subset analysis, we further adjusted for use of oral contraceptives, as this

information was available from 1995 and onwards in the Danish Prescription Registry.

However, as this additional adjustment did not alter the results considerably, these subgroup

results are not presented further. The significance of variables was tested using Wald tests.

Level of statistical significance was set at 0.05. All p values were two-sided. Statistical

analyses were conducted using the statistical software package R, version 3.0.2. The study

was approved by the Danish Data Protection Agency.

Results

The risk of ovarian cancer associated with PID was analyzed for 1,318,929 women. The

median length of follow-up was 35.0 years (interquartile range 33.4–35.0), resulting in

40,336,107 person-years of follow-up. A total of 81,281 women were diagnosed with PID

during the study period, and 5,356 women developed epithelial ovarian cancer (2784 serous,




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651 mucinous, 738 endometrioid, 307 clear cell and 876 other epithelial ovarian cancers).

Characteristics of women in the cohort are presented in Table 1. The higher age at entry and

the shorter follow-up in the exposed period reflect the study design with time-dependent

variables, as all women accrued person-years in the unexposed group until a diagnosis of PID.

Table 2 shows the hazard ratios for the association between PID and risk of ovarian cancer.

The risk of ovarian cancer overall was not associated with a history of PID (HR = 1.05; 95%

CI: 0.92–1.20), age at first PID, time since first PID or number of PID episodes. However, in

histotype-specific analyses, we noted a statistically significantly increased risk of serous

ovarian cancer among women with PID (HR = 1.19; 95% CI: 1.00–1.41; p = 0.047). For

serous cancer, we also observed a statistically significantly increased risk among women

having PID before the age of 25 years (HR = 1.44; 95% CI: 1.01–2.04). The risk estimates for

the remaining categories of age at PID were not statistically significant, but a decreasing risk

of serous ovarian cancer with increasing age at first PID was noted (p trend = 0.03). For

analyses according to time since PID, no clear pattern in risk of serous cancer was noted (p

trend = 0.63); however, the risk estimate was highest for the category 1–4 years since PID.

Concerning risk of serous ovarian cancer according to number of PID episodes, we observed a

pattern of an increasing risk with increasing number of episodes (p trend = 0.04). For the non-

serous histotypes, no marked associations with any of the PID variables were found, except

for a suggestion of an increased risk of clear cell and mucinous ovarian cancer among women

with PID at the age of 35 years or older.

Discussion

In this large nationwide cohort study, we observed no association between PID and risk of

ovarian cancer overall. However, in histotype-specific analyses, we found a modestly




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increased risk of serous ovarian cancer among women with a history of PID after adjustment

was performed for parity, endometriosis, hysterectomy and tubal ligation, while no

convincing associations were noted for any of the other histotypes of ovarian cancer.

Inflammation is a well-established contributing factor in the development of several cancer

types (1) and has also been proposed to be involved in ovarian carcinogenesis (2, 28).

Inflammation involves the release of free radicals, growth factors, cytokines and

prostaglandins with the potential for genetic and epigenetic changes to the DNA, including

mutations in tumor suppressor genes, thus increasing the risk of neoplastic transformation (1).

In addition, cell death associated with inflammation results in a compensatory increased cell

proliferation, thus increasing the risk of DNA replication errors (29).

Results from the existing literature on the association between PID and risk of ovarian cancer

have been inconsistent. In line with our results, two case-control studies (16, 17) and one

pooled analysis of 13 case-control studies (21) also found no association between PID and

risk of ovarian cancer overall. Conversely, results from one case-control study (14) and two

cohort studies (11, 12) demonstrated an increased risk of ovarian cancer among women with a

history of PID with relative risks ranging from 1.9–4.0. However, ovarian cancer is a highly

heterogeneous disease with differences in risk factors, underlying genetic mutations and

proposed origin between histotypes (4), and in analyses of all ovarian cancers combined

histotype-specific associations may be missed. However, only few studies have investigated

the role of PID in ovarian carcinogenesis according to histotype (15, 18, 21). Results from our

recent, large pooled analysis of 13 case-controls studies indicated a differential impact of PID

on the various histotypes of ovarian cancer with an association suggested only for the low-




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grade serous subtype (21). The other two studies providing histotype-specific results were

both included in the pooled analysis from OCAC.

Given the hypothesis that serous ovarian cancer originates in the fallopian tube and involves

the ovary secondarily (30), it is likely that salpingitis—which is included in the definition of

PID—has a particular impact on the risk of serous tumors (5). In support hereof, chronic

salpingitis has been found more often in fallopian tube specimens from women with serous

ovarian tumors than in specimens from women with non-serous ovarian tumors or non-

neoplastic ovaries (31). Furthermore, chronic salpingitis has also been implicated in the

pathogenesis of serous fallopian tube cancers (32). In accordance with these observations, we

also observed an increased risk of the serous subtype among women with a history of PID.

However, the association was modest and only just statistically significant. Unfortunately, we

had no information on grade and could therefore not investigate the risk of high- and low-

grade serous cancers separately. We also observed suggestions of an increased risk of clear

cell and mucinous ovarian cancer with PID after 35 years of age. These are likely spurious

findings as PID status was not associated with an increased risk of these histotypes and may

be due to chance.

Strengths of the present study include the population-based design using nationwide high-

quality registries, the large study population, the large number of ovarian cancers, the long

follow-up, and the information on physician-verified PID diagnoses from registries rather

than self-report thus eliminating recall bias, which was a limitation in most previous studies.

Moreover, the completeness of the registries resulted in virtually no loss to follow-up and

identification of all incident cases of histologically verified ovarian cancer, therefore our

results are not influenced by selection bias. Further, we were able to adjust for several




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important potential confounders, including parity, endometriosis, tubal ligation, hysterectomy

and oral contraceptive use.

However, some limitations should also be mentioned. First, some misclassification of PID

exposure is present in our data due to the lack of information on PID diagnosed before 1978,

but we tried to minimize misclassification caused by left truncation of the registries by

restricting the study population to women born between 1940 and 1970. In addition, we had

no information on PID treated in non-hospital settings and in outpatient clinics before 1995.

Further, some PID episodes are subclinical and will not be captured. Our unexposed

population therefore contains some women with a PID likely resulting in an underestimation

of the association. However, primarily having hospitalized women means that only the most

severe cases of PID are included. As severity of PID has been shown to be related to risk of

tubal factor infertility (33), it seems reasonable to assume that severe PID is associated with a

greater inflammatory response and therefore perhaps also a greater risk of malignant

transformation. Thus, as we mostly lack information on mild cases of PID, this may not have

had a large impact on our results. Second, an episode of PID may have been caused by an

undiagnosed ovarian cancer or early cancer symptoms may have been misinterpreted as an

episode of PID. However, we believe this is not a major problem in our study as most women

referred to hospital for PID will have an ultrasound scan performed, thereby revealing a

potential underlying ovarian cancer. Furthermore, we included a lag-phase of 1 year from first

PID episode to reduce the influence of reverse causation. Third, we cannot rule out that our

results may have been influenced by unmeasured confounding from important ovarian cancer

risk factors that we had no information on (e.g. menopausal status). Finally, despite the large

sample size, we still had limited power in the analyses for non-serous ovarian cancers.




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In conclusion, this study demonstrated a modestly increased risk of serous ovarian cancer

among women diagnosed with PID. In contrast, no convincing associations between PID and

risk of the other histotypes of ovarian cancer were observed. Although the increased risk of

serous ovarian cancer associated with PID was statistically significant, the association was

modest in strength, indicating that PID is not a strong risk factor for ovarian cancer.

Acknowledgements

This work was supported by the MERMAID project (MERMAID III).




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Table 1. Characteristics of women in the cohort

Characteristic Women with PID Unexposeda

Number of women 81,281 1,318,929

Age at entry, years (mean ±SD) 30.51 ±9.05 23.41 ±9.43

Follow-up, years (mean ±SD) 22.21 ±9.02 29.50 ±10.57

Parity statusb

0 11,636 (14.32) 230,525 (17.48)

1 17,630 (21.69) 287,551 (21.80)

2 31,625 (38.91) 503,891 (38.20)

≥3 20,390 (25.06) 296,962 (22.52)

Endometriosisb (n (%)) 5,068 (6.24) 25,191 (1.91)

Hysterectomyb (n (%)) 12,917 (15.89) 108,959 (8.26)

Tubal ligationb (n (%)) 12,771 (15.71) 114,930 (8.71)

Abbreviations: n: number; PID: pelvic inflammatory disease; SD: standard deviation a All women contributed person-years in the unexposed group until a diagnosis of PID b Status at the end of follow-up in the unexposed and exposed group




Table 2. Hazard ratios and 95% confidence intervals for the association between pelvic inflammatory disease and risk of ovarian cancer, overall and by histotype

Abbreviations: CI: confidence interval; HR: hazard ratio; NA: not applicable because of no events; PID: pelvic inflammatory disease; —: could not be estimated a Adjusted for parity (0,1,2, ≥3), endometriosis, hysterectomy and tubal ligation

Overall Serous Mucinous Endometriod Clear cell

Person-years n HRa 95% CI n HRa 95% CI n HRa 95% CI n HRa 95% CI n HRa 95% CI

Unexposed women 38,542,650 5110 1.00 Referent 2639 1.00 Referent 624 1.00 Referent 712 1.00 Referent 293 1.00 Referent Women with PID 1,713,002 246 1.05 0.92; 1.20 145 1.19 1.00; 1.41 27 0.91 0.62, 1.34 26 0.77 0.52; 1.14 14 0.96 0.56; 1.66

Number of PID

Unexposed 38,542,650 5110 1.00 Referent 2639 1.00 Referent 624 1.00 Referent 712 1.00 Referent 293 1.00 Referent

1 1,444,912 208 1.04 0.91; 1.20 121 1.16 0.97; 1.40 24 0.95 0.63; 1.44 22 0.77 0.50; 1.18 13 1.06 0.61; 1.86 2 207,070 32 1.17 0.83; 1.66 18 1.27 0.80; 2.03 3 0.85 0.27; 2.66 4 0.97 0.36; 2.61 1 0.56 0.08; 3.97 ≥3 61,020 6 0.82 0.37; 1.82 6 1.59 0.71; 3.55 0 NA — 0 NA — 0 NA —

P trend 0.91 0.04 — — —

Time since first PID

Unexposed 38,542,650 5110 1.00 Referent 2639 1.00 Referent 624 1.00 Referent 712 1.00 Referent 293 1.00 Referent 1-4 313,014 24 1.28 0.86; 1.92 14 1.59 0.94; 2.69 4 1.26 0.47; 3.39 3 1.20 0.38; 3.73 1 0.95 0.13; 6.80 5-9 370,409 30 0.95 0.67; 1.37 17 1.12 0.70; 1.81 4 0.79 0.30; 2.12 3 0.66 0.21; 2.04 2 1.10 0.27; 4.43

10-19 614,886 92 1.09 0.88; 1.34 47 1.12 0.84; 1.50 13 1.10 0.63; 1.91 13 1.01 0.58; 1.75 7 1.28 0.60; 2.74 ≥ 20 414,693 100 1.01 0.82; 1.23 67 1.19 0.93; 1.52 6 0.62 0.28; 1.40 7 0.50 0.24; 1.07 4 0.64 0.24; 1.74 P trend 0.51 0.63 0.34 0.30 0.34

Age at first PID

Unexposed 38,542,650 5110 1.00 Referent 2639 1.00 Referent 624 1.00 Referent 712 1.00 Referent 293 1.00 Referent

<25 674,718 48 1.09 0.82; 1.46 33 1.44 1.01; 2.04 5 0.67 0.27; 1.62 5 0.83 0.34; 2.02 1 0.38 0.05; 2.74 25-29 385,776 46 1.02 0.76; 1.37 28 1.21 0.83; 1.76 5 0.82 0.34; 2.00 3 0.46 0.15; 1.45 2 0.63 0.16; 2.54 30-34 305,827 46 0.91 0.68; 1.22 31 1.19 0.83; 1.70 3 0.47 0.15; 1.46 6 0.80 0.36; 1.80 1 0.33 0.05; 2.33

≥35 346,681 106 1.12 0.92; 1.36 53 1.07 0.81; 1.40 14 1.43 0.84; 2.43 12 0.86 0.49; 1.53 10 1.74 0.92; 3.28 P trend 0.73 0.03 0.14 0.65 0.10

on August 4, 2018. ©

2016 Am

erican Association for C

ancer Research.

cebp.aacrjournals.org D

ownloaded from

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anuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Author M

anuscript Published O

nlineFirst on S

eptember 26, 2016; D

OI: 10.1158/1055-9965.E

PI-16-0459


1

Figure legends

Figure 1. Flow chart for establishment of the study population. Abbreviations: PID, pelvic

inflammatory disease




Women alive and living in Denmark during 1978–2012

from birth cohorts 1940–1970

N = 1,319,155

The Danish Cancer Registry

Women with ovarian cancer before

start of follow-up

N = 220

Women included in the final analysis cohort

N = 1,318,929

The Danish National Patient

Registry

Women with bilateral oophorectomy

before start of follow-up

N = 6

Women with PID

during 1978–2011

N = 81,281

Women with ovarian

cancer during 1978–2012

N = 5,110

Women with no PID

during 1978–2011

N = 1,237,648

Women with ovarian

cancer during 1978–2012

N = 246

The Danish Civil Registration System

The Danish National Patient Registry

The Danish Cancer Registry

Figure 1




Published OnlineFirst September 26, 2016.Cancer Epidemiol Biomarkers Prev Christina B. Rasmussen, Allan Jensen, Vanna Albieri, et al. Is pelvic inflammatory disease a risk factor for ovarian cancer?

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