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. Author manuscript; available in PMC: 2019 Oct 15.
Published in final edited form as: Int J Cancer. 2018 Jul 10;143(8):1858–1867. doi: 10.1002/ijc.31581

Preterm delivery is associated with an increased risk of epithelial ovarian cancer among parous women

Camilla Sköld 1, Tone Bjørge 2,3, Anders Ekbom 4, Anders Engeland 2,5, Mika Gissler 6,7, Tom Grotmol 3, Laura Madanat 8,9, Anne Gulbech Ording 10, Olof Stephansson 11, Britton Trabert 12, Steinar Tretli 3, Rebecca Troisi 12, Henrik Toft Sørensen 10, Ingrid Glimelius 1,4
PMCID: PMC6128744  NIHMSID: NIHMS965495  PMID: 29737528

Abstract

Epithelial ovarian cancer is a fatal disease of largely unknown etiology. Higher parity is associated with reduced risk of ovarian cancer. However, among parous women, the impact of pregnancy-related factors on risk is not well understood. This population-based case-control study included all parous women with epithelial ovarian cancer in Denmark, Finland, Norway and Sweden during 1967-2013 (n=10,957) and up to 10 matched controls (n=107,864). We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for pregnancy-related factors and ovarian cancer risk by histological subtype. Preterm delivery was associated with an increased risk [pregnancy length (last pregnancy) ≤30 versus 39-41 weeks, OR 1.33 (95%CI 1.06-1.67), adjusted for number of births]; the OR increased as pregnancy length decreased (p for trend<0.001). Older age at first and last birth were associated with a decreased risk [first birth: 30-39 versus <25 years: adjusted OR 0.76 (95%CI 0.70-0.83); last birth 30-39 versus <25 years: adjusted OR 0.76 (95%CI 0.71-0.82)]. Increasing number of births was protective [≥4 births versus 1; OR 0.63 (95%CI 0.59-0.68)] for all subtypes, most pronounced for clear-cell tumors [OR 0.30, (95%CI 0.21-0.44), p-heterogeneity<0.001]. No associations were observed for multiple pregnancies, preeclampsia or offspring size. In conclusion, in addition to high parity, full-term pregnancies and pregnancies at older ages were associated with decreased risk of ovarian cancer. Our findings favor the cell clearance hypothesis, i.e. a recent pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes, mediated by placental or ovarian hormones.

INTRODUCTION

Ovarian cancer is the most lethal gynecological malignancy. The incidence in the Nordic countries is among the highest in the world with 9.5 cases per 100,000 women-years.1 The etiology is complex and only partly understood. Epithelial ovarian cancer is not one distinct disease, but rather several histologically and clinically distinct subtypes: serous (70-75%), mucinous (5-10%), clear cell (10%) and endometrioid (10%). The carcinogenesis of epithelial ovarian cancer has been described by a dualistic model,2 with two pathways involving different precursor lesions. Mucinous, clear cell, endometrioid and low-grade serous tumors are thought to develop from transformation of implant cysts on the ovary and have a better prognosis, while high-grade serous tumors are thought to develop from premalignant lesions in the fallopian tube and have a poorer prognosis.3 The risk of epithelial ovarian cancer is lower in parous women, with a protective effect across all epithelial subtypes.4–9 Results are conflicting for other pregnancy-related factors such as pre- and postterm delivery,10–12 maternal age at first and last birth,4,7,13–17 birth weight,10,14 preeclampsia14,18 and multiple pregnancies.14,19,20

In this large population-based Nordic study, we evaluated the risk of epithelial ovarian cancer and its specific histologic subtypes in parous women in relation to pregnancy and birth characteristics, particularly pregnancy length and maternal age at birth.

PATIENTS AND METHODS

This case-control study was undertaken as a Nordic collaboration, using linked data from two nationwide population-based registries:

  • Medical birth registries (MBR) were founded in 1973 (Denmark), 1987 (Finland), 1967 (Norway), and 1973 (Sweden). They contain information from antenatal, obstetric, and neonatal medical records and are based on mandatory reporting of all births.21–25 The attending physician/midwife completes a standardized form shortly after birth, documenting maternal health and pregnancy characteristics prior to, during, and at birth, and selected fetal outcomes.

  • Cancer registries, founded in 1943 (Denmark), 1953 (Finland and Norway), and 1958 (Sweden), are based on compulsory reporting of all incident cancer cases, including date of diagnosis and tumor histology. Case reporting is essentially complete.1,26–28

Record linkage across these registries is possible through the personal identification number assigned to each citizen and permanent resident in the Nordic countries at birth or upon immigration.

Outcomes and definition of cases/controls

We included all parous women registered in the MBRs at childbirth (Table 1), who had a subsequent diagnosis of epithelial ovarian cancer recorded in a cancer registry during 1973-2011 in Denmark (n=2494), 1987-2012 in Finland (n=567), 1967-2013 in Norway (n=4223), and 1973-2013 in Sweden (n=3673) (Table 2). Cases were free of other cancers at time of inclusion. Information on every pregnancy for each woman was included in the linkage to the MBR; however, since many women had had pregnancies prior to the start of the MBR, data was most complete for the most recent pregnancy before the case’s date of diagnosis. Ovarian cancer was defined by ICD-10/ICD-O-3 code C56.9, and by ICD-7 code 175.0 in Denmark before 1978 and in Sweden before 1993, and to identify epithelial ovarian cancer we used ICD-O-2/ICD-O-3 code 8010-8231, 8246-8576, 9014-9015 and 9110 and WHO/HS/CAN/C24.1 codes 096, 196 and 146 according to the International Agency for Research on Cancer’s29 definition (sTable 1). For each case, we sampled up to ten female controls that were alive and cancer-free at the time of the cases’ diagnosis and who were registered in a MBR with a prior pregnancy lasting longer than 22 weeks. Controls were matched by country and the case´s year of birth.

Table 1.

Maternal and offspring characteristics of epithelial ovarian cancer patients and matched controls, Nordic countries, 1968-2013*

Variable Cases Controls
n % n %
TOTAL 10,957 100 107,864 100
MATERNAL
Year of birth
 1925-1939 1311 12.0 13,031 12.1
 1940-1949 4619 42.2 45,933 42.6
 1950-1959 3527 32.2 34,812 32.3
 1960-1969 1259 11.5 12,073 11.2
 1970-1992 241 2.2 2015 1.9
Pregnancy length (weeks)1,2
 ≤30 86 0.8 668 0.6
 31-33 126 1.2 1059 1.0
 34-36 495 4.6 4331 4.1
 37-38 2629 24.5 25,173 23.8
 39-41 6467 60.2 65,048 61.5
 ≥42 942 8.8 9420 8.9
 Missing 121 – 1463 –
Age at diagnosis/matching
 <40 1458 13.3 13,031 12.1
 40-49 3170 28.9 31,688 29.4
 50-59 3909 35.7 39,011 36.2
 60-69 2052 18.7 20,451 19.0
 ≥70 368 3.4 3683 3.4
Number of births
 1 1922 17.5 19,438 13.3
 2 4585 41.8 44,039 40.8
 3 2776 25.3 28,790 27.9
 ≥4 1674 15.3 30,052 18.0
Age at first birth (years)
 <25 2944 45.2 26,880 43.1
 25-29 2144 32.9 21,552 34.6
 30-39 1354 20.8 13,137 21.1
 ≥40 71 1.1 788 1.3
 Missing 4444 – 45,507 –
Age at last birth (years)
 <25 1455 13.3 11,271 10.4
 25-29 3454 31.5 32,317 30.0
 30-39 5556 50.7 58,266 54.0
≥40 492 4.5 6010 5.6
Time since first birth (years)
 <10 817 12.5 7015 11.2
 10-19 1599 24.6 15,747 25.3
 20-29 2287 35.1 22,287 35.7
 ≥30 1810 27.8 17,308 27.8
 Missing 4444 – 45,507 –
Time since last birth (years)
 <10 1837 16.8 18,547 17.2
 10-19 3177 29.0 32,485 30.1
 20-29 3645 33.3 35,062 32.5
 ≥30 2298 21.0 21,770 20.2
Smoking during any pregnancy
 No 743 75.1 7963 78.4
 Yes 276 27.9 2194 21.6
 Missing 9405 – 92,786 –
Preeclampsia in any pregnancy
 No 10,329 94.3 101,783 94.4
 Yes 628 5.7 6081 5.6
Multiple birth (any)3
 No 10,732 97.9 105,648 97.9
 Yes 225 2.1 2216 2.1
OFFSPRING
Offspring length (cm) 1,2
 <48 892 8.3 8552 8.1
 48-54 9292 86.4 91,818 86.7
 >54 576 5.4 5554 5.2
 Missing 105 – 1238 –
Offspring weight (g) 1,2
 <1500 92 0.8 695 0.6
 1500-2499 405 3.7 3746 3.5
 2500-4500 10,021 92.4 99,121 92.7
 >4500 326 3.0 3387 3.2
 Missing 21 – 213 –
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*

Percentages are presented without including missing cases.

1

Data from last pregnancy.

2

To make sure that short pregnancy length/short offspring lentgh/low birthweight secondary to premature delivery caused by ovarian cancer was not driving the risk, we excluded cases diagnosed with ovarian cancer within six months after giving birth (n=92 cases/702 controls).

3

222 cases and 2173 controls with twin birth. 3 cases and 42 controls with triplets or more.

Table 2.

Epithelial ovarian cancer by histological subtype and country, Nordic countries, 1968-2013

(Diagnostic year) Denmark
(1977-2011)		 Finland
(1988-2012)		 Norway
(1968-2013)		 Sweden
(1979-2013)
Mean age at diagnosis 51 45 54 52
n % n % n % n %
Epithelial total 2494 22.8 567 5.2 4223 38.5 3673 33.5
Epithelial subtypes1
 Serous 1295 63.5 275 52.4 2075 66.1 1605 70.7
 Mucinous 341 16.7 150 28.6 408 13.0 385 17.0
 Clear cell 126 6.2 30 5.7 193 6.2 90 4.0
 Endometrioid 278 13.6 70 13.3 461 14.7 189 8.3
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1

Epithelial subtype known for 7971 cases. Unspecified cases excluded (n = 2986, 27.3%).

Exposures

We examined the following exposures: Number of births at the time of matching; age at first and last birth; time since first and last birth; preeclampsia and multiple pregnancy (in any pregnancy). Pregnancy length in completed weeks and birth length and weight of the offspring were ascertained from the cases’ and controls’ most recent pregnancy before the case’s date of diagnosis. Many of the cases’ first pregnancies occurred before the MBRs started, thus, the most recent pregnancy provided the most complete data. Information on smoking habits during (any) pregnancy was available in Denmark 1991-2010, Finland 1987-2012, Norway 1998-2013, and Sweden 1982-2013.

Statistical analyses

We used conditional logistic regression (conditioned on birth year of the case and country) to estimate the impact of pregnancy-related factors. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed for epithelial ovarian cancer by histologic subtype. In analyses of pregnancy length and birth length/weight of offspring, women who were diagnosed with ovarian cancer within six months after giving birth were excluded (92 cases, 702 controls), to minimize the possibility that associations were related to preterm delivery due to the cancer.

We performed analysis adjusted for number of births. We also performed analyses stratified by number of births. Offspring length/weight were adjusted for pregnancy length (as a continuous variable), as a measure of fetal growth.

We stratified analyses by birth year (<1940, 1940-1959, and ⩾1960) to evaluate differences over time and during time periods reflecting changing use of oral contraceptives, and by three age categories, <50 years (as a proxy for premenopausal status), 50-59 years and ⩾60 years. Since coding of mucinous ovarian cancers has changed over time, we conducted a sensitivity analysis evaluating cases diagnosed since 2005. When different patterns of associations were observed, we tested for heterogeneity (p-het) of associations over strata in stratified analyses, using a likelihood ratio test. R version 3.3.2 was used for all analyses.30

Ethics

We obtained approval from Ethics Committees in Norway and Sweden, from the Data Protection Agency in Denmark, and from the National Institute for Health and Welfare in Finland after consulting its Data Protection Authority.

RESULTS

The study included 10,957 cases and 107,864 controls with a median age at ovarian cancer diagnosis/matching of 52 years (range 19-85 years) (Table 1). Due to the later establishment of the Finnish birth registry, there were fewer cases from Finland and mean age at diagnosis was lower (Table 2). Analysis by histological subtype was possible for 7,971 cases (Table 2).

Increasing number of births was inversely associated with the risk of epithelial ovarian cancer (Table 3), with an additional risk reduction for each subsequent pregnancy.

Table 3.

Risk of epithelial ovarian cancer conditioned on birth year (of the case) and country*

Unadjusted Adjusted for number of births
OR 95% CI OR 95% CI
Number of births 1 1.0 Ref 1.0 Ref
2 0.79 0.74-0.83 0.79 0.74-0.83
3 0.69 0.65-0.74 0.69 0.65-0.74
≥4 0.63 0.59-0.68 0.63 0.59-0.68
Per birth 0.89 0.88-0.91 0.89 0.88-0.91
Pregnancy length (weeks)1,2 ≤30 1.31 1.04-1.64 1.33 1.06-1.67
31-33 1.21 1.00-1.45 1.20 1.00-1.45
34-36 1.16 1.05-1.28 1.16 1.05-1.27
37-38 1.07 1.01-1.13 1.06 1.00-1.12
39-41 1.0 Ref 1.0 Ref
≥42 1.00 0.93-1.08 1.00 0.93-1.07
Per week 0.98 0.97-0.99 0.98 0.97-0.99
<37 weeks 1.16 1.07-1.26 1.16 1.07-1.26
Age at first birth (years) <25 1.0 Ref 1.0 Ref
25-29 0.88 0.82-0.94 0.83 0.78-0.89
30-39 0.87 0.80-0.95 0.76 0.70-0.83
≥40 0.63 0.46-0.87 0.50 0.37-0.69
Per year age 0.97 0.97-0.98 0.97 0.97-0.98
Age at last birth (years) <25 1.0 Ref 1.0 Ref
25-29 0.82 0.77-0.88 0.85 0.80-0.91
30-39 0.71 0.66-0.76 0.76 0.71-0.82
≥40 0.56 0.50-0.64 0.64 0.56-0.72
Per year age 0.97 0.97-0.98 0.98 0.97-0.98
Time since first birth (years) <10 0.72 0.61-0.85 0.56 0.47-0.66
10-19 0.79 0.69-0.90 0.68 0.60-0.78
20-29 0.90 0.82-1.00 0.84 0.76-0.93
≥30 1.0 Ref 1.0 Ref
Per year 1.02 1.01-1.02 1.03 1.02-1.04
Time since last birth (years) <10 0.53 0.46-0.60 0.61 0.54-0.69
10-19 0.68 0.61-0.75 0.75 0.68-0.83
20-29 0.86 0.80-0.93 0.90 0.84-0.98
≥30 1.0 Ref 1.0 Ref
Per year 1.03 1.03-1.03 1.02 1.02-1.03
Smoking3 No 1.0 Ref 1.0 Ref
Yes 1.37 1.18-1.59 1.40 1.20-1.62
Preeclampsia4 No 1.0 Ref 1.0 Ref
Yes 1.02 0.94-1.11 1.03 0.95-1.12
Multiple birth4 No 1.0 Ref 1.0 Ref
Yes 1.00 0.87-1.15 1.10 0.96-1.27
Offspring length (cm)1,2,5 <48 0.97 0.89-1.05 0.96 0.89-1.04
48-54 1.0 Ref 1.0 Ref
>54 1.05 0.95-1.14 1.06 0.96-1.16
Offspring weight (g)1,2,5 <1500 1.24 0.90-1.70 1.25 0.91-1.71
1500-2499 1.00 0.88-1.13 0.99 0.87-1.12
2500-4500 1.0 Ref 1.0 Ref
>4500 0.97 0.86-1.09 1.00 0.89-1.13
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*

Odds ratio (OR) and 95% confidence intervals (CIs) from conditional logistic regression models, conditioned on birth year (of the case) and country, adjusted for number of births.

1

Data from last pregnancy.

2

To make sure that short pregnancy length/short offspring lentgh/low birthweight secondary to premature delivery caused by ovarian cancer was not driving the risk, we excluded cases diagnosed with ovarian cancer within six months after their last birth (n=92 cases/702 controls).

3

Smoking during any pregnancy.

4

Preeclampsia/multiple pregnancy in any pregnancy.

5

Adjusted for pregnancy length (last pregnancy) as a continous variable.

Pregnancy characteristics and preterm delivery

Preterm delivery in a woman’s last pregnancy was associated with an increased risk of ovarian cancer - the shorter the pregnancy, the stronger the association [pregnancy length ≤30 versus 39-41 weeks: adjusted OR 1.33 (95%CI 1.06-1.67)]. The OR was 0.98 (95%CI 0.97-0.99) for each added gestational week (Figure 1). The results remained when we adjusted for age at first or last birth (i.e. OR for each added gestational week: 0.98 (95%CI 0.97-0.99) when adjusted for age at last birth in addition to number of births). The OR for preterm delivery overall, defined as <37 weeks of gestation, versus 37-42 weeks, was 1.16 (95%CI 1.07-1.26). Further adjustment for smoking had no impact on results (i.e., OR <37 pregnancy-weeks, versus 37-42 weeks: 1.16 (95%CI 1.07-1.26). Postterm pregnancies (≥42 weeks) compared with 39-41 weeks were not associated with risk (Table 3). The OR for preterm delivery in the woman’s last pregnancy did not vary by number of births (sTable 2). Results were similar for pregnancy length in the woman’s first pregnancy (data not shown). As described earlier, women who were diagnosed with ovarian cancer within six months after giving birth were excluded to minimize the possibility that associations were related to preterm delivery due to the cancer. Results were also similar if women diagnosed with cancer within one year after pregnancy were excluded. There were no associations between ovarian cancer and preeclampsia, multiple births, or offspring birth length, neither overall nor by subtype (Table 3). Results did not change when the association of offspring birth length and weight and preeclampsia and ovarian cancer were adjusted for smoking.

Figure 1.

Figure 1

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Age at birth and time since birth

Older age at first and last birth and shorter time since first and last birth were all inversely associated with ovarian cancer risk (Table 3). First birth at age 30-39, versus before 25 years, was associated with decreased risk [OR 0.76 (95%CI 0.70-0.83)]; similar results were seen with age at last birth [30-39 versus <25 years: OR 0.76 (95%CI 0.71-0.82)]. In addition, shorter time since first and last birth were associated with decreased risk (Table 3). The OR for age at first and last birth and time since first and last birth did not vary by number of births (sTable 2). Since age at first and last birth is the same among women with only one pregnancy, we also performed a sensitivity analysis where 1-para cases were excluded, which did not alter the results (i.e. per year increase in age at last birth: all cases: OR 0.98 (95% CI 0.97-0.98); >1 births: OR 0.98 (95% CI 0.97-0.98).

Histological subtype

Among cases with known histology, 5250 (66%) were serous, 1284 (16%) mucinous, 998 (12%) endometrioid, and 439 (6%) clear cell carcinomas (Table 4). The inverse association observed with increasing number of births was strongest for the clear cell subtype [per birth: OR 0.74, 95%CI 0.67-0.81) p-het <0.001, Table 4], but was observed for all subtypes. The inverse association with older age at last birth was most pronounced for the endometrioid subtype (>40 years versus <25 years OR 0.39 (95%CI 0.24-0,65; p-het <0.001). Smoking was associated with mucinous ovarian cancer (OR 2.37 (95%CI 1.78-3.15); p-het 0.003). In addition, low offspring birth weight in the last pregnancy was associated with mucinous ovarian cancer [adjusted for pregnancy length and parity: 1500-2499g versus 2500-4500g OR 1.47 (95%CI 1.07-2.01) also when additionally adjusted for smoking: OR 1.46 (95%CI: 1.06-2.00)]. In a sensitivity analysis in which we restricted the mucinous group to cases diagnosed since 2005 (n=459), the results were similar. Higher offspring birth weight was associated with endometrioid ovarian cancer. [>4500g versus 2500-4500: OR 1.62 (95%CI 1.15-2.29), p-het 0.02]

Table 4.

Risk of epithelial ovarian cancer by subtype1, conditioned on birth year (of the case) and country*

Cases/controls Serous (all) Mucinous Clear cell Endometrioid
5250/52,048 (66%)1 1284/12,441 (16%)1 439/4364 (6%)1 998/9905 (13%)1
OR 95% CI OR 95% CI OR 95% CI OR 95 % CI
Number of births
 1 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 2 0.82 0.75-0.89 0.79 0.67-0.93 0.64 0.49-0.83 0.87 0.72-1.05
 3 0.76 0.69-0.83 0.70 0.58-0.84 0.49 0.37-0.67 0.64 0.51-0.79
 ≥4 0.70 0.63-0.77 0.70 0.58-0.84 0.30 0.21-0.44 0.54 0.42-0.69
 Per birth 0.92 0.89-0.94 0.92 0.87-0.97 0.74 0.67-0.81 0.83 0.78-0.89
 P for subtype heterogeneity <0.001
Pregnancy length (weeks)2,3
 ≤30 1.39 1.01-1.92 1.49 0.77-2.91 1.48 0.51-4.26 1.00 0.45-2.19
 31-33 1.00 0.76-1.33 1.21 0.66-2.23 1.57 0.66-3.73 1.99 1.19-3.34
 34-36 1.08 0.94-1.25 1.52 1.15-2.01 1.05 0.61-1.79 0.92 0.65-1.28
 37-38 1.01 0.94-1.10 1.15 0.99-1.34 1.38 1.06-1.80 1.05 0.88-1.25
 39-41 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 ≥42 0.96 0.86-1.07 1.14 0.92-1.42 1.53 1.09-2.13 1.01 0.79-1.30
 P for subtype heterogeneity 0.08
Age at first birth (years)
 <25 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 25-29 0.85 0.77-0.93 0.76 0.63-0.91 0.86 0.62-1.18 0.76 0.61-0.94
 30-39 0.78 0.69-0.88 0.78 0.62-0.99 0.66 0.44-0.99 0.71 0.54-0.93
 ≥40 0.54 0.34-0.86 1.45 0.66-3.17 0.26 0.05-1.26 0.41 0.12-1.40
 P for subtype heterogeneity 0.45
Age at last birth (years)
 <25 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 25-29 0.81 0.73-0.89 1.07 0.88-1.30 1.12 0.80-1.56 1.01 0.81-1.26
 30-39 0.78 0.70-0.86 0.80 0.65-0.98 0.71 0.50-1.01 0.74 0.59-0.93
 ≥40 0.58 0.48-0.70 0.93 0.65-1.34 1.01 0.57-1.79 0.39 0.24-0.65
 P for subtype heterogeneity <0.001
Time since first birth (years) (years)2
 <10 0.56 0.43-0.72 0.68 0.41-1.13 0.28 0.11-0.71 0.52 0.29-0.93
 10-19 0.65 0.55-0.78 0.77 0.50-1.20 0.35 0.19-0.66 0.73 0.48-1.09
 20-29 0.81 0.71-0.82 0.85 0.59-1.24 0.74 0.49-1.13 0.94 0.70-1.27
 ≥30 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 P for subtype heterogeneity 0.79
Time since last birth (years)
 <10 0.68 0.56-0.82 0.45 0.30-0.67 0.36 0.19-0.70 0.48 0.32-0.73
 10-19 0.83 0.73-0.95 0.59 0.42-0.83 0.40 0.25-0.63 0.64 0.47-0.88
 20-29 0.94 0.85-1.04 0.77 0.57-1.03 0.69 0.49-0.97 0.83 0.64-1.06
 ≥30 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 P for subtype heterogeneity 0.07
Smoking4
 No 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 Yes 1.12 0.90-1.40 2.37 1.78-3.15 1.17 0.57-2.39 0.86 0.54-1.38
 P for subtype heterogeneity 0.003
Offspring weight (g)2,3,5
 <1500 1.23 0.85-1.77 1.53 0.75-3.09 1.32 0.43-4.11 1.07 0.49-2.33
 1500-2499 0.91 0.77-1.08 1.47 1.07-2.0188 0.92 0.53-1.59 0.93 0.64-1.37
 2500-4500 1.0 Ref 1.0 Ref 1.0 Ref 1.0 Ref
 >4500 1.01 0.86-1.20 0.91 0.64-1.29 0.53 0.24-1.14 1.62 1.15-2.29
 P for subtype heterogeneity 0.02
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*

Odds ratio (OR) and 95% confidence intervals (CIs) from conditional logistic regression models, conditioned on birth year (of the case) and country, adjusted for number of births.

1

Histological coding of epithelial subtype was missing in 2453 cases (23.5%), which were not included in calculation.

2

Data from last pregnancy.

3

To make sure that short pregnancy length/low birthweight secondary to premature delivery caused by ovarian cancer was not driving the risk, we excluded cases diagnosed with ovarian cancer within six months after giving birth (n=92 cases/702 controls).

4

Smoking during any pregnancy.

5

Adjusted for pregnancy length (last pregnancy) as a continous variable.

Age and year of birth

When stratifying on the mother’s age at diagnosis (<50, 50-59, and ≥60 years, sTable 3)31,32, each additional birth was associated with a 15% risk reduction for ovarian cancer in the premenopausal group, but only a 7% risk reduction in the oldest age category (≥60 years [P-het 0.007]. The risk associations were similar among the age groups when stratified by the mother’s year of birth (sTable 4).

DISCUSSION

In the largest study to date on epithelial ovarian cancer among parous women, we found that preterm delivery was associated with increased ovarian cancer risk. Higher age at both first and last birth were inversely associated with ovarian cancer risk, and the associations persisted regardless of a woman’s total number of births.

Pregnancy length

While abortion (induced or spontaneous) does not seem to be associated with risk of ovarian cancer,33 few previous studies have examined the associations with preterm delivery. Mucci et al. reported that preterm deliveries were associated with an increased risk of ovarian cancer in a cohort with 1017 cases (including a subset of the 3,673 Swedish cases in our study from year 1973-2001) with a mean age of 43 years at diagnosis.10 The same research group also showed an increased risk among women with postterm delivery.11 However, only 31 of 316 ovarian cancer patients in the study had a postterm delivery, and mean age at diagnosis was equally low. Preterm delivery in any pregnancy was associated with increased risk in an Australian case-control study of 1203 cases:12 in that study only 74 cases experienced preterm delivery. We could examine the associations with preterm delivery in greater detail, categorized in intervals of 2-3 weeks and found that additional weeks of preterm delivery were associated with an increased risk. Preterm delivery (n=707 cases) was associated with increased risk in both younger (<50 years) and older (≥60 years) women at diagnosis. Mucci et al.10 found the strongest associations with pregnancy length among women with one birth, while Jordan et al.12 found this association among multiparous women. In our data, the increased risk associated with short length of a woman’s last pregnancy was present independent of number of births. Unlike previous studies, we could analyze the association between pregnancy length and ovarian cancer subtypes and found the same trend for all.

Age at birth and time since birth

Most previous studies have reported reduced ovarian cancer risk with higher age at first or last birth.4,7,13,15–17 Four studies mutually adjusted for age at first and last birth with conflicting results.7,15–17 Two studies, a pooled case-control study of 620 cases by Whiteman et al.15 and a registry-based, cohort study of 1271 cases by Albrektsen et al.7 (including a subset of the 4,223 Norwegian cases in our study from year 1967-1991), found that only age at last birth remained statistically significant after adjustment. In contrast, in a recently published pooled case-control study of 1632 cases, Wu et al.17 found that only age at first birth remained significant after adjustment. Neither age at first or last birth was related materially to ovarian cancer risk when mutually adjusted in a smaller case-control study (n=563 cases).16

Risk reductions from pregnancies are most pronounced during the first decade after last birth,7,15,16 as our findings also indicate. An increasing number of births had a stronger effect on risk in younger than older women, which is also consistent with the difference in risk by time (younger women are more likely to have a shorter time since last birth).

Histological subtypes

The association between number of births and histologic subtype differ, with the strongest inverse associations observed for clear cell and endometrioid subtypes6,8,9 and weaker associations for serous and mucinous carcinomas.6,8,9,34 Our results on only parous women are in line with studies comparing nulliparous to parous women, including the subtype specific results from the Ovarian Cancer Cohort Consortium.6 Smoking was associated with an increased risk of mucinous carcinomas, as reported earlier.35,36 For other risk factors, results by subtype were comparable. We had a higher proportion of the mucinous subtype than expected, especially before 2005. However, when we restricted the analysis to mucinous cases diagnosed from 2005 or applied stricter coding in the selection of mucinous tumors, the results remained unchanged. Any misclassification with gastrointestinal tumors in our study would be random with respect to the pregnancy factors we analyzed, resulting in bias towards the null.

Biological mechanisms

The mechanism underlying the reduced risks associated with pregnancies is not known, although there are several hypotheses. Based on our findings we favor “the cell clearance hypothesis”, whereby a full-term pregnancy provides protection through clearance of precancerous cells from the ovarian epithelium/fallopian tubes, mediated by placental or ovarian hormones13. Since hormone levels that mediate cell clearance increase during the last trimester of pregnancy,37 our finding of increased risk with shorter pregnancy length is consistent with the cell clearance hypothesis. Moreover, since both increasing time since pregnancy and older age at pregnancy increase the risk of accumulating premalignant cells, shorter time since last pregnancy, and pregnancies at older ages (a more recent cell clearance), are associated with lower risk and these results are also consistent with the cell clearance hypothesis.

Some preclinical data support cell clearance mediated by progesterone, which rises during pregnancy.37 Administration of progesterone to a human ovarian carcinoma cell line increased the expression of TP53 tumor suppressor gene and induced apoptosis.38 Further, a study of sheep ovarian cancer cells indicated that progesterone is involved in the restoration or apoptosis of ovarian surface epithelial cells containing damaged DNA after ovulation.39 Synthetic progestin induces apoptosis in ovarian cancer cell lines,40 and treatment with progestin induces apoptosis in the ovarian epithelium of macaques41,42 and chickens.43 Further, oral contraceptives with high-progestin potency seem to provide greater protection against ovarian cancer than low-progestin formulations.44 However, the effects of synthetic progestin might differ from the effects of endogenous progesterone in pregnancy.

The earlier most accepted hypothesis is the incessant ovulation hypothesis,45 proposing that the disruption and repair of ovarian epithelium can cause mutations in ovarian epithelial cells, resulting in a higher risk of cancer. However, the risk reduction occurring with nine months of pregnancy is stronger than the risk reduction associated with nine months of missed ovulatory cycles due to other causes.46 The association we found for increased risk with shorter length of pregnancy could have several causes, such as fewer ovulatory cycles, lack of hormone exposure in the last trimester, or shorter exposure to pregnancy hormones. However, the inverse association seen with increasing age at pregnancy cannot be explained only by reduction in ovulatory cycles, since pregnancy at any age would then be expected to have the same effect on risk. Thus, pregnancies likely provide protection through other mechanisms (such as cell clearance), rather than solely reduction in ovulatory cycles.

Strength and limitations

This large population-based study has a number of notable strengths: 1) almost complete information on reproductive history collected from birth registries avoided recall bias; 2) cancer diagnoses were collected in a similar and standardized manner from nationwide registries in four Nordic countries;1 and 3) the study’s large size (larger than most previous studies) provided a sufficient number of cases for disaggregation by subtype and facilitated more precise risk estimates.

Because the analysis was restricted to parous women (pregnancy characteristics were the exposures of interest), the cancer cases were relatively young with a mean age at diagnosis of 52 years. However, our findings are consistent with cohort studies that included primarily sporadic ovarian cancers in postmenopausal women.5,6

A study weakness was lack of information on possible confounders, most notably use of oral contraceptives. Oral contraceptives were introduced in the Nordic countries during the 1960s; use has since increased and is most frequent among younger women.47,48 This suggests that women born before 1940 are less likely to have used oral contraceptives. Thus, since our results did not differ by birth year of the mother, they are unlikely to be affected by oral contraceptive use. In addition, adjusting for oral contraceptive use in previous studies had no major impact on estimates of parity and number of births5,6,15 or age at birth.17 We also lacked information on oophorectomy/salpingectomy or hysterectomy, and thus could not exclude controls who had undergone gynecological surgery. However, since the prevalence of oophorectomy/hysterectomy in the Nordic countries is low (200 per 100.000 women), this is unlikely to have had a major effect on our risk estimates.49 Moreover, we lacked information on other potential confounders such as age at menarche, body mass index, and history of endometriosis. Finally, the influence of pregnancy loss (prior to week 22) could not be investigated.

Conclusions

In this large population based case-control study including over 10,000 epithelial ovarian cancer cases, we found that preterm delivery was associated with an increased risk of ovarian cancer. Older age at both first and last birth was associated with a lower risk of ovarian cancer. Our findings are in line with the cell clearance hypothesis, which might help us to better understand this fatal disease. Learning how pregnancy removes precancerous cells could possibly provide a clinical opportunity for prevention of ovarian cancer.

Supplementary Material

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Novelty and Impact.

In the largest study to date on epithelial ovarian cancer among parous women, preterm birth was associated with an increased risk. The odds ratios increased as pregnancy length decreased. Increasing number of births and pregnancies at older ages were associated with decreased risk of ovarian cancer. This clearly favors the cell clearance hypothesis, i.e. a recent full-term pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes.

Acknowledgments

We are grateful to Maria Grünewald at Scandinavian Development Services for valuable comments and statistical support.

Funding: This study was supported by the Nordic Cancer Union, the National Cancer Institute, the Intramural program of the National Cancer Institute, National Institutes of Health, the Uppsala County Sweden and Lion’s research fund at Uppsala Akademiska Hospital. Ingrid Glimelius was supported by the Swedish Cancer Society (CAN 2016/440) and the Gullstrand Foundation, Uppsala County, Sweden.

Footnotes

Disclaimers: The authors have no disclaimers

References

  • 1.Engholm G, Ferlay J, Christensen N, et al. NORDCAN–a Nordic tool for cancer information, planning, quality control and research. Acta Oncol. 2010;49:725–36. doi: 10.3109/02841861003782017. [DOI] [PubMed] [Google Scholar]
  • 2.Kurman RJ, Shih Ie M. The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded. Am J Pathol. 2016;186:733–47. doi: 10.1016/j.ajpath.2015.11.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Steffensen KD, Waldstrom M, Grove A, Lund B, Pallisgard N, Jakobsen A. Improved classification of epithelial ovarian cancer: results of 3 danish cohorts. International journal of gynecological cancer: official journal of the International Gynecological Cancer Society. 2011;21:1592–600. doi: 10.1097/IGC.0b013e31822a0f6b. [DOI] [PubMed] [Google Scholar]
  • 4.Riman T, Dickman PW, Nilsson S, et al. Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study. Am J Epidemiol. 2002;156:363–73. doi: 10.1093/aje/kwf048. [DOI] [PubMed] [Google Scholar]
  • 5.Fortner RT, Ose J, Merritt MA, et al. Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: Results from the EPIC cohort. International journal of cancer. 2015;137:1196–208. doi: 10.1002/ijc.29471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Wentzensen N, Poole EM, Trabert B, et al. Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium. J Clin Oncol. 2016;34:2888–98. doi: 10.1200/JCO.2016.66.8178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Albrektsen G, Heuch I, Kvale G. Reproductive factors and incidence of epithelial ovarian cancer: a Norwegian prospective study. Cancer Causes Control. 1996;7:421–7. doi: 10.1007/BF00052668. [DOI] [PubMed] [Google Scholar]
  • 8.Merritt MA, De Pari M, Vitonis AF, Titus LJ, Cramer DW, Terry KL. Reproductive characteristics in relation to ovarian cancer risk by histologic pathways. Hum Reprod. 2013;28:1406–17. doi: 10.1093/humrep/des466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Yang HP, Trabert B, Murphy MA, et al. Ovarian cancer risk factors by histologic subtypes in the NIH-AARP Diet and Health Study. International journal of cancer. 2012;131:938–48. doi: 10.1002/ijc.26469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Mucci LA, Dickman PW, Lambe M, et al. Gestational age and fetal growth in relation to maternal ovarian cancer risk in a Swedish cohort. Cancer Epidemiol Biomarkers Prev. 2007;16:1828–32. doi: 10.1158/1055-9965.EPI-06-0962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Cnattingius S, Eloranta S, Adami HO, et al. Placental weight and risk of invasive epithelial ovarian cancer with an early age of onset. Cancer Epidemiol Biomarkers Prev. 2008;17:2344–9. doi: 10.1158/1055-9965.EPI-08-0390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Jordan SJ, Green AC, Nagle CM, et al. Beyond parity: association of ovarian cancer with length of gestation and offspring characteristics. Am J Epidemiol. 2009;170:607–14. doi: 10.1093/aje/kwp185. [DOI] [PubMed] [Google Scholar]
  • 13.Adami HO, Hsieh CC, Lambe M, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet (London, England) 1994;344:1250–4. doi: 10.1016/s0140-6736(94)90749-8. [DOI] [PubMed] [Google Scholar]
  • 14.Mogren I, Stenlund H, Hogberg U. Long-term impact of reproductive factors on the risk of cervical, endometrial, ovarian and breast cancer. Acta Oncol. 2001;40:849–54. doi: 10.1080/02841860152703481. [DOI] [PubMed] [Google Scholar]
  • 15.Whiteman DC, Siskind V, Purdie DM, Green AC. Timing of pregnancy and the risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2003;12:42–6. [PubMed] [Google Scholar]
  • 16.Titus-Ernstoff L, Perez K, Cramer DW, Harlow BL, Baron JA, Greenberg ER. Menstrual and reproductive factors in relation to ovarian cancer risk. Br J Cancer. 2001;84:714–21. doi: 10.1054/bjoc.2000.1596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Wu AH, Pearce CL, Lee AW, et al. Timing of births and oral contraceptive use influences ovarian cancer risk. International journal of cancer. 2017 doi: 10.1002/ijc.30910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Calderon-Margalit R, Friedlander Y, Yanetz R, et al. Preeclampsia and subsequent risk of cancer: update from the Jerusalem Perinatal Study. American journal of obstetrics and gynecology. 2009;200:63.e1–5. doi: 10.1016/j.ajog.2008.06.057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Whiteman DC, Murphy MF, Cook LS, et al. Multiple births and risk of epithelial ovarian cancer. J Natl Cancer Inst. 2000;92:1172–7. doi: 10.1093/jnci/92.14.1172. [DOI] [PubMed] [Google Scholar]
  • 20.Lambe M, Wuu J, Rossing MA, Hsieh CC. Twinning and maternal risk of ovarian cancer. Lancet (London, England) 1999;353:1941. doi: 10.1016/S0140-6736(99)02000-0. [DOI] [PubMed] [Google Scholar]
  • 21.Gissler M, Louhiala P, Hemminki E. Nordic Medical Birth Registers in epidemiological research. Eur J Epidemiol. 1997;13:169–75. doi: 10.1023/a:1007379029182. [DOI] [PubMed] [Google Scholar]
  • 22.Stockholm: Centre for Epidemiology TNBoHaW. The Swedish Medical Birth Register: A Summary of Content and Quality. 2003. (Report no. 2003-112-3). [Google Scholar]
  • 23.Cnattingius S, Ericson A, Gunnarskog J, Kallen B. A quality study of a medical birth registry. Scand J Soc Med. 1990;18:143–8. doi: 10.1177/140349489001800209. [DOI] [PubMed] [Google Scholar]
  • 24.Irgens LM. The Medical Birth Registry of Norway. Epidemiological research and surveillance throughout 30 years. Acta Obstet Gynecol Scand. 2000;79:435–9. [PubMed] [Google Scholar]
  • 25.Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull. 1998;45:320–3. [PubMed] [Google Scholar]
  • 26.Stockholm: Centre for Epidemiology TNBoHaW, Sweden. Cancer Incidence in Sweden 2004. 2005 [Google Scholar]
  • 27.Larsen IK, Smastuen M, Johannesen TB, et al. Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer. 2009;45:1218–31. doi: 10.1016/j.ejca.2008.10.037. [DOI] [PubMed] [Google Scholar]
  • 28.Storm HH, Michelsen EV, Clemmensen IH, Pihl J. The Danish Cancer Registry–history, content, quality and use. Dan Med Bull. 1997;44:535–9. [PubMed] [Google Scholar]
  • 29.IARC. https://www.iarc.fr/en/publications/pdfs-online/epi/sp164/CI5volX-04.pdf.
  • 30.R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing; 2016. Vienna, Austria. URL https://www.R-project.org/ [Google Scholar]
  • 31.Thomas F, Renaud F, Benefice E, de Meeus T, Guegan JF. International variability of ages at menarche and menopause: patterns and main determinants. Hum Biol. 2001;73:271–90. doi: 10.1353/hub.2001.0029. [DOI] [PubMed] [Google Scholar]
  • 32.te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8:141–54. doi: 10.1093/humupd/8.2.141. [DOI] [PubMed] [Google Scholar]
  • 33.Dick ML, Siskind V, Purdie DM, Green AC, Australian Cancer Study G, Australian Ovarian Cancer Study G Incomplete pregnancy and risk of ovarian cancer: results from two Australian case-control studies and systematic review. Cancer Causes Control. 2009;20:1571–85. doi: 10.1007/s10552-009-9402-3. [DOI] [PubMed] [Google Scholar]
  • 34.Gates MA, Rosner BA, Hecht JL, Tworoger SS. Risk factors for epithelial ovarian cancer by histologic subtype. Am J Epidemiol. 2010;171:45–53. doi: 10.1093/aje/kwp314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Collaborative Group on Epidemiological Studies of Ovarian C. Beral V, Gaitskell K, et al. Ovarian cancer and smoking: individual participant meta-analysis including 28,114 women with ovarian cancer from 51 epidemiological studies. Lancet Oncol. 2012;13:946–56. doi: 10.1016/S1470-2045(12)70322-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Faber MT, Kjaer SK, Dehlendorff C, et al. Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. Cancer Causes Control. 2013;24:989–1004. doi: 10.1007/s10552-013-0174-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Costa MA. The endocrine function of human placenta: an overview. Reprod Biomed Online. 2016;32:14–43. doi: 10.1016/j.rbmo.2015.10.005. [DOI] [PubMed] [Google Scholar]
  • 38.Bu SZ, Yin DL, Ren XH, et al. Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines. Cancer. 1997;79:1944–50. doi: 10.1002/(sici)1097-0142(19970515)79:10<1944::aid-cncr15>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  • 39.Murdoch WJ. Perturbation of sheep ovarian surface epithelial cells by ovulation: evidence for roles of progesterone and poly(ADP-ribose) polymerase in the restoration of DNA integrity. J Endocrinol. 1998;156:503–8. doi: 10.1677/joe.0.1560503. [DOI] [PubMed] [Google Scholar]
  • 40.Rodriguez GC, Turbov J, Rosales R, et al. Progestins inhibit calcitriol-induced CYP24A1 and synergistically inhibit ovarian cancer cell viability: An opportunity for chemoprevention. Gynecol Oncol. 2016;143:159–67. doi: 10.1016/j.ygyno.2016.04.022. [DOI] [PubMed] [Google Scholar]
  • 41.Rodriguez GC, Nagarsheth NP, Lee KL, et al. Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta. J Natl Cancer Inst. 2002;94:50–60. doi: 10.1093/jnci/94.1.50. [DOI] [PubMed] [Google Scholar]
  • 42.Rodriguez GC, Walmer DK, Cline M, et al. Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis? J Soc Gynecol Investig. 1998;5:271–6. doi: 10.1016/s1071-5576(98)00017-3. [DOI] [PubMed] [Google Scholar]
  • 43.Rodriguez GC, Barnes HJ, Anderson KE, et al. Evidence of a chemopreventive effect of progestin unrelated to ovulation on reproductive tract cancers in the egg-laying hen. Cancer Prev Res (Phila) 2013;6:1283–92. doi: 10.1158/1940-6207.CAPR-12-0426. [DOI] [PubMed] [Google Scholar]
  • 44.Schildkraut JM, Calingaert B, Marchbanks PA, Moorman PG, Rodriguez GC. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst. 2002;94:32–8. doi: 10.1093/jnci/94.1.32. [DOI] [PubMed] [Google Scholar]
  • 45.Fathalla MF. Incessant ovulation–a factor in ovarian neoplasia? Lancet (London, England) 1971;2:163. doi: 10.1016/s0140-6736(71)92335-x. [DOI] [PubMed] [Google Scholar]
  • 46.Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136:1212–20. doi: 10.1093/oxfordjournals.aje.a116429. [DOI] [PubMed] [Google Scholar]
  • 47.Lindh I, Skjeldestad FE, Gemzell-Danielsson K, et al. Contraceptive use in the Nordic countries. Acta Obstet Gynecol Scand. 2017;96:19–28. doi: 10.1111/aogs.13055. [DOI] [PubMed] [Google Scholar]
  • 48.Makkonen K, Hemminki E. Different contraceptive practices: use of contraceptives in Finland and other Nordic countries in the 1970s and 1980s. Scand J Soc Med. 1991;19:32–8. doi: 10.1177/140349489101900106. [DOI] [PubMed] [Google Scholar]
  • 49.Socialstyrelsen. http://www.socialstyrelsen.se/statistik/statistikefteramne/slutenvard.

Associated Data

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Supplementary Materials

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Supp TableS3
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