- Email: [email protected]
Time since Last Birth and the Risk of Ovarian Cancer
Gynecologic Oncology 81, 233–236 (2001) doi:10.1006/gyno.2001.6136, available online at http://www.idealibrary.com on
Time since Last Birth and the Risk of Ovarian Cancer Francesca Chiaffarino,* Fabio Parazzini,* ,† Eva Negri,* Guido Benzi,† Giovanna Scarfone,† Silvia Franceschi,‡ and Carlo La Vecchia* ,§ *Istituto di Ricerche Farmacologiche “Mario Negri,” 20157 Milano, Italy; †Prima Clinica Ostetrico Ginecologica, Universita` degli Studi di Milano, 20129 Milano, Italy; ‡International Agency for Research on Cancer, 69372 Lyon, France; and §Istituto di Statistica Medica e Biometria, Universita` degli Studi di Milano, 20133 Milano, Italy Received October 6, 2000
has been suggested that the high levels of progesterone characterizing pregnancy may induce apoptosis in ovarian carcinoma cell lines [7], and apoptosis has been shown to prevent development of several types of cancer in rodents [8 –9]. However, the role of time since last birth is far from being established and quantified. We analyzed data from a large case– control study conducted in northern Italy, focusing our attention on the role of pregnancy timing on the risk of ovarian cancer.
Objectives. While parity is a protective factor in ovarian cancer, the role of time factors of pregnancy and birth is still controversial. We considered therefore the role of birth timing in the risk in ovarian cancer from a large case– control study. Methods. Cases were 971 women (age range 22–74 years, median age 54) with histologically confirmed, incident epithelial ovarian cancer, interviewed between 1983 and 1991 in a network of hospitals in Milan, Italy. Controls were 2758 women (age range 23–74 years, median age 52) admitted to the same hospitals where cases were identified for acute, nonneoplastic conditions. Results. In comparison with nulliparous women, the multivariate odds ratios (OR) were 0.8 for women reporting one or two and 0.6 for those with three or more births. No clear association emerged between time since last birth and ovarian cancer. Compared to women who had last given birth since >20 years, a moderately increased risk of ovarian cancer was observed in the first 10 years after last birth, with an OR of 1.7 (95% confidence interval, CI 1.0 –2.9). When we considered only multiparous women and included in the multivariate analysis allowance for age at first birth, the OR decreased to 1.2 (95% CI 0.6 –2.4). No consistent pattern of trends was observed >10 years since last pregnancy. Conclusions. This study confirms the protective effect of parity on ovarian carcinogenesis, but shows no consistent pattern of risk across time since last birth. © 2001 Academic Press
MATERIALS AND METHODS
INTRODUCTION
Between 1983 and 1991, we conducted a case– control study of ovarian cancer [10]. Data were collected in the major teaching and general hospitals in the greater Milan area. Cases were 971 women (age range 22–74 years, median age 54) with histologically confirmed epithelial ovarian cancer, diagnosed within 1 year before the interview. Control subjects were 2758 women (age range 23–74 years, median age 52), admitted to the same hospitals where cases were identified, for acute conditions not related to gynecological, hormonal, or neoplastic diseases and who had not undergone bilateral oophorectomy. Of these, 34% had traumatic conditions (mostly fractures and sprains), 30% nontraumatic orthopedic disorders (mostly low back pain and disc disorders), 16% acute surgical conditions (mostly abdominal, such as acute appendicitis or strangulated hernia), and 20% miscellaneous other illnesses, such as eye, ear, nose and throat, and dental disorders. Approximately 4% of cases and controls approached refused the interview. The questionnaire included information on marital status, education, and other socioeconomic indicators, personal characteristics and habits, such as smoking, alcohol use, and coffee drinking, anthropometric variables, diet, menstrual and reproductive factors (such as age at menarche, menstrual cycles, number of abortions and births, and age at first and last birth), selected medical conditions, and lifelong history of use of oral contraceptives and hormone replacement therapy. Odds ratios (OR) of ovarian cancer and the corresponding 95% confidence intervals (CI) were derived using uncondi-
The protective role of parity on the risk of epithelial ovarian cancer is well recognized [1– 4]. However, some aspects of the role of parity in ovarian cancer epidemiology are still unclear. In particular, the role of time since last birth remains controversial. A cohort study of Norwegian women [5] and a pooled analysis of data from four case– control studies from the United States [6] showed an increased risk of epithelial ovarian cancer with increasing time since last birth which, however, tended to level off for multiparous women. In order to explain these findings, an effect of pregnancy on the late stage of the process of ovarian carcinogenesis has been postulated. In particular, it 233
0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
234
CHIAFFARINO ET AL.
TABLE 1 Distribution of 971 Cases of Ovarian Cancer and 2758 Controls a According to Age and Selected Variables and Corresponding Odds Ratios (OR) and 95% Confidence Intervals (CI), Milan, Italy, 1983–1991 Cases
Age (years) ⱕ35 36–45 46–55 56–65 ⱖ66 Education (years) ⬍7 7–11 ⱕ12 2 Number of births 0 1 2 ⱖ3 2 Oral contraceptive use Never Ever
Controls OR (95% CI) b
No.
%
No.
%
84 144 312 299 132
8.7 14.8 32.1 30.8 13.6
284 513 746 741 474
10.3 18.6 27.1 26.9 17.2
560 233 178
57.7 24.0 18.3
1593 686 179
57.8 24.9 17.4
1c 1.1 (0.9–1.4) 1.2 (1.0–1.5) 3.1, P⫽0.08
237 204 304 226
24.4 21.0 31.3 23.3
590 660 842 666
21.4 23.9 30.5 24.2
1c 0.8 (0.7–1.0) 0.8 (0.7–1.1) 0.6 (0.5–0.8) 10.7, P⫽0.001
908 63
93.5 6.5
2499 259
90.6 9.4
1c 0.8 (0.6–1.1)
a
In some cases the sum does not add up to the total because of missing values. b Multiple logistic regression estimates including terms for age and area of residence. c Reference category.
tional multiple logistic regression models, fitted by the method of maximum likelihood [11]. All regression equations included terms for age, area of residence, parity, and, when specified, age at first birth. RESULTS Table 1 shows the distribution of cases and control according to age, education, and parity. In comparison with women reporting less than 7 years of education, the OR was 1.2 (95% CI 1.0 –1.5) for those reporting 12 years or more. Ovarian cancer risk was inversely associated with number of births. In comparison with nulliparous women, the ORs were 0.8 for women reporting one or two, and 0.6 for those with three or more births. Table 2 considers the relation between time since last birth and ovarian cancer. No clear relation emerged with time since last birth. When we included all parous women, compared with women who had last given birth since ⱖ20 years, an increased risk of ovarian cancer was reported in the first 10 years after last birth, with an OR of 1.7 (95% CI 1.0 –2.9). When we considered only multiparous women (i.e., women reporting
two or more births) and included in the multivariate analysis allowance for age at first birth, the OR decreased, however, to 1.2 (95% CI 0.6 –2.4). No consistent pattern of risk was observed ⱖ10 years since last pregnancy. Further allowance for age at last birth among multiparous women led to ORs of 1.4 (95% CI 0.6 –3.1) for 9 years or less, 0.9 (95% CI 0.5–1.5) for 10 –14 years, and 1.1 (95% CI 0.7–1.6) for 15–19 years since last birth when compared with women who had last given birth since ⱖ20 years. However, inclusion of an additional term of age at last birth introduced a substantial collinearity, making the estimates difficult to interpret. The increased risk in the first years after last birth was apparently stronger at younger ages, but the ORs remained above unity in women aged ⱖ40 years. Likewise, the ORs in the 10 years since last birth were above unity across strata of parity (Table 3). DISCUSSION This study confirms the well-established protective effect of parity on ovarian carcinogenesis, but shows no consistent pattern of risk across time since last birth. This was a hospital-based study, with the related weaknesses and strengths. In particular, hospital controls are preferable for analysis of parity-related factors, particularly in the few years after birth, since women with small children may selectively TABLE 2 Distribution of 971 Cases of Ovarian Cancer and 2578 Controls a According to Time since Last Birth and Corresponding Odds Ratios (OR) and 95% Confidence Intervals (CI), Milan, Italy, 1983–1991 Cases No. Time since last birth (among all parous women) b ⱕ9 10–14 15–19 ⱖ20 Time since last birth (among multiparous women) c ⱕ9 10–14 15–19 ⱖ20
%
Controls No.
%
OR (95% CI)
76 10.4 215 9.9 68 9.3 263 12.2 122 16.7 378 17.5 465 63.6 1306 60.4
1.7 (1.0–2.9) 0.9 (0.6–1.4) 1.1 (0.8–1.4) 1d
49 9.3 53 10.1 98 18.6 327 62.1
1.2 (0.6–2.4) 0.8 (0.5–1.2) 1.0 (0.7–1.4) 1d
138 9.2 202 13.5 294 19.6 868 57.8
a In some cases the sum does not add up to the total because of missing values. b Multiple logistic regression estimates including terms for age, area of residence, and parity. c Multiple logistic regression estimates including terms for age, area of residence, parity, and age at first birth. d Reference category.
235
TIME SINCE LAST BIRTH AND THE RISK OF OVARIAN CANCER
TABLE 3 Odds Ratios (OR) and 95% Confidence Intervals (CI) of Ovarian Cancer According to Time since Last Birth and Parity, in Separate Strata of Age, Milan, Italy, 1983–1991 Time since last birth (years) a
Age (years) ⱕ40 41–55 Number of births 1 2 ⱖ3
⬍10 b
10–14 b
15–19 b
ⱖ20 b
1.7 (0.6–4.8) 1.4 (0.8–2.4)
1.0 (0.3–3.2) 0.9 (0.6–1.3)
1c 1.0 (0.7–1.4)
— 1c
1.4 (0.6–3.1) 1.4 (0.7–2.9) 1.4 (0.6–3.4)
0.9 (0.4–1.9) 0.9 (0.5–1.7) 0.8 (0.4–1.4)
0.9 (0.5–1.6) 1.1 (0.7–1.6) 1.1 (0.7–1.8)
1c 1c 1c
a
Nulliparae excluded. Multiple logistic regression estimates including terms for age, area of residence, and parity. c Reference category. b
participate in (or be excluded from) population-based studies [12]. Our control group, moreover, was broadly comparable with the northern Italian population with reference to fertility pattern and oral contraceptive use [12–15]. With further reference to selection bias, the catchment areas of cases and controls were comparable. With regard to confounding, simultaneous allowance for several confounding factors did not materially modify any of the risk estimates. Available evidence on the role of birth recency on ovarian cancer risk is scant. In a cohort study conducted in Norway based on 1694 women with epithelial ovarian cancer [5], the risk was about 30% higher in women reporting their last birth 20 or more years before diagnosis, in comparison with those reporting their last birth 10 to 14 years before. This pattern of risk was present among uniparous women but tended to disappear with higher order pregnancies. In a model including nulliparous women in the analyses and additional terms of age at first and last birth and time since last birth, no consistent pattern of trend was observed with time since last birth (OR ⫽ 0.94). In a reanalysis of four North American case– control studies including 807 cases and 3958 controls [6], the OR of ovarian cancer was about twofold higher in parous women reporting their last birth ⬎25 years before diagnosis in comparison with those reporting their last birth less than 10 years before. Moreover, in a Swedish cohort study [16], the risk of ovarian cancer was reduced soon after birth, and the protection seemed to decline with time since delivery. Two main hypotheses have been proposed to explain the role of reproductive factors on ovarian carcinogenesis: the incessant ovulation [17] and the gonadotropin hypotheses [18]. However, the potential role of pregnancy recency cannot be totally explained by ovulation or ovulatory years [19]. Our results did not confirm the presence of a short-term effect of parity on ovarian cancer risk, and they indicate that the protection of pregnancy and birth on ovarian carcinogen-
esis is long lasting. A preliminary analysis of this case– control study, limited to 123 cases and 252 controls below the age of 45 [20], also showed an increased risk in the few years after birth. For breast cancer, pregnancy confers a transient increase in risk followed by a long-term protection [21], and Moolgavkar et al. [22] proposed a two-stage model of breast carcinogenesis, where pregnancy acts as an anti-initiator, as well as a promoter. Although breast and ovarian carcinogenesis share some common aspects [23], the role of pregnancy recency and in particular that of time since last birth in ovarian carcinogenesis remains controversial, nonetheless, in several aspects.
ACKNOWLEDGMENTS This work was conducted with the contribution of the Italian Association for Cancer Research, Milan. The authors thank Mrs. Ivana Garimoldi for editorial assistance.
REFERENCES 1. Parazzini F, Franceschi S, La Vecchia C, Fasoli M. The epidemiology of ovarian cancer. Gynecol Oncol 1991;43:9 –23. 2. Negri E, Franceschi S, Tzonou A, et al. Pooled analysis of 3 European case– control studies: I. Reproductive factors and risk of epithelial ovarian cancer. Int J Cancer 1991;49:50 – 6. 3. Whittemore AS, Harris R, Itnyre J, and the Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: Collaborative Analysis of 12 US case– control studies. II. Invasive Epithelial ovarian cancer in white women. Am J Epidemiol 1992;136:1184 –203. 4. Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 1994;140:585–97. 5. 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.
236
CHIAFFARINO ET AL.
6. Cooper GS, Schildkraut JM, Whittemore AS, Marchbanks PA. Pregnancy recency and risk of ovarian cancer. Cancer Causes Control 1999;10:397– 402. 7. 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. 8. Chan LN, Zhang S, Cloyd M, Chan TS. N-(4-Hydroxyphenyl) retinamide prevents development of T-lymphomas in AKR/J mice. Anticancer Res 1997;17:499 –503. 9. Inada T, Ichikawa A, Kubota T, Ogata Y, Moossa A, Hoffman RM. 5-FU-induced apoptosis correlates with efficacy against human gastric and colon cancer xenografits in nude mice. Anticancer Res 1997;17:1965–71. 10. Parazzini F, Negri E, La Vecchia C, Restelli C, Franceschi S. Family history of reproductive cancers and ovarian cancer risk: An Italian case– control study. Am J Epidemiol 1992;135:35– 40. 11. Breslow NE, Day NE. Statistical methods in cancer research. Vol. I. The analysis of case– control studies. IARC Scientific Publications No. 32. International Agency for Research on Cancer, Lyon, France, 1980. 12. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Hormonal contraception and post-menopausal hormonal therapy, Lyon, IARC, Vol. 72, 1999. 13. Spinelli A, Figa`-Talamanca I, Lauria L, European Study Group on Infertility and Subfecundity. Patterns of contraceptive use in 5 European countries. Am J Public Health 2000;90:1403– 8.
14. Oddens BJ. Contraceptive use and attitudes in Italy. Hum Reprod 1996; 11:533–9. 15. The ESHRE Capri Workshop Group. Social determinants of human reproduction. Hum Reprod, in press 2001. 16. Adami HO, Hsieh C-C, Lambe M, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet 1994;344:1250 – 4. 17. Casagrande JT, Louie EW, Pike MC, et al. Incessant ovulation and ovarian cancer. Lancet 1979;2:170 –3. 18. Helzsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995; 274:1926 –30. 19. La Vecchia C, Franceschi S, Gallus G, et al. Incessant ovulation and ovarian cancer: A critical approach. Int J Epidemiol 1983;12:161– 4. 20. Tavani A, Negri E, Franceschi S, Parazzini F, La Vecchia C. Risk factors for epithelial ovarian cancer in women under age 45. Eur J Cancer 1993;29A:1297–301. 21. Bruzzi P, Negri E, La Vecchia C, et al. Short term increase in risk of breast cancer after full term pregnancy. BMJ 1988;297:1096 – 8. 22. Moolgavkar SH, Day NE, Stevens RG. Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J Natl Cancer Inst 1980; 65:559 – 69. 23. Pike MC. Age-related factors in cancers of the breast, ovary, and endometrium. J Chron Dis 1987;40:59 – 69S.
Time since Last Birth and the Risk of Ovarian Cancer Francesca Chiaffarino,* Fabio Parazzini,* ,† Eva Negri,* Guido Benzi,† Giovanna Scarfone,† Silvia Franceschi,‡ and Carlo La Vecchia* ,§ *Istituto di Ricerche Farmacologiche “Mario Negri,” 20157 Milano, Italy; †Prima Clinica Ostetrico Ginecologica, Universita` degli Studi di Milano, 20129 Milano, Italy; ‡International Agency for Research on Cancer, 69372 Lyon, France; and §Istituto di Statistica Medica e Biometria, Universita` degli Studi di Milano, 20133 Milano, Italy Received October 6, 2000
has been suggested that the high levels of progesterone characterizing pregnancy may induce apoptosis in ovarian carcinoma cell lines [7], and apoptosis has been shown to prevent development of several types of cancer in rodents [8 –9]. However, the role of time since last birth is far from being established and quantified. We analyzed data from a large case– control study conducted in northern Italy, focusing our attention on the role of pregnancy timing on the risk of ovarian cancer.
Objectives. While parity is a protective factor in ovarian cancer, the role of time factors of pregnancy and birth is still controversial. We considered therefore the role of birth timing in the risk in ovarian cancer from a large case– control study. Methods. Cases were 971 women (age range 22–74 years, median age 54) with histologically confirmed, incident epithelial ovarian cancer, interviewed between 1983 and 1991 in a network of hospitals in Milan, Italy. Controls were 2758 women (age range 23–74 years, median age 52) admitted to the same hospitals where cases were identified for acute, nonneoplastic conditions. Results. In comparison with nulliparous women, the multivariate odds ratios (OR) were 0.8 for women reporting one or two and 0.6 for those with three or more births. No clear association emerged between time since last birth and ovarian cancer. Compared to women who had last given birth since >20 years, a moderately increased risk of ovarian cancer was observed in the first 10 years after last birth, with an OR of 1.7 (95% confidence interval, CI 1.0 –2.9). When we considered only multiparous women and included in the multivariate analysis allowance for age at first birth, the OR decreased to 1.2 (95% CI 0.6 –2.4). No consistent pattern of trends was observed >10 years since last pregnancy. Conclusions. This study confirms the protective effect of parity on ovarian carcinogenesis, but shows no consistent pattern of risk across time since last birth. © 2001 Academic Press
MATERIALS AND METHODS
INTRODUCTION
Between 1983 and 1991, we conducted a case– control study of ovarian cancer [10]. Data were collected in the major teaching and general hospitals in the greater Milan area. Cases were 971 women (age range 22–74 years, median age 54) with histologically confirmed epithelial ovarian cancer, diagnosed within 1 year before the interview. Control subjects were 2758 women (age range 23–74 years, median age 52), admitted to the same hospitals where cases were identified, for acute conditions not related to gynecological, hormonal, or neoplastic diseases and who had not undergone bilateral oophorectomy. Of these, 34% had traumatic conditions (mostly fractures and sprains), 30% nontraumatic orthopedic disorders (mostly low back pain and disc disorders), 16% acute surgical conditions (mostly abdominal, such as acute appendicitis or strangulated hernia), and 20% miscellaneous other illnesses, such as eye, ear, nose and throat, and dental disorders. Approximately 4% of cases and controls approached refused the interview. The questionnaire included information on marital status, education, and other socioeconomic indicators, personal characteristics and habits, such as smoking, alcohol use, and coffee drinking, anthropometric variables, diet, menstrual and reproductive factors (such as age at menarche, menstrual cycles, number of abortions and births, and age at first and last birth), selected medical conditions, and lifelong history of use of oral contraceptives and hormone replacement therapy. Odds ratios (OR) of ovarian cancer and the corresponding 95% confidence intervals (CI) were derived using uncondi-
The protective role of parity on the risk of epithelial ovarian cancer is well recognized [1– 4]. However, some aspects of the role of parity in ovarian cancer epidemiology are still unclear. In particular, the role of time since last birth remains controversial. A cohort study of Norwegian women [5] and a pooled analysis of data from four case– control studies from the United States [6] showed an increased risk of epithelial ovarian cancer with increasing time since last birth which, however, tended to level off for multiparous women. In order to explain these findings, an effect of pregnancy on the late stage of the process of ovarian carcinogenesis has been postulated. In particular, it 233
0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
234
CHIAFFARINO ET AL.
TABLE 1 Distribution of 971 Cases of Ovarian Cancer and 2758 Controls a According to Age and Selected Variables and Corresponding Odds Ratios (OR) and 95% Confidence Intervals (CI), Milan, Italy, 1983–1991 Cases
Age (years) ⱕ35 36–45 46–55 56–65 ⱖ66 Education (years) ⬍7 7–11 ⱕ12 2 Number of births 0 1 2 ⱖ3 2 Oral contraceptive use Never Ever
Controls OR (95% CI) b
No.
%
No.
%
84 144 312 299 132
8.7 14.8 32.1 30.8 13.6
284 513 746 741 474
10.3 18.6 27.1 26.9 17.2
560 233 178
57.7 24.0 18.3
1593 686 179
57.8 24.9 17.4
1c 1.1 (0.9–1.4) 1.2 (1.0–1.5) 3.1, P⫽0.08
237 204 304 226
24.4 21.0 31.3 23.3
590 660 842 666
21.4 23.9 30.5 24.2
1c 0.8 (0.7–1.0) 0.8 (0.7–1.1) 0.6 (0.5–0.8) 10.7, P⫽0.001
908 63
93.5 6.5
2499 259
90.6 9.4
1c 0.8 (0.6–1.1)
a
In some cases the sum does not add up to the total because of missing values. b Multiple logistic regression estimates including terms for age and area of residence. c Reference category.
tional multiple logistic regression models, fitted by the method of maximum likelihood [11]. All regression equations included terms for age, area of residence, parity, and, when specified, age at first birth. RESULTS Table 1 shows the distribution of cases and control according to age, education, and parity. In comparison with women reporting less than 7 years of education, the OR was 1.2 (95% CI 1.0 –1.5) for those reporting 12 years or more. Ovarian cancer risk was inversely associated with number of births. In comparison with nulliparous women, the ORs were 0.8 for women reporting one or two, and 0.6 for those with three or more births. Table 2 considers the relation between time since last birth and ovarian cancer. No clear relation emerged with time since last birth. When we included all parous women, compared with women who had last given birth since ⱖ20 years, an increased risk of ovarian cancer was reported in the first 10 years after last birth, with an OR of 1.7 (95% CI 1.0 –2.9). When we considered only multiparous women (i.e., women reporting
two or more births) and included in the multivariate analysis allowance for age at first birth, the OR decreased, however, to 1.2 (95% CI 0.6 –2.4). No consistent pattern of risk was observed ⱖ10 years since last pregnancy. Further allowance for age at last birth among multiparous women led to ORs of 1.4 (95% CI 0.6 –3.1) for 9 years or less, 0.9 (95% CI 0.5–1.5) for 10 –14 years, and 1.1 (95% CI 0.7–1.6) for 15–19 years since last birth when compared with women who had last given birth since ⱖ20 years. However, inclusion of an additional term of age at last birth introduced a substantial collinearity, making the estimates difficult to interpret. The increased risk in the first years after last birth was apparently stronger at younger ages, but the ORs remained above unity in women aged ⱖ40 years. Likewise, the ORs in the 10 years since last birth were above unity across strata of parity (Table 3). DISCUSSION This study confirms the well-established protective effect of parity on ovarian carcinogenesis, but shows no consistent pattern of risk across time since last birth. This was a hospital-based study, with the related weaknesses and strengths. In particular, hospital controls are preferable for analysis of parity-related factors, particularly in the few years after birth, since women with small children may selectively TABLE 2 Distribution of 971 Cases of Ovarian Cancer and 2578 Controls a According to Time since Last Birth and Corresponding Odds Ratios (OR) and 95% Confidence Intervals (CI), Milan, Italy, 1983–1991 Cases No. Time since last birth (among all parous women) b ⱕ9 10–14 15–19 ⱖ20 Time since last birth (among multiparous women) c ⱕ9 10–14 15–19 ⱖ20
%
Controls No.
%
OR (95% CI)
76 10.4 215 9.9 68 9.3 263 12.2 122 16.7 378 17.5 465 63.6 1306 60.4
1.7 (1.0–2.9) 0.9 (0.6–1.4) 1.1 (0.8–1.4) 1d
49 9.3 53 10.1 98 18.6 327 62.1
1.2 (0.6–2.4) 0.8 (0.5–1.2) 1.0 (0.7–1.4) 1d
138 9.2 202 13.5 294 19.6 868 57.8
a In some cases the sum does not add up to the total because of missing values. b Multiple logistic regression estimates including terms for age, area of residence, and parity. c Multiple logistic regression estimates including terms for age, area of residence, parity, and age at first birth. d Reference category.
235
TIME SINCE LAST BIRTH AND THE RISK OF OVARIAN CANCER
TABLE 3 Odds Ratios (OR) and 95% Confidence Intervals (CI) of Ovarian Cancer According to Time since Last Birth and Parity, in Separate Strata of Age, Milan, Italy, 1983–1991 Time since last birth (years) a
Age (years) ⱕ40 41–55 Number of births 1 2 ⱖ3
⬍10 b
10–14 b
15–19 b
ⱖ20 b
1.7 (0.6–4.8) 1.4 (0.8–2.4)
1.0 (0.3–3.2) 0.9 (0.6–1.3)
1c 1.0 (0.7–1.4)
— 1c
1.4 (0.6–3.1) 1.4 (0.7–2.9) 1.4 (0.6–3.4)
0.9 (0.4–1.9) 0.9 (0.5–1.7) 0.8 (0.4–1.4)
0.9 (0.5–1.6) 1.1 (0.7–1.6) 1.1 (0.7–1.8)
1c 1c 1c
a
Nulliparae excluded. Multiple logistic regression estimates including terms for age, area of residence, and parity. c Reference category. b
participate in (or be excluded from) population-based studies [12]. Our control group, moreover, was broadly comparable with the northern Italian population with reference to fertility pattern and oral contraceptive use [12–15]. With further reference to selection bias, the catchment areas of cases and controls were comparable. With regard to confounding, simultaneous allowance for several confounding factors did not materially modify any of the risk estimates. Available evidence on the role of birth recency on ovarian cancer risk is scant. In a cohort study conducted in Norway based on 1694 women with epithelial ovarian cancer [5], the risk was about 30% higher in women reporting their last birth 20 or more years before diagnosis, in comparison with those reporting their last birth 10 to 14 years before. This pattern of risk was present among uniparous women but tended to disappear with higher order pregnancies. In a model including nulliparous women in the analyses and additional terms of age at first and last birth and time since last birth, no consistent pattern of trend was observed with time since last birth (OR ⫽ 0.94). In a reanalysis of four North American case– control studies including 807 cases and 3958 controls [6], the OR of ovarian cancer was about twofold higher in parous women reporting their last birth ⬎25 years before diagnosis in comparison with those reporting their last birth less than 10 years before. Moreover, in a Swedish cohort study [16], the risk of ovarian cancer was reduced soon after birth, and the protection seemed to decline with time since delivery. Two main hypotheses have been proposed to explain the role of reproductive factors on ovarian carcinogenesis: the incessant ovulation [17] and the gonadotropin hypotheses [18]. However, the potential role of pregnancy recency cannot be totally explained by ovulation or ovulatory years [19]. Our results did not confirm the presence of a short-term effect of parity on ovarian cancer risk, and they indicate that the protection of pregnancy and birth on ovarian carcinogen-
esis is long lasting. A preliminary analysis of this case– control study, limited to 123 cases and 252 controls below the age of 45 [20], also showed an increased risk in the few years after birth. For breast cancer, pregnancy confers a transient increase in risk followed by a long-term protection [21], and Moolgavkar et al. [22] proposed a two-stage model of breast carcinogenesis, where pregnancy acts as an anti-initiator, as well as a promoter. Although breast and ovarian carcinogenesis share some common aspects [23], the role of pregnancy recency and in particular that of time since last birth in ovarian carcinogenesis remains controversial, nonetheless, in several aspects.
ACKNOWLEDGMENTS This work was conducted with the contribution of the Italian Association for Cancer Research, Milan. The authors thank Mrs. Ivana Garimoldi for editorial assistance.
REFERENCES 1. Parazzini F, Franceschi S, La Vecchia C, Fasoli M. The epidemiology of ovarian cancer. Gynecol Oncol 1991;43:9 –23. 2. Negri E, Franceschi S, Tzonou A, et al. Pooled analysis of 3 European case– control studies: I. Reproductive factors and risk of epithelial ovarian cancer. Int J Cancer 1991;49:50 – 6. 3. Whittemore AS, Harris R, Itnyre J, and the Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: Collaborative Analysis of 12 US case– control studies. II. Invasive Epithelial ovarian cancer in white women. Am J Epidemiol 1992;136:1184 –203. 4. Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 1994;140:585–97. 5. 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.
236
CHIAFFARINO ET AL.
6. Cooper GS, Schildkraut JM, Whittemore AS, Marchbanks PA. Pregnancy recency and risk of ovarian cancer. Cancer Causes Control 1999;10:397– 402. 7. 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. 8. Chan LN, Zhang S, Cloyd M, Chan TS. N-(4-Hydroxyphenyl) retinamide prevents development of T-lymphomas in AKR/J mice. Anticancer Res 1997;17:499 –503. 9. Inada T, Ichikawa A, Kubota T, Ogata Y, Moossa A, Hoffman RM. 5-FU-induced apoptosis correlates with efficacy against human gastric and colon cancer xenografits in nude mice. Anticancer Res 1997;17:1965–71. 10. Parazzini F, Negri E, La Vecchia C, Restelli C, Franceschi S. Family history of reproductive cancers and ovarian cancer risk: An Italian case– control study. Am J Epidemiol 1992;135:35– 40. 11. Breslow NE, Day NE. Statistical methods in cancer research. Vol. I. The analysis of case– control studies. IARC Scientific Publications No. 32. International Agency for Research on Cancer, Lyon, France, 1980. 12. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Hormonal contraception and post-menopausal hormonal therapy, Lyon, IARC, Vol. 72, 1999. 13. Spinelli A, Figa`-Talamanca I, Lauria L, European Study Group on Infertility and Subfecundity. Patterns of contraceptive use in 5 European countries. Am J Public Health 2000;90:1403– 8.
14. Oddens BJ. Contraceptive use and attitudes in Italy. Hum Reprod 1996; 11:533–9. 15. The ESHRE Capri Workshop Group. Social determinants of human reproduction. Hum Reprod, in press 2001. 16. Adami HO, Hsieh C-C, Lambe M, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet 1994;344:1250 – 4. 17. Casagrande JT, Louie EW, Pike MC, et al. Incessant ovulation and ovarian cancer. Lancet 1979;2:170 –3. 18. Helzsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995; 274:1926 –30. 19. La Vecchia C, Franceschi S, Gallus G, et al. Incessant ovulation and ovarian cancer: A critical approach. Int J Epidemiol 1983;12:161– 4. 20. Tavani A, Negri E, Franceschi S, Parazzini F, La Vecchia C. Risk factors for epithelial ovarian cancer in women under age 45. Eur J Cancer 1993;29A:1297–301. 21. Bruzzi P, Negri E, La Vecchia C, et al. Short term increase in risk of breast cancer after full term pregnancy. BMJ 1988;297:1096 – 8. 22. Moolgavkar SH, Day NE, Stevens RG. Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J Natl Cancer Inst 1980; 65:559 – 69. 23. Pike MC. Age-related factors in cancers of the breast, ovary, and endometrium. J Chron Dis 1987;40:59 – 69S.