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Treatment for Fertility and Risk of Ovarian Tumors of Borderline Malignancy
GYNECOLOGIC ONCOLOGY ARTICLE NO.
68, 226 –228 (1998)
GO974928
Treatment for Fertility and Risk of Ovarian Tumors of Borderline Malignancy Fabio Parazzini,*,† Eva Negri,* Carlo La Vecchia,*,‡ Simona Moroni,† Anna Polatti,† Francesca Chiaffarino,* Matteo Surace,* and Elena Ricci* *Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ via Eritrea 62, 20157 Milano, Italy; †Prima Clinica Ostetrico Ginecologica, Universita` di Milano, via Commenda 12, 20122 Milano, Italy; and ‡Istituto di Statistica Medica e Biometria, Universita` di Milano, via Venezian 1, 20133 Milano, Italy Received July 22, 1997
tility drugs and risk of borderline ovarian tumor using data from a case– control study conducted in Italy between 1986 and 1991 [10].
The relationship between fertility drug use and risk of borderline ovarian cancer has been analyzed using data from a case– control study. Cases were 93 women aged 23 to 64 years with histologically confirmed diagnosis of borderline ovarian tumor (according to the World Health Organization criteria) who were admitted to the Obstetrics and Gynecology Clinics of the University of Milan. Control subjects were 273 women (ages 24 – 64 years) admitted for acute nongynecological, nonhormonal, and nonneoplastic conditions. Four cases (4.3%) and no control reported fertility drugs use: this difference was statistically significant (Fisher’s exact test P 5 0.004). © 1998 Academic Press
MATERIALS AND METHODS
INTRODUCTION
The cases were 93 women ages 23 to 64 years with histologically confirmed borderline ovarian tumors (according to [11]) who were admitted to the Obstetrics and Gynecology Clinics of the University of Milan. The control subjects were 273 women (ages 24 – 64 years) admitted for acute nongynecological, nonhormonal, and nonneoplastic conditions to the Ospedale Maggiore (including the four major teaching and general hospitals in Milan) and several specialized university clinics, serving a catchment area comparable to that of the hospitals where the cases had been identified. Of these, 30% were admitted for traumatic conditions (mostly fractures and sprains), 28% had nontraumatic orthopedic disorders (mostly low back pain and disk disorders), 17% acute abdominal diseases generally requiring surgery, and 25% other miscellaneous illnesses, such as disorders of the ear, nose, throat, or teeth. They were recruited within the framework of a case– control surveillance of female genital tract neoplasms [12]. Less than 2% of cases and controls refused to be interviewed. Information was obtained on general characteristics, gynecological and obstetric data, and infertility-related variables, including use of fertility drugs. Information on the type of fertility drugs was not available. A history of difficulty in conception was defined as an unsuccessful active effort at pregnancy for . 2 years. Cases considered in this report were not included in previous papers on the relationship between fertility drugs and risk of invasive epithelial ovarian cancer [7–9]. Odds ratios (OR), together with the corresponding 95% confidence intervals (CI), were computed using unconditional multiple logistic regression, fitted by the method of maximum likelihood [13]. Included in the regression equations were terms for age, education, parity, and oral contraceptive use.
The potential association between the use of fertility drugs and the risk of invasive ovarian neoplasm has become a topic of considerable scientific and public health interest. At least four cohort studies [1– 4] and several case– control studies on ovarian cancer from the United States and Italy have analyzed the relationship [5–9]. The results are controversial: two cohort studies [1, 4] and two Italian case– control studies [7–9] found no association and the others showed a positive relationship. A pooled analysis of the American case– control study [6] and a cohort of American infertile women [3] presented separately information regarding invasive and borderline ovarian cancers: in both studies the association between fertility drugs and ovarian neoplasms tended to be stronger for borderline conditions. The pooled analysis of American case– control studies showed that the risk of epithelial ovarian tumors of low malignant potential among women who had used fertility drugs was about fourfold higher than that of women with no history of fertility drug use or infertility [6]. In the American cohort study of infertile women the age-standardized incidence ratio of borderline ovarian tumor was 2.5 in women who used fertility drugs [3], although expected numbers of cases are subjected to ascertainment and certification bias for borderline neoplasms. In this paper we considered the relationship between fer0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
226
FERTILITY DRUGS AND BORDERLINE OVARIAN TUMORS
TABLE 1 Distribution of 93 Cases of Borderline Ovarian Cancer and 273 Controls According to Selected Characteristics, Milan, Italy 1986 –1991
Age (years) ,30 30–39 40–49 50–59 60–64 Education (years) #6 7–11 $12 Parity 0 1–2 $3 Oral contraceptive use Never used Ever used Difficulty in conception Noc Yes Fertility drugs use Never usedd Ever used
No. of cases (%)
No. of controls (%)
OR (95% CI)a
32 (34.4) 16 (17.2) 12 (12.9) 20 (21.5) 13 (14.0)
86 (31.5) 55 (20.1) 36 (13.2) 57 (20.9) 39 (14.3)
— — — — —
33 (35.5) 28 (30.1) 32 (34.4)
102 (37.4) 92 (33.7) 79 (28.9)
1b 1.0 (0.5–2.0) 1.3 (0.6–2.6)
37 (39.8) 44 (47.3) 12 (12.9)
101 (37.0) 118 (43.2) 54 (19.8)
1b 1.2 (0.6–2.3) 0.6 (0.2–1.5)
84 (90.3) 9 (9.7)
205 (74.7) 68 (25.3)
1b 0.3 (0.1–0.6)
90 (96.8) 3 (3.2)
273 (100.0) 0 (—)
89 (95.7) 4 (4.3)
273 (100.0) 0 (—)
a OR, odds ratio; CI, confidence interval. Multivariate estimates including terms for age, education, parity, and oral contraceptive use. b Reference category. c Fisher’s exact test: P 5 0.002. d Fisher’s exact test: P 5 0.004.
227
controls were identified in institutions covering comparable catchment areas, and participation was almost complete. Our interviewers were not blind to the case– control status, but they were not aware of the specific endpoints of this analysis. Cases may be more sensitized than controls in reporting fertility drugs. However, the use of drugs for infertility was collected in standard format for cases and controls. With regard to selective mechanisms, infertility has been associated with the risk of ovarian cancer [12, 13]. In consideration of the low number of subjects using infertility drugs, we were unable to consider potential bias. Likewise, although previous studies have suggested that the association between fertility drug use and risk of ovarian neoplasia may vary by parity status, the small numbers of users do not provide the opportunity of analyzing the potential interaction between parity and fertility drug use on the risk of borderline ovarian cancer. Although the results of this study are consistent with previous findings on the issue, caution is still required in the interpretation of the association between fertility drug use and risk of borderline tumors. First, considering together the present study and the two above-mentioned investigations [3, 6], only 11 cases of borderline ovarian cancer cases who used fertility drug have been reported. Further, no information on the type of drugs used was available for the present study, or for the pooled analysis of American case– control studies [6]. In biological terms, the elevated risk of ovarian borderline tumor in women using fertility drugs is consistent with the ‘‘incessant ovulation’’ hypothesis in ovarian carcinogenesis [14]. Otherwise, it is also consistent with the hypothesis that a high level of gonodotrophins may be implicated in the development of ovarian neoplasias. ACKNOWLEDGMENTS
RESULTS The distribution of cases and controls according to age, selected factors, and fertility drugs use are presented in Table 1. The cases were less frequently oral contraceptive users. No clear association emerged between education, parity, and risk of borderline ovarian cancer. Three cases and no control reported a history of difficulties in conception (Fisher’s exact test P value 5 0.004). Four cases (4.3%) and no control reported fertility drug use. This difference was of statistical significance, the Fisher’s exact test P value being 0.004. Of the four cases reporting fertility drug use, two were nulliparous and two reported a clinical history of difficulties in conception. COMMENTS The results of the study give some support to a potential association between fertility drugs and risk of borderline ovarian tumors. In relation to potential sources of bias, selection should not markedly influence the findings, since cases and
This study was conducted within the framework of the Italian National Research Council (CNR) Applied Projects ‘‘Risk Factors for Disease’’ (Contract 95.00952.PF41), and ‘‘Clinical Applications of Oncological Research’’ (Contract 95.00562.PF39), and with the contribution of the Italian Association for Cancer Research, Milan. The authors thank Marina Parazzini, Sc.D., for help in data management and Mrs. J. Baggott and Mrs. Ivana Garimoldi for editorial assistance.
REFERENCES 1. Brinton LA, Melton LJ, Malkasian GD, Bond A, Hoover R: Cancer risk after evaluation for infertility. Am J Epidemiol 129:712–722, 1989 2. Ron E, Lunenfeld B, Menczer J, Blumsteim T, Katz L, Oelsner G, Serr D: Cancer incidence in a cohort of infertile women. Am J Epidemiol 125: 780 –790, 1987 3. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG: Ovarian tumors in a cohort of infertile women. N Engl J Med 331:771–776, 1994 4. Venn A, Watson L, Lumley J, Giles G, King C, Healy D: Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 346:995–1000, 1995 5. Whittemore AS, Harris R, Intyre J: The Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative anal-
228
6.
7.
8. 9.
PARAZZINI ET AL.
ysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 136:1184 –1203, 1992 Harris R, Whittemore AS, Intyre J: Collaborative Ovarian Cancer Group: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case– control studies. Am J Epidemiol 136:1204 –1211, 1992 Franceschi S, La Vecchia C, Negri E, Guarneri S, Montella M, Conti E, Parazzini F: Fertility drugs and risk of epithelial ovarian cancer in Italy. Hum Reprod 9:1673–1675, 1994 La Vecchia C, Negri E, Parazzini F, Franceschi S: Fertility drugs and breast and ovarian cancer. Lancet 346:1628, 1995 Parazzini F, Negri E, La Vecchia C, Moroni S, Franceschi S, Crosignani PG: Treatment for infertility and risk of invasive epithelial ovarian cancer. Hum Reprod 12:2159 –2161, 1997
10. Parazzini F, Restelli C, La Vecchia C, Negri E, Chiari S, Maggi R, Mangioni C: Risk factors for epithelial ovarian tumours of borderline malignancy. Int J Epidemiol 20:871– 877, 1991 11. Serov SF, Scully RE, Sobin I: International Histologic Classification of Tumours. No. 9: Histological Typing of Ovarian Tumors. Geneva: WHO, 1973 12. 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 135:35– 40, 1992 13. Baker RJ, Nelder JA: The GLIM System. Release 3. Oxford: Numerical Algorithms Group, 1978 14. Parazzini F, Franceschi S, La Vecchia C, Fasoli M: The epidemiology of ovarian cancer. Gynecol Oncol 43:9 –23, 1991
68, 226 –228 (1998)
GO974928
Treatment for Fertility and Risk of Ovarian Tumors of Borderline Malignancy Fabio Parazzini,*,† Eva Negri,* Carlo La Vecchia,*,‡ Simona Moroni,† Anna Polatti,† Francesca Chiaffarino,* Matteo Surace,* and Elena Ricci* *Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ via Eritrea 62, 20157 Milano, Italy; †Prima Clinica Ostetrico Ginecologica, Universita` di Milano, via Commenda 12, 20122 Milano, Italy; and ‡Istituto di Statistica Medica e Biometria, Universita` di Milano, via Venezian 1, 20133 Milano, Italy Received July 22, 1997
tility drugs and risk of borderline ovarian tumor using data from a case– control study conducted in Italy between 1986 and 1991 [10].
The relationship between fertility drug use and risk of borderline ovarian cancer has been analyzed using data from a case– control study. Cases were 93 women aged 23 to 64 years with histologically confirmed diagnosis of borderline ovarian tumor (according to the World Health Organization criteria) who were admitted to the Obstetrics and Gynecology Clinics of the University of Milan. Control subjects were 273 women (ages 24 – 64 years) admitted for acute nongynecological, nonhormonal, and nonneoplastic conditions. Four cases (4.3%) and no control reported fertility drugs use: this difference was statistically significant (Fisher’s exact test P 5 0.004). © 1998 Academic Press
MATERIALS AND METHODS
INTRODUCTION
The cases were 93 women ages 23 to 64 years with histologically confirmed borderline ovarian tumors (according to [11]) who were admitted to the Obstetrics and Gynecology Clinics of the University of Milan. The control subjects were 273 women (ages 24 – 64 years) admitted for acute nongynecological, nonhormonal, and nonneoplastic conditions to the Ospedale Maggiore (including the four major teaching and general hospitals in Milan) and several specialized university clinics, serving a catchment area comparable to that of the hospitals where the cases had been identified. Of these, 30% were admitted for traumatic conditions (mostly fractures and sprains), 28% had nontraumatic orthopedic disorders (mostly low back pain and disk disorders), 17% acute abdominal diseases generally requiring surgery, and 25% other miscellaneous illnesses, such as disorders of the ear, nose, throat, or teeth. They were recruited within the framework of a case– control surveillance of female genital tract neoplasms [12]. Less than 2% of cases and controls refused to be interviewed. Information was obtained on general characteristics, gynecological and obstetric data, and infertility-related variables, including use of fertility drugs. Information on the type of fertility drugs was not available. A history of difficulty in conception was defined as an unsuccessful active effort at pregnancy for . 2 years. Cases considered in this report were not included in previous papers on the relationship between fertility drugs and risk of invasive epithelial ovarian cancer [7–9]. Odds ratios (OR), together with the corresponding 95% confidence intervals (CI), were computed using unconditional multiple logistic regression, fitted by the method of maximum likelihood [13]. Included in the regression equations were terms for age, education, parity, and oral contraceptive use.
The potential association between the use of fertility drugs and the risk of invasive ovarian neoplasm has become a topic of considerable scientific and public health interest. At least four cohort studies [1– 4] and several case– control studies on ovarian cancer from the United States and Italy have analyzed the relationship [5–9]. The results are controversial: two cohort studies [1, 4] and two Italian case– control studies [7–9] found no association and the others showed a positive relationship. A pooled analysis of the American case– control study [6] and a cohort of American infertile women [3] presented separately information regarding invasive and borderline ovarian cancers: in both studies the association between fertility drugs and ovarian neoplasms tended to be stronger for borderline conditions. The pooled analysis of American case– control studies showed that the risk of epithelial ovarian tumors of low malignant potential among women who had used fertility drugs was about fourfold higher than that of women with no history of fertility drug use or infertility [6]. In the American cohort study of infertile women the age-standardized incidence ratio of borderline ovarian tumor was 2.5 in women who used fertility drugs [3], although expected numbers of cases are subjected to ascertainment and certification bias for borderline neoplasms. In this paper we considered the relationship between fer0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
226
FERTILITY DRUGS AND BORDERLINE OVARIAN TUMORS
TABLE 1 Distribution of 93 Cases of Borderline Ovarian Cancer and 273 Controls According to Selected Characteristics, Milan, Italy 1986 –1991
Age (years) ,30 30–39 40–49 50–59 60–64 Education (years) #6 7–11 $12 Parity 0 1–2 $3 Oral contraceptive use Never used Ever used Difficulty in conception Noc Yes Fertility drugs use Never usedd Ever used
No. of cases (%)
No. of controls (%)
OR (95% CI)a
32 (34.4) 16 (17.2) 12 (12.9) 20 (21.5) 13 (14.0)
86 (31.5) 55 (20.1) 36 (13.2) 57 (20.9) 39 (14.3)
— — — — —
33 (35.5) 28 (30.1) 32 (34.4)
102 (37.4) 92 (33.7) 79 (28.9)
1b 1.0 (0.5–2.0) 1.3 (0.6–2.6)
37 (39.8) 44 (47.3) 12 (12.9)
101 (37.0) 118 (43.2) 54 (19.8)
1b 1.2 (0.6–2.3) 0.6 (0.2–1.5)
84 (90.3) 9 (9.7)
205 (74.7) 68 (25.3)
1b 0.3 (0.1–0.6)
90 (96.8) 3 (3.2)
273 (100.0) 0 (—)
89 (95.7) 4 (4.3)
273 (100.0) 0 (—)
a OR, odds ratio; CI, confidence interval. Multivariate estimates including terms for age, education, parity, and oral contraceptive use. b Reference category. c Fisher’s exact test: P 5 0.002. d Fisher’s exact test: P 5 0.004.
227
controls were identified in institutions covering comparable catchment areas, and participation was almost complete. Our interviewers were not blind to the case– control status, but they were not aware of the specific endpoints of this analysis. Cases may be more sensitized than controls in reporting fertility drugs. However, the use of drugs for infertility was collected in standard format for cases and controls. With regard to selective mechanisms, infertility has been associated with the risk of ovarian cancer [12, 13]. In consideration of the low number of subjects using infertility drugs, we were unable to consider potential bias. Likewise, although previous studies have suggested that the association between fertility drug use and risk of ovarian neoplasia may vary by parity status, the small numbers of users do not provide the opportunity of analyzing the potential interaction between parity and fertility drug use on the risk of borderline ovarian cancer. Although the results of this study are consistent with previous findings on the issue, caution is still required in the interpretation of the association between fertility drug use and risk of borderline tumors. First, considering together the present study and the two above-mentioned investigations [3, 6], only 11 cases of borderline ovarian cancer cases who used fertility drug have been reported. Further, no information on the type of drugs used was available for the present study, or for the pooled analysis of American case– control studies [6]. In biological terms, the elevated risk of ovarian borderline tumor in women using fertility drugs is consistent with the ‘‘incessant ovulation’’ hypothesis in ovarian carcinogenesis [14]. Otherwise, it is also consistent with the hypothesis that a high level of gonodotrophins may be implicated in the development of ovarian neoplasias. ACKNOWLEDGMENTS
RESULTS The distribution of cases and controls according to age, selected factors, and fertility drugs use are presented in Table 1. The cases were less frequently oral contraceptive users. No clear association emerged between education, parity, and risk of borderline ovarian cancer. Three cases and no control reported a history of difficulties in conception (Fisher’s exact test P value 5 0.004). Four cases (4.3%) and no control reported fertility drug use. This difference was of statistical significance, the Fisher’s exact test P value being 0.004. Of the four cases reporting fertility drug use, two were nulliparous and two reported a clinical history of difficulties in conception. COMMENTS The results of the study give some support to a potential association between fertility drugs and risk of borderline ovarian tumors. In relation to potential sources of bias, selection should not markedly influence the findings, since cases and
This study was conducted within the framework of the Italian National Research Council (CNR) Applied Projects ‘‘Risk Factors for Disease’’ (Contract 95.00952.PF41), and ‘‘Clinical Applications of Oncological Research’’ (Contract 95.00562.PF39), and with the contribution of the Italian Association for Cancer Research, Milan. The authors thank Marina Parazzini, Sc.D., for help in data management and Mrs. J. Baggott and Mrs. Ivana Garimoldi for editorial assistance.
REFERENCES 1. Brinton LA, Melton LJ, Malkasian GD, Bond A, Hoover R: Cancer risk after evaluation for infertility. Am J Epidemiol 129:712–722, 1989 2. Ron E, Lunenfeld B, Menczer J, Blumsteim T, Katz L, Oelsner G, Serr D: Cancer incidence in a cohort of infertile women. Am J Epidemiol 125: 780 –790, 1987 3. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG: Ovarian tumors in a cohort of infertile women. N Engl J Med 331:771–776, 1994 4. Venn A, Watson L, Lumley J, Giles G, King C, Healy D: Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 346:995–1000, 1995 5. Whittemore AS, Harris R, Intyre J: The Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative anal-
228
6.
7.
8. 9.
PARAZZINI ET AL.
ysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 136:1184 –1203, 1992 Harris R, Whittemore AS, Intyre J: Collaborative Ovarian Cancer Group: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case– control studies. Am J Epidemiol 136:1204 –1211, 1992 Franceschi S, La Vecchia C, Negri E, Guarneri S, Montella M, Conti E, Parazzini F: Fertility drugs and risk of epithelial ovarian cancer in Italy. Hum Reprod 9:1673–1675, 1994 La Vecchia C, Negri E, Parazzini F, Franceschi S: Fertility drugs and breast and ovarian cancer. Lancet 346:1628, 1995 Parazzini F, Negri E, La Vecchia C, Moroni S, Franceschi S, Crosignani PG: Treatment for infertility and risk of invasive epithelial ovarian cancer. Hum Reprod 12:2159 –2161, 1997
10. Parazzini F, Restelli C, La Vecchia C, Negri E, Chiari S, Maggi R, Mangioni C: Risk factors for epithelial ovarian tumours of borderline malignancy. Int J Epidemiol 20:871– 877, 1991 11. Serov SF, Scully RE, Sobin I: International Histologic Classification of Tumours. No. 9: Histological Typing of Ovarian Tumors. Geneva: WHO, 1973 12. 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 135:35– 40, 1992 13. Baker RJ, Nelder JA: The GLIM System. Release 3. Oxford: Numerical Algorithms Group, 1978 14. Parazzini F, Franceschi S, La Vecchia C, Fasoli M: The epidemiology of ovarian cancer. Gynecol Oncol 43:9 –23, 1991