Int. J . Cancer: 48, 816-820 (1991) 0 1991 Wiley-Liss, Inc.
Publication of the International Union Against Cancer Publication de I’Union lnternationale Contre le Cancer
SPONTANEOUS AND INDUCED ABORTIONS AND RISK OF BREAST CANCER Fabio PARAZZINI’,~, Car10 LA VECCHIA”~ and Eva NEGRI’ ‘Istituto di Ricerche Farmacologiche “Mario Negri” , 20157 Milan, Italy; and 21nstitute of Social and Preventive Medicine, University of Lausanne, 1005 Lausanne, Switzerland. The relationship between spontaneous or induced abortion and the risk of breast cancer was analyzed in a case-control study conducted in the greater Milan area on 2,394 cases of breast cancer and 2,218 controls in hospital for a spectrum of acute conditions, not gynecological, hormonal or neoplastic. No consistent relationship emerged between spontaneous or induced abortion and breast cancer: compared with women reporting no abortions (spontaneous or induced), the multivariate relative risk (RR) was I .O (95% confidence interval, CI, 0.9 to I.2) in those reporting one abortion and 0.9 (95% CI 0.7 to I .O) In those reporting two or more. This lack of association was consistent in strata of age and parity, including younger women. We further analyzed the risk of breast cancer associated with an abortion before and after full-term pregnancy. Compared with parous women reporting no induced or spontaneous abortions, those who had an abortion before their first full-term pregnancy had about a 20% higher risk of breast cancer. This finding, however, was not statistically significant (RR 1.2, 95% CI 0.9 to 1.7). No increased risk was observed in women who had had a first abortion after a fullterm pregnancy (RR 0.9, 95% CI 0.8 to 1.0). This study does not support the hypothesis that spontaneous or induced abortion appreciably influences subsequent breast-cancer risk.
breast cancer in the greater Milan area (La Vecchia et al., 1987). Trained interviewers identified and questioned women admitted for breast cancer and for a wide spectrum of other conditions to teaching and general hospitals in the area under surveillance. Overall participation rate was 97% for cases and 98% for controls. A standard questionnaire was used to obtain information on personal characteristics and habits, gynecological and obstetric data, related medical history, dietary habits and a detailed history of lifetime use of oral contraceptives and other female hormones. Information was specifically obtained on the number of births, miscarriages (defined as fetal loss before the 28th week of pregnancy) and induced abortions, and on the age at first and last pregnancy and birth. Study population The cases considered in this report were women below the age of 75, with histologically confirmed breast cancer diagnosed within the year before the interview (2,394 subjects, median age 52 years, range 23 to 74) who had been admitted to the National Cancer Institute and the Ospedale Maggiore (which includes the 4 largest teaching and general hospitals in Milan). Controls were women aged below 75 years admitted for acute conditions to the same network of hospitals where cases had been identified. Women were not included if they had been admitted for gynecological, hormonal or neoplastic disease. A total of 2,218 subjects (median age 53 years, range 22 to 74) were interviewed. Of these, 32% were admitted for traumatic conditions (mostly fractures and sprains), 27% had non-traumatic orthopedic disorders (mostly low back pain and disc disorders), 17% were admitted for acute surgical conditions (mostly abdominal, such as acute appendicitis or strangulated hernia) and 24% had other illnesses, such as ear, nose, throat or teeth disorders. Although cases and controls were not individually matched, their distribution according to 5-year age groups was comparable.
Several epidemiological findings have suggested that a term pregnancy, and its early occurrence in life, is a long-term protective factor against the risk of breast cancer (Kelsey, 1979). Its effect has been interpreted in terms of promotion of breast growth and induction of full cellular differentiation of the mammary gland in pregnant women (Russo et al., 1982). Epidemiological and biological evidence is more confused in relation to incomplete pregnancy. It has been suggested that abortion interrupts this process and can increase the susceptibility of the breast to potential carcinogenic factors, due to incomplete differentiation of the cells in the breast glands during the first trimester (Russo and Russo, 1980). This effect could be stronger before a full-term pregnancy (or in younger women) when the breast gland structures are less differenti- Data analysis ated. Odds ratios, as estimators of relative risks (RR) of breast Conflicting epidemiological evidence has been published on cancer, together with their 95% approximate confidence interthe relationship between breast cancer and spontaneous or in- vals (CI), were first computed from data stratified in 5-year duced abortion, showing positive (Valaoras et al., 1969; Lin et intervals of age by the Mantel-Haenszel (1959) procedure. al., 1970; Yuasa and MacMahon, 1970; Stavraky and Em- When a factor could be classified in more than 2 levels, the mons, 1974; Soini, 1977; Choi et al., 1978; Toti et al., 1980; significance of the linear trend was assessed by the test deKelsey et al., 1981; Pike et al., 1981; Brinton et al., 1983; scribed by Mantel (1963). RRs were then obtained after simulHirohata et al., 1985; Ewertz and Duffy, 1988; Rosenberg et taneous allowance for potential confounding effects of age, al., 1988; Howe et al., 1989; Hadjimichael et al., 1986), education, marital status, age at first birth, parity, age at inverse (Ravnihar et al., 1971; Paffenbarger et al., 1980; Ves- menarche, age at menopause, estrogen replacement therapy, sey et al., 1982; Lindefors Harris et al., 1989) or no relation- body mass index and, in turn, number of induced and spontaship (Salber et al., 1969; Helmrich et al., 1983). However, neous abortions (Baker and Nelder, 1978). some studies have shown an increased risk of breast cancer in women reporting spontaneous or induced abortion at a younger RESULTS age (Howe et al., 1989) or before first birth (Pike et al., 1981; Brinton et al., 1983; Hadjimichael et al., 1986). The distribution of cases and controls according to age and To provide further information on the issue, we examined the relationship between abortions and breast-cancer risk, using data from a large case-control study conducted in Northern ’To whom correspondence and reprint requests should be addressed, at Italy. Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy.
SUBJECTS AND METHODS
Since 1983 we have been conducting a case-control study of
Received: January 19, 1991 and in revised form April 15, 1991.
8 17
ABORTION A N D BREAST-CANCER RISK
selected co-variates (including the best recognized risk factors for breast cancer) is shown in Table I. Cases tended to be more educated, reported earlier age at menarche, later age at menopause and later age at first birth than controls. The relationship between spontaneous or induced abortions and the risk of breast cancer is shown in Table 11. No consistent association emerged: compared with women reporting no spontaneous or induced abortion, the multivariate RR for breast cancer was 1.O (95%CI 0.9.to 1.2) in those reporting 1 and 0.9 (95% CI 0.7 to 1.0) in those reporting 2 or more abortions. This was confirmed when the analysis was conducted in strata of age (Table 111) and parity (Table IV). No significant relationship emerged in women aged below 40 years. In this stratum, the estimated RR for breast cancer was 1.4 (95% CI 0.9 to 2.2) in women reporting spontaneous abortions compared with those who did not, but the risk did not increase with the number of spontaneous abortions (data not shown). Furthermore, the risk was below unity considering induced abortions (RR 3 1 induced abortions vs. no induced abortion 0.7,95%CI 0.5 to 1 . 1 ) and consequently, was 0.9 (95% CI 0.7 to 1.4) when induced and spontaneous abortions were considered together (Table 111). Similarly, no heterogeneity across strata of parity was evident (Table IV). The risk associated with the occurrence of first abortion before or after a full-term pregnancy is analyzed in Table V. Compared with parous women reporting no induced or spontaneous abortions, those who had at least one abortion before their first full-term pregnancy had about a 20% higher (not statistically significant) risk of breast cancer (multivariate RR 1.2, 95% CI 0.9 to 1.7), but no increase in risk was observed in women who had their first abortion after a full-term pregnancy (RR 0.9, 95% CI 0.8 to 1.0). No significant heterogeneity, however, was observed across these exposure catego-
ries, or when the analysis was performed considering spontaneous and induced abortions separately. DISCUSSION
The general findings of our study show that spontaneous or induced abortions do not materially affect the risk of breast cancer; the point estimate for 2 or more abortions was 0.9, with an upper confidence limit of 1.O. Parous women reporting at least 1 spontaneous or induced abortion before their first fullterm pregnancy had about a 20%higher risk of the disease, but this finding was not significant. Likewise, no relationship emerged in young women. It is unlikely that the present results were severely affected by bias, since cases and controls were identified in hospitals covering a comparable catchment area, and response rate was almost complete. In relation to recall bias, it is conceivable that healthy control subjects may tend to under-report legally induced abortions more frequently than do cases. However, we included in our comparison groups only hospitalized women, who were interviewed in a condition comparable with cases, and no difference in RR estimates was found when an exploratory analysis was performed considering separately the different main diagnostic groups of controls. Furthermore, no differences in the estimated RR emerged between spontaneous and induced abortions. Thus, it is unlikely that the case or control status influenced reporting of spontaneous or induced abortions. In relation to confounding, allowance for major potential distorting factors (including indicators of socioeconomic status and the best recognized risk factors for breast cancer) did not materially modify any of the estimated relative risks. Finally, the major strength of this study is the large sample, with consequent narrow confidence interval of the estimates.
TABLE I - DISTRIBUTION OF 2,394' CASES OF BREAST CANCER AND 2,218 CONTROLS ACCORDING TO AGE AND SELECTED VARIABLES, MILAN, ITALY, 1983-1990 Breast-cancer cases
Age 2 Age at first birth 30
Controls
Number
%
Number
98 498 701 630 467
4 21 29 26 20
156 390 612 612 448
7 18 28 28 20
2,150 244
90 10
1,928 290
87 13
1,261 654 479
53 27 20
1,352 526 340
61 24 15
2,053 341
86 14
1,815 403
82 18
1,023 646 558 167
43 27 23 7
826 750 492 150
37 34 22 7
440 592 1,362
18 25 57
449 539 1,230
20 24 56
787 752 415
33 31 17
854 624 29 1
39 28 13
'In some cases the sum does not equal this total because of missing values.
%
818
PARAZZINI ET AL. TABLE II - RELATIVE RISK OF BREAST CANCER ACCORDING TO HISTORY OF spommmus OR INDUCED ABORTION, MILAN, ITALY, 198?-1990 Breast-cancer cases
>2
x2, trend Induced abortions 0 1 >2
1,893 340
1,735 311
161
172
2,135 149
1,966
110
121
131
xzltrend Total abortions 0 1
1,682 423
>2
MLR~
MH’ ~~
Spontaneous abortions 0 1
Relative risk (95% confidence interval)
ConmIs ~
13
13
1 .o (0.8-1.2) 0.8 (0.7-1.0) 2.63
1.0 (0.8-1.1) 0.8 (0.7-1.1) 2.15
13
13
1.0 (0.8-1.3) 0.8 (05-1.1) 1.12
1.0 (0.8-1.3) 0.9 (0.7-1.2) 0.62
(0.9-1.21 0.9 (0.7-1 .O) 1.53
(0.9-1.21 0.9 (0.7-1.0) 1.72
1 ,54g4 366
289
302
xz, trend
‘Adjusted for age by the Mantel-Haenszel (M-H) procedure.-’Estimates from multiple logistic regression (MLR) equations including terms for age, education, marital,status, age at tint birth, parity, age at menarche, age at menopause estrogen replacement therapy, body mass index and, in turn, spontaneous abortions, induced abortions and total abortions. Maximum likelihood deviance: 6221 (4586 degrees of freedom) for spontaneous and total abortions and 6222 for induced aboztions. -3Reference category.-4The sum does not equal the total of controls because of missing values. TABLE 111- RELATIVE RISK’ (AND CORRESPONDING 95% CONFIDENCE INTERVALS) OF ARI‘AST CANCER ACCORDING TO HISTORY OF SPONTANEOUS AND INDUCED ABORTIONS IN SEPARATE STRATA OF AGE. MILAN, ITALY, 1983-1990 Aee m u 0
1 Induced abortions 0 >1 Total abortions 0 >1
w
9
(vearsl 5&59
rM)
1’ (233)3 1.4 (45) (0.9-2.2)
1* (535) 0.8 (152) (0.61.O)
1’ (522) 0.9 (142) (0.7-1.2)
l2 (603) 1.0 (162) (0.8-1.3)
1’ (235) 0.7 (43) (0.5-1.1)
l 2 (603) 0.8 (84) (0.61.2)
1’ (598) 1.1 (66) (0.7-1.6)
1’ (699) 1.2 (66) (0.8-1.8)
l 2 (198) 0.9 (80) (0.7-1.4)
1’ (467) 0.8 (220) (0.61.1)
1’ (470) 1.O(194) (0.7-1.2)
(547) 1 . 1 (218) (0.9-1.4) 12
‘Estimates from multiple logistic regression equations including terms for parity, education, age at first birth, marital status and. in turn, the variables listed above. -’Reference categ~ry-~Numbers of cases are given in parentheses.
The relationship between abortion and breast-cancer risk has already been analyzed in at least 23 previous papers (Russo and Russo, 1980; Salber et al., 1969; Valaoras et al., 1969; Lin et al., 1970; Lowe and MacMahon, 1970; Yuasa and MacMahon, 1970; Ravnihar et al., 1971; Stavraky and Emmons, 1974; Soini, 1977; Choi et al., 1978; Paffenbarger et al., 1980; Totietal., 1980;Kelseyetal., 1981; Pikeetal., 1981; Vessey et al., 1982; Brinton et al., 1983; Helmrich et al., 1983; Hirohata et al., 1985; Ewertz and Duffy, 1988; Rosenberg et al., 1988; Howe et al., 1989; Lindefors Harris et at., 1989; Hadjimichael et al., 1986), but available evidence remains under discussion. Most studies (Valaoras et al., 1969; Lin et al., 1970; Yuasa and MacMahon, 1970; Stavraky and Emmons, 1974; Soini, 1977; Choi et al., 1978; Toti et al., 1980; Kelsey et al., 1981; Pike et al., 1981; Brinton et al., 1983; Hirohata et al., 1985; Ewertz and Duffy, 1988; Rosenberg el al., 1988; Howe et al., 1989; Hadjimichael et al., 1986) have reported an increased risk of breast cancer, but no or a negative relationship emerged from others (Salber et al., 1969;Ravnihar et al.,
1971; Paffenbarger et al., 1980; Vessey et al.. 1982; Helmrich et al., 1983; Lindefors Harris et al., 1989). To further com-
plicate the issue, it has been suggested that the association could be restricted to women aged below 40 to 45 years (Howe et al., 1989), and consequently that abortion (and its hormonal correlates) could cause a short-term increase in the risk of breast cancer. In the framework of the multistage process of carcinogenesis, this finding could be interpreted in terms of a late-stage effect of abortions on breast carcinogenesis. A similar pattern of risk has been found for parity (Bruzzi et a f . , 1988) and suggested for oral contraceptive use. In biological terms, this hypothesis is consistent with the promotion of breast-cell growth observed in the first trimester of pregnancy, and is supported by animal data (Russo et al., 1982). In our study no association emerged between spontaneous or induced abortion and breast-cancer risk, although a moderate, non-significant, risk was observed in parous women reporting an abortion before their first full-term pregnancy. Such an association emerged from other case-control studies conducted
819
ABORTION AND BREAST-CANCER RISK
TABLE IV - RELATIVE RISK’ (AND CORRESPONDING 95% CONFlDENCE INTERVALS) OF BREAST CANCER ACCORDING TO HISTORY OF SPOMANEOUS AND INDUCED ABORTIONS IN SEPARATE STRATA OF PARITY, MILAN, ITALY, 1983-1990
Paritv 0
1
>2
l 2 (397)3 1.4 (43) (0.8-2.2)
l 2 (469) 1.0 (123) (0.7-1.3)
1’(1,027) 0 . 9 (335) (0.7-1.0)
l 2 (422) 0.8 (18) (0.4-1.5)
1’ (535) 1 . 1 (57) (0.7-1.6)
12(1,178) 0.9 (184) (0.8- 1.2)
1’ (370) 1.2 (61) (0.8-1 .8)
1’ (420) 1 . 1 (172) (0.8-1.4)
1’ (883) 0.9 (479) (0.8-1.1)
Spontaneous abortions
0 >1 Induced abortions 0 >1
Toral abortions 0 >1
‘Estimates from multiple logistic regression equations including terms for age, education, age at first birth, marital status and, in turn,the variables listed above.-’Reference ~ategory.-~Numbersof cases are given in parentheses; in some cases the sum does not equal the total studied because of some missing values. TABLE V - RELATIVE RISK OF BREAST CANCER ACCORDING TO HISTORY OF ABORTIONS IN RELATION TO FIRST BIRTH, MILAN, ITALY, 1983-1990
Breast-cancer cases
Relative risk (95% confidence interval)
Controls M-HI
No abortions Abortions’ before first birth Abortions5 only after first birth
1,303 100
1 ,4503 65
55 1
55 1
MLR~
14
14
1.3 (0.9-1.8) 0.9 (0.8-1. I )
1.2 (0.9-1.7) 0.9 (0.8-1.0)
‘Adjusted for age by the M-H procedure.-2Estimates from multiple logistic regression (MLR) equations including terms for age, education. marital status, age at first birth, parity, age at menarche, age at menopause, estrogen replacement therapy and body mass inde~.-~The sum does not add up to the total studied because of some missing val~es.-~Referencecategory. -51ncluding spontaneous and induced abortions.
in the United States (Pike et al., 1981; Brinton et al., 1983; Hadjimichael et al., 1986). In the study by Brinton et al. (1983), however, the risk was observed only in women who had had two or more abortions before first birth and is consistent with the observation that an increase in the number of induced abortions in North European countries was accompanied by an increase in the incidence of breast cancer in young women (Swedish National Board of Health and Welfare, 1987). An increased risk of breast cancer in women reporting induced abortions was reported in a study conducted in the Soviet Union; this association was apparently stronger in women who had had their first induced abortion early in life (Dvoirin and Medvedev, quoted by Remennick, 1990). However no relationship was found in an English case-control study (Vessey et al., 1982) or in a Swedish cohort study considering only legally induced abortions (Lindefors Harris et al., 1989). The power of our study to analyze abortions before first birth was, however, limited, on account of the low frequency of induced abortions in younger Italian women and the risk estimate is based on 100 exposed cases and 65 controls only.
The present study provides evidence against the existence of an appreciable overall relationship between spontaneous or induced abortions and risk of breast cancer, although it leaves open the possibility of an increased risk of the disease in women who had an abortion before a full-term pregnancy. This latter finding could represent public health concern in view of the increasing frequency of induced abortions in teen-agers in several developed countries in the last decades. ACKNOWLEDGEMENTS
This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project “Oncology” (Contract 88. 00719-44) and “Prevention and Control of Disease Factors”. The contributions of the Italian League against Tumors and the Italian Association for Cancer Research, Milan, Italy, are gratefully acknowledged. We are grateful to Ms. F. Perego, Ms. J. Baggott and the Pfeiffer Memorial Library staff for editorial assistance.
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Publication of the International Union Against Cancer Publication de I’Union lnternationale Contre le Cancer
SPONTANEOUS AND INDUCED ABORTIONS AND RISK OF BREAST CANCER Fabio PARAZZINI’,~, Car10 LA VECCHIA”~ and Eva NEGRI’ ‘Istituto di Ricerche Farmacologiche “Mario Negri” , 20157 Milan, Italy; and 21nstitute of Social and Preventive Medicine, University of Lausanne, 1005 Lausanne, Switzerland. The relationship between spontaneous or induced abortion and the risk of breast cancer was analyzed in a case-control study conducted in the greater Milan area on 2,394 cases of breast cancer and 2,218 controls in hospital for a spectrum of acute conditions, not gynecological, hormonal or neoplastic. No consistent relationship emerged between spontaneous or induced abortion and breast cancer: compared with women reporting no abortions (spontaneous or induced), the multivariate relative risk (RR) was I .O (95% confidence interval, CI, 0.9 to I.2) in those reporting one abortion and 0.9 (95% CI 0.7 to I .O) In those reporting two or more. This lack of association was consistent in strata of age and parity, including younger women. We further analyzed the risk of breast cancer associated with an abortion before and after full-term pregnancy. Compared with parous women reporting no induced or spontaneous abortions, those who had an abortion before their first full-term pregnancy had about a 20% higher risk of breast cancer. This finding, however, was not statistically significant (RR 1.2, 95% CI 0.9 to 1.7). No increased risk was observed in women who had had a first abortion after a fullterm pregnancy (RR 0.9, 95% CI 0.8 to 1.0). This study does not support the hypothesis that spontaneous or induced abortion appreciably influences subsequent breast-cancer risk.
breast cancer in the greater Milan area (La Vecchia et al., 1987). Trained interviewers identified and questioned women admitted for breast cancer and for a wide spectrum of other conditions to teaching and general hospitals in the area under surveillance. Overall participation rate was 97% for cases and 98% for controls. A standard questionnaire was used to obtain information on personal characteristics and habits, gynecological and obstetric data, related medical history, dietary habits and a detailed history of lifetime use of oral contraceptives and other female hormones. Information was specifically obtained on the number of births, miscarriages (defined as fetal loss before the 28th week of pregnancy) and induced abortions, and on the age at first and last pregnancy and birth. Study population The cases considered in this report were women below the age of 75, with histologically confirmed breast cancer diagnosed within the year before the interview (2,394 subjects, median age 52 years, range 23 to 74) who had been admitted to the National Cancer Institute and the Ospedale Maggiore (which includes the 4 largest teaching and general hospitals in Milan). Controls were women aged below 75 years admitted for acute conditions to the same network of hospitals where cases had been identified. Women were not included if they had been admitted for gynecological, hormonal or neoplastic disease. A total of 2,218 subjects (median age 53 years, range 22 to 74) were interviewed. Of these, 32% were admitted for traumatic conditions (mostly fractures and sprains), 27% had non-traumatic orthopedic disorders (mostly low back pain and disc disorders), 17% were admitted for acute surgical conditions (mostly abdominal, such as acute appendicitis or strangulated hernia) and 24% had other illnesses, such as ear, nose, throat or teeth disorders. Although cases and controls were not individually matched, their distribution according to 5-year age groups was comparable.
Several epidemiological findings have suggested that a term pregnancy, and its early occurrence in life, is a long-term protective factor against the risk of breast cancer (Kelsey, 1979). Its effect has been interpreted in terms of promotion of breast growth and induction of full cellular differentiation of the mammary gland in pregnant women (Russo et al., 1982). Epidemiological and biological evidence is more confused in relation to incomplete pregnancy. It has been suggested that abortion interrupts this process and can increase the susceptibility of the breast to potential carcinogenic factors, due to incomplete differentiation of the cells in the breast glands during the first trimester (Russo and Russo, 1980). This effect could be stronger before a full-term pregnancy (or in younger women) when the breast gland structures are less differenti- Data analysis ated. Odds ratios, as estimators of relative risks (RR) of breast Conflicting epidemiological evidence has been published on cancer, together with their 95% approximate confidence interthe relationship between breast cancer and spontaneous or in- vals (CI), were first computed from data stratified in 5-year duced abortion, showing positive (Valaoras et al., 1969; Lin et intervals of age by the Mantel-Haenszel (1959) procedure. al., 1970; Yuasa and MacMahon, 1970; Stavraky and Em- When a factor could be classified in more than 2 levels, the mons, 1974; Soini, 1977; Choi et al., 1978; Toti et al., 1980; significance of the linear trend was assessed by the test deKelsey et al., 1981; Pike et al., 1981; Brinton et al., 1983; scribed by Mantel (1963). RRs were then obtained after simulHirohata et al., 1985; Ewertz and Duffy, 1988; Rosenberg et taneous allowance for potential confounding effects of age, al., 1988; Howe et al., 1989; Hadjimichael et al., 1986), education, marital status, age at first birth, parity, age at inverse (Ravnihar et al., 1971; Paffenbarger et al., 1980; Ves- menarche, age at menopause, estrogen replacement therapy, sey et al., 1982; Lindefors Harris et al., 1989) or no relation- body mass index and, in turn, number of induced and spontaship (Salber et al., 1969; Helmrich et al., 1983). However, neous abortions (Baker and Nelder, 1978). some studies have shown an increased risk of breast cancer in women reporting spontaneous or induced abortion at a younger RESULTS age (Howe et al., 1989) or before first birth (Pike et al., 1981; Brinton et al., 1983; Hadjimichael et al., 1986). The distribution of cases and controls according to age and To provide further information on the issue, we examined the relationship between abortions and breast-cancer risk, using data from a large case-control study conducted in Northern ’To whom correspondence and reprint requests should be addressed, at Italy. Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy.
SUBJECTS AND METHODS
Since 1983 we have been conducting a case-control study of
Received: January 19, 1991 and in revised form April 15, 1991.
8 17
ABORTION A N D BREAST-CANCER RISK
selected co-variates (including the best recognized risk factors for breast cancer) is shown in Table I. Cases tended to be more educated, reported earlier age at menarche, later age at menopause and later age at first birth than controls. The relationship between spontaneous or induced abortions and the risk of breast cancer is shown in Table 11. No consistent association emerged: compared with women reporting no spontaneous or induced abortion, the multivariate RR for breast cancer was 1.O (95%CI 0.9.to 1.2) in those reporting 1 and 0.9 (95% CI 0.7 to 1.0) in those reporting 2 or more abortions. This was confirmed when the analysis was conducted in strata of age (Table 111) and parity (Table IV). No significant relationship emerged in women aged below 40 years. In this stratum, the estimated RR for breast cancer was 1.4 (95% CI 0.9 to 2.2) in women reporting spontaneous abortions compared with those who did not, but the risk did not increase with the number of spontaneous abortions (data not shown). Furthermore, the risk was below unity considering induced abortions (RR 3 1 induced abortions vs. no induced abortion 0.7,95%CI 0.5 to 1 . 1 ) and consequently, was 0.9 (95% CI 0.7 to 1.4) when induced and spontaneous abortions were considered together (Table 111). Similarly, no heterogeneity across strata of parity was evident (Table IV). The risk associated with the occurrence of first abortion before or after a full-term pregnancy is analyzed in Table V. Compared with parous women reporting no induced or spontaneous abortions, those who had at least one abortion before their first full-term pregnancy had about a 20% higher (not statistically significant) risk of breast cancer (multivariate RR 1.2, 95% CI 0.9 to 1.7), but no increase in risk was observed in women who had their first abortion after a full-term pregnancy (RR 0.9, 95% CI 0.8 to 1.0). No significant heterogeneity, however, was observed across these exposure catego-
ries, or when the analysis was performed considering spontaneous and induced abortions separately. DISCUSSION
The general findings of our study show that spontaneous or induced abortions do not materially affect the risk of breast cancer; the point estimate for 2 or more abortions was 0.9, with an upper confidence limit of 1.O. Parous women reporting at least 1 spontaneous or induced abortion before their first fullterm pregnancy had about a 20%higher risk of the disease, but this finding was not significant. Likewise, no relationship emerged in young women. It is unlikely that the present results were severely affected by bias, since cases and controls were identified in hospitals covering a comparable catchment area, and response rate was almost complete. In relation to recall bias, it is conceivable that healthy control subjects may tend to under-report legally induced abortions more frequently than do cases. However, we included in our comparison groups only hospitalized women, who were interviewed in a condition comparable with cases, and no difference in RR estimates was found when an exploratory analysis was performed considering separately the different main diagnostic groups of controls. Furthermore, no differences in the estimated RR emerged between spontaneous and induced abortions. Thus, it is unlikely that the case or control status influenced reporting of spontaneous or induced abortions. In relation to confounding, allowance for major potential distorting factors (including indicators of socioeconomic status and the best recognized risk factors for breast cancer) did not materially modify any of the estimated relative risks. Finally, the major strength of this study is the large sample, with consequent narrow confidence interval of the estimates.
TABLE I - DISTRIBUTION OF 2,394' CASES OF BREAST CANCER AND 2,218 CONTROLS ACCORDING TO AGE AND SELECTED VARIABLES, MILAN, ITALY, 1983-1990 Breast-cancer cases
Age 2 Age at first birth 30
Controls
Number
%
Number
98 498 701 630 467
4 21 29 26 20
156 390 612 612 448
7 18 28 28 20
2,150 244
90 10
1,928 290
87 13
1,261 654 479
53 27 20
1,352 526 340
61 24 15
2,053 341
86 14
1,815 403
82 18
1,023 646 558 167
43 27 23 7
826 750 492 150
37 34 22 7
440 592 1,362
18 25 57
449 539 1,230
20 24 56
787 752 415
33 31 17
854 624 29 1
39 28 13
'In some cases the sum does not equal this total because of missing values.
%
818
PARAZZINI ET AL. TABLE II - RELATIVE RISK OF BREAST CANCER ACCORDING TO HISTORY OF spommmus OR INDUCED ABORTION, MILAN, ITALY, 198?-1990 Breast-cancer cases
>2
x2, trend Induced abortions 0 1 >2
1,893 340
1,735 311
161
172
2,135 149
1,966
110
121
131
xzltrend Total abortions 0 1
1,682 423
>2
MLR~
MH’ ~~
Spontaneous abortions 0 1
Relative risk (95% confidence interval)
ConmIs ~
13
13
1 .o (0.8-1.2) 0.8 (0.7-1.0) 2.63
1.0 (0.8-1.1) 0.8 (0.7-1.1) 2.15
13
13
1.0 (0.8-1.3) 0.8 (05-1.1) 1.12
1.0 (0.8-1.3) 0.9 (0.7-1.2) 0.62
(0.9-1.21 0.9 (0.7-1 .O) 1.53
(0.9-1.21 0.9 (0.7-1.0) 1.72
1 ,54g4 366
289
302
xz, trend
‘Adjusted for age by the Mantel-Haenszel (M-H) procedure.-’Estimates from multiple logistic regression (MLR) equations including terms for age, education, marital,status, age at tint birth, parity, age at menarche, age at menopause estrogen replacement therapy, body mass index and, in turn, spontaneous abortions, induced abortions and total abortions. Maximum likelihood deviance: 6221 (4586 degrees of freedom) for spontaneous and total abortions and 6222 for induced aboztions. -3Reference category.-4The sum does not equal the total of controls because of missing values. TABLE 111- RELATIVE RISK’ (AND CORRESPONDING 95% CONFIDENCE INTERVALS) OF ARI‘AST CANCER ACCORDING TO HISTORY OF SPONTANEOUS AND INDUCED ABORTIONS IN SEPARATE STRATA OF AGE. MILAN, ITALY, 1983-1990 Aee m u 0
1 Induced abortions 0 >1 Total abortions 0 >1
w
9
(vearsl 5&59
rM)
1’ (233)3 1.4 (45) (0.9-2.2)
1* (535) 0.8 (152) (0.61.O)
1’ (522) 0.9 (142) (0.7-1.2)
l2 (603) 1.0 (162) (0.8-1.3)
1’ (235) 0.7 (43) (0.5-1.1)
l 2 (603) 0.8 (84) (0.61.2)
1’ (598) 1.1 (66) (0.7-1.6)
1’ (699) 1.2 (66) (0.8-1.8)
l 2 (198) 0.9 (80) (0.7-1.4)
1’ (467) 0.8 (220) (0.61.1)
1’ (470) 1.O(194) (0.7-1.2)
(547) 1 . 1 (218) (0.9-1.4) 12
‘Estimates from multiple logistic regression equations including terms for parity, education, age at first birth, marital status and. in turn, the variables listed above. -’Reference categ~ry-~Numbers of cases are given in parentheses.
The relationship between abortion and breast-cancer risk has already been analyzed in at least 23 previous papers (Russo and Russo, 1980; Salber et al., 1969; Valaoras et al., 1969; Lin et al., 1970; Lowe and MacMahon, 1970; Yuasa and MacMahon, 1970; Ravnihar et al., 1971; Stavraky and Emmons, 1974; Soini, 1977; Choi et al., 1978; Paffenbarger et al., 1980; Totietal., 1980;Kelseyetal., 1981; Pikeetal., 1981; Vessey et al., 1982; Brinton et al., 1983; Helmrich et al., 1983; Hirohata et al., 1985; Ewertz and Duffy, 1988; Rosenberg et al., 1988; Howe et al., 1989; Lindefors Harris et at., 1989; Hadjimichael et al., 1986), but available evidence remains under discussion. Most studies (Valaoras et al., 1969; Lin et al., 1970; Yuasa and MacMahon, 1970; Stavraky and Emmons, 1974; Soini, 1977; Choi et al., 1978; Toti et al., 1980; Kelsey et al., 1981; Pike et al., 1981; Brinton et al., 1983; Hirohata et al., 1985; Ewertz and Duffy, 1988; Rosenberg el al., 1988; Howe et al., 1989; Hadjimichael et al., 1986) have reported an increased risk of breast cancer, but no or a negative relationship emerged from others (Salber et al., 1969;Ravnihar et al.,
1971; Paffenbarger et al., 1980; Vessey et al.. 1982; Helmrich et al., 1983; Lindefors Harris et al., 1989). To further com-
plicate the issue, it has been suggested that the association could be restricted to women aged below 40 to 45 years (Howe et al., 1989), and consequently that abortion (and its hormonal correlates) could cause a short-term increase in the risk of breast cancer. In the framework of the multistage process of carcinogenesis, this finding could be interpreted in terms of a late-stage effect of abortions on breast carcinogenesis. A similar pattern of risk has been found for parity (Bruzzi et a f . , 1988) and suggested for oral contraceptive use. In biological terms, this hypothesis is consistent with the promotion of breast-cell growth observed in the first trimester of pregnancy, and is supported by animal data (Russo et al., 1982). In our study no association emerged between spontaneous or induced abortion and breast-cancer risk, although a moderate, non-significant, risk was observed in parous women reporting an abortion before their first full-term pregnancy. Such an association emerged from other case-control studies conducted
819
ABORTION AND BREAST-CANCER RISK
TABLE IV - RELATIVE RISK’ (AND CORRESPONDING 95% CONFlDENCE INTERVALS) OF BREAST CANCER ACCORDING TO HISTORY OF SPOMANEOUS AND INDUCED ABORTIONS IN SEPARATE STRATA OF PARITY, MILAN, ITALY, 1983-1990
Paritv 0
1
>2
l 2 (397)3 1.4 (43) (0.8-2.2)
l 2 (469) 1.0 (123) (0.7-1.3)
1’(1,027) 0 . 9 (335) (0.7-1.0)
l 2 (422) 0.8 (18) (0.4-1.5)
1’ (535) 1 . 1 (57) (0.7-1.6)
12(1,178) 0.9 (184) (0.8- 1.2)
1’ (370) 1.2 (61) (0.8-1 .8)
1’ (420) 1 . 1 (172) (0.8-1.4)
1’ (883) 0.9 (479) (0.8-1.1)
Spontaneous abortions
0 >1 Induced abortions 0 >1
Toral abortions 0 >1
‘Estimates from multiple logistic regression equations including terms for age, education, age at first birth, marital status and, in turn,the variables listed above.-’Reference ~ategory.-~Numbersof cases are given in parentheses; in some cases the sum does not equal the total studied because of some missing values. TABLE V - RELATIVE RISK OF BREAST CANCER ACCORDING TO HISTORY OF ABORTIONS IN RELATION TO FIRST BIRTH, MILAN, ITALY, 1983-1990
Breast-cancer cases
Relative risk (95% confidence interval)
Controls M-HI
No abortions Abortions’ before first birth Abortions5 only after first birth
1,303 100
1 ,4503 65
55 1
55 1
MLR~
14
14
1.3 (0.9-1.8) 0.9 (0.8-1. I )
1.2 (0.9-1.7) 0.9 (0.8-1.0)
‘Adjusted for age by the M-H procedure.-2Estimates from multiple logistic regression (MLR) equations including terms for age, education. marital status, age at first birth, parity, age at menarche, age at menopause, estrogen replacement therapy and body mass inde~.-~The sum does not add up to the total studied because of some missing val~es.-~Referencecategory. -51ncluding spontaneous and induced abortions.
in the United States (Pike et al., 1981; Brinton et al., 1983; Hadjimichael et al., 1986). In the study by Brinton et al. (1983), however, the risk was observed only in women who had had two or more abortions before first birth and is consistent with the observation that an increase in the number of induced abortions in North European countries was accompanied by an increase in the incidence of breast cancer in young women (Swedish National Board of Health and Welfare, 1987). An increased risk of breast cancer in women reporting induced abortions was reported in a study conducted in the Soviet Union; this association was apparently stronger in women who had had their first induced abortion early in life (Dvoirin and Medvedev, quoted by Remennick, 1990). However no relationship was found in an English case-control study (Vessey et al., 1982) or in a Swedish cohort study considering only legally induced abortions (Lindefors Harris et al., 1989). The power of our study to analyze abortions before first birth was, however, limited, on account of the low frequency of induced abortions in younger Italian women and the risk estimate is based on 100 exposed cases and 65 controls only.
The present study provides evidence against the existence of an appreciable overall relationship between spontaneous or induced abortions and risk of breast cancer, although it leaves open the possibility of an increased risk of the disease in women who had an abortion before a full-term pregnancy. This latter finding could represent public health concern in view of the increasing frequency of induced abortions in teen-agers in several developed countries in the last decades. ACKNOWLEDGEMENTS
This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project “Oncology” (Contract 88. 00719-44) and “Prevention and Control of Disease Factors”. The contributions of the Italian League against Tumors and the Italian Association for Cancer Research, Milan, Italy, are gratefully acknowledged. We are grateful to Ms. F. Perego, Ms. J. Baggott and the Pfeiffer Memorial Library staff for editorial assistance.
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