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Oral Contraceptives and Breast Cancer (1991)

Chapter: Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature

« Previous: Appendix A: Oral Contraceptives and Breast Cancer: A Review of the Epidemiological Evidence with an Emphasis on Younger Women
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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B

Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature

DAVID B. THOMAS

Analysis of many of the risk factors for breast cancer suggests that endogenous ovarian hormones are of importance in the genesis of human mammary carcinomas. For example, risk is inversely related to age at menarche, and the younger a woman is at the time of her first full-term pregnancy, the lower her risk, suggesting that endocrinologic changes in a woman's early adult life can alter her susceptibility to breast cancer. Subsequent pregnancies after the first, and prolonged lactation, may reduce risk, whereas a first full-term pregnancy after about age 30 appears to enhance risk, suggesting that endocrinologic alterations during a woman's later reproductive years may also influence her risk. Finally, risk is inversely related to a woman's age at natural menopause or oophorectomy, indicating that endogenous hormonal changes late in reproductive life can have an impact on breast cancer development.

Because endogenous hormones presumably play an important role in breast cancer development, it is reasonable to ask whether exogenous hormones might also alter the risk of breast cancer. Unfortunately, the specific endocrinologic changes that mediate the various

David B. Thomas is professor of Epidemiology at the University of Washington andhead of the Program in Epidemiology, Division of Public Health Sciences, at the Fred Hutchinson Cancer Research Center, Seattle, Washington.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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risk factors for breast cancer are unknown; thus, it is impossible to predict a priori which exogenous hormonal preparations, if any, would be expected to enhance or reduce risk. It is reasonable, however, to suspect that the effects of these preparations on the risk of breast cancer may vary, depending on their compositions and the time during a woman's life when they are taken.

The purpose of this report is to critically review the results of epidemiologic studies of breast cancer in relation to combined oral contraceptives. Risk in relation to various features of use, and use at different times in a woman's life, are considered, as is use by women in various countries, and by women with and without other risk factors for breast cancer.

Sequential oral contraceptives contain only an estrogen for approximately two weeks of a cycle of daily use, and an estrogen-progestin combination for an additional week. These preparations have not been adequately studied in relation to breast cancer and are therefore not considered in this review. For the same reason, progestogenonly and triphasic pills are also not considered. Results of studies of benign breast lesions and oral contraceptives are also not included in this review. The author has, however, recently reviewed this topic (Thomas, 1989) and little new information has been published since that review was written.

METHODS

The author reviewed all reports known to him of case-control and cohort studies of breast cancer in relation to use of oral contraceptives and ascertained estimates of relative risks of breast cancer in relation to various measures of use from each study. When results of multiple studies of a particular exposure were available, the results of each were summarized in tabular form; when appropriate, if sufficient detail was available in the published reports, summary relative risks based on data from all relevant studies, and 95 percent confidence intervals of these summary relative risks, were estimated according to methods developed by Prentice (Prentice and Thomas, 1986). When these estimates were made, a chi-square test for heterogeneity of the estimates from the various studies was also performed. A statistically significant (p < .05) chi-square for heterogeneity suggests that the results of the summarized studies are not consistent and that nonbiological reasons for the variations in findings should be considered. Summary relative risks were calculated separately for case-control and cohort studies because these two investigative techniques are prone to different sources of bias.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

RESULTS

Risk of Oral Contraceptive Users of All Ages in Developed Countries

Table B-1 shows results from 15 case-control studies that were conducted in developed countries and included women of all ages who were at risk of prior exposure to oral contraceptives. Excluded from this table are studies that did not report results for women of all ages combined (Lubin et al., 1982; McPherson et al., 1987); studies that were part of a larger collaborative study (e.g., Ellery et al., 1986); a study that used women with benign breast disease as controls (Clavel et al., 1981); and reports of studies that have been updated by subsequent reports (e.g., Brinton et al., 1982). Only one of the studies summarized in Table B-1 found a relative risk of breast cancer in

TABLE B-1 Relative Risks of Breast Cancer in Women in Developed Countries Who Have Ever Used Oral Contraceptives: Case-Control Studies of Women of All Ages at Risk of Exposure

First Author (Date)

Upper Age Limit (years)

No. of Cases/Controls Users

Nonusers

Estimate of Relative Risk (Confidence Interval) a

Henderson (1974)

64

59/69

248/238

0.7[0.5,1.2]

Paffenbarger (1977)

50

226/398

226/474

1.1[0.9,1.4]

Sartwell (1977)

74

22/34

262/333

0.9(0.5,1.5)

Ravnihar (1979)

64

30/65

160/315

0.9[0.6,1.5]

Kelsey (1981)

74

30/141

300/1,207

0.9(0.6,1.3)

Harris (1982)

54

36/189

73/279

1.0(0.6,1.4)

Vessey (1983)

50

537/554

639/622

1.0(0.8,1.2)

Rosenberg (1984)

59

397/2,558

794/2,468

0.9(0.8,1.1)

Talamini (1985)

79

15/23

353/351

0.7(0.4,1.4)

CASH b (1986)

54

2,743/2,802

1,870/1,774

1.0(0.9,1.1)

Paul (1986)

54

310/708

123/189

0.9(0.7,1.3)

La Vecchia (1986)

60

104/178

672/1,104

1.1(0.8,1.5)

Ravnihar (1988)

54

162/467

372/1,522

1.6(1.3,2.1)

Stanford (1989)

>60

481/515

1,541/1,668

1.0(0.9,1.2)

WHO (1990) c

62

438/1,496

716/1,888

1.1(0.9,1.3)

Summary relative risk

     

1.0[1.0,1.1] d

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

b CASH = Cancer and Steroid Hormone Study.

c WHO = World Health Organization.

dp value of chi-square test for heterogeneity = .08.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-2 Relative Risks of Breast Cancer in Women Who Have Ever Used Oral Contraceptives: Cohort Studies

   

No. of Cases per 1,000 Person-Years

 

First Author (Date)

Upper Age Limit (years)

“Ever” Users

“Never” Users

Estimate of Relative Risk (Confidence Interval) a

Trapido (1981) b

>50

0.93 (85)

1.11 (370)

0.84(0.7,1.10)

Vessey (1981) c

45

0.50 (39)

0.52 (33)

0.96(0.59,1.63)

Kay (1988) c

64

0.64

(143) 0.52 (96)

1.22(0.93,1.60)

Romieu (1989) d

65

1.45 (717)

1.76 (1,041)

1.07(0.97,1.19)

Mills (1989) e

67

0.93 (29)

1.65 (64)

1.54(0.94,2.53)

Summary relative risk

       

Excluding Mills (1989)

     

1.04[0.96,1.13] f

Including Mills (1989)

     

1.06[0.97,1.15] g

a Confidence interval of 95 percent used; [ ] confidence intervals estimated from published reports.

b Conducted in the Boston area.

c Study conducted in Britain.

d Nurses Health Study (U.S.A.)

e Conducted among Seventh Day Adventists (U.S.A.).

fp value of chi-square test for heterogeneity = .18.

gp value of chi-square test for heterogeneity = .13.

women who had ever used oral contraceptives that was significantly greater than 1.0 (Ravnihar et al., 1988), and the summary relative risk is close to unity, with narrow confidence limits. The variability of the relative risk estimates among studies was not statistically significant (p = .08).

Table B-2 summarizes relative risk estimates from five cohort studies of women who have ever used oral contraceptives. Results from the Vessey study (1981) have been updated (Vessey et al., 1989) but not reported for women of all ages combined, and the updated results therefore could not be included in this table, or in Table B-4 and Table B-6. The study of Mills and colleagues (1989) was conducted among Seventh Day Adventists, who tend to have rates of breast cancer that are somewhat lower than women in the general U.S. population. Summary relative risks were therefore calculated with and without inclusion of data from that study. Both summary estimates are close to 1.0, with narrow confidence limits that barely include 1.0. The heterogeneity of the estimates from the individual studies could have occurred readily by chance. All of the relative risk estimates from the individual studies have 95 percent confidence intervals that include 1.0; although three are of borderline statistical significance.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-3 Relative Risks of Breast Cancer in Long-term Users of Oral Contraceptives in Developed Countries: Case-Control Studies of Women of all Ages at Risk of Exposure

     

No. of Cases/Controls

 

First Author (Date)

Minimum Years of Use

Age of Cases (years)

Long-term Users

Nonusers

Estimate of Relative Risk (Confidence Interval) a

Harris (1982)

5

35-54

17/99

73/279

0.8(0.5,1.4)

Ravnihar (1988)

7

25-54

34/66

372/1,522

2.4(1.5,3.8) b

Paffenbarger (1977)

8

<50

17/26

104/195

1.7[0.9,3.3]

Vessey (1983)

8

16-50

66/66

639/622

1.0(0.7,1.5)

WHO (1990) c

8

<62

89/206

716/1,888

1.4(1.0,1.9)

Rosenberg (1984)

10

20-59

25/128

794/2,468

0.8(0.5,1.3)

CASH d (1986)

15

20-54

45/69

1,870/1,774

0.6(0.4,0.9)

Paul (1986)

10

25-54

63/130

123/189

1.0[0.7,1.4]

Stanford (1989)

15

<40->60

8/13

1,541/1,668

0.7(0.3,1.6)

Summary relative risk

       

1.1[0.9,1.2] e

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

bp value of test for trend of increasing risk with duration of use < .05. No significant trends were observed in other studies.

c WHO = World Health Organization; based on data from three developed countries only (Israel, German Democratic Republic, and Australia).

d CASH = Cancer and Steroid Hormone Study.

ep value of chi-square test for heterogeneity = .0005.

Table B-3 shows estimates from nine case-control studies of the relative risk of breast cancer in long-term users of oral contraceptiges. As in Table B-1, the studies shown are restricted to those in developed countries that include women of all ages at risk of exposure. The summary relative risk is not appreciably or significantly greater than 1.0, although there is considerable variation in results among the various studies. Only one study (Ravnihar et al., 1988) found a significant trend of increasing risk with duration of exposure.

Estimates of relative risks in long-term users from four cohort studies are shown in Table B-4. The results from the studies of Trapido (1981) and Romieu and colleagues (1989) refer to duration of use prior to entering the cohort, and do not include women who used oral contraceptives after the cohort was established. The Vessey study (1989) is not included in the table because results were not presented for women of all ages combined. As in Table B-2, summary relative risks are shown including and excluding results from the Seventh Day Adventist Study (Mills et al., 1989), although the numbers of long-term users in that study were too small to influence the value of the summary relative risk appreciably. A (nonsignificant) relative

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-4 Relative Risks of Breast Cancer in Long-term Users of Oral Contraceptives: Cohort Studies

     

Cases per 1,000 Person-Years (No. of Cases)

 

First Author/Date

MinimumYears of Use

Upper Age Limit of Cases (years)

Long-term Users

Nonusers

Estimate of Relative Risk (Confidence Interval) a

Trapido (1981)

5

>50

0.96 (15)

1.11 (370)

0.86[0.52,1.43]

Kay (1988)

10

65

0.75 (22)

0.52 (96)

1.44(0.91,2.29)

Romieu (1989)

10

65

1.73 (63)

1.76 (1,041)

1.09[0.84,1.41] b

Mills (1989)

10

67

1.20 (2)

1.65 (64)

1.42(0.34,5.98)

Summary relative risk

         

Excluding Trapido

       

1.17[0.94,1.46] c

Excluding Mills

       

1.11[0.90,1.36] d

No exclusions

       

1.11[0.91,1.36] e

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

b Estimated by combining relative risks of 1.09(0.83,1.43) and 1.06(0.49,2.76) for users of 10-15 and >15 years, respectively.

cp value of chi-square test for heterogeneity = .57.

dp value of chi-square test for heterogeneity = .34.

ep value of chi-square test for heterogeneity = .52.

TABLE B-5 Relative Risks of Breast Cancer Long After Initial Use of Oral Contraceptives: Case-Control Studies of Women of All Ages for Risk of Exposure

     

No. of Cases/Controls

 

First Author/ Date

Upper Age Limit of Cases (years)

Minimum Years Since First Use

Long-term Users

Nonusers

Estimate of Relative Risk (Confidence Interval) a

Harris (1982)

54

15

15/45

73/279

1.4(0.8,2.4)

Vessey (1983)

50

12

112/154

639/622

0.7(0.5,1.0)

Rosenberg (1984)

59

15

101/347

794/2,468

1.1(0.9,1.4)

CASH b (1986)

54

20

Not given

1,872/1,774

0.8(0.7,1.0)

La Vecchia (1986)

60

10

63/72

672/1,104

1.5(1.0,2.1)

Paul (1986)

54

15

217/431

123/198

0.9[0.7,1.2]

Ravnihar (1988)

54

12

60/195

372/1,522

1.4(1.0,2.0) c

Stanford (1989)

>60

15

98/127

1,541/1,668

0.8(0.6,1.1)

WHO (1990) d

62

15

96/350

716/1,888

0.9(0.7,1.2)

Summary relative risk

       

1.0[0.9,1.1]e

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

b CASH = Cancer and Steroid Hormone Study.

cp value of test for trend of increasing risk with duration of use = < .05. No significant trends observed in other studies.

d WHO = World Health Organization; based on data from three developed countries only (Israel, German Democratic Republic, and Australia).

ep value of chi-square test for heterogeneity = .004.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-6 Relative Risks of Breast Cancer Long After Initial Use of Oral Contraceptives: Cohort Studies

     

Cases per 1,000 Persons (No. of Cases)

 

First Author (Date)

Minimum Years Since First Use

Upper Age Limit of Cases (years)

Long-term Users

Nonusers

Estimate of Relative Risk (Confidence Interval) a

Trapido (1981)

10

>50

1.13 (31)

1.11 (370)

1.0[0.7,1.5]

Vessey (1981)

12

45

0.82 (7)

0.52 (33)

1.6[0.7,3.6]

Kay (1988)

10

64

0.96 (17)

0.52 (96)

1.9(1.1,3.1) b

Romieu (1989)

20

65

1.75 (143)

1.76(1,041)

1.0(0.9,1.2)

Summary relative risk

       

1.1[0.9,1.3] c

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

bp value of chi-square test for linear trend = .01. No significant trends were observed in other studies.

cp value of chi-square test for heterogeneity = .13.

risk of 1.11 in long-term users was estimated by combining results from all four studies. When results were considered only from the three studies that provided estimates in users of more than 10 years ' duration, a combined relative risk of 1.17 was obtained; but the 95 percent confidence interval of this estimate also includes 1.0. The results of the four studies are not significantly heterogeneous. No significant trends of increasing risk with longer duration of use were observed in any of the studies.

Table B-5 summarizes results from nine case-control studies that attempted to assess risk long after initial exposure to combined oral contraceptives. No consistent increase in risk 10 to 20 years since first exposure is evident. The relative risks of 0.7 and 0.8 in the investigations by Vessey and colleagues (1983) and the Cancer and Steroid Hormone Study (1986), and of 1.4 in the studies by La Vecchia and coworkers (1986) and Ravnihar and colleagues (1988), were of borderline statistical significance; but only the Ravnihar study found a significant trend in risk with time since initial exposure. Although the summary relative risk is close to 1.0, the corresponding chi-square test for heterogeneity is statistically significant (p < .05), suggesting that caution should be exercised in interpreting this summary relative risk estimate. Results from three of four cohort studies (Table B-6) do not show a significant alteration in risk long after initial exposure to oral contraceptives, but one (Kay and Hannaford, 1988) found a significant trend of increasing risk with time since first use. The

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

reasons for these discrepant findings are not known, but such varying results indicate that interpretations should be made with caution. In the aggregate, the information summarized in Table B-5 and Table B-6 suggests that the use of oral contraceptives has not greatly influenced the risk of breast cancer in women of all ages combined, one to two decades after initial exposure.

Risk in Oral Contraceptive Users in Developing Countries

Results were recently published from a large hospital-based case-control study that was conducted primarily to determine whether possible relationships between oral contraceptives and breast (and other) cancers differ in developing and developed countries (World Health Organization [WHO], 1990). Such countries tend, respectively, to have relatively lower and higher rates of breast cancer. Based on data from three developed countries (Australia, German Democratic Republic, and Israel) and seven developing countries (Chile, Colombia, China, Kenya, Mexico, the Philippines, and Thailand), relative risks were found to be 1.07 (95 percent confidence interval (CI) = 0.91,1.26) and 1.24 (CI = 1.05,1.47), respectively, in women who had ever used oral contraceptives. The data also showed that women in developing countries had stronger trends of increasing risk with longer duration of use, and of decreasing risk with years since first or last exposure, than women in developed countries. Although it was concluded that a combination of chance and minor sources of bias and confounding could not be ruled out as the cause of the findings in developing countries, no specific reason for the results being spurious was identified, and a causal interpretation must also be considered.

Two smaller, population-based case-control studies in Costa Rica (Lee et al., 1987) and China (Yuan et al., 1988) yielded results that are not inconsistent with those of the WHO study. Results from all three investigations are summarized in Table B-7. Summary relative risks, based on data from the three studies, were estimated to be 1.21 (CI = 1.05,1.38) for “ever” users of oral contraceptives, and 1.59 (CI = 1.15,2.20) for long-term users (more than 8 to 10 years of use), respectively. The relative risk estimates from each of the three studies are not significantly heterogeneous. The relative risk for users of oral contraceptives that was observed in the Seventh Day Adventists Study (Mills et al., 1989), which was higher than those in other cohort studies (Table B-2), also supports the idea that relative risks of breast cancer in users of oral contraceptives are higher in low-risk than in high-risk populations.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-7 Relative Risks of Breast Cancer in Users of Oral Contraceptives in Developing Countries: Summary of Three Case-Control Studies

   

Cases/Controls

   
         

Relative Risk (Confidence Interval) a

First Author (Date)

Country

Nonusers

Ever Users

Long-term Users

Ever Use

Long-term Use

Lee (1987)

Costa Rica

97/427

58/321

6/29 b

1.2

0.9

         

(0.8,1.8)

(0.4,2.6)

Yuan (1988)

China

435/439

99/95

16/12 b

1.06

1.40

         

(0.74,1.51)

(0.62,3.17)

WHO c (1989)

Developing countries d

679/6,752

282/2,930

34/211 e

1.24

1.88

         

(1.05,1.47)

(1.27,2.78)

Summary relative risk

       

1.21

1.59

         

[1.05,1.38] f

[1.15,2.20] g

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated by approximate methods.

b Long-term = longer than 10 years.

c WHO = World Health Organization.

d Includes Chile, Colombia, China, Kenya, Mexico, the Philippines, and Thailand.

e Long-term = longer than 8 years.

fp value of chi-square test for heterogeneity = .43.

gp value of chi-square test for heterogeneity = .10.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

Two possible biological reasons for these results have been proposed. One is that oral contraceptives could exert a small additive effect on risk, independent of the influence of other risk factors (WHO, 1990). Such an effect would give rise to higher relative risks in low-risk populations, even if the absolute increase in risk in users of oral contraceptives was the same in all populations. The other possible hypothesis, developed by Stalsberg and colleagues (1989), is that oral contraceptives enhance risk in low-risk populations by stimulating proliferation of the stem cells of the lobules; this phenomenon occurs to a greater extent in low risk populations (in which the lobular epithelium is not close to being maximally stimulated by other factors) than in high-risk populations (in which the lobular epithelium has reached its maximum proliferative capacity and thus cannot readily respond to the additional stimulus of exposure to oral contraceptives). In support of this hypothesis, Stalsberg and colleagues noted that tubular and lobular carcinomas, which probably arise from the lobular ductal epithelium, are more strongly related to oral contraceptives (and other presumably hormonally mediated risk factors) than are other histological types, which are more likely to arise from ductal epithelium.

Risk in Oral Contraceptive Users With and Without Various Risk Factors for Breast Cancer

If either of the above explanations for the possible higher relative risks of breast cancer among oral contraceptive users in low-risk populations is correct, then one might expect also to observe higher relative risks in women without other risk factors for breast cancer than in women with such risk factors. Alternatively, if oral contraceptives enhance risk by potentiating the effect of other risk factors, then one would expect to observe higher relative risks in users with the other risk factors than in users without them. Results from studies that assessed risk in users with and without various risk factors are in this section.

As shown in Table B-8, the WHO study (WHO, 1990) found a somewhat higher relative risk in users of low socioeconomic status (who tend to be at relatively low risk of breast cancer) than in women of higher status. This was not observed by Miller and colleagues (1989), however.

Nulliparous women tend to be at higher risk of breast cancer. Some nulliparous women are infertile and less likely than other women to use oral contraceptives; consequently, several studies (Table B-9), have assessed risk of breast cancer in relation to oral contraceptive use

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

separately for nulliparous women. The results are inconsistent. Two studies found increasing risk with longer duration of use in young women (Stadel et al., 1989; U.K. National Case-Control Study Group, 1989), and another (Meirik et al., 1986) found significantly elevated relative risks in nulliparous women regardless of duration of use. Other equally well-designed and well-conducted studies, however, found no increase in risk in nulliparous users.

Risk of breast cancer increases with the age of a woman at the time of her first live birth. Table B-10 shows relative risks in relation to use of oral contraceptives in women of varying ages at the time of their first live birth. No trends of increasing or decreasing relative risk associated with age at first birth are seen in any study.

Women of high parity tend to be at low risk of breast cancer. Table B-11 shows that no studies have shown a trend in relative risks in users of oral contraceptives related to number of children that a woman has had.

Table B-12 shows relative risks in users of oral contraceptives who do and do not have a family history of breast cancer. None of the studies summarized showed appreciable differences in the magnitude of relative risks between women with and without various affected relatives.

Some studies have shown that obese women are at increased risk of breast cancer, especially in their postmenopausal years. As shown

TABLE B-8 Relative Risk of Breast Cancer in Women of Various Socioeconomic Strata Who Have Ever Used Oral Contraceptives

First Author (Date)

Measure of Socioeconomic Status

Level

Relative Risk

Confidence Interval (95%)

Miller (1989)

Years of education

<13

2.3

Includes 1.0 a

   

13-16

1.6

Includes 1.0

   

>17

2.8

Includes 1.0 b

WHO c (1990)

Socioeconomic index d

4 (low)

1.86

1.07,3.24

   

3

1.13

0.91,1.40

   

2

1.14

0.94,1.39

   

1 (high)

1.12

0.94,1.32

a In multivariate analysis, relative risk = 2.7 (95 percent confidence interval [CI] excludes 1.0).

b In multivariate analysis, relative risk = 3.9 (95 percent CI excludes 1.0).

c WHO = World Health Organization.

d Based on years of education and occupation.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-9 Relative Risks of Breast Cancer in Nulliparous Women Who Have Ever Used Oral Contraceptives

First Author/Date (Study Design)

Restrictions on Study Population

Use of Oral Contraceptives

Estimate of Relative Risk (Confidence Interval) a

Paffenbarger/1977 (case-control)

15-39 years old

Any

4.6 /p = .16

 

40-44 years old

Any

0.6 /p = .75

 

45-49 years old

Any

0.8 /p = .99

 

All ages

Any

1.1 /p = .99

Trapido/1981 (cohort)

None

Any

2.1(0.9,5.0)

Harris/1982 (case-control)

None

Any

0.8(0.2,2.6)

Hennekens/1984 (cohort)

None

Any

1.0(0.6,1.8)

Rosenberg/1984 (case-control)

None

<1 year

1.2(0.6,2.3)

   

1-4 years

0.8(0.4,1.6)

   

>5 years

1.1(0.6,2.3)

   

Any

1.1(0.7,1.7)

La Vecchia/1986 (case-control)

None

Any

1.16 (N.G.) d

Miller/1986 (case-control)

<45 years old

Any

1.0(0.2,3.9)

Kay/1988 (cohort)

None

Any

1.14(0.72,1.8)

Meirik/1989 (case-control)

<45 years old

<4 years

2.8(1.1,7.4)

   

4-7 years

1.0(0.3,3.3)

   

>8 years

4.3(1.4,13.1)

Stadel/1989 (case-control)

20-44 years old

<3 years

1.2(0.8,1.8)

   

4-7 years

1.7(1.0,2.8)

   

8-11 years

1.6(0.9,2.8)

   

>12 years

2.5(0.9,6.7)

 

45-54 years old

<3 years

0.6(0.3,1.1)

   

4-7 years

1.2(0.2,6.0)

   

8-11 years

0.3(0.0,1.6)

   

>12

0.3(0.1,1.4)

Stanford/1989 (case-control)

None

Any

0.89(0.5,1.4)

U.K. National Case-Control Study Group/1989 (case-control)

<36 years old

1-3 years

0.981 (N.G.) b

   

4-8 years

1.37

   

>9 years

(N.G.) 2.30 (N.G.)

WHO c /1990 (case-control)

None

Any

0.84(0.56,1.25)

a Confidence interval of 95 percent used.

bp value of test for trend = .005.

c WHO = World Health Organization.

d NG = Not given.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-10 Relative Risks of Breast Cancer in Parous Women Who Have Ever Used Oral Contraceptives by Age at First Live Birth

 

Age in Years at First Live Birth

First Author/Date (Study Design)

<20

20-24/<24

25-29/>25

>30

Trapido/1981 (cohort)

0.5

0.7

1.2

0.6

Miller/1989 (case-control)

2.9 a

2.1 a

2.6 a

N.a.

Stanford/1989 (case-control)

0.74

0.93

1.09

1.04

WHO b /1990 (case-control)

N.a.

1.17

1.27

1.13

N.a: Not available.

a Confidence intervals of 95 percent exclude 1.0.

b WHO = World Health Organization.

Table B-13, Miller and colleagues (1989) observed a trend of increasing relative risks in relation to oral contraceptive use with increasing body mass index. This trend was not observed by Stanford and colleagues (1989). The former study was restricted to women under age 45, when obesity has a minimal impact on risk of breast cancer; the latter study included older women.

Table B-14 shows the results of studies that assessed risk of breast cancer in oral contraceptive users with a history of benign breast disease. Risks were elevated in all three studies that confined analyses to young women (Lees et al., 1978; Paffenbarger et al., 1980; Janerich et al., 1983) with two of the studies showing an increasing risk with

TABLE B-11 Relative Risks of Breast Cancer in Women Who Have Ever Used Oral Contraceptives by Number of Children

 

Number of Children

First Author/Date (Study Design)

0

1/>1

1-2

2-3/>3

>4

La Vecchia/1986 (case-control)

1.16

1.00

N.a.

N.a.

N.a.

Kay/1988 (cohort)

1.14

5.88 a

N.a.

1.01

0.71

Miller/1989 (case-control)

N.a.

N.a.

2.4 a

2.9 a

N.a.

N.a.: Not available.

a Confidence intervals of 95 percent exclude 1.0.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-12 Relative Risks of Breast Cancer in Relation to Use of Oral Contraceptives in Women With and Without a Family History of Breast Cancer

First Author/Date (Study Design)

Restrictions on Study Population

Relative with Breast Cancer

Use of Oral Contraceptives

Estimate of Relative Risk (Confidence Interval) a

Kelsey/1981 (case-control)

None

Any

Any

No increase (data not given)

Vessey/1983 (case-control)

None

Any

None

1.0

     

<48 mo

0.6

     

>49 mo

1.1

Hennekens/1984 (case-control)

None

Not mother

Any

1.1(0.9,1.2)

   

Mother

Any

1.0(0.6,1.7)

   

Not sister

Any

1.1(0.9,1.3)

   

Sister

Any

1.4(0.7,3.0)

Rosenberg/1984 (case-control)

None

Any

>5 yr

0.9(0.4,2.1)

CASH b /1986 (case-control)

None

None

Any

1.0(0.9,1.2)

   

First degree

Any

1.1(0.8,1.6)

   

Second degree

Any

0.9(0.7,1.2)

Lipnick/1986 (cohort)

None

Mother

Any

0.8(0.4,1.6)

   

Sister

Any

0.9(0.5,1.5)

Miller/1989 (case-control)

<45 yr old

None

Any

2.0(includes 1.0)

   

Any

Any

1.9(includes 1.0) c

Stanford/1989 (case-control)

None

Not mother

Any

1.0(0.8,1.2)

   

Mother

Any

0.8(0.5,1.2)

   

Not sister

Any

1.1(0.9,1.4)

   

Sister

Any

1.2(0.6,2.5)

WHOb/1990 (case-control)

 

None

Any

1.1(1.01,1.27)

   

Any

Any

1.3(0.75,2.16)

a Confidence interval of 95 percent used.

b CASH = Cancer and Steroid Hormone Study; WHO = World Health Organization.

c Relative risk = 3.4 in multivariate analysis (95 percent confidence interval includes 1.0).

duration of use. Pike and colleagues (1981) confined their analyses of data from young women to use of oral contraceptives before a woman 's first pregnancy. They found risk associated with such use to be particularly high in women with a history of benign breast disease. On the other hand, no trends of risk increasing with duration of use were observed by Paffenbarger and colleagues (1980) in postmeno-pausal women, or by Vessey and coworkers (1983) or Rosenberg and colleagues (1984) in studies that were not confined to young women. Because young women tend to have fibroadenomas, whereas older women tend to have various forms of fibrocystic disease, these findings suggest that oral contraceptives may enhance the risk of breast cancer in women with specific histological types of benign lesions. No studies have been completed that assess risk of breast cancer in users with benign lesions and include as part of the investigation an independent review of slides from the benign lesions. Such studies are in progress, however.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-13 Relative Risk of Breast Cancer in Women with Varying Body Mass Indices Who Have Ever Used Oral Contraceptives

First Author (Date)

Body Mass Index a

Relative Risk

Confidence Interval (95%)

Miller (1989)

<21

1.6

Includes 1.0

 

21-25

1.8

Includes 1.0

 

>26

3.5 b

Includes 1.0

Stanford (1989)

<21

0.80

0.5,1.3

 

22-23

0.89

0.6,1.2

 

24-25

0.94

0.7,1.3

 

>26

0.88

0.5,1.5

a Weight (in kilograms)/height (in centimeters)2.

b Relative risk = 4.2 (95 percent confidence interval excludes 1.0) in multivariate analysis.

Because oral contraceptives apparently protect against benign breast lesions, the assessment of the risk of breast cancer in users of oral contraceptives with prior benign lesions becomes complex. Stadel and Schlesselman (1986) have reviewed this issue and sensibly suggest that only oral contraceptive use after diagnosis of benign lesions should be considered when determining whether risk of breast cancer in women with benign breast disease is enhanced by use of oral contraceptives. This has been done in three studies summarized in Table B-15. None found an increased risk of breast cancer in women who took oral contraceptives after developing a benign breast lesion. None of these three studies are confined to young women.

Risk in Relation to Early Use of Oral Contraceptives

Because early menarche is associated with increased risk, and risk is reduced by an early first full-term pregnancy, it is reasonable to ask whether oral contraceptives used early in a woman's life, or before her first pregnancy, alter her risk of breast cancer. In 1981, Pike and colleagues confirmed earlier findings of Paffenbarger and col-

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-14 Relative Risks of Breast Cancer in Relation to Use of Oral Contraceptives in Women with Benign Breast Diseases: Case-Control Studies

First Author (Date)

Restrictions on Study Population

Use of Oral Contraceptives

Estimate of Relative Risk

Lees (1978)

30-49 yrs of age

None

1.0

   

<12 mo

1.0 (p>.05)

   

13-59 mo

2.3 (p>.05)

   

>60 mo

9.2 (p<.02)

Paffenbarger (1980)

Premenopausal

None

1.0

   

1-24 mo

0.5 (p>.05)

   

25-48 mo

3.0 (p>.05)

   

49-72 mo

1.2 (p>.05)

   

>73 mo

3.2 (p>.05)

 

Postmenopausal

None

1.0

   

1-24 mo

2.9 (p>.05)

   

25-48 mo

1.0 (p> 05)

   

49-72 mo

1.0 (p> 05)

   

>73 mo

0.8 (p> 05)

Kelsey (1978, 1981)

None

Any

No increase (data not given)

Janerich (1983)

<45 yrs

Any

2.5(1.1,5.3) a

Vessey (1983)

None

None

1.0

   

<48 mo

0.7

   

>49 mo

0.7

Rosenberg (1984)

None

>5 yrs

0.8(0.4,1.7) a

a ( ) = Confidence interval of 95 percent.

leagues (1980) that in women young enough to have used the pill before their first full-term pregnancy, risk increased with duration of use before that event. (Table B-16 summarizes results from these and subsequent investigations of this issue.) Four additional studies (Harris et al., 1982; McPherson et al., 1986; U.K. National Case-Control Study Group, 1989; Lund et al., 1989) showed strong trends of increasing risk with duration of use before a woman's first full-term pregnancy, and six others (Stadel et al., 1985; Miller et al., 1986; Jick et al., 1989; Miller et al., 1989; Olsson et al., 1989; WHO, 1990) showed weaker associations between such use and breast cancer that were not statistically significant. Conversely, four studies (Vessey et al., 1982; Rosenberg et al., 1984; Paul et al., 1986; Stanford et al., 1989) found no association between use before a first birth and breast cancer. The results from Stanford and colleagues (1989) are not presented in Table B-16 because they were not published in tabular form. A summary relative risk estimate of 1.44 (CI = 1.23,1.69) in long-term users before their first birth was obtained by combining results from all studies shown in the table. There is significant heterogeneity of results among studies, however, and this summary estimate should therefore be interpreted with caution. Table B-17 shows results from two cohort studies that are generally not supportive of this association. The reasons for the discrepant results are not known. Both population-based and hospital-based case-control studies of equally rigorous design have yielded conflicting results. Only the study by Olsson and coworkers (1989) has an obvious potential bias; in that study, physicians interviewed cases in the hospital, and interviewers interviewed controls in their homes by telephone.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

McPherson and colleagues (1986) have suggested that the reason for the discrepant findings is that the studies that showed no association were unable to assess risk after a long potential latent period. As shown in Table B-18, however, four studies have shown that risk is not particularly enhanced more than a decade after exposure to oral contraceptives before a first birth (McPherson et al., 1987; Vessey et al., 1989; Paul et al., 1990) or after 15 years following the first birth in women who used the pill prior to that birth (Schlesselman et al., 1988).

It should also be noted that in two of the studies in Table B-16

TABLE B-15 Relative Risk of Breast Cancer in Women Who Used Oral Contraceptives Before and After Diagnosis of a Benign Breast Lesion

   

Estimate of Relative Risk (Confidence Interval)a

First Author (Date)

Use of Oral Contraceptives

Before Benign Breast Disease

After Benign Breast Disease

CASH b (1986)

Any

0.7(0.5,0.97)

0.8(0.5,1.2)

Stanford (1989)

Any

1.22(0.7,2.1)

0.87(0.6,1.3)

 

<5 years

1.48(0.8,2.7)

0.91(0.5,1.5)

 

>5 years

0.55(0.2,1.7)

0.80(0.4,1.5)

WHO b (1990)

Any

1.30(0.75,2.27)

0.97(0.54,1.72)

Summary relative risk

Any

0.90[0.70,1.16] c

0.86[0.66,1.12] d

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated by approximate methods.

b CASH = Cancer and Steroid Hormone Study; WHO = World Health Organization.

cp value of chi-square test for heterogeneity = .08.

dp value of chi-square test for heterogeneity = .87.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-16 Relative Risks of Breast Cancer in Relation to Duration of Use of Oral Contraceptives Before First Full-term Pregnancy: Case-Control Studies

     

No. of Subjects

   

First Author (Date)

Ages of Cases at Diagnosis

Months of Use

Cases

Controls

Estimate of Relative Risk (Confidence Interval) a

p Valueof Test for Trend

Paffenbarger (1980)

Premeno-pausal

0

57

1,146

1.0

Not given

   

11-17

12

9

2.6[1.1,5.9]

 
   

>18

18

9

16

2.6[1 .3,4.0]

 

Pike (1981)

<32

0

79

141

1.0

 
   

1-48

53

103

1.0[0.6,1.5]

.009

   

>49

31

26

2.5(1.4,4.5)

 

Harris (1982)

35-54

<12

61

249

1.0

 
   

13-48

4

12

3.8(1.3,11.3)

.01

   

>49

1

1

12.9(0.6,265.6)

 

Vessey (1982)

16-50

0

995

996

1.0

 
   

1-12

28

25

0.8[0.5,1.4]

 
   

13-48

18

22

0.7[0.4,1.5]

 
   

>49

8

6

0.9[0.3,2.3]

 

Rosenberg (1984)

<59

0

643

1,946

1.0

 
   

<12

14

149

0.8(0.4,1.5)

>.05

   

13-35

21

133

1.3(0.7,2.3)

 
   

>36

10

91

0.9(0.4,1.8)

 

Stadel (1985)

<44

0

Not given

Not given

1.0

 
   

<12

   

1.3(1.0,1.7)

>.05

   

13-48

   

1.1(0.9,1.5)

 
   

>49

   

1.2(0.9,1.6)

 

Miller (1986)

<45

0

209

214

1.0

>.05

   

<12

35

41

0.7(0.4,1.2)

 
   

13-24

46

33

1.4(0.7,2.6)

 
   

25-48

26

25

0.8(0.4,1.6)

 
   

49-72

22

12

1.5(0.6,4.0)

 
   

>73

18

15

1.4(0.6,3.2)

 

Paul (1986)

25-54

0

268

472

1.0

.14

   

<24

60

147

0.9[0.6,1.2]

 
   

24-47

26

82

0.8[0.5,1.3]

 
   

48-71

11

41

0.7[0.4,1.4]

 
   

>72

11

52

0.6[0.3,1.1]

 

McPherson et al. (1987)

<45

0

235

273

1.0

<.01

   

1-12

27

26

1.0(0.5,1.9)

 
   

13-48

43

29

2.0(1.0,3.8)

 
   

>48

46

23

2.6(1.3,5.4)

 

Jick (1989)

<43

0

>48

75

1.0

.2

   

<12

1

4

0.3(0.0,3.5)

 
   

12-47

15

29

0.8(0.3,2.0)

 
   

>48

12

11

1.3(0.3,4.6)

 

Lund (1989) Sweden

<44

0

51

56

1.0

Not given

   

<47

73

71

1.1(0.7,1.9)

 
   

48-95

32

33

1.0(0.6,2.0)

 
   

>96

13

10

1.5(0.6,3.9)

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

Norway

<40

0

30

67

1.0

Not given

   

<47

19

30

1.4(0.6,3.0)

 
   

>48

6

5

1.8[0.6,5.1] b

 

Miller (1989)

<45

0

85

109

1.0

Not given

   

<12

27

21

1.5(0.7,3.7)

 
   

12-59

59

32

2.5(1.2,5.2)

 
   

>69

14

12

1.3(0.4,4.0)

 

Olsson (1989)

Premeno-pausal

0

91

305

1.0

<.08

   

<36

38

71

1.8(1.0,3.2)

 
   

37-95

30

58

2.1(1.1,3.8)

 
   

>96

13

21

2.0(0.8,4.7)

 

U.K. National Case-Control Study Group (1989)

<36

0

247

259

1.0

.02

   

1-48

219

254

1.0[0.8,1.3]

 
   

49-96

112

88

1.5[1.4,2.1]

 
   

>97

17

15

1.4[0.7,2.9]

 

WHO c (1990)

<62

0

1,691

9,660

1.00

Not given

   

<24

56

405

0.8(0.6,1.1)

 
   

>24

29

110

1.2(0.8,2.0)

 

Summary relative risk

 

Longest

   

1.4[1.2,1.7] d

 

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

b Calculated by combining relative risks of 2.2(0.5,9.8) and 1.4(0.1,26.7) for users of 48-95 and >96 months of use before their first full-term pregnancy.

c WHO = World Health Organization.

dp value of chi-square test for heterogeneity = .05.

(Miller et al., 1989; U.K. National Case-Control Study Group, 1989), equally strong associations were observed between risk of breast cancer and use after a woman's first live birth. In addition, in 1983 Pike and coworkers published an update of their earlier study. They did not present data on use before a first full-term pregnancy, but claimed that use at an early age (regardless of whether before or after first pregnancy) was more important than use before a first full-term pregnancy in increasing the risk of breast cancer. They reported an increase in risk with duration of use before the age of 25.

As shown in Table B-19, findings similar to those of Pike and colleagues (1983) were observed by Olsson and colleagues (1989), and to a lesser extent also by Meirik and coworkers (1986) and the WHO

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-17 Relative Risks of Breast Cancer in Relation to Duration of Use of Oral Contraceptives Before First Full-term Pregnancy: Cohort Studies

First Author (Date)

Months of Use

Cases per 1,000 Person-Years (No. of Cases)

Estimate of Relative Risk (Confidence Interval) a

Vessey (1989) b

0

0.57 (84)

1.00

 

<47

0.83 (15)

1.46[0.84,2.53]

 

>48

0.62 (7)

1.09[0.51,2.34]

Romieu (1989) c

0

1.60 (371)

1.00

 

1-11

1.00 (52)

0.98(0.72,1.35)

 

12-35

1.01 (34)

1.12(0.77,1.63)

 

>36

0.81 (9)

0.84(0.43,1.66)

Summary relative risk

Longest

 

0.94[0.57,1.55] d

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

b Rates are age adjusted.

c Rates are not age adjusted.

dp value of chi-square test for heterogeneity = .62.

study (1990). The CASH (1986) study yielded equivocal results, with increased relative risks in some categories of years of use, but no trend of increasing risk with duration of exposure before age 25. Conversely, two studies (Miller et al., 1986; Paul et al., 1986) found no association between breast cancer and use before age 25.

Other investigators of early use did not publish their findings in such a manner that they could be included in Table B-19. McPherson and colleagues (1987) did not find an association with duration of use before age 25, but they did not publish relative risk estimates. Stanford and coworkers (1989) estimated the relative risk to be 0.96 (0.6,1.7) in women who had ever used oral contraceptives before age 25; this estimate, however, was based on only 26 exposed cases and 30 exposed controls, all of whom used oral contraceptives for less than five years before the age of 25. One cohort study (Vessey et al., 1989) found relative risks of 0.92 and 1.21 in women who had used oral contraceptives before age 25 for less than four years and for four or more years, respectively (based on 17 and 1 exposed cases, respectively). Thus, results from studies not included in Table B-19, like those shown in the table, have also yielded inconsistent results.

Other investigators have not presented results specifically for users before the age of 25, but have nevertheless published results that

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

are broadly compatible with early oral contraceptive use being a risk factor for breast cancer. Miller and coworkers (1989) found increased risks in women who used the pill for more than five years in each of four age categories under the age of 44, and the U.K. National Case-Control Study Group (1989) found increasing risks with duration of use in women under age 36 who first used the pill at various ages. Because the authors of these studies (and some others summarized in Table B-16, Table B-20, and Table B-21, but not included in Table B-19) did not specifically publish results of use before age 25, the reports that have

TABLE B-18 Relative Risks of Breast Cancer in Relation to Duration of Use of Oral Contraceptives Before a Woman's First Full-term Pregnancy, After Varying Potential Latent Periods

   

Excluding Use Before First Full-term Pregnancy Within the Following Years Prior to Diagnosis

First Author (Date) a

Months of Use Before First Full-term Pregnancy

No Exclusions

6 Years

10 Years

14 Years

20 Years

McPherson (1987)

0

1.00

1.00

1.00

1.00

 
 

1-12

1.02

1.24

1.20

1.74

 
 

13-48

1.97

1.83

2.45

1.37

 
 

>48

2.59

2.30

1.65

1.97

 

Vessey (1989)

0

1.00

1.00

1.00

   
 

1-12

0.48

0.46

0.72

   
 

13-47

1.66

1.40

2.44

   
 

>48

1.18

1.03

0.87

   

Paul (1990) b

0

1.00

1.00

1.00

1.00

1.00

 

<24

0.89

0.89

0.83

0.80

0.49

 

25-47

0.81

0.81

0.86

0.96

2.0

 

>48

0.60

0.65

0.44

0.43

 

Schlesselman (1988) c

0

1.0

1.0

1.0

1.0

 
 

<2

0.6

0.9

1.3

1.0

 
 

2-3

0.5

1.2

1.4

1.0

 
 

4-6

0.7

0.9

1.0

1.0

 
 

>6

0.6

0.7

1.1

   

a All studies are case-control designs except Vessey, which is a cohort design.

b In this research periods of 5 years (rather than 6) and 15 years (rather than 14) were used.

c The Schlesselman study reported on years from first full-term pregnancy to diagnosis. Categories used were 0-4 years (rather than “No Exclusions ”), 5-9 years (rather than “6 Years”), 10-14 years (rather than “10 Years”), and longer than 15 years (rather than “14 Years”).

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-19 Relative Risks of Breast Cancer in Relation to Duration of Use of Oral Contraceptives Before Age 25: Case-Control Studies

     

No. of Subjects

   

First Author (Date)

Ages of Cases at Diagnosis

Months of Use

Cases

Controls

Estimate of Relative Risk (Confidence Interval) a

p Value of Test for Trend

Pike (1983)

<37

0

65

93

1.0

<.0001

   

<2

106

118

1.3(0.8,2.0)

 
   

2-3

79

67

1.7(1.0,2.7)

 
   

4-5

40

29

2.0(1.1,3.6)

 
   

>6

24

7

4.9(1.9,13.4)

 

Meirik (1986)

<44

0

177

242

1.0

Not given

   

<3

186

228

1.1(0.8,1.5)

 
   

4-7

51

54

1.1(0.7,1.8)

 
   

>8

8

3

2.7(0.7,11.0)

 

Paul (1986)

25-54

0

292

465

1.0

.4

   

<2

81

191

1.2[1.0,1.5]

 
   

2-3

44

141

1.0[0.7,1.4]

 
   

4-5

11

65

0.7[0.4,1.3]

 
   

>6

5

35

0.6[0.3,1.4]

 

CASH (1986) b

<44

0

257

259

1.0

Not sig.

 
   

1-2

395

395

1.3(1.0,1.6)

 
   

3-4

266

267

1.3(1.0,1.8)

 
   

5-6

113

110

1.5(1.1,2.1)

 
   

>6

17

30

1.0(0.5,2.0)

 

Miller (1986)

<45

0

207

214

1.0

Not sig.

   

<1

26

35

0.8(0.4,1.5)

 
   

1-2

59

56

1.0(0.6,1.6)

 
   

3-4

43

33

1.3(0.7,2.3)

 
   

>5

14

16

1.1(0.4,2.9)

 

Olsson (1989)

Premeno-pausal

0

87

286

1.0

<.001

   

<2

35

85

1.6(0.9,2.8)

 
   

3-5

34

69

2.0(1.1,3.5)

 
   

>5

15

19

5.3(2.1,13.2)

 

WHO c (1990)

<62

0

1,908

11,104

1.0

.31

   

<1

82

881

1.0(0.7,1.3)

 
   

1-2

37

421

0.8(0.6,1.1)

 
   

2-3

29

207

1.5(1.0,2.3)

 
   

>3

29

243

1.5(1.0,2.3)

 

Summary relative risk

 

Longest

   

1.5[1.2,2.0] d

 

a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.

b CASH = Cancer and Steroid Hormone Study. Unpublished data provided by P. Wingo.

c WHO = World Health Organization.

dp value of chi-square test for heterogeneity = .002.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-20 Relative Risks of Breast Cancer in Women Under 45 Years of Age Who Have Ever Used Oral Contraceptives: Summary of Results from Case-Control Studies

   

Cases/Controls

 

First Author (Date)

Age of Cases

Nonusers

Users

Estimate of RelativeRisk (Confdence Interval) a

Kelsey (1978)

20-44

59/65

40/34

1.6(0.8,2.4)

Vessey (1983)

<45

N.g. b

N.g. b

0.81[0.6,1.03]c

Janerich (1983)

<45

120/264

133/233

1.22(0.88,1.69)

Rosenberg (1984)

20-39

68/872

149/1,804

1.13[0.78,1.63] c

Paul (1986)

25-44

26/69

165/501

0.97[0.63,1.50] c

Miller (1986)

<45

207/214

314/307

0.9(0.7,1.4)

Lee (1987)

25-44

27/225

37/273

1.15[0.7,2.0] c

Ravnihar (1988)

25-44

112/556

115/345

1.64[1.19,2.26] c

Jick (1989)

<43

28/29

78/124

0.9(0.4,1.9)

Miller (1989)

<45

125/176

282/248

2.0(1.4,2.9)

Stanford (1989)

<45

112/144

172/183

1.13[0.7,1.85] c

WHO d (1990)

<35

141/2,722

160/1,613

1.26(0.95,1.66)

CASH e

<45

387/403

1,654/1,619

1.14(0.96,1.35)

Summary relative risk

     

1.16[1.05,1.28] f

a Confidence interval of 95 percent used; [ ] = confidence interval estimated from published data.

b N.g. = number not given.

c Relative risk estimated by combining results from more than one age group under 45 years.

d WHO = World Health Organization.

e CASH = Cancer and Steroid Hormone Study. Unpublished data provided by P. Wingo.

fp value of chi-square test for heterogeneity = .006.

included such results may be biased in favor of including a disproportionate number with positive findings. Because of this likelihood and the significant heterogeneity of results among the studies in Table B-19 (and among those not included in this table), the summary relative risk of 1.53 (CI = 1.16,2.02) for long-term users before the age of 25 should be interpreted with caution.

Studies of breast cancer in relation to use of oral contraceptives at an early age have, of necessity, been confined largely to breast cancer in young women because the pill was not available when older women with breast cancer were in their early reproductive years. However, focusing attention on early use, rather than the effect of any long-term use on risk of breast cancer in young women, may have obscured underlying consistencies of results among studies. Table B-20 shows estimates from 13 studies of the relative risk of breast cancer in women under age 45 who have ever used oral contraceptives.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-21 Relative Risks of Breast Cancer in Women Under 45 Years of Age with Long-term Oral Contraceptive Use: Summary of Results from Case-Control Studies

     

Cases/Controls

 

First Author (Date)

Age of Cases

Years of Use

Nonusers

Users

Estimate of Relative Risk (Confidence Interval) a

Kelsey (1978)

20-44

>5

59/65

9/6

1.7 (0.5,5.4)

Janerich (1983)

<45

>6

120/264

36/64

1.18 (0.94,1.45)

Rosenberg (1984)

20-39

>5

68/872

42/398

1.25 [0.84,1.85] b

Meirik (1986)

<45

>12

96/156

39/23

2.2 (1.2,4.0)

Miller (1986)

<45

>7

207/214

18/15

1.4 (0.6,3.2)

Paul (1986)

25-44

>10

26/69

32/83

1.10 [0.60,2.04] c

McPherson (1987)

<45

>12

111/122

21/20

1.78 (0.82,3.87)

Jick (1989)

<43

>10

28/29

17/15

1.4 (0.4,4.6)

Miller (1989)

<45

>10

125/176

26/16

4.1 (1.8,9.3)

U.K. National Case-Control Study Group (1989)

<36

>8

67/80

198/143

1.74 [1.29,2.33]

WHO d (1990)

<35

>4

5/292

141/27,224

1.45 (0.97,2.21) e

CASH f

<45

>10

387/403

205/174

1.23 (0.97,1.56) g

Summary relative risk

       

1.42 [1.25,1.63] h

a Confidence interval of 95 percent used; [ ] = confidence interval estimated from published data.

b Value computed by combining relative risks of 0.8 and 1.3 in women in the age groups 20-29 and 30-39 years.

c Value computed by combining relative risks of 4.6 and 0.84 in women in the age groups 25-34 and 35-44 years.

d WHO = World Health Organization.

e Value computed by combining relative risks of 1.60 and 0.93 for users of 4-8 and >8 years, respectively.

f CASH = Cancer and Steroid Hormone Study. Unpublished data provided by P. Wingo.

g Value computed by combining relative risks of 1.28 and 0.93 for users of 10-14 years and >15 years, respectively.

hp value of chi-square test for heterogeneity = .21.

Although the 95 percent confidence interval of the summary relative risk does not include 1.0, the point estimate is only 1.16, and there is considerable (and statistically significant) heterogeneity among the estimates from the individual studies.

More uniformity of results is seen when duration of use is considered. Table B-21 shows re-

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

sults from 12 case-control studies that reported estimates of the relative risk of breast cancer in women under the age of 45 in relation to duration of use of oral contraceptives. In 2 of the studies, estimates from two age groups under 45 were combined, and in 2 others estimates from two categories of duration of use were combined, to provide more stable estimates for presentation in the table. The differences among the estimated relative risks can be explained on the basis of chance variation (p = .21), and a summary estimate of 1.42, with narrow confidence limits, was obtained by combining results from all studies in the table.

Although findings from a number of other case-control studies were not published in sufficient detail for inclusion in this table, most are broadly supportive of the results shown. Three reported increased relative risks in women under age 45, but did not present results in relation to duration of use (Fasal and Paffenbarger, 1979; Lee et al., 1987; Stanford et al., 1989). Two others reported increased relative risks in long-term users under age 45, but did not publish sufficient information for estimation of their confidence intervals (Lubin et al., 1982; Ravnihar et al., 1988). In four more studies, results were published only in relation to certain features of early use: two of these (Pike et al., 1983; Olsson et al., 1989) reported an increase in risk in relation to duration of use before age 25; three of the four (Paffenbarger et al., 1980; Harris et al., 1982; Olsson et al., 1989) reported an increased risk in relation to duration of use before a first full-term pregnancy. In addition, one of these studies (Olsson et al., 1989) reported that the relative risk of breast cancer in women who had ever used oral contraceptives increased with decreasing age at first use. Reanalysis of the data from these studies could well produce results similar to those in Table B-21.

Also supportive of the findings in Table B-21 are the recent results of one cohort study (Kay and Hannaford, 1988), which showed a strong trend of increasing risk related to duration of use in 30- to 34-year-old women (Table B-22). In the Nurses Health Study, Romieu and colleagues (1989) found a small increase in risk in women under age 45 who were using oral contraceptives when the cohort was established, but not in prior users. Although no significant increase in risk related to duration of use of oral contraceptives was found in 25-to 44-year-old women in the Oxford-Family Planning Association contraceptive cohort study (Vessey et al., 1989), rates are very slightly higher in users of more than 72 months' duration than in shorter-term users or nonusers.

Selective reporting of only positive results does not appear to be a likely explanation for the relative consistency of findings among studies. Only two case-control studies not shown in Table B-21, that have

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-22 Relative Risks of Breast Cancer in Women Under 45 Years of Age Who Have Ever Used Oral Contraceptives: Summary of Results from Cohort Studies

First Author (Date)

Age at Diagnosis

Years of Use

Cases per 1,000 Person-Years (No. of Cases)

Estimate of Relative Risk (Confidence Interval) a

Kay (1988)

<35

None

0.10(6)

1.00

   

Ever

.24(27)

2.38(0.98,5.76)

 

30-34

None

0.12(4)

1.00

   

<2

0.36(4)

3.00(0.85,10.69)

   

2-3

0.40(6)

3.33(0.94,11.80)

   

4-5

0.49(6)

4.08(1.15,14.46)

   

6-7

0.26(2)

2.17(0.40,11.85)

   

8-9

0.30(1)

2.50(0.28,22.37)

   

<10

1.22(1)

10.17(1.14,90.99)

Romieu (1989)

30-34

None

0.52(9)

1.00

   

Current

0.37(3)

0.71(0.19,2.60)

   

Past

0.35(18)

0.67(0.30,1.40)

 

35-39

None

0.83(43)

1.00

   

Current

0.90(6)

1.00(0.43,2.35)

   

Past

0.88(100)

1.05(0.74,1.51)

 

40-44

None

1.12(104)

1.00

   

Current

2.98(13)

2.66(1.53,4.63)

   

Past

1.28(153)

1.14(0.89,1.46)

 

<44

None

0.96(156)

1.00

   

Current

1.15(22)

1.20[0.90,1.60]

   

Past

0.95(271)

0.99[0.81,1.20]

Vessey (1989)

25-44

None

0.62(49)

1.00

   

<2

0.56(9)

0.90[0.44,1.82]

   

2-3

0.50(11)

0.81[0.42,1.55]

   

4-5

0.61(16)

0.98[0.56,1.73]

   

6-7

0.64(15)

1.03[0.57,1.85]

   

8-9

0.65(12)

1.05[0.56,1.97]

   

>10

0.65(14)

1.05[0.58,1.89]

a Confidence interval of 95 percent used; [ ] = estimates from published data.

specifically addressed the issue of oral contraceptive use and risk of breast cancer in young women have not shown some evidence of an enhanced risk. One (Vessey et al., 1983) found relative risks of 1.01, 0.71, and 1.01 in users of more than eight years' duration among 16-to 35-year-old, 36- to 40-year-old, and 41- to 45-year-old women, respectively. The other study (La Vecchia et al., 1986) reported a relative risk of 0.87 in women under age 40 who had ever used oral contraceptives. No confidence intervals were given in the reports of either study. If the estimate of approximately a 40 percent increase in risk in young women who were long-term users is correct, a few studies could have failed to detect such a small enhancement in risk because of chance or insufficient statistical power.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

Table B-1 and Table B-2 illustrated that the relative risk of breast cancer in women of all ages combined who have ever used oral contraceptives is close to unity, with narrow confidence limits; it was also shown that there has been little overall increase in risk in long-term users (Table B-3 and Table B-4), or in women long after initial exposure (Table B-5 and Table B-6). Three possible interpretations of findings for young women are not incompatible with these overall results. One is that the proportion of cases under age 45 in most of the studies of women of all ages was relatively small, and the increased risk in young women may have contributed too little to the overall estimated value of the relative risk to elevate it appreciably above unity. A second possible interpretation is that women who have used oral contraceptives may tend to have their tumors diagnosed earlier than do nonusers, due to more screening or breast self-examination (screening bias). A third possibility is that oral contraceptives stimulate growth of breast carcinomas, so that women who are destined to develop them tend to do so at an earlier age (growth stimulation). The latter two explanations would eventually result in an observed reduction in risk in women at some time beyond age 45, and no overall alteration of risk.

Table B-23 shows relative risks in long-term users for women in various age groups above and below 45 years. Three of the studies (Paul et al., 1986; McPherson et al., 1987; Vessey et al., 1989) are supportive of either of the latter two possibilities given above, in that relative risks are greater than 1.0 in young women, and under 1.0 in older women. The three other studies shown in the table, however, do not show this variation in relative risks by age.

Other evidence that oral contraceptives are associated with earlier diagnosis or tumor growth stimulation would be a rise, and then a fall, in relative risk with duration of use in current users (as a surrogate for risk in relation to time from initial exposure in women who continue to take the pill). The first three studies shown in Table B-24 reported relative risks by duration of use in women who were last exposed within the previous year. As shown in column 1 of the table, two of these studies (Rosenberg et al., 1984; CASH, 1986) showed some increase and then a fall in relative risk in relation to duration of use in current users, but the WHO (1990) study did not. One might also expect to see a decline in risk with time since last exposure in women in those duration-of-use categories in which an increase in risk in current users was observed. This trend is apparent only in the WHO study.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-23 Relative Risks of Breast Cancer in Long-term Users of Oral Contraceptives by Age at Diagnosis

First Author (Date) a

Duration of Use

Age at Diagnosis

Relative Risk

Vessey (1983)

>8 years

16-35

1.01

   

36-40

0.71

   

41-45

1.01

   

46-50

1.07

Rosenberg (1984)

>5 years

20-29

0.8

   

30-39

1.3

   

40-49

0.9

   

50-59

1.7

Paul (1986)

>10 years

25-34

4.6

   

35-44

0.84

   

45-54

0.96

McPherson (1987)

>12 years

<45

1.78

   

>45

0.84

Ravnihar (1988)

>7 years

25-34

1.26

   

35-44

2.63

   

45-54

2.15

Vessey (1989)

>10 years

25-44

1.05

   

>45

0.48

a All studies in the table are case-control designs except Vessey, which is a cohort design.

A consideration of the histological features of breast tumors that have developed in users of oral contraceptives provides some suggestion that these products may stimulate tumor growth. Romieu and colleagues (1989) found tumors in users to be larger and more often metastatic at diagnosis than those in nonusers (although this has not been observed by others, as indicated in the next section); Kay and Hannaford (1988) found that tumors in women under age 35 were of a somewhat higher grade in users than nonusers; and Stanford and coworkers (1989) observed, in women in a screening program, a relative risk for in situ tumors of 0.57 in relation to more than five years of oral contraceptive use, but relative risks of 1.54 and 1.37 for small and large invasive tumors, respectively.

Screening Bias

If an observed association between oral contraceptives and breast cancer is a result of users being diagnosed because of more intensive

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-24 Relative Risk of Breast Cancer by Duration of Use and Time Since Last Use of Oral Contraceptives

First Author (Date)

Years of Use

Years Since Last Use

         
   

<1

1-4

5-9

10-14

>10

>15

Rosenberg (1984)

<1

0

1.0

1.1

0.7

 

1.2

 

1-4

0.7

0.8

1.0

1.1

 

0.8

 

5-9

1.4

0.9

1.3

 

1.7

 
 

>10

0.9

0.9

0.6

 

1.1

 
   

<1

1-4

5-9

10-14

 

>15

CASH a (1986)

<1

1.0

1.2

1.0

0.8

 

1.0

 

1-2

1.5

1.0

1.4 b

0.9

 

0.9

 

3-5

1.5

1.6 b

1.1

1.0

 

0.8

 

6-9

1.1

1.2

1.3

1.1

 

0.1 b

 

10-14

1.0

1.1

1.3

1.0

   
 

>15

0.5

1.1

0.2 b

     
     

<5

5-9

10-14

 

>15

Miller (1989)

>5

 

2.7

1.7

1.7

 

6.0

     

3

6

9

12

 

U.K. National Case-Control Study Group (1989) d

1-4

 

1.01

1.29

1.08

0.95

 
 

5-8

 

1.42

1.47

1.63

1.23

 

>8

 

2.22

3.10

     
   

<1/4

1/4-3

4-9

 

>10

 

WHO c (1990)

<1

2.07

1.23

1.23

 

1.01

 
 

1-2

1.41

1.63

1.10

 

0.88

 
 

3-8

1.19

1.53

1.20

 

0.60

 
 

>8

2.16

1.38

1.12

 

0.76

 

a CASH = Cancer and Steroid Hormone Study.

b Ninety-five percent confidence interval of estimate excludes 1.0.

c WHO = World Health Organization.

d Calculated by eliminating and controlling for use before years since last use shown.

screening (or breast self-examination), then one would expect tumors in users, and perhaps especially in long-term and recent users, to be smaller and more locally confined than tumors in nonusers. The U.K. National Case-Control Study Group (1989), Kay and Hannaford (1988), and Miller and coworkers (1989) all found trends of increasing relative risk in young women with duration of use (Table B-21 and Table B-22), but none of these three studies found convincing evidence for a screening bias. Only small differences between users and nonusers in the size of tumors and in the extent of the disease at diagnosis were observed by the U.K. group and by the Miller team. In addition, in the former study, breast self-examination was practiced with equal frequency by users and nonusers, although a higher proportion of exposed than unexposed women had had a breast examination in the past year. The results of Kay and Hannaford (1988) could not be explained by differential screening in users because few women (6 percent of users and 4 percent of nonusers) had their tumor diagnosed as a result of screening for breast cancer.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

In the WHO (1990) study risk was particularly enhanced in relation to use in low-risk countries, and in relation to long-term and recent use. Yet, individuals characterized by such use were not more likely than other users or nonusers to have smaller tumors or more localized disease at diagnosis. A small increase in risk in women who had used oral contraceptives for more than three years before age 25 was also observed in that study and such users did tend to have small tumors, but users of shorter duration, with an equally high relative risk, did not. The small increase in relative risk in relation to use before a woman's first live birth that was observed in the WHO study was found to be confined to women who had had an aborted pregnancy or stillbirth prior to their first live birth. In those cases the tumors tended to be smaller than the tumors in other women, suggesting the possibility of enhanced surveillance for breast cancer in this small group.

On balance, it appears unlikely that the major positive finding from these studies (and by inference from other studies as well) can be explained by enhanced screening in users of oral contraceptives.

Risk in Relation to Use of Oral Contraceptives Near the Age of Menopause

Women who go through the menopause late in life are at higher risk for breast cancer than women with an early natural or artificial menopause. If use of oral contraceptives late in a woman's potentially reproductive years were to simulate endocrinologically a late menopause, one would expect such use to increase a woman's risk of breast cancer. This possibility has not been adequately investigated, but results of analyses relevant to this question are summarized in Table B-25. The findings are equivocal. Three studies show increased relative risks in users over age 45 (Vessey et al., 1979; Yuan et al., 1988) or over age 50 (Jick et al., 1980), but this was not observed by Rosenberg and colleagues (1984). In addition, although use of oral contraceptives

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-25 Relative Risks of Breast Cancer in Women Who Used Combined Oral Contraceptives Near the Age of Menopause

First Author (Date)

Definition of Exposure

Age or Years of Use

Relative Risk

Confidence Interval (95%)

Vessey (1979)

Use in past year

41-45 years old

0.85

Not given

   

46-50 years old

2.57

Not given

Jick (1980)

Current use

41-45 years old

0.8

0.1,4.6

   

46-50 years old

4.0

1.8,9.0

   

51-55 years old

15.5

5.2,46

Rosenberg (1984)

Use in past year

40-49 years old

0.9

0.4,1.9

   

50-59 years old

1.0

0.1,1.7

Yuan (1988)

Any use after age 45

Any use

4.00

1.15,16.59

Stanford (1989)

Premenopausal years of use after age 40

<2 years

0.95

Includes 1.0

   

2-3 years

1.46

Includes 1.0

   

4-5 years

1.03

Includes 1.0

   

6-7 years

1.18

Includes 1.0

   

>8 years

1.05

Includes 1.0

 

Postmenopausal years of use after age 40

<2 years

0.76

Includes 1.0

   

2-3 years

0.51

Includes 1.0

   

4-5 years

0.97

Includes 1.0

   

6-7 years

1.49

Includes 1.0

   

>8 years

1.00

Includes 1.0

Romieu (1989)

Use up to 2 years before diagnosis

40-44 years old

2.66

1.53,4.63

   

45-49 years old

1.63

0.81,3.27

   

50-54 years old

1.13

0.28,4.45

up to two years prior to diagnosis was associated with an elevated risk in three age groups above 39 years in the Nurses Health Study (Romieu et al., 1989), the relative risks were lower in 50- to 54-year-old women than in younger women. There is a suggestion of an increase in risk in users of from six to seven years after age 40 in postmenopausal women in the study of Stanford and colleagues (1989), but not in users of eight or more years' duration. Data from other studies should be analyzed to address this issue further, with particular emphasis on use that extends into the sixth decade of life.

Individual Formulations and Constituents of Oral Contraceptives

In 1983, Pike and coworkers reported that risk of breast cancer was particularly increased in association with use before age 25 of oral contraceptives with a high progestin potency, as determined by the

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

delay of menses test. This result may have been an artifact, however, that arose from the erroneous classification of one particular product as being of high potency (Armstrong, 1986). For purposes of comparison, results from the CASH Study (Stadel et al., 1985) were presented using the same classification scheme, and relative risks in users of products classified as of high progestin potency were not found to be significantly increased. Relative risks associated with four categories of duration, the longest being greater than 74 months, varied from 1.1 to 1.3 but did not increase with length of exposure. Miller and colleagues (1986) also did not confirm the findings of the Pike study. Relative risks of 1.0 (CI = 0.5,2.2) and 1.1 (CI = 0.4,3.0) were observed in users of two “high progestin potency” pills (Ovral and Ovulen 1, respectively).

In 1987, McPherson and coworkers reported an increase in risk in relation to duration of use before a woman's first full-term pregnancy with oral contraceptives that contain the estrogen ethinyl estradiol, but not in relation to similar use of preparations containing mestranol. However, this result was not confirmed by Schlesselman and coworkers (1987) or Vessey and colleagues (1989).

Three groups of investigators have reported relative risks in relation to use at any time of preparations containing ethinyl estradiol and mestranol. As shown in Table B-26, no study shows a stronger association with breast cancer for one type of estrogen than the other. Table B-27 similarly shows that no specific type of progestin has been implicated as being particularly associated with breast cancer risk. It should be noted that all of the progestins shown in the table except megestrol acetate are derivatives of 19-nor-testosterone. Formulations containing 17-α-hyroxyprogesterone derivatives (i.e., medroxyprogesterone acetate and chlormadinone) were shown to cause mammary tumors in beagle dogs, and were subsequently withdrawn from the market in many countries, including the United States. These products are in use in some countries of the world and were investigated in the WHO (1990) study. Analyses to assess the relative risk of breast cancer in users of such products are in progress, but results are not yet available.

Finally, results from three studies that estimated relative risks of breast cancer in relation to specific pill types are summarized in Table B-28. No single formulation is consistently related to breast cancer across all three studies. Also, relative risks do not appear to be uniformly higher for the higher dose products (shown near the top of each section of the table) than for the lower dose pills. In support of these observations, Ravnihar and colleagues (1988) and Vessey and coworkers (1989) found no appreciable differences in the distributions of cases and controls by type of pill used. In addition, Vessey and colleagues found no difference in the distributions of person-years of exposure of cases and controls to specific formulations.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-26 Associations Between Breast Cancer and Dosages of Mestranol and Ethinyl Estradiol in Oral Contraceptives

First Author (Date)

Dosage

Measure of Association

Mestranol

Ethinyl Estradiol

CASH a (1986)

<1.0 mg-mo b

Relative risk

0.8(0.7,1.1)

1.1(0.8,1.4)

 

1.0-2.9 mg-mo

 

1.0(0.8,1.2)

0.9(0.7,1.2)

 

3.0-4.9 mg-mo

 

1.1(0.9,1.4)

1.3(0.9,1.9)

 

>5.0 mg-mo

 

1.1(0.9,1.3)

0.8(0.5,1.2)

 

Any use

 

1.0(0.9,1.1)

1.0(0.8,1.2)

U.K. National Case-Control Study Group (1989)

<50/<100 micrograms c

Relative risk a ,d

1.08

1.04

 

>50/>100 micrograms e

 

1.03

1.12

 

Any strength

 

1.09

1.08

Vessey (1989)

30/50 micrograms f

Mean months used in cases/mean months in controls

1.02

1.04

 

50/100 micrograms g

 

0.82

0.86

 

100/__ micrograms h

 

N.a.

0.60

 

Any strength

 

0.95

0.89

N.a. = Not applicable.

a CASH = Cancer and Steroid Hormone Study.

b mg-mo = Milligram - months of use.

c <50 Micrograms ethinyl estradiol or <100 micrograms mestranol.

d Estimated from published report by calculating mean relative risks weighted by woman-months of use.

e>50 Micrograms ethinyl estradiol or >100 micrograms mestranol.

f 30 Micrograms ethinyl estradiol or 50 micrograms mestranol.

g 50 Micrograms ethinyl estradiol or 100 micrograms mestranol.

h 100 Micrograms ethinyl estradiol.

TABLE B-27 Associations Reported in Two Studies Between Breast Cancer and Types of Progestins in Oral Contraceptives

Progestin

CASH a (1986)

Vessey b (1989)

Ethynodiol diacetate c

1.1(0.9,1.4)

0.7

Norethindrone

1.1(1.0,1.3)

1.1

Norethindrone acetate c

1.1(0.7,1.6)

1.3

Norethynodrel

0.8(0.6,0.9)

 

Norgestrel (LorDL)

1.0(0.8,1.3)

1.0

Lynoestrenol c

 

0.9

Megestrol acetate

 

0.9

a CASH = Cancer and Steroid Hormone Study. Relative risks in women who only took oral contraceptives with the specific progestin shown. Parentheses indicated 95 percent confidence intervals.

b Ratios of mean months of use in cases to mean months of use in controls.

c Metabolized to norethindrone (Norethisterone).

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

TABLE B-28 Relative Risks of Breast Cancer in Women Who Have Ever Used Specific Types of Oral Contraceptives

 

Progestin

     

Micrograms of Mestranol

Type

Milligrams

CASH (1986) a

Miller (1989) b

U.K. Study c (1989)

100

Ethynodiol diacetate

1.0

1.1(0.9,1.4)

1.1(0.4,2.9)

0.95

100

Norethynodrel

2.5

0.7(0.5,0.9)

2.6(0.6,11)

 

100

Norethisterone

2.0

1.3(1.0,1.7)

1.9(0.5,7.1)

1.18

80

Norethisterone

1.0

1.0(0.8,1.3)

0.7(0.2,2.6)

 

75

Lynestrenol

2.5

   

0.87

75

Norethynodrel

5.0

0.8(0.5,1.3)

   

60

Norethisterone

10.0

0.6(0.3,1.3)

   

50

Norethisterone

1.0

1.2(0.9,1.5)

3.3(1.5,7.1)

1.10

Micrograms of Estradiol

         

50

Ethynodiol diacetate

1.0

1.0(0.6,1.6)

1.0(0.3,3.6)

1.26

50

Lynestrenol

2.5

   

1.13

50

Megestrol acetate

4.0

   

0.96

50

Norethisterone acetate

4.0

   

1.36

50

Norethisterone acetate

3.0

   

1.09

50

Norethisterone acetate

2.5

   

1.21

50

Norethisterone acetate

1.0

1.6(0.9,2.8)

1.0(0.2,5.4)

1.11

50

Norgestrel

0.5

0.9(0.7,1.2)

1.8(1.0,3.3)

1.05 d

35

Norethisterone

0.5

0.8(0.5,1.2)

 

1.18

32

Levonorgestrel

0.09

   

0.83

30

Norgestrel

0.30

0.7(0.4,1.3)

0.8(0.3,2.1)

 

30

Levonorgestrel

0.25

   

1.00

30

Levonorgestrel

0.15

   

1.08

20

Norethisterone acetate

1.0

   

1.36

a CASH = Cancer and Steroid Hormone Study; ( ) = confidence interval of 95 percent.

b ( ) = confidence interval of 95 percent.

c U.K. Study = U.K. National Case-Control Study Group.

d Relative risk was estimated by calculating the mean of the relative risks for two different products that contain 0.25 milligrams Levonorgestrel, weighted by woman-months of use.

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

CONCLUSIONS, INTERPRETATIONS, AND RECOMMENDATIONS FOR FURTHER RESEARCH

Oral contraceptives, as they have been used to date, have caused little or no overall increase in the risk of breast cancer in women in developed countries. Risks in women of all ages combined have not been appreciably enhanced by more than a decade of exposure or after a potential latent period of up to two decades.

Limited information from developing countries, where rates of breast cancer are much lower than in the developed countries where most studies of oral contraceptives and breast cancer have been conducted, suggests that oral contraceptive use may moderately enhance risk in women in low-risk populations. A possible mechanism for this increase is the stimulation of proliferative activity in the stem cells of the lobular epithelium. Such stimulation may not occur to a measurable extent in high-risk populations of women, whose lobular epithelia may already be maximally stimulated by other (unknown) factors that put these women at high risk. Further studies in low-risk populations are warranted.

Oral contraceptives do not appear to have a differential impact on risk in women with and without such risk factors for breast cancer as high socioeconomic status, nulliparity, low parity, a late first fullterm pregnancy (or live birth), or a family history of breast cancer. Compared to risks of breast cancer among countries, which may differ by a factor of 10, the risks in women with and without each of these risk factors differ by a factor of only about 2 or 3. The potential for the lobular epithelium of the breast of women without these risk factors to be further stimulated by oral contraceptives, compared with this potential in women with these factors, may thus be smaller than the differential potential for lobular stimulation in women in low-and high-risk populations. (It may also be too small to measure by epidemiological means.) Further study of the influence of oral contraceptives in women with and without the generally recognized risk factors for breast cancer should not receive high priority.

Limited information suggests that oral contraceptives (whether used before or after a benign lesion) may enhance the risk of breast cancer in young women with a prior history of benign breast disease but not in older women with such a history. Because the benign lesions in younger women are more likely than the benign lesions in older women to be fibroadenomas, further study of this issue should include young women in particular. It should also include a slide review to characterize the prior benign lesion histologically. In women of all ages combined, the use of oral contraceptives after benign lesions has not

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

been shown to enhance risk. The suggested study in young women should distinguish between use before and after the prior benign condition.

Multiple studies of varying types have not consistently shown women who used oral contraceptives before the birth of their first child, or before the age of 25 years, to be at increased risk of breast cancer. Results among studies are more consistent for an increase in risk in women under the age of 45 who were long-term users of oral contraceptives (regardless of whether use occurred before or after a first birth or a particular age). Such users would, of course, tend to have been young at their initial use.

This observed increase in risk is not likely to be due to differential screening for breast cancer in oral contraceptive users. There is suggestive but inconsistent evidence that it could be a result of the pill stimulating growth in preexisting tumors. Alternatively, oral contraceptives, when used early in life, could be causing a small absolute increase in risk in young women. It is of extreme importance to determine which of these two possible biological mechanisms may be operating. If it is the former, then oral contraceptives are not causing any new breast cancers; if it is the latter, they are, and this could theoretically continue and become even more of a problem with the aging of the cohort of women who have been exposed early in life. Rigorous epidemiological studies should therefore be conducted to continue monitoring for any enhanced risk of breast cancer among women in birth cohorts exposed at a young age to prolonged use of oral contraceptives. Such studies should not be confined to women below a specific arbitrary age. They should include a pathological component to measure indices of proliferative activity and determine the likely cells of origin of the tumors (whether ductal or lobular). The analyses of both the histologic and epidemiological data should be planned to provide evidence for or against the two above-mentioned biological mechanisms.

Studies of survival in women with breast cancer would also be of value. If oral contraceptive users have more favorable survival than nonusers, this pattern would be evidence for a screening bias (or suggest that breast tumors that develop in response to oral contraceptives are less aggressive than other breast tumors). If survival is less favorable in users than in nonusers, this pattern would be evidence that oral contraceptives stimulate tumor growth (or suggest that breast tumors that develop in response to oral contraceptives are more aggressive than other breast tumors).

Limited evidence suggests that use of oral contraceptives near the time of menopause may increase a woman's risk of breast cancer. A

Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

possible mechanism for this is endocrinologic simulation of a delayed menopause by the exogenous estrogens and progestins. Further investigation of this issue is also warranted, perhaps most efficiently by reanalysis of data from existing studies, to estimate relative risks in relation to duration of use in women in their late 40s and 50s.

No difference in possible associations with breast cancer has been observed between oral contraceptive formulations that contain mestranol and those that contain ethinyl estradiol. This finding is not surprising because the former is metabolized to the latter and the active estrogen is thus the same in both types of preparations. The progestins in almost all contraceptives that have been considered in studies of breast cancer to date are derivatives of 19-nor-testosterone. None have consistently been shown to be more strongly associated with breast cancer than others. Results of studies of oral contraceptives that contain 17-α-hydroxyprogesterone derivatives have not been published. Recent studies from New Zealand (Paul et al., 1989) and Costa Rica (Lee et al., 1987) have shown a possible increase in risk of breast cancer in some categories of users of the long-acting progestational agent depot-medroxyprogesterone acetate (DMPA), which is a 17-α-hydroxyprogesterone derivative.

Results from the WHO (1990) study of both DMPA and oral contraceptives that contain chlormadinone are pending. In view of the existing findings on DMPA and reports of these progestational agents causing breast cancer in beagle dogs, additional studies of breast cancer in relation to products with these types of progestins may be warranted, particularly if the results from the WHO study are not reassuring.

ACKNOWLEDGMENTS

The statistical analyses reported in this appendix were performed by Elizabeth A. Noonan. The author thanks James Schlesselman and David Skegg for their helpful comments.

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×

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Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

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Stalsberg, H., D. B. Thomas, E. A. Noonan, and the WHO Collaborative Study of Neoplasia and Steroid Contraceptives 1989. Histologic types of breast carcinoma in relation to international variation and breast cancer risk factors. International Journal of Cancer 44: 399-409

Stanford, J. L., L. A. Brinton, and R. N. Hoover. 1989. Oral contraceptives and breast cancer: Results from an expanded case-control study. British Journal of Cancer 60: 375-381

Talamini, R., C. La Vecchia, S. Franceschi, F. Colombo, A. Decarli, E. Grattoni, E. Grigoletto, and G. Tognoni. 1985. Reproductive and hormonal factors and breast cancer in a northern Italian population. International Journal of Epidemiology 14: 70-74

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Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
×

Vessey, M. P., K. McPherson, L. Villard-Mackintosh, and D. Yeates. 1989. Oral contraceptives and breast cancer: Latest findings in a large cohort study. British Journal of Cancer 59: 613-617

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Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 103
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 104
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 105
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 106
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 107
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 108
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 109
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 110
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 112
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 114
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 115
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 116
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 117
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 118
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 119
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 120
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 121
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 122
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 123
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 124
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 125
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 126
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 128
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 129
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 130
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 131
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 132
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 133
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 134
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 135
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 136
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 137
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 138
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 139
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 140
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 141
Suggested Citation:"Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature." Institute of Medicine. 1991. Oral Contraceptives and Breast Cancer. Washington, DC: The National Academies Press. doi: 10.17226/1814.
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Page 142
Next: Appendix C: The Evolving Formulations of Oral Contraceptives »
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At least 10.7 million American women use oral contraceptives (OCs). The potential connection with breast cancer has caused concern among these OC users and uncertainty among many of their physicians. This new volume offers the most up-to-date information available on this critical topic.

While the best available knowledge does not support any fundamental change in clinical practice with respect to the use of OCs, this book offers specific recommendations for more research to fully resolve the relationship between OCs and breast cancer. Noting consumer confusion, the volume includes a concise summary of benefits, risks, and other practical information for contraceptive users and their doctors.

The volume presents current data on changes in patterns of OC use, differences in risk at different ages, the benefits of OCs, and more.

Oral Contraceptives and Breast Cancer will be important reading for obstetricians/gynecologists and other health professionals, their patients who use OCs, contraceptive manufacturers, women's health advocates, policymakers, and researchers.

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