ARTICLE

Dual Effect of Parity on Breast Cancer Risk in African-American Women

Julie R. Palmer, Lauren A. Wise, Nicholas J. Horton, Lucile L. Adams-Campbell, Lynn Rosenberg

Affiliations of authors: J. R. Palmer, L. A. Wise, L. Rosenberg, Slone Epidemiology Center, Boston University, Boston, MA; N. J. Horton, Department of Biostatistics, Boston University School of Public Health, Boston; L. L. Adams-Campbell, Howard University Cancer Center, Washington, DC.

Correspondence to: Julie R. Palmer, Sc.D., Slone Epidemiology Center, Boston University, 1010 Commonwealth Ave., Boston, MA 02215 (e-mail: jpalmer{at}slone.bu.edu).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: In the United States, breast cancer incidence is higher among African-American women than among white women before age 45 but lower at older ages. To explore whether differences in childbearing patterns can explain this observation, we assessed the relation of several childbearing variables to breast cancer risk in a large prospective cohort study of U.S. African-American women. Methods: Black Women’s Health Study participants were enrolled in 1995 and were followed by mailed questionnaires every 2 years (in 1997 and 1999). Of the 64 500 women enrolled, 56 725 (88%) completed at least one of the follow-up questionnaires. During 214 862 person-years of follow-up, participants reported 349 breast cancers, of which 128 were among women younger than 45 years and 221 were among women aged 45–70 years. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were derived from age-stratified Cox regression models that adjusted for each of the childbearing variables (parity, age at first birth, and time since last birth). Results: Compared with primiparity, high parity was associated with an increased risk of breast cancer among women younger than 45 years (IRR for four or more births = 2.4, 95% CI = 1.1 to 5.1) and a decreased risk among women aged 45 years and older (IRR = 0.5, 95% CI = 0.3 to 0.9). The IRR for late age at first birth compared with early age was 2.5 (95% CI = 1.1 to 5.8) among the younger women and was not elevated among older women. We found no statistically significant association of time since last birth with breast cancer risk among either younger or older women. Conclusions: Parity has a dual association with breast cancer risk in African-American women; among women younger than 45 years, parity is associated with an increased risk and among women 45 years and older it is associated with a decreased risk. This dual effect may explain some of the observed differences in breast cancer incidence rates among African-American and white women.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Breast cancer incidence is higher among African-American women than among white U.S. women before age 45 but lower at older ages (1). It has been suggested that different patterns of childbearing among African-American and white U.S. women may provide an explanation (2). In general, African-American women give birth at younger ages and have more children than white women (3). In studies of white women, higher parity confers a reduced risk of breast cancer for older women, i.e., those aged 45 years or older (4), but there may be a transient increase in risk associated with each pregnancy (5,6). Because most research studies have not included appreciable numbers of African-American women, it has not been possible to evaluate the effect of childbearing on the risk of early and late breast cancer in African-American women. Here, we assessed the relation of childbearing to the risk of breast cancer in data from the first 4 years of follow-up in the Black Women’s Health Study (7).


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The study protocol was approved by the Institutional Review Board of Boston University. The Black Women’s Health Study (7) is a prospective cohort study of African-American women from all regions of the United States. From March 1995 through December 1995, 64 500 women aged 21–69 years were enrolled after responding to questionnaires mailed to subscribers of Essence magazine (a popular magazine targeted to African-American women), members of several African-American professional associations, and friends of early respondents. The baseline questionnaire obtained information on adult height, current weight, demographic characteristics, reproductive history, medical history, use of medications, use of cigarettes and alcohol, and usual diet. Follow-up questionnaires that update information on reproductive history and other exposures and identify new occurrences of serious illnesses, including breast cancer, are mailed to participants every 2 years. The present study evaluated data from the baseline questionnaire and the 1997 and 1999 follow-up questionnaires; 56 725 (88%) of participants completed at least one of the follow-up questionnaires.

An attempt was made to obtain medical records for all 349 participants who reported incident breast cancer on the 1997 and 1999 questionnaires. Records were obtained for 167 (48%) potential case subjects. The primary reason for not obtaining records was nonconsent, with many participants citing concerns about privacy and confidentiality. A diagnosis of breast cancer was confirmed for all 167 reviewed case subjects, with 136 case subjects classified as having invasive breast cancers and 31 as having carcinoma in situ. These results suggest that a self-report of breast cancer by Black Women’s Health Study participants is acceptably accurate. Therefore, all first occurrences of breast cancer reported on the 1997 and 1999 questionnaires were included in the present analysis, for a total of 349 case subjects.

Data were obtained on the outcome of each pregnancy and the participant’s age at each full-term pregnancy. The number of years since the last pregnancy was calculated from the participant’s age at most recent full-term pregnancy and age at each follow-up. Thus, it was possible to classify each participant as to number of births, years since last birth, and age at first birth at the beginning of follow-up and at the end of each of the 4 years of follow-up.

Statistical Analysis

All analyses were carried out separately among women younger than 45 years and women 45 years or older at the beginning of each follow-up period. Age-stratified Cox regression models were used to derive incidence rate ratios (IRRs) for breast cancer in relation to three childbearing variables—parity, age at first birth, and years since last birth (8). Multivariable age-stratified Cox proportional hazards regression models controlled for family history of breast cancer, age at menarche, duration of oral contraceptive use, years of education, and body mass index (in kilograms per square meter) and included all three of the childbearing variables. Departures from the proportional hazards assumption were tested by a likelihood ratio test comparing models with and without age by covariate interaction terms. No statistically significant violations of this assumption were found. IRRs for nulliparity relative to one birth were estimated in models in which the reference category was women of the median age at first birth (age 20–24) and the median time since last birth (5–9 years for women younger than 45 years and >=25 years for women 45 years or older). All 95% confidence intervals (CIs) are two-sided. SAS statistical software (version 8.02; SAS Institute, Inc., Cary, NC) was used to perform the analyses.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Of the 349 case subjects diagnosed with breast cancer during the 4 years of follow-up, 128 were diagnosed before age 45 years and 221 were diagnosed at age 45 years or older. The baseline distribution of parity, age at first birth, and years since last birth by decade of age for the 56 725 Black Women’s Health Study participants who completed at least one follow-up questionnaire is given in Table 1Go. Among women aged 50 years or older at baseline, i.e., those who would have already completed childbearing, 10%–12% were nulliparous and 23%–34% had had four or more births. Among women aged 40–49 years, 19% were nulliparous and 9% had had four or more births. Most of the parous women had had their first full-term pregnancy at an early age: 33%–38% of those aged 40 years or older had had their first full-term pregnancy before age 20 and 71%–78% before age 25. Years since last birth increased with increasing age. Approximately 2% of participants could not be classified as to number of births, age at first birth, or years since last birth and were excluded from further analysis.


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Table 1. Parity, age at first birth, and years since last birth at baseline, according to age at baseline, in 56 725 women from the Black Women’s Health Study
 
We first determined the relation of parity to risk of breast cancer (Table 2Go). For women younger than 45 years at the beginning of each year of follow-up, the multivariable IRR for nulliparous women relative to parous women was 1.0 (95% CI = 0.6 to 1.7). Relative to primiparous women, IRRs for women who had had three births and four or more births were 2.2 (95% CI = 1.2 to 3.9) and 2.4 (95% CI = 1.1 to 5.1), respectively. These multivariable IRRs were somewhat higher than those derived from the age-adjusted models. The difference was largely a result of confounding by age at first birth. Women who had had three or more births were more likely to have been younger at the time of their first birth. Thus, the increased risk from higher parity was attenuated before adjustment for age at first birth.


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Table 2. Parity in relation to breast cancer risk among women from the Black Women’s Health Study
 
Among women diagnosed at age 45 years or older, nulliparity was associated with a small increase in the risk of breast cancer, with a multivariable IRR of 1.3 (95% CI = 0.9 to 2.1). High parity was associated with a reduced risk of breast cancer for women who had had four or more births (IRR = 0.5, 95% CI = 0.3 to 0.9), and a test for trend by number of births was statistically significant (P = .01). The apparent interaction between age and parity in relation to breast cancer risk was tested by including an age–parity interaction term in a model that included all strata of person-time and main terms for age younger than 45 years and age 45 years or older and number of births. The interaction was highly statistically significant (P = .005).

We next examined whether late age at first birth was associated with an increased risk of breast cancer before age 45. For women whose first birth was at age 30 years or older, the multivariable IRR was 2.5 (95% CI = 1.1 to 5.8) relative to women whose first birth was at an age younger than 20 years (Table 3Go). A less consistent association was observed for breast cancer diagnosed at age 45 years or older: the IRR for women whose first birth was at age 25–29 years was 1.5 (95% CI = 0.9 to 2.2), but the IRR for women whose first birth was at age 30 years or older was 0.7 (95% CI = 0.4 to 1.4).


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Table 3. Age at first birth in relation to breast cancer risk among women from the Black Women’s Health Study
 
To examine the relation between interval since last birth and risk of breast cancer, we excluded nulliparous women and women who had had only one birth because, for primiparous women, the last birth is also the first birth and, therefore, age at first birth cannot be properly controlled. Among women who had had two or more births, those who had a shorter interval since last birth were compared with those who had a relatively long interval since last birth, which was greater than or equal to 15 years for women aged younger than 45 years and greater than or equal to 25 years for women aged 45 years or older (Table 4Go). Among younger women, the IRRs for those with a short interval since last birth (<5 years or 5–9 years) were 1.5 in the age-adjusted models. However, in multivariable analysis, which included adjusting for age at first birth and parity, the IRRs were reduced to approximately 1.0 (Table 4Go). Among older women, the IRR for those with a short interval since last birth (<10 years) was 2.0 (95% CI = 0.6 to 6.3), but there were relatively few case subjects and person-years in this category.


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Table 4. Time since last birth among parous women in the Black Women’s Health Study who had two or more births
 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The results of our study suggest that high parity has a dual association with breast cancer risk in African-American women. Among women diagnosed with breast cancer before age 45 years, high parity was associated with an increased risk, whereas among women diagnosed at older ages, parity was associated with a decreased risk. These results may shed light on the puzzling differences in breast cancer incidence rates for African-American and white U.S. women. Relative to white women, African-American women have a higher breast cancer risk before age 45 years and a lower risk at older ages. Because, generally, African-American women have more children and bear them earlier than white women (3), it has been hypothesized that different childbearing patterns may explain the differences in breast cancer incidence rates (2). Our study supports this hypothesis by demonstrating a dual association with parity in African-American women.

Studies of white women (4,9) have suggested that multiparity modestly decreases the risk of breast cancer in older women. Janerich and Hoff (10) hypothesized that full-term pregnancy may increase the risk of breast cancer at younger ages, and a number of studies of white women (1115) have provided data supporting the hypothesis. Using large datasets, Lambe et al. (6) and Liu et al. (5) demonstrated that there is a small transient increase in risk of breast cancer associated with each full-term birth, followed by a reduction in risk many years later. The increase is greatest for the first birth, but subsequent births also appear to be associated with a small transient increase in risk. Lambe et al. (6) and others (10,13) have speculated that full-term pregnancy may have several effects that could influence the risk of breast cancer. The most striking effect, demonstrated by Russo et al. (16) in rat experiments, may be the terminal differentiation of lobular mammary cells that occurs at completion of a full-term pregnancy, which would leave mammary cells less susceptible to malignant transformation. Therefore, women whose first birth occurs at a young age may ultimately have a reduced risk of breast cancer because they have had a shorter period, i.e., the time between onset of menarche and first birth, during which breast cells are at risk of transformation. This line of reasoning would also explain why nulliparous women have a higher risk of breast cancer than parous women at older ages. In addition, the increased hormone levels that occur in each full-term pregnancy may promote the growth of cells that have already undergone malignant transformation. In this case, there would be some period of increased risk associated with each full-term pregnancy. With the passage of time, the increased risk would dissipate and a reduced risk would be observed, resulting from the differentiation of additional breast cells with each pregnancy. Liu et al. (5) estimated that the small increased risk of breast cancer associated with each pregnancy reaches its highest level at approximately 5 years after the birth and disappears approximately 15 years later.

Our finding of an increased risk of breast cancer associated with increased parity among women younger than age 45 years is consistent with the hypothesized transient increase in breast cancer risk after each pregnancy (5,6), which could be caused by the additional hormone exposure during the pregnancy. Given this finding, one might have expected to observe an association between time since last birth and breast cancer risk. Among women aged 45 years or older, we observed a relative risk of 2.0 for those with the shortest interval since last birth. However, this estimate was made on the basis of only five case subjects and was not statistically significant. After controlling for the number of births and age at first birth, there was no apparent association between time since last birth and breast cancer risk among the younger women. One possible explanation for the lack of association is the small sample size; a much larger sample would be required to demonstrate the small effect of time since last birth. From the Swedish Fertility Register, with over 30 000 breast cancer case subjects available for study, Liu et al. (5) documented a small increase in the risk of breast cancer for each of the first few years after a birth, with adjustment for age at delivery in 1-year increments. Other studies, with considerably smaller numbers of white women, have produced mixed results: some observed an increased risk for shorter interval since last birth (1719) and a few found no association (15,20,21).

In our study, late age at first birth was associated with an increased risk of breast cancer before age 45 years, but there was little evidence of such an association among older women. Age at first birth is considered an established risk factor for breast cancer (22), although the magnitude of the association is unclear, with population-based and more recent studies showing weak associations (4,9,23,24).

Most previous work on childbearing in relation to breast cancer risk has been based on data from white women. Moreover, only two studies (25,26) have reported the relation of these factors to breast cancer risk in African-American women separately for younger and older women. Mayberry (25) analyzed data on 490 African-American breast cancer case subjects and their matched controls from the Cancer and Steroid Hormone Study. Although increased parity was associated with a reduced risk of breast cancer both among women younger than 40 years and among those aged 40–54 years, the association was statistically significant only among the older women. Age at first birth was not associated with risk of breast cancer among the younger women and was weakly positively associated with that among the older women. Brinton et al. (26) analyzed data on 281 case subjects and their matched controls from a more recent multicenter case–control study. Among women younger than 40 years, those with two or more births had a somewhat higher risk than primiparous women, but the increase was not statistically significant. Among women aged 40–54 years, higher parity was not associated with a reduced risk relative to primiparity. Age at first birth was strongly associated with increased risk among younger women (i.e., those younger than 40 years) but not among older women, in accordance with Mayberry’s findings (25) and with the findings of the present study.

Because our data are from a prospective cohort study with a low loss to follow-up, it is likely that information provided on the number and timing of births was unbiased with regard to subsequent development of breast cancer. Data were obtained by self-administered, self-coded questionnaires, and some participants did appear to confuse pregnancy with full-term birth and vice versa. Thus, approximately 2% of participants were excluded from analysis because of missing data on the key pregnancy variables or conflicting information on those variables. Nevertheless, there were probably other women who were misclassified with regard to the timing and, perhaps, the number of their births. Such nondifferential misclassification of pregnancy variables would have resulted in underestimation of incidence rate ratios.

The Black Women’s Health Study cohort under-represents African-American women from the lowest socioeconomic strata. Indeed, 97% of the Black Women’s Health Study participants had graduated from high school, whereas approximately 83% of African-American women of the same ages have done so (27). In general, less educated women have more children and have them at an earlier age than do more educated women. The parity and ages at first birth of the Black Women’s Health Study participants are thus not representative of all African-American women. However, we consider that the etiologic results are most likely generalizable to all African-American women because there is no reason to believe that the underlying biology would differ across socioeconomic strata.

In summary, our study is the first, to our knowledge, to demonstrate a dual association of parity with breast cancer risk in African-American women. The findings provide an explanation, at least in part, for the relatively high incidence of breast cancer in young African-American women. In the future, with the occurrence of more breast cancers in the Black Women’s Health Study participants, it may be possible to compare age-specific incidence rates in this cohort with rates in a comparable cohort of white women and examine whether differences in incidence are attenuated by adjustment for parity and age at first birth.


    NOTES
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Supported by Public Health Service grant R01CA58420 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.


    REFERENCES
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Manuscript received September 24, 2002; revised January 8, 2003; accepted January 17, 2003.


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