Risk of Late-stage Breast Cancer after a Childbirth
Jan Wohlfahrt1,
Per Kragh Andersen1,2,
Henning T. Mouridsen3 and
Mads Melbye1
1 Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark.
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
3 Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen, Denmark.
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ABSTRACT
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A pregnancy may lead to hormone-induced growth of breast tumors. The authors investigated whether women in the first years after childbirth had a higher incidence of breast cancer and, in particular, a higher incidence of late-stage tumors (i.e., a large tumor, nodal involvement, or histologic grading II + III). The study was based on a population-based cohort of 1.5 million Danish women born between 1935 and 1978. Between 1978 and 1994, 10,790 incident cases of breast cancer were identified in a nationwide cancer registry. Overall, uniparous and biparous mothers experienced a transient increased risk that did not appear to be attributable to delayed cancer diagnosis. The risk of being diagnosed with a tumor whose diameter was larger than 5 cm was, on average, 53% higher during the first 10 years after birth compared with later. The risk of tumors of less than 2 cm was not significantly associated with time since the latest birth. In conclusion, after a childbirth, mothers experience a transient increased risk of breast cancer and, in particular, a relatively high risk of late-stage disease. This finding suggests that pregnancy-related factors transiently induce a high growth rate in cells that are already malignant and stimulate new tumor growth.
breast neoplasms; cohort studies; reproductive history
Abbreviations:
CRS, Civil Registration System; DBCG, Danish Breast Cancer Cooperative Group
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INTRODUCTION
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It is well established that the birth of a child decreases a mother's long-term risk of breast cancer (1
). However, several studies have found that the risk of breast cancer may be elevated in the years immediately after childbirth (2

5
). This observation has been explained by a growth-enhancing effect on malignant or premalignant cells induced by the hormonal changes during pregnancy (4
). If this observation is correct, the tumors promoted by pregnancy should have a particularly rapid growth and, therefore, be likely to be diagnosed at a later stage on average, i.e., the transient increase should be especially pronounced for the rate of late-stage breast cancer. To evaluate this hypothesis of the pregnancy-induced rapid growth of occult tumors, we studied the overall rate of breast cancer in the years after a birth and, in particular, the rate of late-stage tumors, by taking advantage of the detailed registration of breast cancer characteristics in Denmark.
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MATERIALS AND METHODS
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Study cohort
Since April 1, 1968, the Civil Registration System (CRS) in Denmark has assigned a individual national registration number to all citizens. Through this number, the CRS keeps updated information on dates of livebirths, emigration, and vital status. The CRS number also permits accurate, individual-based linkage of information from other registries. We used the CRS registry to establish a national parity database that included all women born between April 1, 1935, and March 31, 1978, as described earlier (6
, 7
). To study breast cancer rates during pregnancy, we added information on induced and spontaneous abortions and the gestational ages of births as contained in the National Registry of Induced Abortions, the National Discharge Registry, and the Danish National Birth Registry.
Detailed information on registered invasive primary breast cancers for the period January 1, 1978 to September 30, 1994, including the size of the tumor, the number of positive nodes, and the histologic grading, was obtained from the Danish Breast Cancer Cooperative Group (DBCG) registry. The DBCG initiated a series of national prospective studies in 1977 to evaluate breast cancer treatment programs systematically. A detailed description of this registry has been given elsewhere (8
, 9
). During a limited time period (19771981), the DBCG collected additional information such as the date on which the woman experienced the first symptom(s) of her disease and the date of her first consultation with a physician (10
). Through a linkage between the DBCG registry and the Danish Cancer Registry, the DBCG registry was found to contain information on 94 percent of all breast cancer patients reported to the Danish Cancer Registry. The Danish Cancer Registry is considered to be close to complete regarding incident cases of malignant neoplasms diagnosed in Denmark since 1943 (11
).
Statistical analyses
The impact of time since birth on the incidence of breast cancer with a specific tumor characteristic was investigated in a follow-up study analyzed by using log-linear Poisson regression models (12
). Each stage-specific diagnosis of breast cancer was analyzed separately. Tumor size, nodal involvement, and histologic grading are used as indicators of stage. All women entered follow-up for each of the stage-specific breast cancer diagnoses on January 1, 1978 or on their twelfth birthday, whichever came last. The period at risk continued until breast cancer (whatever stage), death, emigration, or September 30, 1994, whichever occurred first. Incidence rate ratios are referred to as relative risks. All variables were treated as time dependent. Calculations were performed by using the SAS procedure PROC GENMOD (13
). Adjustment was made for age (quadratic splines with knots: 30, 35, 40, 45, 50, and 55 years) (14
) and calendar period (19781982, 19831987, 19881992, and 19931994). Use of age in 1-year categories in the overall analysis had no impact on the conclusions. In the analysis of time since latest birth, we furthermore adjusted for age at first birth (nulliparous, 1219, 2024, 2529, 3034, and >34 years) and parity (nulliparous, 1, 2 , 3, and
4). Estimation of the effect of time since the latest birth with adjustment for age and age at first birth when uniparous women are included is discussed in the paper by Heuch et al. (15
). The test for effect modification by parity (1, 2, and
3) was performed as a test for interaction between categorical variables.
In an alternative approach, we compared the mother's risk with what her risk would have been if she had not delivered a child. This was done according to the time since each delivery, categorized as less than 2, 23, 45, 67, 89, and 10 or more years, i.e., four time-dependent variables representing time since the first, second, third, and fourth births were included in the model. In these analyses, women were followed until a possible fifth birth. In addition to age and calendar period, we adjusted for age at the first, second, third, and fourth births. Because we found only minor, insignificant effects of age at the first to fourth births during the first 10 years after birth, we added only the effects of age at the first to fourth births in the model 10 years after birth. This was done by further categorizing the category "
10 years" in each of the four "time since birth" variables according to age at birth (1224, 2529, 3034, and
35 years). In other words, the "short-term" effect of a birth (<10 years) was categorized according to the time since birth, and the "long-term" effect (
10 years) was categorized according to age at birth.
In an additional analysis, we estimated the rate of breast cancer during pregnancy by using a similar approach, including additional information on interrupted pregnancies and gestational age at delivery. A woman was considered to be pregnant from the time of conception (estimated by gestational age) until birth or the time of interruption of the pregnancy. Her parous status during pregnancy was the number of births prior to the pregnancy.
To evaluate whether an increased risk after childbirth could be ascribed to delayed diagnosis, we estimated the cumulative difference between the observed number of incident breast cancer cases in newly pregnant nulliparous and uniparous women in the cohort according to the time since the latest birth and the predicted number of cases had they not had the latest birth. The prediction was based on a model that included age, calendar period, parity, and age at first birth. The deficit of cases in these women during pregnancy was estimated by using the distribution of person-years in uniparous and biparous women with less than 1 year since the latest birth (multiplied by 9/12), assuming that they were 1 year younger and had had one less childbirth.
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RESULTS
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Overall, 1,529,512 women were included in the cohort. A total of 10,790 primary invasive breast cancers were observed during 22.3 million person-years of follow-up. Of these, 1,295 women were nulliparous at time of diagnosis.
The association between time since the latest birth and the incidence of breast cancer is shown in table 1. Overall, there was a small, but significant, association between the time since the latest birth and the breast cancer rate (p = 0.0002). After adjustment for the differences in age and other confounders, the risk was highest (1.16-fold) 23 years after delivery compared with 1014 years after delivery. Table 1 furthermore shows the association between the time interval since the latest birth and the risk of breast cancer by tumor size at diagnosis. The rate of large tumors was significantly associated with the time interval since the latest birth (p = 0.002). For instance, women with 23 years since the latest birth had a 2.27-fold (95 percent confidence interval: 1.49, 3.44) higher risk of breast cancer compared with women with 1014 years since the latest birth. Overall, the risk of being diagnosed with a tumor with a diameter larger than 5 cm was 53 percent higher during the first 10 years after birth compared with later. There was no association between the time since the latest birth and the rate of small tumors (<21 mm) (p = 0.17). The rate of medium-sized tumors (2150 mm) was only slightly associated with the time since the latest birth (p = 0.06). The association between the time since the latest birth and large tumors was not modified by parity (p = 0.56). We found similar patterns of an increased risk of tumors with adverse features when the cases were divided according to nodal status or histologic grading (table 2).
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TABLE 1. Adjusted* relative risk of breast cancer overall and by tumor size at diagnosis, according to time since latest birth, Denmark, 19781994
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TABLE 2. Adjusted* relative risk of breast cancer according to time since latest birth, by nodal status and histologic grading at diagnosis, Denmark, 19781994
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In an alternative approach, we compared a mother's risk with what her risk would have been had she not delivered a child. In the first 10 years after the first and second births, the breast cancer risk was increased by ratios of 1.07 (95 percent confidence interval: 0.97, 1.19) and 1.07 (95 percent confidence interval: 0.98, 1.15) compared with nulliparous and uniparous women, respectively. Overall, the increase during the first 10 years after the first and second births was 1.07 (95 percent confidence interval: 1.01, 1.13), and according to the time since birth, for less than 2 years, relative risk = 0.97 (95 percent confidence interval: 0.82, 1.15); for 23 years, relative risk = 1.13 (95 percent confidence interval: 0.99, 1.29); for 45 years, relative risk = 1.08 (95 percent confidence interval: 0.96, 1.21); for 67 years, relative risk = 1.11 (95 percent confidence interval: 1.00, 1.22); and for 89 years, relative risk = 1.06 (95 percent confidence interval: 0.97, 1.15). In the first 10 years after the third and fourth births, there was no increased risk (relative risk = 0.99, 95 percent confidence interval: 0.90, 1.08 and relative risk = 0.89, 95 percent confidence interval: 0.74, 1.07, respectively). As illustrated in figures 1 and 2, we performed the same analyses according to tumor size at diagnosis. During the first 10 years after the second and third births, mothers had up to a twofold higher risk of being diagnosed with a tumor larger than 50 mm. The relative risk for the first 10 years after the fourth birth compared with triparous women was 1.34 (95 percent confidence interval: 0.74, 2.43) for being diagnosed with tumors larger than 5 cm and 0.88 (95 percent confidence interval: 0.72, 1.08) for being diagnosed with tumors of 5 cm or smaller. The same type of analysis was not informative for uniparous women because there was an overall higher rate of late-stage tumors in nulliparous women, as mentioned in the Discussion.

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FIGURE 1. Relative risk of being diagnosed with a breast tumor of 50 mm ( ) and >50 mm () (on a log scale) by time since the second birth compared with uniparous mothers, adjusted for age; period; and effects of first, second, third, and fourth births, Denmark, 19781994. The exact estimates for 50 mm are: <2 years: relative risk = 0.94, 95% confidence interval: 0.73, 1.21; 23 years: relative risk = 1.11, 95% confidence interval: 0.90, 1.35; 45 years: relative risk = 1.02, 95% confidence interval: 0.86, 1.22; 67 years: relative risk = 1.14, 95% confidence interval: 0.98, 1.31; 89 years, relative risk = 1.05, 95% confidence interval: 0.92, 1.19; and >50 mm: 2 years: relative risk = 1.29, 95% confidence interval: 0.59, 2.83; 23 years: relative risk = 1.88, 1.05-3.38; 45 years, relative risk = 1.38, 95% confidence interval: 0.80, 2.38; 67 years: relative risk = 1.26, 95% confidence interval: 0.78, 2.03; 89 years: relative risk = 1.02, 95% confidence interval: 0.65, 1.61.
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FIGURE 2. Relative risk of being diagnosed with a breast tumor of 50 mm ( ) and >50 mm () (on a log scale) by time since the third birth compared with biparous mothers adjusted for age; period; and effects of first, second, third, and fourth births, Denmark, 19781994. The exact estimates for 50 mm are: <2 years: relative risk = 0.79, 95% confidence interval: 0.57, 1.09; 23 years: relative risk = 0.76, 95% confidence interval: 0.57, 1.01; 45 years: relative risk = 0.92, 95% confidence interval: 0.74, 1.15; 67 years: relative risk = 1.00, 95% confidence interval: 0.83, 1.21; 89 years: relative risk = 1.01, 95% confidence interval: 0.85, 1.19; and for >50 mm: <2 years: relative risk = 0.70, 95% confidence interval: 0.22, 2.20; 23 years: relative risk = 2.39, 95% confidence interval: 1.31, 4.36; 45 years: relative risk = 1.79, 95% confidence interval: 0.96, 3.33; 67: relative risk = 0.73, 95% confidence interval: 0.32, 1.67; 89: relative risk = 1.01, 95% confidence interval: 0.54, 1.88.
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On the basis of 20 cases of breast cancer detected in pregnant women during 706,234 years of follow-up, we estimated that the rate of breast cancer in pregnant women was 72 percent (95 percent confidence interval: 51 percent, 84 percent) lower than expected. To evaluate whether this lower rate of breast cancer during pregnancy could explain the increased risk of breast cancer in the first years after the first and second births, we estimated the cumulative difference between the observed number of incident breast cancer cases in the newly pregnant nulliparous and uniparous women in the cohort and the expected number of cases had they not had the latest birth. During pregnancy, we estimated that there was a total deficit of approximately 31 breast cancer cases compared with those for nonpregnant women. However, in the first 10 years after birth, the women who had been pregnant experienced an excess of 88 cases. Assuming that the deficit of cases during pregnancy was exclusively due to postponed diagnosis, the postponement could account only for the excess during 4 to 5 years after birth.
For a subgroup of women diagnosed in the period 19781982, we had information about the time interval between the first symptoms observed by the women and their first visit to a physician (patient's delay) and between the first visit to the physician and the time of definitive surgery or biopsy (physician's delay) (10
). There was no significant relation between the two measures of diagnostic delay and the time since the latest birth when the associations were evaluated by using a Mann-Whitney U test. Within 5 years after a birth, the median patient's and physician's delay was 12 and 29 days, respectively. During 59 years after a childbirth, the similar numbers were 11 and 30 days, respectively, and in the subsequent years, the numbers were 7 and 28 days, respectively.
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DISCUSSION
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This study documented that a mother's age-adjusted risk of breast cancer is highest in the first 10 years after the latest birth and, in particular, that the risk of late-stage tumors is significantly elevated. It has been observed previously that the overall breast cancer risk is increased after a childbirth (2

5
), but the finding that the risk of late-stage breast cancer is elevated is a novel observation that may give further insight to the mechanisms behind the increased risk.
The high rate of late-stage breast cancer in the first years after a birth could be due to delayed diagnosis/surgery of breast cancer during pregnancy, either because of difficulties in detecting the tumor during pregnancy or because breast surgery was postponed until after the delivery. A delayed diagnosis/surgery due to pregnancy would result in larger tumors after the delivery, but the breast cancer rate during pregnancy should also be correspondingly low. In concordance with three previous studies (4
, 16
, 17
), we observed a 72 percent lower risk of breast cancer during pregnancy. Some of this lower rate might very well be explained by a "healthy women" effect, but even when we assumed that the lower rate during pregnancy should be explained exclusively by delayed diagnosis, we found that such a diagnostic delay could account only for an excess of cases equivalent to, for example, the observed increased breast cancer rate in the first 4 or 5 years after the first and second deliveries. Thus, delayed diagnosis/surgery due to pregnancy did not appear to explain the entire excess of cases in the years after pregnancy.
We investigated, furthermore, whether the higher rate of late-stage breast cancers after the first years could be due to delayed detection because a woman's primary attention was devoted to childcare during the first years after delivery. However, based on detailed referral information on a subset of the women in this study, we found no elevated diagnostic delay in women diagnosed in the these years after a childbirth compared with later years. Altogether, delayed diagnosis during pregnancy and delayed detection in the first years after birth appeared to be unable to explain the significantly elevated age-adjusted risk of late-stage breast cancer in the first 10 years after a birth.
Part of the higher rate of late-stage breast cancer in the first 10 years after a birth is probably explained by cases diagnosed in the first 10 years being initiated before the birth, whereas the malignant process in cases diagnosed after the first 10 years more likely are initiated after the birth, where the rate is reduced by the protective effect of an additional birth. However, if this were the only explanation for the higher rate of breast cancer after a delivery, we would anticipate that uniparous mothers in the first years after childbirth had the same overall risk as nulliparous women (and likewise when comparing biparous with uniparous women) or maybe even a lower risk in the first years due to a healthy women effect. Nevertheless, in additional analyses, we observed that uniparous and biparous women had a slightly increased overall breast cancer risk in the first 10 years after the latest birth when compared with women with one less birth. Such analyses suggest that a mother has a transiently higher risk compared with what her risk would have been if she had not delivered a child. The analyses therefore directly support the idea that pregnancy-related factors, e.g., the elevated hormonal level during pregnancy, transiently increase a mother's overall risk of breast cancer by stimulating a high growth rate in already malignant cells and/or inducing a new tumor growth.
An enhanced tumor growth after a birth might just mean that relatively indolent tumors are accelerated and therefore are discovered sooner, but at the same stage as without a growth-rate change. However, after performing the same kind of analysis on the rate of late-stage tumors, we observed an even more dramatic transient increase of the rate of late-stage breast cancer after second and third deliveries. During the first years after the second or third birth, we observed a more than twofold higher risk of late-stage cancer when the risk in this period was compared with that of women with everything else equal but the latest birth. This novel observation should not alarm the average pregnant women, since the rate of late-stage breast cancer is very small. In other words, the absolute effect is small and therefore has no direct implications for primary prevention, but the finding is of etiologic interest because it supports the hypothesis that the transient increased risk of breast cancer after birth is due to an increased growth rate in malignant and premalignant cells that, to some extent, leads to discovery at a later stage compared with what would have been the case had the women not delivered a child.
The stage-specific analysis should be considered with due caution. We have previously shown that the rate of late-stage tumors in general is much higher in nulliparous compared with parous women, which can be either because a woman's reproductive history influences the time of detection or because it affects the progression rate of the tumor (18
). The lack of a transient increased risk of late-stage breast cancer after the first birth is most likely due to this generally lower risk of late-stage breast cancer in uniparous compared with nulliparous women. Because of this phenomenon, in this paper, we have also focused on comparisons between mothers with the same number of births, thereby excluding differences in the rate of late-stage breast cancer attributable to parity per se. Using this approach, we observed the same association between the time since latest birth and the rate of late-stage breast cancer irrespective of parity, which suggests that, regardless of the number of previous births, a recent pregnancy transiently increases the number of late-stage cases of breast cancer.
We have used two different analytic approaches with different features. In one approach, we compare the risk in mothers at a given time interval after the birth with what their risk would have been if they had not delivered a child. With such an approach, one is able to estimate the transient increase, which is of etiologic interest. However, as one estimates the combined effect of the birth and the time interval, one cannot determine whether differences in the effects according to stage is related to the birth per se, the time interval, or both. In the other approach, we avoid this problem by comparing the risk according to the time since the latest birth between women with the same number of births. This approach cannot be used, however, to estimate the transient increase (19
), and furthermore, it has been argued that one cannot estimate the effect of time since the latest birth in uniparous women while adjusting for age at first birth and age (5
). However, estimation in uniparous women is possible when nulliparous women are included and a common age effect for all women is assumed (15
). A recent paper reveals that this approach is reasonable (20
). Nevertheless, in table 1, we have provided results in which uniparous women are excluded.
The study was performed as a prospective analysis on a large, population-based cohort and was based on mandatory reported exposure and outcome information, making information bias on exposure and selection bias on cases unlikely. As noted by Hsieh et al. (3
), the cohort follow-up design is more powerful than a case-control design when studying a time-dependent variable such as time since latest birth, since all births, not just the last birth, are included in the study. A limitation of the study was the lack of data on other reproductive breast cancer risk factors such as age at menarche, age at menopause, family history, and use of exogenous hormones.
In conclusion, a recent childbirth results in a transiently increased risk of breast cancer in the mother and, in particular, a relatively high risk of late-stage disease. These findings suggest that pregnancy-related factors transiently stimulate a high growth rate in already malignant cells and induce new tumor growth.
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ACKNOWLEDGMENTS
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Supported by US Army Breast Cancer Research Program (grant DAMD17961632) and the Danish National Research Foundation.
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NOTES
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Correspondence to Professor Mads Melbye, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark (e-mail: mme{at}ssi.dk).
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Received for publication January 4, 2000.
Accepted for publication October 20, 2000.