A breast cancer diagnosis coinciding with pregnancy represents a clinical dilemma and potentially can have a devastating effect for both the pregnant woman and the fetus. A small but not negligible proportion of breast cancers in young women are diagnosed in association with childbearing.1 In Sweden, one tenth of all breast cancers are diagnosed in women younger than 45 years,2 of whom an estimated 4% will be pregnant at the time of detection. In the age group 25–29 years, where childbearing is most frequent, results from earlier studies indicate that at least one in five breast cancers coincide with pregnancy or lactation.3 Pregnancy-associated breast cancer commonly refers to instances in which the initial diagnosis of a breast malignancy is made during pregnancy or within 1 or 2 years after delivery.4 Earlier attempts to assess the occurrence of pregnancy-associated breast cancer have varied from 1 in 10,000 to 1 in 3,000 deliveries, depending on study population and definitions used.3,5–10
Several studies have found evidence of a delayed diagnosis in pregnant women.1,3,11–14 Also, results from some studies indicate that women with pregnancy- associated breast cancer have larger tumors and are more likely to have positive nodes, metastases, and vascular invasion compared with nonpregnant women with breast cancer.13,15–18 The majority of studies to date on pregnancy-associated breast cancer have been based on case series or small selected materials, and only a few studies have been based on unselected population-based materials.3,8,10
Because women in many countries tend to postpone childbearing to older age, the incidence of breast cancer coinciding with pregnancy is likely to increase. In Sweden, the mean age at first birth increased from 24 years in 1970 to 29 years in 2006. The change has been especially dramatic in urban areas—in Stockholm, the mean age at first delivery increased from 25 years to 32 years during the same period (www.scb.se). In the United States, the number of first births per 1,000 women among women aged 35 to 39 years increased by 36% between 1991 and 2001, and the rate among women aged 40 to 44 years leapt by 70%.19
We conducted a nationwide Swedish study to estimate the incidence of pregnancy-associated breast cancer and whether the incidence had changed over time. To illustrate indirectly possible delays in diagnosis, we also assessed observed compared with expected number of breast cancers diagnosed during pregnancy and the first and second year after delivery.
MATERIALS AND METHODS
The present study was based on data from two national registers in Sweden: The Swedish Cancer Register and the Swedish Multi-Generation Register. The registers were linked using the national registration number, a unique identifier assigned to all Swedish residents at time of birth or permanent residency.
The nationwide, population-based Swedish Cancer Register was established in 1958 and has been used extensively as a source of data in epidemiological studies.20,21 Clinicians and pathologists/cytologists are mandated by law to report all newly diagnosed malignant tumors. The register is updated yearly. In 1998, the overall reporting rate to the Cancer Register was estimated to be about 96% of all diagnosed cases.22
The Swedish Multi-Generation Register includes index persons born in 1932 or later who were alive in 1961, with links to their parents, siblings, and offspring. In the year 2000, the database encompassed almost 11 million persons with national registration numbers. The database is being used in epidemiologic research to assess familial cancer risks.23
From the Swedish Cancer Register, we identified all malignant breast cancer cases (International Classification of Diseases-7 code 170) among girls and women aged 15–44 years from 1963 through 2002. Using information from the Swedish Multi-Generation Register, pregnancy-associated breast cancer was defined as a breast cancer diagnosed from 9 months before to 2 years after date of delivery. The number of pregnancy-associated breast cancer cases was divided into different time windows by time of diagnosis: during pregnancy (ie, 1–3, 4–6, and 7–9 months before delivery), first year after delivery (further divided into 6-month periods), and second year after delivery.
Proportions of pregnancy-associated breast cancer among all breast cancer diagnoses in girls and women ages 15–44 years were assessed for different age groups (15–24, 25–29, 30–34, 35–39, and 40–44 years) and calendar periods (1963–1974, 1975–1989, and 1990–2002).
The incidence of pregnancy-associated breast cancer per 100,000 deliveries was calculated based on the number of deliveries among girls and women aged 15 to 44 years between 1963 and 2002. We estimated the overall incidence of pregnancy-associated breast cancer as well as the incidence in different time windows (during pregnancy, first year after delivery divided into two 6-month periods, and second year after delivery). The incidence of pregnancy-associated breast cancer also was assessed by calendar period (1963–1974, 1975–1989, and 1990–2002).
To estimate the expected number of pregnancy-associated breast cancer cases, we used population-incidence rates by 5-year age groups and calendar periods. We estimated observed compared with expected numbers of cases for four time windows around delivery (during pregnancy, first year after delivery divided into two 6-month periods, and second year after delivery). Each delivery contributed 9 months of risk time during pregnancy, and the first and second years after delivery contributed 1 year each. To decide which age group a woman contributed risk time to, we defined the woman’s age at risk during pregnancy as the age at delivery minus 4.5 months, which averages the true age at risk. Similarly, we defined the woman’s age at risk during the first 6 months after the delivery as the age at delivery plus 3 months, her age at risk during months 7 to 12 after the delivery as the age at delivery plus 9 months, and her age at risk during the second year after delivery as the age at delivery plus 18 months. The same technique was used to define to which calendar year a woman contributed risk time. After defining the age and year at risk, women were grouped into 5-year age groups and 5-year calendar-period groups and the number of observed and expected cancer cases were calculated. Confidence intervals (CIs) for observed compared with expected number of pregnancy-associated breast cancer cases were estimated assuming that the number of pregnancy-associated breast cancer cases were Poisson distributed. All analyses were performed using SAS 9.1 (SAS Institute, Cary, NC). The study was approved by the institutional review board at Karolinska Institutet.
Between 1963 and 2002, we identified 1,161 cases of pregnancy-associated breast cancer among a total of 16,620 breast cancer cases in girls and women aged 15 to 44 years. The largest proportion of pregnancy-associated breast cancer (30.1%) was found within the age group 25–29 years, with 31.5%, 31.1%, and 27.9% for each calendar period, respectively (Table 1). Pregnancy-associated breast cancer was least frequent among the oldest women (40–44 years), in whom the breast cancer incidence was highest (proportions ranging from 1.2% to 1.7%). Among women aged 30 years and older, the proportion of pregnancy-associated breast cancer was higher in the last calendar period under study (1990–2002) compared with earlier periods.
A total of 4,156,190 deliveries were recorded between 1963 and 2002. The majority of the 1,161 pregnancy-associated breast cancer cases were diagnosed between 7 and 24 months after delivery, with only a few cases (n=27) identified in the first two trimesters of pregnancy (Table 2). The overall incidence of pregnancy-associated breast cancer increased from 16.0 to 37.4 per 100,000 deliveries during the study period (Table 2), with the largest increase occurring between the two earlier periods. After stratifying by age, we saw an increased incidence of pregnancy-associated breast cancer from the period of 1963–1974 to 1975–1989 in all age groups; the incidence remained stable or decreased somewhat between the periods 1975–1989 and 1990–2002 (Fig. 1). Hence, the increase between the latter periods shown in Table 2 appears confounded by increasing maternal age over the calendar periods. The incidence also was influenced by time of diagnosis in relation to delivery. During pregnancy, the incidence was 2.38 per 100,000 deliveries; the incidence during the first and second years after delivery was 10.6 and 15.0 per 100,000 deliveries, respectively. Hence, there was both a calendar effect and an effect of time of diagnosis in relation to delivery.
Fewer pregnancy-associated breast cancer cases than expected were diagnosed during pregnancy and the first 6 months after delivery (Table 3). The ratio of observed to expected number of breast cancer cases diagnosed during pregnancy was 0.30 (95% CI 0.25–0.37), and the corresponding rate for the first 6 months after delivery was 0.59 (95% CI 0.50–0.69). Thereafter, there was no longer any difference between observed compared with expected number of breast cancer cases.
Since the 1960s, there has been an increase in the incidence of breast cancer diagnosed both during pregnancy and within 2 years after delivery. The largest proportion of pregnancy-associated breast cancer cases was found among 25-year-old to 29-year-old women. In this age group, in which childbearing is most frequent, almost one third of all breast cancers occurred during pregnancy or within 2 years after delivery.
We found an overall incidence of pregnancy-associated breast cancer cases of 27.9 per 100,000 deliveries, 2.38 per 100,000 deliveries when considering breast cancer diagnosed during pregnancy, and 13.0 per 100,000 when considering diagnoses during pregnancy and first year after delivery. This is in line with previous studies. Haas8 found an incidence of 1.33 when considering only breast cancer diagnosed during pregnancy. Smith et al10 found an overall incidence of 19 per 100,000 deliveries and Lambe et al3 an incidence of 11 per 100,000 deliveries for breast cancer during pregnancy and first year after delivery.
Few patients were diagnosed with breast cancer during childbearing, and when compared with the incidence in the general population, the observed-to-expected number of breast cancer cases during pregnancy was 0.30. Also, fewer breast malignancies than expected were diagnosed in the first 6 months after delivery; however, after that, the observed number of pregnancy-associated breast cancer cases was similar to that expected. The observed-to-expected ratios suggest that breast cancer is underdiagnosed in pregnant and lactating women, corroborating earlier findings.1,3,11–14 Unusual signs and symptoms may be interpreted by both the patient and the doctor as being related to physiological changes in the breast during pregnancy and lactation. It has been reported that most pregnancy-associated masses are self-discovered,24 but detection by palpation becomes increasingly difficult with the progression of the pregnancy because of increasing firmness, hypertrophy, and sometimes indistinct nodularity. Also, radiologic and invasive diagnostic procedures probably are less likely to be implemented during pregnancy and lactation.
With women tending to postpone childbearing to older age, the incidence of breast cancer coinciding with pregnancy is expected to increase, which to some extent was supported by our data. Our findings of an increased incidence of pregnancy-associated breast cancer over time can be explained partly by a temporal trend of postponed childbearing. After stratification by maternal age, we still observed a somewhat increased incidence of pregnancy-associated breast cancer over calendar time in the earlier periods under study. Another possible explanation for the increase in the incidence of pregnancy-associated breast cancer is an overall increase in the incidence of breast cancer in Sweden.2
Our study was population-based, covering virtually all breast cancer diagnoses and deliveries in Sweden during four decades. Because we used data retrieved from population-based registries, selection and information bias should not be an issue. One limitation of the present study was the absence of information about pregnancies that ended with abortion. This might explain the small numbers of pregnancy-associated breast cancer cases seen in the first 3 months of pregnancy, when women diagnosed with cancer may have been advised to or chose to terminate the pregnancy.
Breast cancer coinciding with childbearing has been denoted the ultimate challenge by posing extremely difficult questions to the caregiver, the patient, and her family. Because of a continued trend toward postponed childbearing, the incidence of pregnancy-associated breast cancer and related morbidity and mortality is likely to increase. Furthermore, pregnancy-associated breast cancer has been identified as an area where there is a gap in clinical understanding. Outstanding research questions of interest include a more detailed understanding of possible risk factors, clinical presentation, mode and timing of diagnosis, tumor characteristics, and prognosis. An increased awareness of pregnancy-associated breast cancer can improve the clinical management of these young breast cancer patients, for example, by avoiding undue delays in diagnosis and treatment.
1. Merkel DE. Pregnancy and breast cancer. Semin Surg Oncol 1996;12:370–5.
2. National Board of Health and Welfare. Cancer incidence in Sweden 2007. Official Statistics of Sweden. Health and Diseases 2008:11. Stockholm 2008. Available at: http://www.socialstyrelsen.se/Publicerat/2008/10204/2008-125-16.htm
. Retrieved May 19, 2009.
3. Lambe M, Ekbom A. Cancers coinciding with childbearing: delayed diagnosis during pregnancy? BMJ 1995;311:1607–8.
4. Petrek JA. Breast cancer during pregnancy. Cancer 1994;74:518–27.
5. White TT. Carcinoma of the breast and pregnancy; analysis of 920 cases collected from the literature and 22 new cases. Ann Surg 1954;139:9–18.
6. Peete CH Jr, Huneycutt HC Jr, Cherny WB. Cancer of the breast in pregnancy. N C Med J 1966;27:514–20.
7. Anderson JM. Mammary cancers and pregnancy. Br Med J 1979;1:1124–7.
8. Haas JF. Pregnancy in association with a newly diagnosed cancer: a population-based epidemiologic assessment. Int J Cancer 1984;34:229–35.
9. Antonelli NM, Dotters DJ, Katz VL, Kuller JA. Cancer in pregnancy: a review of the literature. Part I. Obstet Gynecol Surv 1996;51:125–34.
10. Smith LH, Danielsen B, Allen ME, Cress R. Cancer associated with obstetric delivery: results of linkage with the California cancer registry. Am J Obstet Gynecol 2003;189:1128–35.
11. Bonnier P, Romain S, Dilhuydy JM, Bonichon F, Julien JP, Charpin C, et al. Influence of pregnancy on the outcome of breast cancer: a case-control study. Societe Francaise de Senologie et de Pathologie Mammaire Study Group. Int J Cancer 1997;72:720–7.
12. Tretli S, Kvalheim G, Thoresen S, Høst H. Survival of breast cancer patients diagnosed during pregnancy or lactation. Br J Cancer 1988;58:382–4.
13. Ishida T, Yokoe T, Kasumi F, Sakamoto G, Makita M, Tominaga T, et al. Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: analysis of case-control study in Japan. Jpn J Cancer Res 1992;83:1143–9.
14. Liberman L, Giess CS, Dershaw DD, Deutch BM, Petrek JA. Imaging of pregnancy-associated breast cancer. Radiology 1994;191:245–8.
15. Petrek JA. Pregnancy-associated breast cancer. Semin Surg Oncol 1991;7:306–10.
16. Petrek JA, Dukoff R, Rogatko A. Prognosis of pregnancy-associated breast cancer. Cancer 1991;67:869–72.
17. Max MH, Klamer TW. Pregnancy and breast cancer. South Med J 1983;76:1088–90.
18. Guinee VF, Olsson H, Möller T, Hess KR, Taylor SH, Fahey T, et al. Effect of pregnancy on prognosis for young women with breast cancer. Lancet 1994;343:1587–9.
19. Heffner LJ. Advanced maternal age–how old is too old? N Engl J Med 2004;351:1927–9.
20. Calltorp J, Adami HO, Aström H, Fryklund L, Rossner S, Trolle Y, et al. Country profile: Sweden. Lancet 1996;347:587–94.
21. Rosén M. National Health Data Registers: a Nordic heritage to public health. Scand J Public Health 2002;30:81–5.
22. Barlow L, Westergren K, Holmberg L, Talbäck M. The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta Oncol 2009;48:27–33.
23. Statistics Sweden. Multi-generation register 2006: a description of contents and quality. Örebro: Statistics Sweden (Statistiska centralbyrån) (SCB); 2007. Available at: http://www.scb.se/statistik/_publikationer/BE9999_2006A01_BR_BE96ST0703.pdf
. Retrieved May 19, 2009.
24. Middleton LP, Amin M, Gwyn K, Theriault R, Sahin A. Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features. Cancer 2003;98:1055–60.