Intrauterine Environment and Breast Cancer Risk in Women: A Population-Based Study

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Abstract
Background: The established risk factors for female breast cancer, including nulliparity, age at first birth, age at menarche, and age at menopause, do not adequately explain the occurrence pattern of this cancer. Therefore, additional factors need to be considered to advance our understanding of the causes of breast cancer. Evidence obtained from animals and humans indicates that the perinatal period may be particularly important. Our earlier studies, based on a subsample of the present investigation, suggested that factors thought to be positively associated with estrogen levels during pregnancy are positively associated with breast cancer risk. However, the associated confidence intervals (CIs) were generally wide, indicating considerable variability in the data. Purpose: We studied a large number of incident breast cancer case patients and evaluated several perinatal variables in relation to breast cancer risk. These variables included some not previously studied, such as gestational age and neonatal jaundice. We also investigated twin membership as a predictor variable and death from breast cancer, in addition to occurrence of breast cancer, as an alternative outcome variable. Methods: Birth records for all deliveries at five different hospitals in Sweden during the period from 1874 through 1961 were used to define a large cohort of women. Incident case patients with breast cancer in this cohort were ascertained through the National Cancer Registry or the Uppsala Regional Cancer Registry from 1958 through 1994. In a case-control study nested in the cohort, we abstracted data from birth records on 1068 women with incident breast cancer and on 2727 control subjects individually matched to the case patients on date of birth. We modeled the data through conditional logistic regression. All P values were derived from two-sided statistical tests. Results: We found a markedly reduced risk for breast cancer in women whose mothers had pregnancy toxemia (odds ratio [OR] = 0.41; 95% CI = 0.22–0.79) and an excess risk on women who had neonatal jaundice (OR = 2.16; 95% CI = 1.27–3.67) or who were born before 33 weeks of gestation (OR = 3.96; 95% CI = 1.45–10.81). Compared with the risk for breast cancer in the singleton, the risk for breast cancer in dizygotic twins was increased, although this increase was not statistically significant (OR = 1.72; 95% CI = 0.92–3.20). There was no evidence in these data for a statistically significant or substantial association of breast cancer risk with birth size indicators (i.e., weight and length at birth and placental weight). Conclusion and Implications: Because pregnancy toxemia is associated with low levels of estrogens and neonatal jaundice, severe prematurity, and dizygotic twins with high levels of estrogens, our findings suggest that estrogens and other hormonal factors, known to influence breast cancer risk in the adult, may also play a critical role during the intrauterine period.