Elsevier

The Lancet

Volume 348, Issue 9041, 7 December 1996, Pages 1542-1546
The Lancet

Articles
Birthweight as a risk factor for breast cancer

https://doi.org/10.1016/S0140-6736(96)03102-9Get rights and content

Summary

Background

The mammary gland is largely undifferentiated before birth and may be particularly susceptible to intrauterine influences that could increase the risk of cancer through acceleration of cell proliferation or other pregnancy-related processes. Studies of migrant populations, animal data, and limited epidemiological evidence suggest that breast cancer may originate in utero. In a nested case-control study we assessed whether birthweight and other perinatal factors are associated with risk of breast cancer.

Methods

This case-control study was nested within the cohorts of the two Nurses' Health Studies. We used self-administered questionnaires to obtain information from the mothers of 582 nurses with invasive breast cancer and the mothers of 1569 nurses who did not have breast cancer (controls). Information on risk factors for breast cancer during adulthood were obtained from the nurses; multiple logistic regression analysis adjusted for these risk factors.

Findings

Birthweight was a significant predictor of breast-cancer risk. With women who weighed 4000 g or more at birth as the reference category, the adjusted odds ratios for breast cancer were 0·86 (95% CI 0·59–1·25) for birthweights of 3500–3999 g, 0·68 (0·48–0·97) for birthweights of 3000–3499 g, 0·66 (0·45–0·98) for birthweights of 2500–2999 g, and 0·55 (0·33–0·93) for birthweights below 2500 g (p for trend 0·004). Prematurity was not significantly associated with risk of breast cancer.

Interpretation

Birthweight is significantly associated with breast-cancer risk, which suggests that intrauterine factors or processes affect the risk of breast cancer in the offspring. High concentrations of pregnancy oestrogens may have an important role in breast carcinogenesis, but other pregnancy hormones or intrauterine factors may also be involved.

Introduction

Before birth the mammary gland is in a partly undifferentiated state and, therefore, may be susceptible to intrauterine influences that could increase the risk of cancer.1, 2, 3 Terminal end buds–undifferentiated structures in the mammary gland–are found only in young animals; of all the structures of the mammary gland they have the longest S-phase during DNA synthesis in the cell cycle and, thus, may be particularly susceptible to mutation.4 Chemically induced rat mammary tumours arise from pre-existing oncogenic ras gene mutations, which occur during early organ development.5

The hypothesis has been raised that human breast cancer may originate in utero.6, 7, 8, 9 The observation that the rate of breast cancer in Japanese migrants becomes similar to that of white Americans only after two or more generations accords with the hypothesis of early-life modulation of breast-cancer risk. By contrast, Japanese migrants' risk of colorectal cancer becomes similar to that of the host population within a few decades of migration, which indicates an important role of lifestyle factors in disease aetiology.10, 11 Ziegler and colleagues' study12 found that an increase in the risk of breast cancer became apparent in first-generation Asian migrants to the USA, but that the difference in risk between Asian and white American women disappeared only after several generations in the USA.

An intrauterine origin of breast cancer could be linked to oestrogens and other hormones produced during pregnancy or to other pregnancy-related processes. The importance of oestrogens in the aetiology and natural history of breast cancer points to high concentrations of pregnancy oestrogens as possible causes,6, 7, 9 but other factors associated with pregnancy could also be important.8, 13 Fetal growth is positively associated with concentrations of oestrogens at the extremes of the corresponding distributions, although evidence for an association throughout the usual range of fetal growth is not clear.14, 15, 16, 17 Le Marchand and colleagues18 found no association between birthweight and breast-cancer risk, but their study had small numbers of cases.18 In a study in Sweden,7 breast-cancer risk tended to increase with birthweight, birth length, and placental weight, but no association was statistically significant. Sanderson et al19 reported a positive association between birthweight and risk of breast cancer in premenopausal women in the USA, but not in postmenopausal women; they interpreted their findings as compatible with the hypothesis that links pregnancy oestrogens to risk of breast cancer.

With two large prospective cohort investigations as our study base, we undertook a nested case-control study to assess the association between birthweight and risk of breast cancer, after adjustment for established risk factors for the disease in adult life.

Section snippets

Methods

The case-control study was nested in two prospective cohort investigations–the Nurses' Health Study (NHS I) and the Nurses' Health Study II (NHS II). The cohorts comprise 121 700 and 116 680 female registered nurses, respectively. The NHS I cohort was established in 1976 and includes women born between 1921 and 1945; the NHS II cohort was founded in 1989 and includes women born between 1946 and 1965. For both cohorts, biennial questionnaires are used to collect information on various exposures

Results

Characteristics of the 582 breast-cancer cases and 1569 controls are shown in Table 1. The median year of birth of the mothers who took part in this study was 1914 for case mothers and 1913 for control mothers. Of the 582 cases, 393 (67%) were premenopausal at diagnosis, 137 (24%) were postmenopausal, and 52 (9%) were perimenopausal or of uncertain menopausal status. Age at menarche of older than 15 years, parity of four or more children, and age at first birth of younger than 24 years tended

Discussion

The early years of life are increasingly thought to be important in the aetiology of breast cancer. In 1969, Cole and MacMahon23 proposed this hypothesis on the basis of the strong risk associations with age at menarche and age at first pregnancy. The hypothesis that breast cancer may, to a certain extent, originate in utero was based on the assumption that endogenous oestrogens are important factors in the aetiology of breast cancer and that first exposure of the mammary gland to high

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