Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort

Data sources

The Uppsala birth cohort comprises all people delivered at the Uppsala Academic Hospital during 1915-29. 12 13 The cohort was followed up initially through parish archives, which record all births, deaths, and changes of residence. Since the introduction of personal identity numbers in the 1950s records could be linked to the registers of deaths and migration and the Swedish Cancer Registry to provide the relevant data for computing incidence rates for breast cancer and to the 1960 and 1970 censuses for data on adult characteristics.

We analysed incidence of breast cancer in 5358 singleton females in this cohort for whom linkage to the 1960 census records was successful and for whom subsequent breast cancer registration (ICD-7 (international classification of diseases, seventh revision) code 170) could be ascertained through the Swedish Cancer Registry (established in 1958).

Birth characteristics recorded at the time of birth included birth weight (measured to the nearest 10 g), birth length (recorded to the nearest 0.5 cm), head circumference, gestational age (calculated as the time between the mother's last day of menses and delivery date), birth order (calculated as the mother's total previous live and stillbirths), and multiple births.

The 1960 and 1970 censuses provided information on proxy variables for some established risk factors for breast cancer. Age at first marriage and single marital status (recorded at 1960 census) were taken as correlates for age at first birth and a crude indicator of nulliparity, respectively; the largest number of children aged less than 15 years living in the household in 1960 or, if available, 1970 as a proxy for parity; and educational level, personal car possession, and occupation in 1960 as markers of adult socioeconomic circumstances.

Statistical methods

We categorised birth weight into four groups (<3000 g, 3000–3499 g, 3500–3999 g, ≥4000 g) for ease of comparison with other studies. 10 11 Ponderal index, a measure of weight relative to length, was calculated as weight/height³. Gestational age was categorised into four groups (30-38, 39, 40, and ≥41 completed weeks of gestation). Birth length, head circumference, and ponderal index were divided into approximate fifths (exact fifths could not be defined due to the discrete nature of the data).

Follow up was calculated from 1 November 1960, the census date, to the date of first diagnosis of breast cancer, emigration, death, or end of follow up (31 December 1998), whichever occurred first. We estimated the effect of each birth characteristic on risk of breast cancer as rate ratios using a Cox proportional hazards regression model, where age defined the time scale. To adjust for cohort effects we stratified the models14 by five year birth cohorts (1915-9, 1920-4, and 1925-9). As breast cancer may have a different aetiology before and after the menopause we examined associations separately at ages <50 years and at older ages, hereafter referred to as premenopausal and postmenopausal ages, respectively. Confidence intervals were computed with robust standard errors to account for correlations among siblings15 and Wald tests were used to assess linearity of effects among consecutive exposure categories.

We adjusted for gestational age by including this covariate in Cox models. When we used z scores of birth characteristics for each gestational age (standardised birth characteristics within each gestational week) our results were similar and thus are not reported here.

Main findings

We have found strong evidence of positive associations between measures of birth size and risk of premenopausal breast cancer, which persisted after we adjusted for markers of adult risk factors and were strengthened after we adjusted for gestational age. In addition, for a given birth size a shorter gestation was associated with a significantly increased risk of premenopausal breast cancer. The positive association with birth size and independent inverse association with gestational age indicate that the rate of fetal growth may underlie the association between birth size and risk of early breast cancer. There was no evidence of an association with postmenopausal risk.

The Uppsala birth cohort study comprises a large population based cohort with long and almost complete follow up and enough events to enable separate analysis at premenopausal and postmenopausal ages. Data on a large number of birth measurements allowed us to examine their independent effects and their effects adjusted for gestational age so we could obtain a measure of the fetal growth rate. As birth characteristics were measured and recorded at the timeof birth they were not affected by recall bias. Other than measures of birth size, however, we did not have any other information about intrauterine factors. We adjusted for risk factors in adult life using proxy markers obtained from census data, although there is still potential for residual confounding. Ascertainment of cases of breast cancer during follow up was virtually complete,16 but a few cases in young women might have been missed if they were diagnosed before the start of follow up in 1960.

Comparison with other studies

Our findings are consistent with those from a British cohort11 and a case-control study nested within the nurses' health study,10 in which positive associations were found with birth weight, particularly at young ages. We did not find evidence for a J shaped association as has been reported elsewhere. 3 4 6 7 Our observed positive association with birth length agrees with findings from two other studies. 3 9 Also Ekbom et al found a significantly increased risk in women who had been born very prematurely, 5 17 though no such association was found in the nurses' health study.10 However, in the nurses' health study maturity at birth was recalled by the participants' mothers and was thus prone to greater error than in our study. Lastly, our adjustment for gestational age or stratification by menopausal status, or both, may have led to differences in magnitude of effects with respect to other studies.9^–11

We found that the associations of birth length and head circumference with premenopausal risk were stronger than those for birth weight and that there was no association with ponderal index, suggesting that linear (bone) growth may be a more sensitive indicator of the relevant biological processes. Length at birth is a stronger predictor of adult height than birth weight. 18 19 Thus, the association of adult height with risk of breast cancer20 may in part reflect prenatal as well as postnatal influences.

Biological plausibility and implications

Trichopoulos hypothesised that prenatal exposure to high concentrations of pregnancy oestrogens influences risk of breast cancer.1 The mammary gland starts to develop in utero, when it is in a partially undifferentiated state, and high concentrations of growth factors may result in an increased number of stem cells or increased mitosis, or both. But although there is strong evidence that a woman's endogenous oestrogen concentrations are important in the aetiology of postmenopausal breast cancer,21 their role at premenopausal ages is less clear.22 Our findings are consistent with those from recent prospective studies that have shown a strong association between high circulating concentrations of insulin-like growth factor I in adulthood and subsequent risk of premenopausal, but not postmenopausal, breast cancer. 23 24

In public health terms, if the findings were real, large birth size would be responsible for only a small proportion of the total number of cases of breast cancer in any population as the incidence at premenopausal ages is low. The association of larger size at birth with an increased risk of premenopausal breast cancer should be considered in light of its opposite association with ischaemic heart disease,13 a much more common condition.

In summary, our results provide strong evidence that there is real association between birth size and risk of breast cancer at premenopausal ages and that fetal growth rate, rather than size at birth alone, may be the aetiological relevant factor.