Papers

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

V A McCormack, research fellow ^a, I dos Santos Silva, clinical senior lecturer ^a, B L De Stavola, senior lecturer ^a, R Mohsen, programmer ^b, D A Leon, professor ^a, H O Lithell, professor ^b. 

^a Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, ^b Department of Geriatrics, Uppsala University, PO Box 609, S751-25 Uppsala, Sweden

Correspondence to: V A McCormack
valerie.mccormack{at}lshtm.ac.uk

	Abstract

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Objective: To investigate whether size at birth and rate of fetal growth influence the risk of breast cancer in adulthood.
Design: Cohort identified from detailed birth records, with 97% follow up.
Setting: Uppsala Academic Hospital, Sweden.
Participants: 5358 singleton females born during 1915-29, alive and traced to the 1960 census.
Main outcome measures: Incidence of breast cancer before (at age <50 years) and after ( 50 years) the menopause.
Results: Size at birth was positively associated with rates of breast cancer in premenopausal women. In women who weighed 4000 g at birth rates of breast cancer were 3.5 times (95% confidence interval 1.3 to 9.3) those in women of similar gestational age who weighed <3000 g at birth. Rates in women in the top fifths of the distributions of birth length and head circumference were 3.4 (1.5 to 7.9) and 4.0 (1.6 to 10.0) times those in the lowest fifths (adjusted for gestational age). The effect of birth weight disappeared after adjustment for birth length or head circumference, whereas the effects of birth length and head circumference remained significant after adjustment for birth weight. For a given size at birth, gestational age was inversely associated with risk (P=0.03 for linear trend). Adjustment for markers of adult risk factors did not affect these findings. Birth size was not associated with rates of breast cancer in postmenopausal women.
Conclusions: Size at birth, particularly length and head circumference, is associated with risk of breast cancer in women aged <50 years. Fetal growth rate, as measured by birth size adjusted for gestational age, rather than size at birth may be the aetiologically relevant factor in premenopausal breast cancer.

What is already known on this topic There is some evidence that birth weight is related to risk of breast cancer The exact nature of any association and whether it differs at premenopausal and postmenopausal ages is unclear Few studies have examined the effect of other measures of birth size and of gestational age What this study adds There are strong positive associations between measures of birth size and rates of breast cancer at premenopausal ages that persisted after adjustment for adult risk factors For a given birth size, gestational age was inversely associated with risk, suggesting that the rate of fetal growth may be aetiologically relevant to premenopausal breast cancer There was no association between birth characteristics and rates of breast cancer at postmenopausal ages

	Introduction

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In 1990, Trichopoulos proposed the hypothesis that breast cancer may originate in utero.¹ Three studies found positive linear associations with birth weight,^2-4 while J shaped associations were found in four others.^5-8 The effect of other measures of birth size ^{2 5 9} and gestational age ^{3 9 10} have been examined less often.

We investigated possible associations between fetal growth and risk of breast cancer using data from a large Swedish cohort with long and virtually complete follow up. The cohort benefits from data on several birth characteristics and on markers of adult risk factors based on census data. These data allowed us to examine the independent effect of each measure of birth size on risk of breast cancer before and after the menopause, while controlling for some established risk factors for breast cancer. In addition, the availability of data on gestational age provides a unique opportunity to assess the effect of fetal growth rate, measured by birth size adjusted for gestational age, distinct from size at birth on risk of breast cancer.

	Methods

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Data sources
The Uppsala birth cohort comprises all people delivered at the Uppsala Academic Hospital during 1915-29. ^{11 12} 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 could be ascertained through the Swedish Cancer Registry. Birth characteristics recorded at the time of birth included birth weight, birth length, head circumference, gestational age, birth order, and multiple births.

The 1960 and 1970 censuses provided information on proxy variables for some established risk factors for breast cancer such as age at first full term birth; marital status, the number of children aged less than 15 years living in the household 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), and calculated the ponderal index 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.

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. We stratified the models¹³ 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.

	Results

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We included 5358 women in the reported analyses. There were 359 cases of breast cancer during the 38 year follow up. The median age at diagnosis was 62 years (range 36-82), with 63 cases occurring in women aged under 50 years. In addition, 1197 (22%) women, who had never been diagnosed with breast cancer, died from other causes (median age 68 years, range 31-83) and 37 (0.7%) emigrated during follow up (median age 49, range 31-74).

Women who developed breast cancer at premenopausal ages had, on average, a larger birth size but a shorter gestational age than those who did not (table 1).

There were positive and significant linear trends in rates of breast cancer at premenopausal ages among categories of birth weight, length, and head circumference (table 2). Each of these associations strengthened considerably after we adjusted for gestational age. Ponderal index showed a positive but non-significant association with risk of premenopausal breast cancer. Women of a higher birth order were at a slightly increased but non-significant risk, but this effect disappeared after we adjusted for birth weight (P=0.98 for linear trend). Maternal age showed no clear pattern with rates of premenopausal breast cancer. There was no evidence of associations between any of the birth size measures available in this study and rates of postmenopausal breast cancer (see bmj.com).

In contrast with the positive associations between measures of birth size and premenopausal risk, for a given birth size a shorter gestation was associated with a significant increase in risk (rate ratio 2.10, 95% confidence interval 1.05 to 4.21, for women born at <39 weeks' gestation v women born at 41 weeks' gestation, P=0.03 for linear trend). No such association was seen for postmenopausal ages (see bmj.com).

Simultaneous modelling of the birth size variables and gestational age showed that head circumference was the measure with the strongest independent association with risk of premenopausal breast cancer (table 3). The association with birth weight was greatly reduced and no longer significant after we adjusted for either birth length or head circumference, whereas that for birth length remained of borderline significance after we adjusted for birth weight.

The proxy markers for risk factors for breast cancer, such as single women, late marriage, living in households with fewer children, and high socioeconomic standing had effects in the expected direction (see bmj.com). There was, however, no evidence that the associations between the birth characteristics and risk of breast cancer were confounded by these adult characteristics (see table 2) nor by maternal socioeconomic status at birth.

	Discussion

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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.

Comparison with other studies
Our findings are consistent with those from a British cohort⁴ and a case-control study nested within the nurses' health study,³ 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.^5-8 Our observed positive association with birth length agrees with findings from two other studies. ^{2 5} Also Ekbom et al found a significantly increased risk in women who had been born very prematurely, ^{9 10} though no such association was found in the nurses' health study.³ 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.^2-4

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. ^{14 15} Thus, the association of adult height with risk of breast cancer¹⁶ 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,¹⁷ their role at premenopausal ages is less clear.¹⁸ 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. ^{19 20}

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,¹² 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.

	Acknowledgments

Contributors: see bmj.com

	Footnotes

Funding: The Uppsala birth cohort study was established on grants provided by the UK Medical Research Council (No 9322050), the Swedish Council for Social Research (No 94/0157), and the Swedish Medical Research Council (No 5446). This work was conducted within the MRC Cooperative on "Life-course and trans-generational influences on disease risk" (G9819083).

Competing interests: None declared.

This is an abridged version; the full version is on bmj.com

	References

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(Accepted 4 November 2002)