Abstract

A high birthweight has been associated with an increased risk of breast cancer later in life. The role of adult variables, possible effect modifiers and cancer characteristics has been little studied. We explored these in two large prospective cohort studies of women, the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II). We collected information on birthweight from 152 608 female nurses participating in NHS and NHS II. During 10 years and 1.3 million person-years of follow-up, invasive breast cancer was newly diagnosed among 828 premenopausal and 2312 postmenopausal women. Data were analyzed using a Cox proportional hazards model. Premenopausal women with a birthweight of <5.5 lbs had a covariate-adjusted hazard ratio (HR) for breast cancer of 0.66 [95% confidence interval (CI) 0.47–0.93] compared with women born at 8.5 lbs or above. Adult height was the only factor explaining some of the association between birthweight and breast cancer incidence; after adjustment for height the HR was 0.73 (95% CI 0.51–1.03). The association between birthweight and the incidence of breast cancer was stronger among women with estrogen-receptor positive and progesterone-receptor positive breast cancer. Among postmenopausal women, no important association between the birthweight and the incidence of breast cancer was detected (HR comparing women with a birthweight of 5.5 lbs or less with women with a birthweight >8.5 lbs: 0.97; 95% CI 0.80–1.16). In these two large prospective cohorts, a low birthweight was associated with a decreased incidence of breast cancer among premenopausal women. This association was independent of other factors operating later in life, except for adult height.

Introduction

Much evidence indicates that breast cancer may originate early in a woman's life ( 1 ). In utero the fetus is exposed to high concentrations of anabolic hormones, including estrogen and progesterone, and to growth hormone, and insulin-like growth factors I and II, all of which may affect mammary cells through proliferation, imprinting and reprogramming ( 1 , 2 ). A high birthweight may be a marker of exposure to high levels of growth factors in utero ( 3 ).

The mammary gland seems particularly susceptible to environmental insults between conception and the phase of rapid growth during sexual maturation ( 4 , 5 ). The immature gland harbors undifferentiated cells vulnerable to the potentially carcinogenic influences of hormones, irradiation and toxins ( 6 ). Partial differentiation occurs during mammary gland growth around puberty and during pregnancy, when breast cells mature to prepare for their designated function of lactation ( 7 ).

Birthweight has been positively associated with the risk of breast cancer in a number of studies ( 8–23 ), whereas other studies found no significant association ( 24–33 ). Links between birthweight and breast cancer have been found mostly among premenopausal women, whereas studies focusing on breast cancer diagnosed after age 50 years fairly consistently reported a lack of association with birthweight (1). The role of adult variables, possible effect modifiers and cancer characteristics has remained unclear.

We have reported previously a positive association between birthweight reported by the mother and breast cancer risk in the daughter using data from a case–control study conducted within the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II) ( 9 ). We here provide the results from prospective analyses of our cohorts, which include 828 incident cases of premenopausal breast cancer from NHS II and 2312 cases of postmenopausal breast cancer from NHS using information on birthweight reported by the study participants. We have given special consideration to the role of adult variables, possible effect modifiers and cancer characteristics.

Research design and methods

Population: NHS and NHS II

The NHS was established in 1976, when 121 700 female registered nurses 30–55 years of age and living in 11 US states completed a mailed questionnaire on their health status and on demographic, anthropometric and lifestyle factors. Since then, participants have received questionnaires biennially to update information on anthropometric and lifestyle factors and on newly diagnosed disease, including breast cancer. The NHS was approved by the institutional review board of the Brigham and Women's Hospital, Boston, MA.

In 1989, 116 671 female registered nurses aged 25–42 years and living in one of 14 US states responded to a baseline questionnaire about their medical histories, demographic factors, and lifestyle, forming the NHS II. Women who reported cancer (except non-melanoma skin cancer) at enrollment were excluded. Questionnaires have been sent to NHS II participants biennially to update information on demographic, anthropometric and lifestyle factors and on medical events. The NHS II was approved by the Institutional Review Boards of the Harvard School of Public Health and the Brigham and Women's Hospital, Boston, MA.

The study population for the present analyses consists of women selected from NHS II participants who provided information on their birthweight in 1991 and were premenopausal throughout follow-up and NHS participants who provided information on their birthweight in 1992 and were postmenopausal throughout follow-up. In our study cohort, the follow-up rate was 99% of total person-years for both NHS II premenopausal women (1991–2001) and NHS postmenopausal women (1992–2002).

Ascertainment of birthweight

In 1991, NHS II participants were asked their birthweight. Response options for the birthweight question were as follows: <5.5 lbs, 5.5 to 6.9 lbs, 7 to 8.4 lbs, 8.5 to 9.9 lbs, 10+ lbs and unknown. Birthweight was provided by 99 940 participants of NHS II. NHS participants were asked the same question in 1992. Response options were as follows: <5 lbs, 5 to 5.5 lbs, 5.5+ to 7 lbs, 7+ to 8.5 lbs, 8.5+ to 10 lbs, 10+ lbs and not sure. Birthweight was provided by 88 728 participants. On both questionnaires we also asked whether the woman was born full-term or 2+ weeks premature.

Birthweight reports were validated in a sample of NHS II participants by comparing their reports with information from their mothers and from their birth certificates ( 34 ). The Spearman's correlation coefficient of birthweight self-reported by 528 validation study participants with birthweight recalled by the mothers was 0.75; with state birth records the correlation coefficient was 0.74. The correlation between state records and mothers' report was 0.85.

Covariate information

Information on other potential risk factors for breast cancer was assessed at baseline and during follow-up. Participants were asked their date of birth, age at menarche, weight at age 18, current weight, adult height, parity, age at first birth, family history of breast cancer (in mother or sister), history of benign breast disease, use of oral contraceptives, menopausal status, use of postmenopausal hormones, physical activity and alcohol consumption at baseline. Covariate data from subsequent questionnaires were used to update individual information as follows: NHS II: current weight (1993, 1995, 1997 and 1999), family history of breast cancer (1997), history of benign breast disease (1993, 1995, 1997 and 1999), parity (1993, 1995, 1997 and 1999), age at first birth (1993, 1995, 1997 and 1999), use of oral contraceptives (1993, 1995, 1997 and 1999), physical activity (1997) and alcohol consumption (1995); NHS: current weight (1994, 1996, 1998 and 2000), family history of breast cancer (1996, 1998 and 2000), history of benign breast disease (1994, 1996, 1998 and 2000), use of oral contraceptives, use of postmenopausal hormones (1994, 1996, 1998 and 2000), physical activity (1994, 1996, 1998 and 2000) and alcohol consumption (1994 and 1998). Information on menopausal status was collected on each questionnaire.

Identification of breast cancer

On each biennial questionnaire participants in both studies were asked whether they had been newly diagnosed with breast cancer during the previous 2 years and, if so, the date of diagnosis. Deaths were reported by family members or by the Postal Service in response to the follow-up questionnaires, and the National Death Index was searched to investigate the deaths of non-responders. When a case of breast cancer was reported, we asked the participant (or next of kin for those who had died) for confirmation of the diagnosis and for permission to obtain relevant hospital records and pathology reports. Medical records were obtained for 90% of cases in NHS II and 95% of cases in NHS. Pathology reports confirmed breast cancer in >99% of women whose reports were reviewed. Only invasive incident cases of breast cancer were included in the current analysis. Cases of carcinoma in situ were censored at the time of diagnosis.

Statistical analysis

Women were followed prospectively from the time they reported their birthweight until the end of follow-up as follows: 1992–2002 in NHS and 1991–2001 in NHS II. Women were excluded from this analysis at baseline (1992 in NHS and 1991 in NHS II) if they did not answer the birthweight question or marked the response option ‘not sure’ in NHS or ‘unknown’ in NHS II, had reported any cancer except non-melanoma skin cancer or (if NHS II participants) were no longer premenopausal. For NHS, 49 595 women who were postmenopausal in 1992 were included, and additional women entered the analytic cohort as they became postmenopausal; person-years of follow-up were calculated as the time from completion of the 1992 questionnaire or reaching menopause, whichever occurred later, until the date of return of the 2002 questionnaire, a diagnosis of invasive breast cancer, a diagnosis of in situ breast cancer, death or loss to follow-up, whichever occurred first. For NHS II, 86 871 women who were premenopausal in 1991 were included; person-years of follow-up were calculated as the time from completion of the 1991 questionnaire to the date of return of the 2001 questionnaire, a diagnosis of invasive breast cancer, a diagnosis of in situ breast cancer, death, loss to follow-up or onset of menopause, whichever occurred first. Women were also censored if they failed to report their weight on three or more questionnaires.

A Cox proportional hazards model ( 35 ) was used to calculate the risk of developing invasive breast cancer associated with a particular birthweight. We first assessed the overall association between birthweight and breast cancer incidence in analyses adjusting only for age (in months). Information on premature birth and family history of breast cancer in first-degree relative(s) was added to the regression models. We assessed the association of birthweight with the risk of breast cancer independent of any effect mediated by other risk factors by adjusting for age at menarche, adult height, body mass index (BMI) at age 18, current BMI, history of benign breast disease, parity, age at first birth, oral contraceptive use, alcohol consumption, physical activity, and among NHS participants additionally for age at menopause and use of postmenopausal hormones. Covariate values were updated in the analysis whenever new information was obtained from the biennial questionnaire.

Analyses were stratified by premature birth of the nurse, living status of the participant's biological mother at the time of reporting birthweight information (mother's living status was assessed in 1993 in NHS II and in 1996 in NHS), family history of breast cancer, BMI at age 18 (<21, ≥21 kg/m 2 ) and current BMI (<26, ≥26 kg/m 2 for NHS and <24, ≥24 kg/m 2 for NHS II). Effect modification was assessed by creating cross-product terms between birthweight and each potential effect modifier. We measured the significance of the interaction using the Wald test. Analyses of the associations between birthweight and breast cancer subtypes defined by estrogen- and progesterone-receptor status were conducted using polytomous logistic regression. Likelihood ratio tests were used to compare a model with different slopes for each outcome with a model with a common slope. Chi-square tests were used to obtain two-sided P -values for the likelihood ratio statistics ( 36 ).

Trend tests used the midpoints of categories as a single variable. All tests of statistical significance were two-sided.

Results

The distribution of birthweight among NHS II participants was <5.5 lbs: 8%; 5.5–6.9 lbs: 31%; 7–8.4 lbs: 48%; and 8.5+ lbs: 13%; and among NHS participants: ≤5.5 lbs: 11%; >5.5–7 lbs: 31%; >7–8.5 lbs: 44%; and >8.5 lbs: 14%. The correlations of birthweight with adult anthropometric variables among NHS II participants were r = 0.22 for height, r = 0.05 for BMI at age 18 and r = 0.03 for current BMI; and among NHS participants were r = 0.21 for height, r = 0.04 for BMI at age 18 and r = 0.05 for current BMI. During 10 years and 1 299 529 person-years of follow-up, 828 incident cases of invasive breast cancer were diagnosed among the premenopausal participants included from NHS II, and 2312 among the postmenopausal participants included from NHS.

In these two large prospective cohorts, a low birthweight was associated with a reduced incidence of breast cancer among premenopausal women, but not among postmenopausal women ( Table I ). Among premenopausal women, those weighing <5.5 lbs at birth had a 31% [95% confidence interval (CI) 6–50%] lower incidence of breast cancer compared with women with a birthweight of 8.5 lbs or above ( P for trend = 0.019). After adjustment for premature birth, age at menarche, BMI at age 18, current BMI, family history of breast cancer, history of benign breast disease, age at first birth, parity, current and past use of oral contraceptives, physical activity and alcohol consumption, the hazard ratio (HR) was 0.66 (95% CI 0.47–0.93). Additionally, adjusting for adult height attenuated the HR to 0.73 (95% CI 0.51–1.03). The HR for breast cancer associated with each 10 cm increase in height was 1.19 (95% CI 1.06–1.32) among premenopausal women in NHS II.

Table I

Hazard ratio (95% CI) of breast cancer by birthweight among premenopausal participants of NHS II (1991–2001) and postmenopausal participants of NHS (1992–2002)

Birthweight (lbs) No. of cases Person-years Age-adjusted HR (95% CI) Covariate-adjusted HR (95% CI) Covariate-adjusted HR (95% CI) 
NHS II premenopausal women 
>8.4 135 102 115 1.0 1.0 1.0 
7.0–8.4 385 363 040 0.76 (0.63–0.93)  0.75 (0.62–0.91) a  0.78 (0.64–0.95) b 
5.5–6.9 250 228 509 0.79 (0.64–0.97)  0.75 (0.61–0.93) a  0.81 (0.65–1.01) b 
<5.5 58 57 579 0.69 (0.50–0.94)  0.66 (0.47–0.93) a  0.73 (0.51–1.03) b 
P for trend    0.019 0.008 0.06 
NHS postmenopausal women 
>8.5 311 74 537 1.0 1.0 1.0 
>7–8.5 1056 244 506 1.05 (0.93–1.20)  1.06 (0.93–1.20) c  1.07 (0.94–1.22) d 
>5.5–7 690 169 046 1.00 (0.87–1.14)  0.99 (0.87–1.14) c  1.03 (0.90–1.19) d 
≤5.5 255 60 197 1.04 (0.88–1.23)  0.97 (0.80–1.16) c  1.02 (0.84–1.23) d 
P for trend    0.99 0.54 0.89 
Birthweight (lbs) No. of cases Person-years Age-adjusted HR (95% CI) Covariate-adjusted HR (95% CI) Covariate-adjusted HR (95% CI) 
NHS II premenopausal women 
>8.4 135 102 115 1.0 1.0 1.0 
7.0–8.4 385 363 040 0.76 (0.63–0.93)  0.75 (0.62–0.91) a  0.78 (0.64–0.95) b 
5.5–6.9 250 228 509 0.79 (0.64–0.97)  0.75 (0.61–0.93) a  0.81 (0.65–1.01) b 
<5.5 58 57 579 0.69 (0.50–0.94)  0.66 (0.47–0.93) a  0.73 (0.51–1.03) b 
P for trend    0.019 0.008 0.06 
NHS postmenopausal women 
>8.5 311 74 537 1.0 1.0 1.0 
>7–8.5 1056 244 506 1.05 (0.93–1.20)  1.06 (0.93–1.20) c  1.07 (0.94–1.22) d 
>5.5–7 690 169 046 1.00 (0.87–1.14)  0.99 (0.87–1.14) c  1.03 (0.90–1.19) d 
≤5.5 255 60 197 1.04 (0.88–1.23)  0.97 (0.80–1.16) c  1.02 (0.84–1.23) d 
P for trend    0.99 0.54 0.89 

a HR and 95% CI adjusted for age (continuous), premature birth (dichotomous), age at menarche (≤10, 11, 12, 13, 14 and 15+ years), BMI at age 18 (continuous), current BMI (continuous), family history of breast cancer (dichotomous), history of benign breast disease (dichotomous), age at first birth (≤24, 25–30 and >30 years), parity (0, 1, 2, 3 and 4+), oral contraceptive use (never user, past user <5 years, past user ≥5 years, current user <5 years, current user 5–9 years and current user 10+ years), physical activity (<3, 3–8, 9–17, 18–26, 27–41 and 42+ mets/week) and alcohol consumption (0, 0.1–7.4, 7.5–14.9, 15–29 and 30+ g/day).

b HR and 95% CI adjusted for the same covariates as in the previous column ( a ) and additionally for height (continuous).

c HR and 95% CI adjusted for adjusted for age (continuous), premature birth (dichotomous), age at menarche (≤11, 12, 13, 14 and 15+ years), BMI at age 18 (continuous), current BMI (continuous), family history of breast cancer (dichotomous), history of benign breast disease (dichotomous), age at first birth (≤24, 25–29, 30–34 and ≥35 years), parity (0, 1, 2, 3 and 4+), past use of oral contraceptives (never, past user <1 year, past user 1–4.9 years, past user 5–9.9 years and past user 10+ years), physical activity (<1, 1–1.9, 2–3.9, 4–6.9 and 7+ h/week), alcohol consumption (0, 0.1–4.9, 5–14.9 and 15+ g/day), age at menopause (continuous) and postmenopausal hormone use (never, past year <5 years, past user 5+ years, current user <5 years and current user 5+ years).

d HR and 95% CI adjusted for the same covariates as in the previous column ( c ) and additionally for height (continuous).

Among postmenopausal women, no important association between the birthweight and the incidence of breast cancer was detected ( Table I ). Compared with women with a birthweight >8.5 lbs, those with a birthweight of 5.5 lbs or less had a covariate-adjusted HR of breast cancer of 0.97 (95% CI 0.80–1.16); after additional adjustment for adult height the HR was 1.02 (95% CI 0.84–1.23). The HR for breast cancer associated with each 10 cm increase in height was 1.13 (95% CI 1.05–1.21) among postmenopausal women in NHS.

When analyses were stratified by mother's living status among NHS II premenopausal participants, the association between low birthweight and a reduced incidence of premenopausal breast cancer was restricted to women whose mother was alive at the time they reported their birthweight, although there was no statistically significant effect modification by mother's living status ( P for heterogeneity = 0.34) ( Table II ). Similarly, the association was somewhat stronger among women without a family history ( P for heterogeneity = 0.38) ( Table II ).

Table II

Birthweight and hazard ratio (95% CI) of breast cancer, stratified by biological mother's living status and family history, and classified by estrogen-receptor and progesterone-receptor status among premenopausal participants of NHS II

 Birthweight (lbs) P for trend  
 <5.5 5.5–6.9 7.0–8.4 >8.4  
Biological mother alive a 
    No. of cases 44 180 297 111  
    Person-years 43 057 180 920 294 736 82 061  
    Covariate-adjusted HR (95% CI) b 0.60 (0.40–0.89) 0.67 (0.52–0.85) 0.69 (0.55–0.86) 1.0 (referent) 0.001 
Biological mother not alive a 
    No. of cases 10 45 53 16  
    Person-years 8576 25 242 35 432 11 006  
    Covariate-adjusted HR (95% CI) 0.81 (0.33–2.02) 1.13 (0.63–2.05) 0.87 (0.49–1.55) 1.0 (referent) 0.804 
With family history c 
    No. of cases 19 81 112 39  
    Person-years 12 100 46 355 72 866 20 605  
    Covariate-adjusted HR (95% CI) 0.63 (0.34–1.19) 0.81 (0.55–1.21) 0.74 (0.51–1.08) 1.0 (referent) 0.239 
Without family history c 
    No. of cases 39 169 273 96  
    Person-years 45 479 182 154 290 174 81 510  
    Covariate-adjusted HR (95% CI) 0.68 (0.45–1.02) 0.74 (0.57–0.95) 0.75 (0.60–0.95) 1.0 (referent) 0.021 
Estrogen-receptor positive d 
    No. of cases 29 150 215 81  
    Person-years 57 605 228 601 363 182 102 162  
    Covariate-adjusted HR (95% CI) 0.56 (0.35–0.89) 0.75 (0.57–0.98) 0.69 (0.54–0.90) 1.0 (referent) 0.021 
Estrogen-receptor negative d 
    No. of cases 16 47 95 31  
    Person-years 57 611 228 695 363 288 102 200  
    Covariate-adjusted HR (95% CI) 0.75 (0.37–1.51) 0.60 (0.38–0.95) 0.82 (0.54–1.23) 1.0 (referent) 0.061 
Progesterone-receptor positive d     
    No. of cases 27 127 219 75  
    Person-years 57 606 228 622 363 179 102 163  
    Covariate-adjusted HR (95% CI) 0.55 (0.34–0.90) 0.68 (0.51–0.91) 0.76 (0.59–0.99) 1.0 (referent) 0.004 
Progesterone-receptor negative d 
    No. of cases 18 65 86 34  
    Person-years 57 610 228 678 363 294 102 200  
    Covariate-adjusted HR (95% CI) 0.85 (0.45–1.62) 0.78 (0.51–1.20) 0.67 (0.45–0.99) 1.0 (referent) 0.532 
 Birthweight (lbs) P for trend  
 <5.5 5.5–6.9 7.0–8.4 >8.4  
Biological mother alive a 
    No. of cases 44 180 297 111  
    Person-years 43 057 180 920 294 736 82 061  
    Covariate-adjusted HR (95% CI) b 0.60 (0.40–0.89) 0.67 (0.52–0.85) 0.69 (0.55–0.86) 1.0 (referent) 0.001 
Biological mother not alive a 
    No. of cases 10 45 53 16  
    Person-years 8576 25 242 35 432 11 006  
    Covariate-adjusted HR (95% CI) 0.81 (0.33–2.02) 1.13 (0.63–2.05) 0.87 (0.49–1.55) 1.0 (referent) 0.804 
With family history c 
    No. of cases 19 81 112 39  
    Person-years 12 100 46 355 72 866 20 605  
    Covariate-adjusted HR (95% CI) 0.63 (0.34–1.19) 0.81 (0.55–1.21) 0.74 (0.51–1.08) 1.0 (referent) 0.239 
Without family history c 
    No. of cases 39 169 273 96  
    Person-years 45 479 182 154 290 174 81 510  
    Covariate-adjusted HR (95% CI) 0.68 (0.45–1.02) 0.74 (0.57–0.95) 0.75 (0.60–0.95) 1.0 (referent) 0.021 
Estrogen-receptor positive d 
    No. of cases 29 150 215 81  
    Person-years 57 605 228 601 363 182 102 162  
    Covariate-adjusted HR (95% CI) 0.56 (0.35–0.89) 0.75 (0.57–0.98) 0.69 (0.54–0.90) 1.0 (referent) 0.021 
Estrogen-receptor negative d 
    No. of cases 16 47 95 31  
    Person-years 57 611 228 695 363 288 102 200  
    Covariate-adjusted HR (95% CI) 0.75 (0.37–1.51) 0.60 (0.38–0.95) 0.82 (0.54–1.23) 1.0 (referent) 0.061 
Progesterone-receptor positive d     
    No. of cases 27 127 219 75  
    Person-years 57 606 228 622 363 179 102 163  
    Covariate-adjusted HR (95% CI) 0.55 (0.34–0.90) 0.68 (0.51–0.91) 0.76 (0.59–0.99) 1.0 (referent) 0.004 
Progesterone-receptor negative d 
    No. of cases 18 65 86 34  
    Person-years 57 610 228 678 363 294 102 200  
    Covariate-adjusted HR (95% CI) 0.85 (0.45–1.62) 0.78 (0.51–1.20) 0.67 (0.45–0.99) 1.0 (referent) 0.532 

a Women with missing information on biological mother's living status at the time of reporting birthweight information were excluded from the analysis.

b HR and 95% CI adjusted for age, premature birth, age at menarche, BMI at age 18, current BMI, family history of breast cancer, history of benign breast disease, age at first birth, parity, current and past use of oral contraceptives, physical activity and alcohol consumption.

c Not adjusted for family history.

d Cases with unknown receptor status were excluded from the analysis.

Analyses stratified by premature birth of the nurse did not reveal effect modification and stratification by BMI at age 18 and by current BMI did not reveal an important difference of the birthweight–breast cancer association among leaner or heavier women (data not shown).

Among premenopausal women, the association of birthweight with estrogen-receptor positive and progesterone-receptor positive breast cancer was stronger than with estrogen-receptor negative and progesterone-receptor negative breast cancer ( Table II ). However, likelihood ratio tests indicated that the association between birthweight and incidence of breast cancer did not differ significantly according to the status of estrogen receptor ( P = 0.860) or progesterone receptor ( P = 0.344).

Discussion

In these two large cohorts of women, we observed a significant association between a self-reported low birthweight and a decreased incidence of breast cancer among the premenopausal participants. We have reported previously an association between low birthweight and a decreased risk of breast cancer using birthweight information collected from the mothers of NHS and NHS II participants in the Nurses' Mothers' Study, a case–control study that included 572 cases of breast cancer diagnosed before 1993 ( 9 ).

Among 26 studies reported from other groups, the relation between a high birthweight and an increase in the risk of breast cancer was confirmed in 16. Of 14 studies in which early-onset breast cancer was evaluated, a positive association with birthweight was detected in 11 ( 8–12 , 15 , 18–20 , 22 , 23 ). Sanderson et al . ( 8 ), Mellemkjaer et al . ( 18 ) and Innes et al . ( 10 ) reported U- or J-shaped associations, with birthweight under 2500 g and over 4000 g both related to a higher risk of breast cancer diagnosed before 45, 40 and 37 years of age, respectively, than birthweights between 2500 and 4000 g. In studies focusing on breast cancer diagnosed after age 50 a lack of association with birthweight was reported fairly consistently ( 8 , 9 , 15 , 16 , 20 , 22 , 23 ).

Generally, in studies that used self-reported birthweight a link with breast cancer was less likely reported ( 27 , 31 , 32 ). It is possible that non-differential misclassification of birthweight may disguise a true relation. Birthweight may be reported with higher accuracy among study participants whose mother is alive, presumably because they can ask their mother about their birthweight if their birth record is not available or does not contain information on birthweight. In a British study, self-reported birthweight was compared with birth records. Among women whose mother was alive, 73% reported their own birthweight within 4 ounces of the recorded data, and 82% were accurate within 8 ounces. Among women whose mother was deceased, only 29% reported their birthweight within 4 ounces and 56% within 8 ounces of the recorded information ( 37 ). However, women whose mother is alive tend to be younger, and the association between birthweight and breast cancer seems to be more pronounced the younger the woman at diagnosis, which could explain a stronger association among women with living mothers.

We found that the association between birthweight and incidence of breast cancer was not mediated through factors later in life, except possibly adult height. Tallness explained some but not a large proportion of the association between birthweight and breast cancer incidence. The correlation between birthweight and height was stronger than with all other anthropometric variables in adult life. Growth hormones influence both birthweight and final height and may thus explain their correlation and their link with an increased incidence of breast cancer. We also found high birthweight to be associated more strongly with estrogen-receptor positive and progesterone-receptor positive breast cancer than with estrogen-receptor negative and progesterone-receptor negative breast cancer indicating a possible mechanistic role of steroid hormones.

The birthweight association was independent of other factors related to the risk of breast cancer, including body mass in early adulthood. In a British population, dos Santos Silva and colleagues also found that the pathways through which birthweight was associated with premenopausal breast cancer risk were largely independent of postnatal factors ( 19 ).

The optimal bodyweight with respect to the risk of breast cancer across the lifespan is complex ( 2 ). Low birthweight, slow growth during childhood ( 20 , 38 ), high body mass during childhood ( 39 , 40 ) and early adulthood ( 41 ), and low body mass after menopause ( 42 ) have all been associated with lower risk of breast cancer. Whether the weight trajectories at different times during life independently predict the risk of breast cancer risk or whether the weight trajectories may interact with each other has not been sufficiently explored. If anovulation explains the inverse association between body mass during adolescence and early adult life and premenopausal breast cancer, women exposed to the lowest levels of growth factors and (perhaps) estrogen perinatally and with the lowest number of lifetime ovulations would be at lowest risk.

In summary, our findings confirm our previous report of a positive association between birthweight and risk of breast cancer. This association was restricted to women who were premenopausal. Birthweight appears to affect the risk of breast cancer independent of factors later in life, except for adult height.

Abbreviations

  • BMI

    body mass index

  • CI

    confidence interval

  • HR

    hazard ratio

  • NHS

    Nurses' Health Study

  • NHS II

    Nurses' Health Study II

The NHS II is supported by research grant CA50385 and the NHS is supported by research grant CA87969 from the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services.

Conflict of Interest Statement : None declared.

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