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. Author manuscript; available in PMC: 2015 Oct 2.
Published in final edited form as: Int J Cancer. 2013 Dec 18;135(1):186–195. doi: 10.1002/ijc.28644

Associations of reproductive time events and intervals with breast cancer risk: a report from the Shanghai Breast Cancer Study

Zhezhou Huang 1,2, Alicia Beeghly-Fadiel 1,*, Yu-Tang Gao 3, Ying Zheng 2, Qi Dai 1, Wei Lu 2, Wei Zheng 1, Xiao-Ou Shu 1
PMCID: PMC4591050  NIHMSID: NIHMS725678  PMID: 24323821

Abstract

While there is clear evidence for an association between later age at first live birth and increased breast cancer risk, associations of other reproductive timings are less clear. As breast tissues undergo major structural and cellular changes during pregnancy, we examined associations between reproductive time events and intervals with breast cancer risk among parous women from the population-based Shanghai Breast Cancer Study (SBCS). Unconditional logistic regression was used to evaluate associations with breast cancer risk for 3,269 cases and 3,341 controls. In addition to later age at first live birth, later ages at first pregnancy and last pregnancy were significantly associated with increased breast cancer risk (P-trend=0.002, 0.015, 0.008, respectively); longer intervals from menarche to first or last live birth were also associated with increased risks (P-trend<0.001, = 0.018, respectively). Analyses stratified by menopausal status and estrogen receptor (ER) / progesterone receptor (PR) status revealed that associations for later age at first pregnancy or live birth and longer intervals from menarche to first or last live birth occurred among pre-menopausal women and ER+/PR+ breast cancers, whereas the association for later age at last pregnancy occurred among postmenopausal women and ER+/PR- or ER-/PR+ breast cancers. Due to high correlation with other reproductive variables, models did not include adjustment for age at first live birth; when included, significance of all associations was attenuated. These findings suggest while reproductive time events and intervals play an important role in breast cancer etiology, contributions may differ by menopausal status and hormone receptor status of breast cancers.

Keywords: reproductive, breast cancer risk, case-control study

Introduction

Breast cancer is the most common cancer among women worldwide 1. Reproductive events and their timing can affect the differentiation of breast tissue, as well as hormonal and immunological profiles, and may thus influence breast cancer risk 2. Epidemiologic studies have clearly demonstrated that many reproductive factors are associated with breast cancer risk; early age at menarche, early age at first birth, increasing number of births, and longer duration of breastfeeding are protective factors for breast cancer 3–5. However, associations of other reproductive time events and intervals with breast cancer risk have not been established and results are controversial. Some studies found that later age at last birth increased the risk of breast cancer 6–8, but this was challenged by other studies which found that age at last birth was no more important than age at any intermediate birth 9,10. Some researchers have postulated that the association between breast cancer risk and age at last birth is in part explained by the association of time since last birth 11. Due to a growth enhancing effect of estrogens during pregnancy on premalignant breast cells 12, a transient increase in breast cancer risk was found among women within 5 years after delivery 13; this may explain why a shorter interval since last birth was related to a higher breast cancer risk 14. Recently, some investigations have focused on the strong influence on breast cancer risk caused by a short interval from first to second birth 15. They theorized that two closely occurring pregnancies might increase breast cancer risk due to stimulatory effects of female steroid hormones and either short-term or lack of breastfeeding of the first child which may leave breast cells more susceptible to carcinogenic influences 16. A long interval from menarche to first live birth was also suggested to be an independent risk factor for breast cancer in a recent study; this was attributed to a high susceptibility to carcinogens during this time period 17.

The majority of studies conducted to date on reproductive timing and breast cancer risk have included only Caucasian women; few studies have been conducted among Asian women. Therefore, we examined the associations of reproductive time events and intervals with breast cancer risk among Chinese women in a large scale case-control study involving 3,443 cases and 3,474 controls.

Material and Methods

Study population

We analyzed data from the Shanghai Breast Cancer Study (SBCS), a population-based case-control study conducted among women in urban Shanghai, China. Details of the SBCS have been described previously 18,19. Briefly, the SBCS had two phases of recruitment, phase I (August 1996–March 1998) and phase II (April 2002–February 2005). Eligibility criteria for the study participants were as follows: permanent resident of urban Shanghai, no prior history of any cancer, aged 25-65 years for phase I, or aged 25–70 years for phase II. A total of 1,602 and 2,388 cases were identified in phase I and II, respectively, through a rapid case-ascertainment system of the Shanghai Cancer Registry. A total of 1,724 and 2,724 controls were randomly selected in phase I and II, respectively, from permanent female residents of the study area through the Shanghai Resident Registry and frequency matched to cases on age by 5-year intervals. A total of 3,443 (response rate: 86.3%) cases and 3,474 (response rate: 78.1%) controls were recruited. Participants were interviewed by trained interviewers using a structured questionnaire that included detailed information on demographic factors, menstrual and reproductive history, hormone use, dietary habits, prior disease history, physical activity, tobacco and alcohol use, weight history, and family history of cancer. Menstrual and reproductive information included age at menarche, timing and outcome of each pregnancy, duration of breastfeeding after each pregnancy, and reasons known if gravidity or lactation were denied. Menopausal status (premenopausal or postmenopausal) was defined by whether participants reported having any menstrual periods in the 12 months prior to completing the baseline questionnaire; bleeding due to use of female hormones was not included as menstrual periods. The information on ER and PR status were obtained by review of medical and pathology records from the participating hospitals or by immunohistochemical staining for those missing ER and PR status (n=299) by the Vanderbilt Molecular Epidemiology Laboratory 19. As all of our cases were diagnosed prior to 2010, cut-offs for ER and PR positivity were ≥10% and ≥1%, respectively. This study was approved by the Institutional Review Boards of all relevant institutions; all participants provided written informed consent.

Statistical methods

Unconditional logistic regression was used to derive odds ratio (OR) and 95% confidence intervals (CIs) for associations between breast cancer and selected reproductive factors. Exposures of interest included age at first pregnancy or live birth, age at last pregnancy or live birth, as well as intervals from menarche to first pregnancy or live birth, menarche to last pregnancy or live birth, first to second live birth, first pregnancy or live birth to reference date (diagnosis date for cases or interview date for controls), and last pregnancy or live birth to reference date. Factors evaluated as potential confounders or effect modifiers included age at menarche, number of live births, duration of breastfeeding (months), menopausal status (Y/N), body mass index (BMI), active smoking (Y/N), drinking (Y/N), physical activity in recent 10 years (Y/N), family history of breast cancer among first degree relatives (Y/N), history of fibroadenoma (Y/N), hormone replacement therapy (HRT) use (Y/N), oral contraceptive use (Y/N), age, education, and study phase. Covariates were considered as confounders and included in the final multivariable models if they changed the estimates of association by 10% or more. Stratified analyses were used to examine if associations with breast cancer risk differed by menopausal status or hormone receptor status (ER / PR). A total of 307 women without a live birth were excluded from our analyses in order to reduce confounding by gravidity. For variables related to the last live birth, all uniparous women were excluded. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). Statistical significance was based on a two-sided probability with a significance level of 0.05.

Results

Table 1 shows demographic and selected characteristics of parous SBCS participants by case-control status. As compared with controls, cases were more likely to have higher educational attainment, be premenopausal, have a later age at menopause, have a positive family history of breast cancer, have a positive history of fibroadenoma and hormone replacement therapy use, and have a greater body mass index (BMI). Cases were less likely than controls to have a later age at menarche, a greater number of pregnancies or live births, longer durations of breastfeeding, and recent physical activity.

Table 1. Demographic and selected breast cancer risk factors among parous participants; the Shanghai Breast Cancer Study.

Characteristic Cases (n=3443) Controls (n=3474) P
n / mean 1 % / sd 2 n / mean 1 % / sd 2
Study Phase
 I 1381 42.25 1495 44.75
 II 1888 57.75 1846 55.25 0.040
Age (years) 3 49.89 8.13 50.28 8.68 0.059
Education
 Elementary School or less 280 8.57 420 12.57
 Junior High School 1300 39.77 1389 41.57
 Senior High School 1224 37.44 1174 35.14
 College or more 465 14.22 358 10.72 <.001
Age at Menarche 14.42 1.63 14.68 1.74 <.001
Menopausal Status
 Premenopausal 1970 60.26 1890 56.59
 Postmenopausal 1299 39.74 1450 43.41 0.002
Age at Menopause a 49.91 3.40 49.33 3.75 <.001
Number of Pregnancies
 1 693 21.20 648 19.40
 2 1154 35.30 1131 33.85
 3 775 23.71 839 25.11
 ≥4 647 19.79 723 21.64 0.052
Number of Live Births
 1 2376 72.68 2285 68.39
 2 629 19.24 698 20.89
 3 184 5.63 239 7.15
 ≥4 80 2.45 119 3.56 <.001
Abortion
 Never 1168 35.73 1156 34.60
 Ever 2101 64.27 2185 65.40 0.336
Breastfeeding
 Never 750 22.94 689 20.62
 Ever 2519 77.06 2652 79.38 0.022
Lifetime Duration of Breastfeeding (months) b 13.2 11.48 14.85 12.97 <.001
Breast Cancer among First Degree Relatives
 Never 3118 95.38 3249 97.25
 Ever 151 4.62 92 2.75 <.001
Ever had Breast Fibroadenoma
 Never 2942 90.25 3158 94.58
 Ever 318 9.75 181 5.42 <.001
Oral Contraceptive Use
 Never 2612 79.90 2647 79.23
 Ever 657 20.10 694 20.77 0.497
Hormone Replacement Therapy
 Never 3140 96.11 3243 97.07
 Ever 127 3.89 98 2.93 0.033
Body Mass Index (BMI) 23.69 3.30 23.35 3.29 <.001
Ever Smoking
 Never 3180 97.28 3245 97.13
 Ever 89 2.72 96 2.87 0.710
Ever Drinking
 Never 3120 95.47 3152 94.43
 Ever 148 4.53 186 5.57 0.053
Physical Activities in recent 10 years
 Never 2467 75.47 2330 69.74
 Ever 802 24.53 1011 30.26 <.001
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1

n for categorical variables or mean for continuous variables

2

% for categorical variables or standard deviation(sd) for continuous variables

3

Age at diagnosis for cases or age at interview for controls

a

Among women with natural menopause

b

Among women who ever breastfed

Table 2 presents the associations of reproductive ages and intervals with breast cancer risk among all women, and women stratified by menopausal status. Among all women, in addition to later age at first live birth, later age at first pregnancy and later age at last pregnancy were also associated with higher breast cancer risks (P-trend=0.002, 0.015, 0.008, respectively). Compared to women aged less than 25, those with a first live birth, first pregnancy, or last pregnancy after age 35, had approximately 51%, 49%, and 16% greater risks of breast cancer, respectively. No association was observed for age at last live birth. Two reproductive intervals were found to be associated with risk; longer interval from menarche to first or last live birth was associated with an increased breast cancer risk (P-trend< 0.001, = 0.018, respectively). While no other interval had significant trends, a transient association was observed for interval from first to last pregnancy. Compared to women with less than three years between their first and last pregnancy, those with 3 to 5 years had a 17% decreased risk of breast cancer (OR=0.83, 95% CI: 0.72-0.96). No difference were seen in additional analysis that examined whether associations varied by study phase (data not shown). No associations with risk were found to significantly differ by menopausal status, however, several associations were more pronounced among subgroups of women. Among pre-menopausal women, later age at first pregnancy or live birth and longer interval from menarche to first or last live birth were associated with increased breast cancer risks (P-trend=0.044, 0.006, 0.004, 0.006, respectively). Among postmenopausal women, later age at last pregnancy was associated with an increased breast cancer risk (P-trend=0.048).

Table 2. Association of reproductive ages and intervals with breast cancer risk, by menopausal status; the Shanghai Breast Cancer Study.

Risk Factors All Women Premenopausal Women Postmenopausal Women Pinteration c
Cases / Controls(3269 / 3341) OR 1, 2 P Cases / Controls(1970 / 1890) OR 1, 2 P Cases / Controls(1299 / 1450) OR 1, 2 P
Ages at:
First Pregnancy (years) a
 <25 1067/1246 1 (reference) 1 - 441/473 1 (reference) 1 - 626/773 1 (reference) 1 -
 25-29 1732/1721 1.04 (0.92-1.17) 0.583 1229/1180 1.06 (0.90-1.25) 0.458 503/541 0.96 (0.79-1.16) 0.673
 30-34 400/326 1.22 (1.01-1.47) 0.035 256/208 1.21 (0.95-1.53) 0.129 144/117 1.22 (0.91-1.65) 0.182
 >=35 70/48 1.49 (1.00-2.20) 0.048 44/29 1.60 (0.96-2.64) 0.070 26/19 1.35 (0.72-2.52) 0.355
 P trend 0.015 0.044 0.248 0.889
First Live Birth (years) a
 <25 759/914 1 (reference) 1 - 252/260 1 (reference) 1 - 507/654 1 (reference) 1 -
 25-29 1819/1878 1.01 (0.87-1.16) 0.936 1254/1281 0.96 (0.78-1.18) 0.666 565/597 1.03 (0.84-1.26) 0.768
 30-34 571/467 1.22 (1.02-1.46) 0.034 385/297 1.21 (0.94-1.56) 0.133 186/169 1.13 (0.85-1.50) 0.395
 >=35 120/82 1.51 (1.10-2.07) 0.011 79/52 1.51 (1.00-2.28) 0.048 41/30 1.43 (0.85-2.40) 0.173
 P trend 0.002 0.006 0.192 0.485
Last Pregnancy (years) a
 <30 1078/1267 1 (reference) 1 - 599/641 1 (reference) 1 - 479/626 1 (reference) 1 -
 30-34 935/918 1.09 (0.97-1.23) 0.133 521/499 1.01 (0.87-1.18) 0.885 414/418 1.20 (1.01-1.43) 0.043
 >=35 560/507 1.16 (1.01-1.33) 0.040 310/268 1.10 (0.91-1.33) 0.320 250/239 1.22 (0.99-1.51) 0.067
 P trend 0.008 0.113 0.048 0.245
Last Live Birth (years) b
 <30 579/722 1 (reference) 1 - 88/107 1 (reference) 1 - 491/615 1 (reference) 1 -
 30-34 253/269 1.04 (0.85-1.27) 0.703 46/40 1.26 (0.76-2.09) 0.379 207/229 0.98 (0.79-1.23) 0.882
 >=35 61/64 1.00 (0.69-1.45) 0.994 17/16 1.08 (0.51-2.28) 0.846 44/48 0.98 (0.63-1.53) 0.935
 P trend 0.602 0.077 0.949 0.935
Intervals from:
Menarche to First live birth (years) a
 <10 747/953 1 (reference) 2 - 261/291 1 (reference) 2 - 486/662 1 (reference) 2 -
 10-14 1565/1612 1.07 (0.93-1.23) 0.321 1057/1083 1.04 (0.85-1.27) 0.690 508/529 1.08 (0.89-1.32) 0.441
 >=15 952/775 1.31 (1.11-1.53) 0.001 650/515 1.31 (1.05-1.63) 0.018 302/259 1.25 (0.98-1.60) 0.076
 P trend <.001 0.004 0.074 0.366
Menarche to Last live birth (years) b
 <10 132/223 1 (reference) 2 - 12/27 1 (reference) 2 - 120/196 1 (reference) 2 -
 10-14 402/485 1.06 (0.87-1.30) 0.582 71/79 1.17(0.63-2.19) 0.626 331/406 1.08 (0.86-1.36) 0.514
 >=15 358/347 1.16 (0.94-1.42) 0.179 68/57 1.48 (0.78-2.82) 0.230 290/290 1.12 (0.88-1.42) 0.371
 P trend 0.018 0.006 0.107 0.952
First to Second Live Birth (years) b
 <1.5 112/112 1 (reference) 1 - 18/18 1 (reference) 1 - 94/94 1 (reference) 1 -
 1.5-2.99 412/517 0.90 (0.73-1.12) 0.357 45/51 0.73 (0.37-1.43) 0.354 367/466 0.94 (0.74-1.20) 0.636
 >=3 366/422 0.88 (0.73-1.07) 0.193 87/92 0.74 (0.42-1.30) 0.300 279/330 0.89 (0.71-1.11) 0.291
 P trend 0.391 0.997 0.360 0.921
First to Last Pregnancy (years) a
 <3 912/877 1 (reference) 1 - 650/630 1 (reference) 1 - 262/246 1 (reference) 1 -
 3-4.99 480/573 0.83 (0.72-0.96) 0.011 271/286 0.87 (0.72-1.05) 0.151 209/287 0.79 (0.62-1.00) 0.050
 5-9.99 785/826 0.99 (0.86-1.13) 0.853 324/338 0.89 (0.74-1.07) 0.206 461/488 1.10 (0.89-1.36) 0.403
 >=10 384/410 1.00 (0.84-1.18) 0.976 176/149 1.07 (0.84-1.36) 0.582 208/261 0.97 (0.75-1.25) 0.786
 P trend 0.787 0.869 0.791 0.085
First to Last Live Birth (years) b
 <3 308/344 1 (reference) 1 - 54/64 1 (reference) 1 - 254/280 1 (reference) 1 -
 3-4.99 239/298 0.88 (0.71-1.10) 0.265 38/51 0.75 (0.43-1.30) 0.305 201/247 0.89 (0.69-1.14) 0.339
 5-9.99 295/348 1.01 (0.79-1.29) 0.941 49/36 1.41 (0.79-2.51) 0.240 246/312 0.93 (0.71-1.23) 0.626
 >=10 49/63 0.95 (0.60-1.48) 0.804 9/10 0.89 (0.33-2.38) 0.817 40/53 0.89 (0.53-1.48) 0.646
 P trend 0.900 0.155 0.737 0.221
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a

Among parous women

b

Among multiparous women

c

Test for interaction of P-trend values between premenopausal and postmenopausal women, calculated using multivariable logistic regression

1

Adjusted for study phase, age, education, age at menarche, menopausal status, number of live births, duration of breastfeeding, body mass index (BMI), physical activities in recent 10 years (Y/N), family history of breast cancer in first degree relative (Y/N), history of fibroadenoma (Y/N) and hormone replacement therapy (HRT) use (Y/N)

2

Adjusted for above except variable which is beginning or ending of the intervals

Associations with reproductive intervals could not be uniformly adjusted for age at first live birth, because this age was involved in the calculation of many intervals, including menarche to first live birth, interval from first to second live birth and interval from first to last live birth. Further, age at first live birth was also highly correlated with other variables, such as age at first pregnancy (correlation coefficient=0.98) and interval from menarche to first live birth (correlation coefficient=0.92). When either age or interval models included adjustment for age at first live birth, significance of all associations was attenuated. Similarly, when regression models for intervals included adjustment for either beginning or ending variables, significance of findings was also attenuated. We also analyzed intervals from first pregnancy or live birth to diagnosis and interval from last pregnancy or live birth to diagnosis; no association with breast cancer risk was observed (results not shown).

To examine if associations of reproductive ages and intervals with breast cancer risk differed by hormone receptor status, we also stratified analyses by ER/PR status (Table 3). Later age at first pregnancy or live birth was associated with ER+/PR+ breast cancers (P-trend=0.035, 0.009, respectively). The association of later age at last pregnancy with breast cancer risk was associated with ER+/PR- or ER-/PR+ breast cancers (P-trend=0.049). Longer interval from menarche to first live birth increased the risk of both ER+/PR+ and ER+//PR- or ER-/PR+ breast cancers (P-trend=0.008, 0.035, respectively), while longer interval from menarche to last live birth was associated with only increased risk of ER+/PR+ breast cancers (P-trend=0.018). Finally, a shorter interval between first and second live birth was associated only with ER+/PR+ breast cancers (P-trend=0.013); this was the only risk factor with a significant degree of heterogeneity across strata (P-homogeneity= 0.002).

Table 3. Reproductive ages and intervals and breast cancer risk, by ER/PR status; the Shanghai Breast Cancer Study.

Risk Factors Controls(n=3341) ER / PR Status Phomogeneity c
ER + / PR + ER + / PR- Or ER - / PR + ER - / PR-
Cases(n=1412) OR 1, 2 P Cases(n=544) OR 1, 2 P Cases(n=748) OR 1, 2 P
Ages at:
First Pregnancy (years) a
 <25 1246 425 1 (reference) 1 - 165 1 (reference) 1 - 270 1 (reference) 1 -
 25-29 1721 777 1.07 (0.91-1.26) 0.407 311 1.15 (0.91-1.45) 0.236 372 0.84 (0.69-1.02) 0.075
 30-34 326 182 1.25 (0.99-1.59) 0.060 59 1.12 (0.79-1.59) 0.535 89 1.00 (0.74-1.34) 0.995
 >=35 48 28 1.46 (0.88-2.40) 0.141 9 1.19 (0.56-2.54) 0.648 17 1.31 (0.73-2.37) 0.365
 P trend 0.035 0.379 0.995 0.132
First Live Birth (years) a
 <25 914 292 1 (reference) 1 - 113 1 (reference) 1 - 185 1 (reference) 1 -
 25-29 1878 811 1.06 (0.88-1.28) 0.536 318 1.14 (0.86-1.51) 0.352 414 0.91 (0.72-1.14) 0.395
 30-34 467 260 1.27 (1.00-1.61) 0.050 95 1.31 (0.93-1.85) 0.124 122 1.01 (0.75-1.36) 0.962
 >=35 82 49 1.53 (1.02-2.29) 0.042 18 1.46 (0.81-2.63) 0.207 27 1.32 (0.80-2.16) 0.279
 P trend 0.009 0.080 0.447 0.206
Last Pregnancy (years) a
 <30 1267 461 1 (reference) 1 - 167 1 (reference) 1 - 262 1 (reference) 1 -
 30-34 918 398 1.05 (0.91-1.22) 0.514 172 1.27 (1.03-1.57) 0.026 199 0.99 (0.82-1.20) 0.918
 >=35 507 236 1.09 (0.91-1.30) 0.370 92 1.20 (0.93-1.56) 0.167 135 1.20 (0.96-1.50) 0.115
 P trend 0.183 0.049 0.199 0.704
Last Live Birth (years) b
 <30 722 223 1 (reference) 1 - 90 1 (reference) 1 - 135 1 (reference) 1 -
 30-34 269 93 0.95 (0.72-1.25) 0.728 46 1.18 (0.81-1.71) 0.389 56 1.01 (0.73-1.41) 0.933
 >=35 64 24 0.86 (0.52-1.42) 0.556 8 0.73 (0.33-1.57) 0.417 17 1.22 (0.69-2.15) 0.496
 P trend 0.920 0.744 0.540 0.937
Intervals from:
Menarche to First live birth (years) a
 <10 953 291 1 (reference) 2 - 115 1 (reference) 2 - 187 1 (reference) 2 -
 10-14 1612 697 1.12 (0.93-1.34) 0.254 266 1.11 (0.84-1.45) 0.464 350 0.93 (0.74-1.16) 0.503
 >=15 775 423 1.31(1.06-1.62) 0.012 162 1.35 (0.99-1.83) 0.055 211 1.11 (0.86-1.44) 0.435
 P trend 0.008 0.035 0.31 0.151
Menarche to Last live birth (years) b
 <10 223 40 1 (reference) 2 - 19 1 (reference) 2 - 32 1 (reference) 2 -
 10-14 485 162 1.17 (0.89-1.54) 0.268 58 1.06 (0.70-1.59) 0.796 100 1.23 (0.88-1.72) 0.217
 >=15 347 138 1.12 (0.84-1.49) 0.432 67 1.39 (0.94-2.06) 0.102 76 1.11 (0.78-1.57) 0.567
 P trend 0.018 0.066 0.426 0.238
First to Second Live Birth (years) b
 <1.5 112 54 1 (reference) 1 - 11 1 (reference) 1 - 18 1 (reference) 1 -
 1.5-2.99 517 162 0.83 (0.62-1.11) 0.201 69 1.33 (0.85-2.07) 0.211 90 1.02 (0.70-1.48) 0.934
 >=3 422 123 0.67 (0.51-0.88) 0.004 64 1.14 (0.78-1.68) 0.499 100 1.20 (0.88-1.65) 0.254
 P trend 0.013 0.679 0.104 0.002
First to Last Pregnancy (years) a
 <3 877 418 1 (reference) 1 - 137 1 (reference) 1 - 212 1 (reference) 1 -
 3-4.99 573 195 0.75 (0.62-0.92) 0.004 87 1.00(0.76-1.31) 0.991 106 0.80(0.63-1.03) 0.082
 5-9.99 826 326 0.95 (0.80-1.13) 0.587 138 1.25 (0.97-1.60) 0.083 180 1.03 (0.82-1.28) 0.814
 >=10 410 151 0.89 (0.71-1.11) 0.304 67 1.23 (0.90-1.68) 0.199 94 1.10 (0.83-1.44) 0.509
 P trend 0.474 0.053 0.485 0.112
First to Last Live Birth (years) b
 <3 344 130 1 (reference) 1 - 46 1 (reference) 1 - 66 1 (reference) 1 -
 3-4.99 298 86 0.72 (0.53-0.99) 0.043 38 1.00 (0.64-1.55) 0.983 53 1.02 (0.70-1.48) 0.938
 5-9.99 348 103 0.85 (0.60-1.19) 0.334 54 1.44 (0.91-2.29) 0.118 75 1.39 (0.94-2.07) 0.099
 >=10 63 20 0.89 (0.49-1.61) 0.690 6 0.89 (0.35-2.27) 0.800 14 1.57 (0.79-3.13) 0.199
 P trend 0.556 0.364 0.071 0.212
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a

Among Parous Women

b

Among Multiparous Women

c

Test for homogeneity of P-trend values among the hormone receptor groups, calculated using multivariable logistic regression

1

Adjusted for study phase, age, education, age at menarche, menopausal status, number of live birth, duration of breastfeeding, body mass index (BMI), physical activities in recent 10 years (Y/N), family history of breast cancer in first degree relative (Y/N), history of fibroadenoma (Y/N) and hormone replacement therapy (HRT) use (Y/N).

2

Adjusted for above except variable which is beginning or ending of the intervals

Discussion

We found that later age at first pregnancy, first live birth and last pregnancy, as well as longer interval from menarche to first or last live birth were significantly associated with increased risks of breast cancer among parous women from the SBCS. Shorter interval between first and second live birth was associated with breast cancer risk only among women with ER+/PR+ breast cancers. No association was found for later age at last live birth, longer interval from first to last pregnancy or live birth, or intervals from any reproductive events to diagnosis. Adjustment for age at first live birth attenuated the significance of all associations found, likely due to its high correlation with other reproductive variables. Given this caveat, our findings must be interpreted with caution.

The inverse association between early age at first live birth and breast cancer risk found in our study is consistent with the results of many other studies that were conducted predominantly among Caucasian women 20–23. This association most evident among premenopausal women and among women with ER+/PR+ breast cancers. Age at first pregnancy was also associated with breast cancer risk in our study. Very little was found in the literature on the association of age at first pregnancy, which can end in not only a live birth but also in an incomplete pregnancy, such as an abortion or miscarriage. Pregnancy has many direct effects on the breast, such as stopping monthly menstrual cycles, changing endogenous hormones, and inducing the differentiation of breast tissue, all of which may result in a long-term reduction in breast cancer risk 24,25. However, induced abortion, which is a kind of incomplete pregnancy, shows no association with breast cancer risk 26. This was also demonstrated in a previous analysis of the SBCS 27. Different trimesters of pregnancy have different effects on breast cells, including proliferation and differentiation 28; the effect of an interruption of pregnancy during different trimesters on breast cancer risk is not clear 29. The association of age at first pregnancy may largely be influenced by the high percent (85.31%) of women for whom their first pregnancy ended in a live birth, and the high correlation between age at first pregnancy and age at first live birth in our study (correlation coefficient=0.98). Prior studies also suspected that because of the seriousness of malignant disease, reporting of incomplete pregnancy was more accurate among breast cancer cases, while underreporting may occur among healthy controls, who may be more reluctant to report on a controversial, emotionally charged subject such as induced abortion 30,31. This may result in an elevated association between age at first pregnancy and breast cancer risk; as a case-control study, this possibility cannot be excluded as a possible contributing factor to our results. However, unlike western countries such as the US, in which induced abortion was legalized only after 1970 and has not reached full social acceptance, induced abortion is an acceptable practice in China, and does not carry the same social stigma as in the US. Thus, underreporting of incomplete pregnancy would not likely be a remarkable source for bias in studies among Chinese women 32.

The most interesting finding in the current study was that a long interval from menarche to first live birth also increased breast cancer risk. Breast tissue is largely undifferentiated and exposed to mitogenic effects of ER and PR during this period, thus particularly susceptible to carcinogens 33. The interval between menarche to first live birth has been described as a “window of high susceptibility” 34. A shorter interval from menarche to first live birth is linked to higher endogenous hormone levels 2. A French prospective cohort study reported that the risk of breast cancer for women in the highest quartile of cumulative number of menstrual cycles before their first birth was 1.42-fold higher 35. A combined analysis of seven case-control studies had similar results 36,37. The association of this interval with breast cancer risk was evident among premenopausal women and those with ER+/PR+ breast cancers. Our findings are consistent with a prior study conducted among women in the US, which showed that this interval was associated with the risk of ER+/PR+ breast cancers, particularly among premenopausal White women, but was absent among premenopausal African-American women, possible due to a sample size limitation (731 cases and 658 controls) 17. However, the number of premenopausal women in our study was larger (1,970 cases and 1,890 controls), and so a sample size limitation is not a concern in the current study. While few studies on this potential risk factor had been reported in the literature, it is unclear whether the association of interval from menarche to first live birth with breast cancer risk differs by race; further research among additional study populations is therefore needed.

In agreement with many other studies 9,10,22, no association with breast cancer risk was found for age at last live birth or time since last live birth in the current study. The association between last live birth and breast cancer risk found in some studies may be due to the short-term increase in breast cancer risk that occurs after a live birth 10. Maternal breast cancer risk reaches its highest level around 5 years after giving birth, and it takes 15 years to lower the risk 13. The participants in our study had a long interval from time of last live birth to diagnosis or reference date (mean=29.87, standard deviation=7.78), and only 658 women had another pregnancy within 5 years of their last live birth; this prohibited us from further investigating the transient risk after pregnancy that has been seen in other studies.

In summary, this large population-based case-control study is the first to comprehensively examine associations of reproductive time events and intervals with breast cancer risk among Chinese women. Strengths of the study include a large population of parous women, and detailed data on reproductive events and timings and tumor characteristics. A potential limitation is recall bias, as data collection occurred after diagnosis for breast cancer cases. While this possibility cannot be alleviated, many of our results are in agreement with those from prospective analyses 8,35, so this is unlikely to be a major concern. In this study, later age at first pregnancy, first live birth, and longer interval from menarche to first or last live birth were associated with increased breast cancer risk; these associations were more apparent for pre-menopausal women and ER+/PR+ breast cancers. Later age at last pregnancy was also associated with breast cancer risk, but this was more apparent among postmenopausal women or women with ER+/PR- or ER-/PR+ breast cancers. Thus, reproductive time events and intervals play an important role in breast cancer etiology among Chinese women, and their effects may differ by menopausal status or tumor characteristics.

What's new?

Early age at menarche and first live birth have been widely reported to be associated with decreased breast cancer risks; however, associations of other reproductive timings is less clear, especially among Asian women. This large population-based case-control study is the first to comprehensively examine associations of reproductive time events and intervals with breast cancer risk among parous women, and one of a few such studies among Chinese women. Findings include that in addition to later age at first live birth, later age at first pregnancy, later age at last pregnancy, and longer intervals from menarche to either first live birth or last live birth were associated with increased breast cancer risk. Further, these associations were found to vary by menopausal status and hormone-receptor status. Notably, significance of all associations was attenuated when adjusted included age at first birth, possibly due to its high correlation with other reproductive events and intervals.

Acknowledgments

The authors thank investigators and staff members of the research teams and study participants for their contributions and support for the study. This study was supported by a grant from the US NIH (R01CA64277). Zhezhou Huang was supported by the Vanderbilt-Shanghai Chronic Disease Research Training Program grant from the Fogarty International Center (D43 TW008313).

Abbreviations

BMI

Body mass inde

CI

Confidence interval

ER

Estrogen receptor

HRT

Hormone replacement therapy

OR

Odds ratio

PR

Progesterone receptor

SBCS

Shanghai Breast Cancer Study

sd

Standard deviation

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