Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies

doi:10.7326/M18-1323

Meta-Analysis

. 2019 Jan 1;170(1):22-30.

doi: 10.7326/M18-1323. Epub 2018 Dec 11.

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies

Hazel B Nichols¹, Minouk J Schoemaker², Jianwen Cai¹, Jiawei Xu¹, Lauren B Wright², Mark N Brook², Michael E Jones², Hans-Olov Adami³, Laura Baglietto⁴, Kimberly A Bertrand⁵, William J Blot⁶, Marie-Christine Boutron-Ruault⁷, Miren Dorronsoro⁸, Laure Dossus⁹, A Heather Eliassen¹⁰, Graham G Giles¹¹, Inger T Gram¹², Susan E Hankinson¹³, Judy Hoffman-Bolton¹⁴, Rudolf Kaaks¹⁵, Timothy J Key¹⁶, Cari M Kitahara¹⁷, Susanna C Larsson¹⁸, Martha Linet¹⁷, Melissa A Merritt¹⁹, Roger L Milne¹¹, Valeria Pala²⁰, Julie R Palmer⁵, Petra H Peeters²¹, Elio Riboli¹⁹, Malin Sund²², Rulla M Tamimi¹⁰, Anne Tjønneland²³, Antonia Trichopoulou²⁴, Giske Ursin²⁵, Lars Vatten²⁵, Kala Visvanathan²⁶, Elisabete Weiderpass²⁷, Alicja Wolk¹⁸, Wei Zheng⁶, Clarice R Weinberg²⁸, Anthony J Swerdlow², Dale P Sandler²⁸

Affiliations

¹ University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina (H.B.N., J.C., J.X.).
² The Institute of Cancer Research, London, United Kingdom (M.J.S., L.B.W., M.N.B., M.E.J., A.J.S.).
³ Karolinska Institutet, Stockholm, Sweden (H.A.).
⁴ University of Pisa, Pisa, Italy (L.B.).
⁵ Slone Epidemiology Center at Boston University, Boston, Massachusetts (K.A.B., J.R.P.).
⁶ Vanderbilt-Ingram Cancer Center and Vanderbilt University School of Medicine, Nashville, Tennessee (W.J.B., W.Z.).
⁷ Institut National de la Santé et de la Recherche Médicale (INSERM) U1018 and Institut Gustave Roussy Centre for Research in Epidemiology and Population Health, Villejuif, France (M.B.).
⁸ Public Health Direction and Biodonostia Research Institute and Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Basque Regional Health Department, San Sebastian, Spain (M.D.).
⁹ International Agency for Research on Cancer, Lyon, France (L.D.).
¹⁰ Brigham and Women's Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health, Boston, Massachusetts (A.H.E., R.M.T.).
¹¹ Cancer Council Victoria and University of Melbourne School of Population and Global Health, Melbourne, Victoria, Australia (G.G.G., R.L.M.).
¹² University of Tromsø, The Arctic University of Norway, Tromsø, Norway (I.T.G.).
¹³ University of Massachusetts Amherst School of Public Health and Health Sciences, Amherst, Massachusetts (S.E.H.).
¹⁴ Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (J.H.).
¹⁵ German Cancer Research Center, Heidelberg, Germany (R.K.).
¹⁶ University of Oxford, Oxford, United Kingdom (T.J.K.).
¹⁷ National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.M.K., M.L.).
¹⁸ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L., A.W.).
¹⁹ School of Public Health, Imperial College London, London, United Kingdom (M.A.M., E.R.).
²⁰ Cancer Registry of Norway, Institute of Population-Based Cancer Research, and University of Oslo, Oslo, Norway, and University of Southern California, Los Angeles, California (V.P.).
²¹ University Medical Center Utrecht, Utrecht, the Netherlands (P.H.P.).
²² Umeå University, Umeå, Sweden (M.S.).
²³ Danish Cancer Society Research Center, Copenhagen, Denmark (A.T.).
²⁴ Hellenic Health Foundation, Athens, Greece (A.T.).
²⁵ Norwegian University of Science and Technology, Trondheim, Norway (G.U., L.V.).
²⁶ Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine, Baltimore, Maryland (K.V.).
²⁷ Karolinska Institutet, Stockholm, Sweden, University of Tromsø, The Arctic University of Norway, Tromsø, Norway, and Folkhälsan Research Center, Helsinki, Finland (E.W.).
²⁸ National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina (C.R.W., D.P.S.).

PMID: 30534999
PMCID: PMC6760671
DOI: 10.7326/M18-1323

Meta-Analysis

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies

Hazel B Nichols et al. Ann Intern Med. 2019.

. 2019 Jan 1;170(1):22-30.

doi: 10.7326/M18-1323. Epub 2018 Dec 11.

Authors

Affiliations

¹ University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina (H.B.N., J.C., J.X.).
² The Institute of Cancer Research, London, United Kingdom (M.J.S., L.B.W., M.N.B., M.E.J., A.J.S.).
³ Karolinska Institutet, Stockholm, Sweden (H.A.).
⁴ University of Pisa, Pisa, Italy (L.B.).
⁵ Slone Epidemiology Center at Boston University, Boston, Massachusetts (K.A.B., J.R.P.).
⁶ Vanderbilt-Ingram Cancer Center and Vanderbilt University School of Medicine, Nashville, Tennessee (W.J.B., W.Z.).
⁷ Institut National de la Santé et de la Recherche Médicale (INSERM) U1018 and Institut Gustave Roussy Centre for Research in Epidemiology and Population Health, Villejuif, France (M.B.).
⁸ Public Health Direction and Biodonostia Research Institute and Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Basque Regional Health Department, San Sebastian, Spain (M.D.).
⁹ International Agency for Research on Cancer, Lyon, France (L.D.).
¹⁰ Brigham and Women's Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health, Boston, Massachusetts (A.H.E., R.M.T.).
¹¹ Cancer Council Victoria and University of Melbourne School of Population and Global Health, Melbourne, Victoria, Australia (G.G.G., R.L.M.).
¹² University of Tromsø, The Arctic University of Norway, Tromsø, Norway (I.T.G.).
¹³ University of Massachusetts Amherst School of Public Health and Health Sciences, Amherst, Massachusetts (S.E.H.).
¹⁴ Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (J.H.).
¹⁵ German Cancer Research Center, Heidelberg, Germany (R.K.).
¹⁶ University of Oxford, Oxford, United Kingdom (T.J.K.).
¹⁷ National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.M.K., M.L.).
¹⁸ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L., A.W.).
¹⁹ School of Public Health, Imperial College London, London, United Kingdom (M.A.M., E.R.).
²⁰ Cancer Registry of Norway, Institute of Population-Based Cancer Research, and University of Oslo, Oslo, Norway, and University of Southern California, Los Angeles, California (V.P.).
²¹ University Medical Center Utrecht, Utrecht, the Netherlands (P.H.P.).
²² Umeå University, Umeå, Sweden (M.S.).
²³ Danish Cancer Society Research Center, Copenhagen, Denmark (A.T.).
²⁴ Hellenic Health Foundation, Athens, Greece (A.T.).
²⁵ Norwegian University of Science and Technology, Trondheim, Norway (G.U., L.V.).
²⁶ Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine, Baltimore, Maryland (K.V.).
²⁷ Karolinska Institutet, Stockholm, Sweden, University of Tromsø, The Arctic University of Norway, Tromsø, Norway, and Folkhälsan Research Center, Helsinki, Finland (E.W.).
²⁸ National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina (C.R.W., D.P.S.).

PMID: 30534999
PMCID: PMC6760671
DOI: 10.7326/M18-1323

Abstract

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.

Objective: To characterize breast cancer risk in relation to recent childbirth.

Design: Pooled analysis of individual-level data from 15 prospective cohort studies.

Setting: The international Premenopausal Breast Cancer Collaborative Group.

Participants: Women younger than 55 years.

Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.

Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.

Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.

Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.

Primary funding source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

PubMed Disclaimer

Figures

**Figure 1.. HR for breast cancer according to years since most recent birth.**
Nulliparous women are the reference group, and HRs are adjusted for attained age, study, and continuous parity. Dashed curves correspond to 95% CIs. Vertical lines represent the quadratic spline knots at 6.1, 13.3, 18.4, 23.3, and 29.3 y after birth. The HR for breast cancer risk peaks at 1.80 (95% CI, 1.63 to 1.99) at 4.6 y, crosses 1 at 23.6 y (CI, 21.9 to 25.0 y), and reaches its lowest observed point (HR, 0.77 [CI, 0.67 to 0.88]) at 34.5 y after birth. HR = hazard ratio.

**Figure 2.. HR for breast cancer according to years since most recent birth for the joint effect of family history and time since most recent birth.**
Nulliparous women without a family history of breast cancer are the reference group, and HRs are adjusted for attained age, study, and continuous parity. Dashed curves correspond to 95% CIs. Vertical lines represent the quadratic spline knots at 6.1, 13.3, 18.4, 23.3, and 29.3 y after birth. Likelihood ratio tests for models with and without interaction terms for time since most recent birth indicated a statistically significant (*P =* 0.044) interaction with family history of breast cancer. Compared with a common reference group of nulliparous women without such a history, women with a family history of breast cancer had an HR of 3.53 (CI, 2.91, 4.29) 4.9 y after first birth and did not cross over toward a protective effect for ≥30 y. As an approximation of the 95% CI around the crossover point, for women without a family history, the lower bound crosses at 22.9 y and the upper bound at 27.4 y. For women with a family history, the lower bound crosses at 34.2 y and the upper bound does not cross 1 during the 34.5 y of follow-up. HR = hazard ratio.

**Figure 3.. HR for breast cancer according to years since most recent birth, stratified by age at first birth (nulliparous or parous with age at first birth <25, 25–34, or 35–39 y).**
Nulliparous women are the reference group, and HRs are adjusted for attained age, study, and parity (0, 1, or ≥2 births). Dashed curves correspond to 95% CIs. Vertical lines represent the quadratic spline knots at 6.1, 13.3, 18.4, 23.3, and 29.3 y after birth. Likelihood ratio tests indicated a statistically significant interaction with age at first birth (*P =* 0.013). All analyses censor at age 55 y; therefore, only the first 15 y of follow-up are analyzed for women in the oldest age group (35–39 y) because they were aged ≥50 y after 15 y. Women who had their first birth before age 25 y had a peak HR for breast cancer of 1.06 (95% CI, 0.67 to 1.66) at <1 y after birth. For women who had their first births at age 25–34 y and 35–39 y, peak HRs were 1.25 (CI, 1.11 to 1.40) at 4.6 y and 1.40 (CI, 1.14 to 1.72) at 6.4 y, respectively, since most recent birth. HR = hazard ratio.

**Figure 4.. HR for breast cancer according to years since most recent birth, stratified by parity (0, 1, 2, or ≥3 births).**
Nulliparous women are the reference group, and HRs are adjusted for attained age and study; estimates for women with ≥3 births are further adjusted for continuous number of births (3–10 births). Dashed curves correspond to 95% CIs. Vertical lines represent the quadratic spline knots at 6.1, 13.3, 18.4, 23.3, and 29.3 y after birth. Likelihood ratio tests indicated a statistically significant interaction with parity (*P =* 0.030). For uniparous women, the peak HR was 1.22 (95% CI, 1.03 to 1.45) and occurred 5.3 y after last birth; crossover toward an inverse association occurred 18.5 y (CI, 16.5 to 20.9 y) after first birth for uniparous women. For biparous women, the peak HR was 1.36 (CI, 1.19 to 1.55) at 4.6 y after last birth; crossover toward an inverse association occurred 14.8 y (CI, 12.7 to 17.2 y) after last birth. For women with ≥3 births, the peak HR was 2.12 (CI, 1.75 to 2.56) at 4.2 y after last birth, crossover toward an inverse association occurred 25.0 y since last birth, and the lower bound of the CI crossed over at 22.6 y. HR = hazard ratio.

**Figure 5.. HR for ER-positive and ER-negative breast cancer according to years since most recent birth, adjusted for attained age, study, and parity (continuous).**
Nulliparous women are the reference group. Dashed curves correspond to 95% CIs. Vertical lines represent the quadratic spline knots at 6.1, 13.3, 18.4, 23.3, and 29.3 y after birth. Tests for interaction with ER status were statistically significant (*P <* 0.001). ER-negative breast cancer risk peaked 2.2 y after birth (HR, 1.77 [95% CI, 1.34 to 2.33]), and the HR decreased to 1.38 (CI, 1.01 to 1.88) at 34.5 y after birth but did not cross over to a protective association. ER-positive breast cancer had a peak HR of 1.88 (CI, 1.62 to 2.20) at 5.3 y, crossing the null value at 25.0 y and reaching an HR of 0.90 (CI, 0.74 to 1.09) at 34.5 y. ER = estrogen receptor; HR = hazard ratio.

See this image and copyright information in PMC

Comment in

Learning From Temporal Relationships: Childbirth and Breast Cancer Risk.
Armstrong K. Armstrong K. Ann Intern Med. 2019 Jan 1;170(1):66-67. doi: 10.7326/M18-3455. Epub 2018 Dec 11. Ann Intern Med. 2019. PMID: 30535335 No abstract available.

Cited by

Risk factors for breast cancer subtypes by race and ethnicity: A scoping review of the literature.
Hurson AN, Ahearn TU, Koka H, Jenkins BD, Harris AR, Roberts S, Fan S, Franklin J, Butera G, Keeman R, Jung AY, Middha P, Gierach GL, Yang XR, Chang-Claude J, Tamimi RM, Troester MA, Bandera EV, Abubakar M, Schmidt MK, Garcia-Closas M. Hurson AN, et al. medRxiv [Preprint]. 2024 Mar 19:2024.03.18.24304210. doi: 10.1101/2024.03.18.24304210. medRxiv. 2024. Update in: J Natl Cancer Inst. 2024 Jul 17:djae172. doi: 10.1093/jnci/djae172 PMID: 39108508 Free PMC article. Updated. Preprint.
Unmutated RRAS2 emerges as a key oncogene in post-partum-associated triple negative breast cancer.
Cifuentes C, Oeste CL, Fernández-Pisonero I, Hortal AM, García-Macías C, Hochart J, Rubira R, Horndler L, Horndler C, Bustelo XR, Alarcón B. Cifuentes C, et al. Mol Cancer. 2024 Jul 10;23(1):142. doi: 10.1186/s12943-024-02054-3. Mol Cancer. 2024. PMID: 38987766 Free PMC article.
Association between triglyceride glucose index and breast cancer in 142,184 Chinese adults: findings from the REACTION study.
Wu X, Wang S, Lin L, Jia X, Hu C, Qi H, Lin H, Zheng R, Li M, Xu Y, Xu M, Chen L, Zeng T, Hu R, Ye Z, Shi L, Su Q, Yu X, Yan L, Wang T, Zhao Z, Zheng J, Qin G, Wan Q, Chen G, Dai M, Tang X, Gao Z, Shen F, Gu X, Luo Z, Qin Y, Chen L, Hou X, Huo Y, Li Q, Wang G, Zhang Y, Liu C, Wang Y, Wu S, Yang T, Deng H, Zhao J, Mu Y, Ning G, Wang W, Bi Y, Chen Y, Lu J. Wu X, et al. Front Endocrinol (Lausanne). 2024 Jun 6;15:1321622. doi: 10.3389/fendo.2024.1321622. eCollection 2024. Front Endocrinol (Lausanne). 2024. PMID: 38904041 Free PMC article.
Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model.
Bernhardt SM, Ozaki MK, Betts C, Bleyle LA, DeBarber AE, Fornetti J, Liberty AL, Wilde De E, Zhang Y, Xia Z, Schedin P. Bernhardt SM, et al. bioRxiv [Preprint]. 2024 Jun 2:2024.05.28.596304. doi: 10.1101/2024.05.28.596304. bioRxiv. 2024. PMID: 38854129 Free PMC article. Preprint.
Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants.
Zhang Z, Ye S, Bernhardt SM, Nelson HD, Velie EM, Borges VF, Woodward ER, Evans DGR, Schedin PJ. Zhang Z, et al. JAMA Netw Open. 2024 Apr 1;7(4):e247421. doi: 10.1001/jamanetworkopen.2024.7421. JAMA Netw Open. 2024. PMID: 38639936 Free PMC article.

See all "Cited by" articles

References

1. Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev. 2017;26:444–57. doi:10.1158/1055-9965.EPI-16-0858 - DOI - PubMed
1. Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;331:5–9. - PubMed
1. Albrektsen G, Heuch I, Kvåle G. The short-term and long-term effect of a pregnancy on breast cancer risk: a prospective study of 802,457 parous Norwegian women. Br J Cancer. 1995;72:480–4. - PMC - PubMed
1. Leon DA, Carpenter LM, Broeders MJ, Gunnarskog J, Murphy MF. Breast cancer in Swedish women before age 50: evidence of a dual effect of completed pregnancy. Cancer Causes Control. 1995;6:283–91. - PubMed
1. Wohlfahrt J, Olsen JH, Melby M. Breast cancer risk after childbirth in young women with family history (Denmark). Cancer Causes Control. 2002;13:169–74. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

[1] Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev. 2017;26:444–57. doi:10.1158/1055-9965.EPI-16-0858 - DOI - PubMed

[2] Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev. 2017;26:444–57. doi:10.1158/1055-9965.EPI-16-0858 - DOI - PubMed

[3] Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;331:5–9. - PubMed

[4] Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;331:5–9. - PubMed

[5] Albrektsen G, Heuch I, Kvåle G. The short-term and long-term effect of a pregnancy on breast cancer risk: a prospective study of 802,457 parous Norwegian women. Br J Cancer. 1995;72:480–4. - PMC - PubMed

[6] Albrektsen G, Heuch I, Kvåle G. The short-term and long-term effect of a pregnancy on breast cancer risk: a prospective study of 802,457 parous Norwegian women. Br J Cancer. 1995;72:480–4. - PMC - PubMed

[7] Leon DA, Carpenter LM, Broeders MJ, Gunnarskog J, Murphy MF. Breast cancer in Swedish women before age 50: evidence of a dual effect of completed pregnancy. Cancer Causes Control. 1995;6:283–91. - PubMed

[8] Leon DA, Carpenter LM, Broeders MJ, Gunnarskog J, Murphy MF. Breast cancer in Swedish women before age 50: evidence of a dual effect of completed pregnancy. Cancer Causes Control. 1995;6:283–91. - PubMed

[9] Wohlfahrt J, Olsen JH, Melby M. Breast cancer risk after childbirth in young women with family history (Denmark). Cancer Causes Control. 2002;13:169–74. - PubMed

[10] Wohlfahrt J, Olsen JH, Melby M. Breast cancer risk after childbirth in young women with family history (Denmark). Cancer Causes Control. 2002;13:169–74. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies

Affiliations

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies

Authors

Affiliations

Abstract

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous

Abstract

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous