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Figure.  Association Between Breastfeeding and Epithelial Ovarian Cancer in 13 Case-Control Studies
Association Between Breastfeeding and Epithelial Ovarian Cancer in 13 Case-Control Studies

Summary odds ratios (ORs) and 95% CIs for the association between ever breastfeeding and risk of invasive ovarian cancer (A) or borderline tumors (B) estimated by random-effects meta-analysis of 13 studies from the Ovarian Cancer Association Consortium (1989-2009) adjusted for age, race/ethnicity, oral contraceptive use, parity, and birth decade. AUS indicates Australian Ovarian Cancer Study37; CON, Connecticut Ovarian Cancer Study38; DOV, Diseases of the Ovary and their Evaluation40; GER, German Ovarian Cancer Study41; HAW, Hawaii Ovarian Cancer Case-Control Study34; HOP, Hormones and Ovarian Cancer Prediction Study35; MAL, Malignant Ovarian Cancer Study33; NCO, North Carolina Ovarian Cancer Study44; NEC, New England Case Control Study42; NJO, New Jersey Ovarian Cancer Study32; SON, Southern Ontario Ovarian Cancer Study39; STA, Family Registry for Ovarian Cancer and Genetic Epidemiology of Ovarian Cancer36; USC, University of Southern California Study of Lifestyle and Women’s Health.43

Table 1.  Pooled ORs and 95% CIs for the Association Between Breastfeeding and Ovarian Cancer Risk in the Ovarian Cancer Association Consortium
Pooled ORs and 95% CIs for the Association Between Breastfeeding and Ovarian Cancer Risk in the Ovarian Cancer Association Consortium
Table 2.  Pooled ORs and 95% CIs for the Association Between Mean Duration of Breastfeeding per Episode and Invasive Ovarian Cancer Risk Stratified by Parity in the Ovarian Cancer Association Consortium
Pooled ORs and 95% CIs for the Association Between Mean Duration of Breastfeeding per Episode and Invasive Ovarian Cancer Risk Stratified by Parity in the Ovarian Cancer Association Consortium
1.
American Cancer Society.  Cancer Facts & Figures 2019. American Cancer Society; 2019.
2.
World Cancer Research Fund/ American Institute for Cancer Research.  Diet, Nutrition, Physical Activity and Cancer: a Global Perspective. World Cancer Research Fund International; 2018.
3.
Chiaffarino  F, Pelucchi  C, Negri  E,  et al.  Breastfeeding and the risk of epithelial ovarian cancer in an Italian population.   Gynecol Oncol. 2005;98(2):304-308. doi:10.1016/j.ygyno.2005.05.006 PubMedGoogle ScholarCrossref
4.
Danforth  KN, Tworoger  SS, Hecht  JL, Rosner  BA, Colditz  GA, Hankinson  SE.  Breastfeeding and risk of ovarian cancer in two prospective cohorts.   Cancer Causes Control. 2007;18(5):517-523. doi:10.1007/s10552-007-0130-2 PubMedGoogle ScholarCrossref
5.
Gaitskell  K, Green  J, Pirie  K,  et al; Million Women Study Collaborators.  Histological subtypes of ovarian cancer associated with parity and breastfeeding in the prospective Million Women Study.   Int J Cancer. 2018;142(2):281-289. doi:10.1002/ijc.31063 PubMedGoogle ScholarCrossref
6.
Greggi  S, Parazzini  F, Paratore  MP,  et al.  Risk factors for ovarian cancer in central Italy.   Gynecol Oncol. 2000;79(1):50-54. doi:10.1006/gyno.2000.5909 PubMedGoogle ScholarCrossref
7.
Gronwald  J, Byrski  T, Huzarski  T,  et al.  Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland.   Breast Cancer Res Treat. 2006;95(2):105-109. doi:10.1007/s10549-005-9051-5 PubMedGoogle ScholarCrossref
8.
Gwinn  ML, Lee  NC, Rhodes  PH, Layde  PM, Rubin  GL.  Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer.   J Clin Epidemiol. 1990;43(6):559-568. doi:10.1016/0895-4356(90)90160-Q PubMedGoogle ScholarCrossref
9.
Harlow  BL, Weiss  NS, Roth  GJ, Chu  J, Daling  JR.  Case-control study of borderline ovarian tumors: reproductive history and exposure to exogenous female hormones.   Cancer Res. 1988;48(20):5849-5852.PubMedGoogle Scholar
10.
Harris  R, Whittemore  AS, Itnyre  J; Collaborative Ovarian Cancer Group.  Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III: epithelial tumors of low malignant potential in white women.   Am J Epidemiol. 1992;136(10):1204-1211. doi:10.1093/oxfordjournals.aje.a116428 PubMedGoogle ScholarCrossref
11.
Hartge  P, Schiffman  MH, Hoover  R, McGowan  L, Lesher  L, Norris  HJ.  A case-control study of epithelial ovarian cancer.   Am J Obstet Gynecol. 1989;161(1):10-16. doi:10.1016/0002-9378(89)90221-4 PubMedGoogle ScholarCrossref
12.
Hirose  K, Tajima  K, Hamajima  N,  et al.  Comparative case-referent study of risk factors among hormone-related female cancers in Japan.   Jpn J Cancer Res. 1999;90(3):255-261. doi:10.1111/j.1349-7006.1999.tb00741.x PubMedGoogle ScholarCrossref
13.
Huusom  LD, Frederiksen  K, Høgdall  EV,  et al.  Association of reproductive factors, oral contraceptive use and selected lifestyle factors with the risk of ovarian borderline tumors: a Danish case-control study.   Cancer Causes Control. 2006;17(6):821-829. doi:10.1007/s10552-006-0022-x PubMedGoogle ScholarCrossref
14.
Jordan  SJ, Green  AC, Whiteman  DC, Webb  PM; Australian Ovarian Cancer Study Group.  Risk factors for benign, borderline and invasive mucinous ovarian tumors: epidemiological evidence of a neoplastic continuum?   Gynecol Oncol. 2007;107(2):223-230. doi:10.1016/j.ygyno.2007.06.006 PubMedGoogle ScholarCrossref
15.
Kurta  ML, Moysich  KB, Weissfeld  JL,  et al.  Use of fertility drugs and risk of ovarian cancer: results from a U.S.-based case-control study.   Cancer Epidemiol Biomarkers Prev. 2012;21(8):1282-1292. doi:10.1158/1055-9965.EPI-12-0426 PubMedGoogle ScholarCrossref
16.
Le  DC, Kubo  T, Fujino  Y,  et al.  Reproductive factors in relation to ovarian cancer: a case-control study in Northern Vietnam.   Contraception. 2012;86(5):494-499. doi:10.1016/j.contraception.2012.02.019 PubMedGoogle ScholarCrossref
17.
McLaughlin  JR, Risch  HA, Lubinski  J,  et al; Hereditary Ovarian Cancer Clinical Study Group.  Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study.   Lancet Oncol. 2007;8(1):26-34. doi:10.1016/S1470-2045(06)70983-4 PubMedGoogle ScholarCrossref
18.
Mink  PJ, Folsom  AR, Sellers  TA, Kushi  LH.  Physical activity, waist-to-hip ratio, and other risk factors for ovarian cancer: a follow-up study of older women.   Epidemiology. 1996;7(1):38-45. doi:10.1097/00001648-199601000-00008 PubMedGoogle ScholarCrossref
19.
Modugno  F, Goughnour  SL, Wallack  D,  et al.  Breastfeeding factors and risk of epithelial ovarian cancer.   Gynecol Oncol. 2019;153(1):116-122. doi:10.1016/j.ygyno.2019.01.017 PubMedGoogle ScholarCrossref
20.
Moorman  PG, Alberg  AJ, Bandera  EV,  et al.  Reproductive factors and ovarian cancer risk in African-American women.   Ann Epidemiol. 2016;26(9):654-662. doi:10.1016/j.annepidem.2016.07.004 PubMedGoogle ScholarCrossref
21.
Mori  M, Harabuchi  I, Miyake  H, Casagrande  JT, Henderson  BE, Ross  RK.  Reproductive, genetic, and dietary risk factors for ovarian cancer.   Am J Epidemiol. 1988;128(4):771-777. doi:10.1093/oxfordjournals.aje.a115030 PubMedGoogle ScholarCrossref
22.
Mori  M, Nishida  T, Sugiyama  T,  et al.  Anthropometric and other risk factors for ovarian cancer in a case-control study.   Jpn J Cancer Res. 1998;89(3):246-253. doi:10.1111/j.1349-7006.1998.tb00555.x PubMedGoogle ScholarCrossref
23.
Pięta  B, Chmaj-Wierzchowska  K, Opala  T.  Past obstetric history and risk of ovarian cancer.   Ann Agric Environ Med. 2012;19(3):385-388.PubMedGoogle Scholar
24.
Salazar-Martinez  E, Lazcano-Ponce  EC, Gonzalez Lira-Lira  G, Escudero-De los Rios  P, Salmeron-Castro  J, Hernandez-Avila  M.  Reproductive factors of ovarian and endometrial cancer risk in a high fertility population in Mexico.   Cancer Res. 1999;59(15):3658-3662.PubMedGoogle Scholar
25.
Titus-Ernstoff  L, Rees  JR, Terry  KL, Cramer  DW.  Breast-feeding the last born child and risk of ovarian cancer.   Cancer Causes Control. 2010;21(2):201-207. doi:10.1007/s10552-009-9450-8 PubMedGoogle Scholar
26.
Tsilidis  KK, Allen  NE, Key  TJ,  et al.  Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition.   Br J Cancer. 2011;105(9):1436-1442. doi:10.1038/bjc.2011.371 PubMedGoogle Scholar
27.
Tung  KH, Goodman  MT, Wu  AH,  et al.  Reproductive factors and epithelial ovarian cancer risk by histologic type: a multiethnic case-control study.   Am J Epidemiol. 2003;158(7):629-638. doi:10.1093/aje/kwg177 PubMedGoogle Scholar
28.
Weiderpass  E, Sandin  S, Inoue  M,  et al.  Risk factors for epithelial ovarian cancer in Japan: results from the Japan Public Health Center-based Prospective Study cohort.   Int J Oncol. 2012;40(1):21-30.PubMedGoogle Scholar
29.
Wentzensen  N, Poole  EM, Trabert  B,  et al.  Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium.   J Clin Oncol. 2016;34(24):2888-2898. doi:10.1200/JCO.2016.66.8178 PubMedGoogle Scholar
30.
Whittemore  AS, Harris  R, Itnyre  J; Collaborative Ovarian Cancer Group.  Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II: invasive epithelial ovarian cancers in white women.   Am J Epidemiol. 1992;136(10):1184-1203. doi:10.1093/oxfordjournals.aje.a116427 PubMedGoogle Scholar
31.
Wilailak  S, Vipupinyo  C, Suraseranivong  V,  et al.  Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case-control study.   BJOG. 2012;119(6):672-677. doi:10.1111/j.1471-0528.2012.03298.x PubMedGoogle Scholar
32.
Bandera  EV, King  M, Chandran  U, Paddock  LE, Rodriguez-Rodriguez  L, Olson  SH.  Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study.   BMC Womens Health. 2011;11:40. doi:10.1186/1472-6874-11-40 PubMedGoogle Scholar
33.
Glud  E, Kjaer  SK, Thomsen  BL,  et al.  Hormone therapy and the impact of estrogen intake on the risk of ovarian cancer.   Arch Intern Med. 2004;164(20):2253-2259. doi:10.1001/archinte.164.20.2253 PubMedGoogle Scholar
34.
Goodman  MT, Lurie  G, Thompson  PJ, McDuffie  KE, Carney  ME.  Association of two common single-nucleotide polymorphisms in the CYP19A1 locus and ovarian cancer risk.   Endocr Relat Cancer. 2008;15(4):1055-1060. doi:10.1677/ERC-08-0104 PubMedGoogle Scholar
35.
Lo-Ciganic  WH, Zgibor  JC, Bunker  CH, Moysich  KB, Edwards  RP, Ness  RB.  Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, or acetaminophen and risk of ovarian cancer.   Epidemiology. 2012;23(2):311-319. doi:10.1097/EDE.0b013e3182456ad3 PubMedGoogle Scholar
36.
McGuire  V, Felberg  A, Mills  M,  et al.  Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations.   Am J Epidemiol. 2004;160(7):613-618. doi:10.1093/aje/kwh284 PubMedGoogle Scholar
37.
Merritt  MA, Green  AC, Nagle  CM, Webb  PM; Australian Cancer Study (Ovarian Cancer); Australian Ovarian Cancer Study Group.  Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer.   Int J Cancer. 2008;122(1):170-176. doi:10.1002/ijc.23017 PubMedGoogle Scholar
38.
Risch  HA, Bale  AE, Beck  PA, Zheng  W.  PGR +331 A/G and increased risk of epithelial ovarian cancer.   Cancer Epidemiol Biomarkers Prev. 2006;15(9):1738-1741. doi:10.1158/1055-9965.EPI-06-0272 PubMedGoogle Scholar
39.
Risch  HA, Marrett  LD, Howe  GR.  Parity, contraception, infertility, and the risk of epithelial ovarian cancer.   Am J Epidemiol. 1994;140(7):585-597. doi:10.1093/oxfordjournals.aje.a117296PubMedGoogle Scholar
40.
Bodelon  C, Cushing-Haugen  KL, Wicklund  KG, Doherty  JA, Rossing  MA.  Sun exposure and risk of epithelial ovarian cancer.   Cancer Causes Control. 2012;23(12):1985-1994. doi:10.1007/s10552-012-0076-xPubMedGoogle Scholar
41.
Royar  J, Becher  H, Chang-Claude  J.  Low-dose oral contraceptives: protective effect on ovarian cancer risk.   Int J Cancer. 2001;95(6):370-374. doi:10.1002/1097-0215(20011120)95:6<370::AID-IJC1065>3.0.CO;2-T PubMedGoogle Scholar
42.
Terry  KL, De Vivo  I, Titus-Ernstoff  L, Shih  MC, Cramer  DW.  Androgen receptor cytosine, adenine, guanine repeats, and haplotypes in relation to ovarian cancer risk.   Cancer Res. 2005;65(13):5974-5981. doi:10.1158/0008-5472.CAN-04-3885 PubMedGoogle Scholar
43.
Wu  AH, Pearce  CL, Tseng  CC, Templeman  C, Pike  MC.  Markers of inflammation and risk of ovarian cancer in Los Angeles County.   Int J Cancer. 2009;124(6):1409-1415. doi:10.1002/ijc.24091 PubMedGoogle Scholar
44.
Moorman  PG, Calingaert  B, Palmieri  RT,  et al.  Hormonal risk factors for ovarian cancer in premenopausal and postmenopausal women.   Am J Epidemiol. 2008;167(9):1059-1069. doi:10.1093/aje/kwn006 PubMedGoogle Scholar
45.
Booth  M, Beral  V, Smith  P.  Risk factors for ovarian cancer: a case-control study.   Br J Cancer. 1989;60(4):592-598. doi:10.1038/bjc.1989.320 PubMedGoogle Scholar
46.
Jordan  SJ, Cushing-Haugen  KL, Wicklund  KG, Doherty  JA, Rossing  MA.  Breast-feeding and risk of epithelial ovarian cancer.   Cancer Causes Control. 2012;23(6):919-927. doi:10.1007/s10552-012-9963-4 PubMedGoogle Scholar
47.
Modugno  F, Ness  RB, Wheeler  JE.  Reproductive risk factors for epithelial ovarian cancer according to histologic type and invasiveness.   Ann Epidemiol. 2001;11(8):568-574. doi:10.1016/S1047-2797(01)00213-7 PubMedGoogle Scholar
48.
Chen  Y, Wu  PC, Lang  JH, Ge  WJ, Hartge  P, Brinton  LA.  Risk factors for epithelial ovarian cancer in Beijing, China.   Int J Epidemiol. 1992;21(1):23-29. doi:10.1093/ije/21.1.23 PubMedGoogle Scholar
49.
Mills  PK, Riordan  DG, Cress  RD.  Epithelial ovarian cancer risk by invasiveness and cell type in the Central Valley of California.   Gynecol Oncol. 2004;95(1):215-225. doi:10.1016/j.ygyno.2004.07.012 PubMedGoogle Scholar
50.
Ness  RB, Grisso  JA, Klapper  J,  et al; SHARE Study Group.  Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives.   Am J Epidemiol. 2000;152(3):233-241. doi:10.1093/aje/152.3.233 PubMedGoogle Scholar
51.
Riman  T, Dickman  PW, Nilsson  S,  et al.  Risk factors for epithelial borderline ovarian tumors: results of a Swedish case-control study.   Gynecol Oncol. 2001;83(3):575-585. doi:10.1006/gyno.2001.6451 PubMedGoogle Scholar
52.
Risch  HA, Weiss  NS, Lyon  JL, Daling  JR, Liff  JM.  Events of reproductive life and the incidence of epithelial ovarian cancer.   Am J Epidemiol. 1983;117(2):128-139. doi:10.1093/oxfordjournals.aje.a113523 PubMedGoogle Scholar
53.
Rosenblatt  KA, Thomas  DB; The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.  Lactation and the risk of epithelial ovarian cancer.   Int J Epidemiol. 1993;22(2):192-197. doi:10.1093/ije/22.2.192 PubMedGoogle Scholar
54.
Yen  ML, Yen  BL, Bai  CH, Lin  RS.  Risk factors for ovarian cancer in Taiwan: a case-control study in a low-incidence population.   Gynecol Oncol. 2003;89(2):318-324. doi:10.1016/S0090-8258(03)00088-X PubMedGoogle Scholar
55.
Zhang  M, Xie  X, Lee  AH, Binns  CW.  Prolonged lactation reduces ovarian cancer risk in Chinese women.   Eur J Cancer Prev. 2004;13(6):499-502. doi:10.1097/00008469-200412000-00006PubMedGoogle Scholar
56.
Perez  A, Vela  P, Masnick  GS, Potter  RG.  First ovulation after childbirth: the effect of breast-feeding.   Am J Obstet Gynecol. 1972;114(8):1041-1047. doi:10.1016/0002-9378(72)90866-6 PubMedGoogle Scholar
57.
Adami  HO, Hsieh  CC, Lambe  M,  et al.  Parity, age at first childbirth, and risk of ovarian cancer.   Lancet. 1994;344(8932):1250-1254. doi:10.1016/S0140-6736(94)90749-8 PubMedGoogle Scholar
58.
Whiteman  DC, Siskind  V, Purdie  DM, Green  AC.  Timing of pregnancy and the risk of epithelial ovarian cancer.   Cancer Epidemiol Biomarkers Prev. 2003;12(1):42-46.PubMedGoogle Scholar
59.
Wu  AH, Pearce  CL, Lee  AW,  et al.  Timing of births and oral contraceptive use influences ovarian cancer risk.   Int J Cancer. 2017;141(12):2392-2399. doi:10.1002/ijc.30910 PubMedGoogle Scholar
60.
Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine.  Ovarian Cancers: Evolving Paradigms in Research and Care. National Academies Press;2016.
61.
Groer  MW, El-Badri  N, Djeu  J, Williams  SN, Kane  B, Szekeres  K.  Suppression of natural killer cell cytotoxicity in postpartum women: time course and potential mechanisms.   Biol Res Nurs. 2014;16(3):320-326. doi:10.1177/1099800413498927 PubMedGoogle Scholar
62.
Stuebe  AM, Rich-Edwards  JW.  The reset hypothesis: lactation and maternal metabolism.   Am J Perinatol. 2009;26(1):81-88. doi:10.1055/s-0028-1103034 PubMedGoogle Scholar
63.
Zhang  D, Li  N, Xi  Y, Zhao  Y, Wang  T.  Diabetes mellitus and risk of ovarian cancer: a systematic review and meta-analysis of 15 cohort studies.   Diabetes Res Clin Pract. 2017;130:43-52. doi:10.1016/j.diabres.2017.04.005 PubMedGoogle Scholar
64.
World Health Organization. Maternal, newborn, child and adolescent health. Accessed February 27, 2020. https://www.who.int/maternal_child_adolescent/topics/child/nutrition/breastfeeding/en/
Limit 200 characters
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    1 Comment for this article
    Backwards figures
    Jenny Allen |
    As usual the results are backwards, citing a reduced risk due to breastfeeding. However, breastfeeding is the biological norm, and should be used as the baseline, not breastfeeding is the deviation from the biological norm, so these results should be written as the increased risk of cancer from not breastfeeding.
    CONFLICT OF INTEREST: None Reported
    Original Investigation
    April 2, 2020

    Association Between Breastfeeding and Ovarian Cancer Risk

    Author Affiliations
    • 1Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    • 3Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 4Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
    • 5Division of Population Sciences, Moffitt Cancer Center, Tampa, Florida
    • 6Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
    • 7The University of Queensland School of Public Health, Brisbane, Queensland, Australia
    • 8Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
    • 9Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • 10Department of Epidemiology, School of Public Health, University of Washington, Seattle
    • 11Department of Population Health Science, Huntsman Cancer Institute, University of Utah, Salt Lake City
    • 12Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
    • 13Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    • 14Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
    • 15Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • 16Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York
    • 17School of Public Health, University of Texas Health Science Center at Houston, Houston
    • 18Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
    • 19Rigshospitalet, Department of Gynaecology, University of Copenhagen, Copenhagen, Denmark
    • 20Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia
    • 21Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
    • 22Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick
    • 23Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
    • 24Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, California
    • 25Epidemiology Center, College of Medicine, University of South Florida, Tampa
    • 26Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor
    • 27Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles
    • 28Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
    • 29Women’s Cancer Research Center, Magee-Womens Research Institute, Hillman Cancer Center, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    • 30Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
    JAMA Oncol. 2020;6(6):e200421. doi:10.1001/jamaoncol.2020.0421
    Key Points

    Question  Is breastfeeding associated with risk of ovarian cancer overall and by histotype?

    Findings  In this pooled analysis including 9973 women with ovarian cancer and 13 843 controls from 13 case-control studies, breastfeeding was associated with a 24% reduced risk of invasive epithelial ovarian cancer. Longer breastfeeding duration and shorter time since last breastfeeding episode were associated with a further decrease in risk.

    Meaning  This large study with extensive information on breastfeeding provides epidemiological evidence that breastfeeding, a potentially modifiable factor, may confer significant reduction in ovarian cancer risk, including high-grade serous, the deadliest subtype.

    Abstract

    Importance  Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent.

    Objective  To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype.

    Design, Setting, and Participants  A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019.

    Exposures  Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies.

    Main Outcomes and Measures  Diagnosis of epithelial ovarian cancer.

    Results  A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02).

    Conclusions and Relevance  Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.

    Introduction

    Ovarian cancer survival remains poor with 5-year survival less than 50%, mostly owing to late detection.1 Prevention is crucial for reducing mortality from this disease. With few modifiable risk factors beyond oral contraceptive (OC) use,1,2 identifying additional modifiable factors is needed to tailor prevention strategies.

    Numerous studies have investigated the association between breastfeeding and ovarian cancer risk, with some showing a significant decrease in risk and others showing no association,3-31 leading the World Cancer Research Fund International to describe evidence of the association as limited.2 Furthermore, relationships between ovarian cancer and breastfeeding patterns, including number of breastfeeding episodes, breastfeeding duration, and timing of breastfeeding, have been inconsistent. Prior studies have had insufficient sample size to evaluate heterogeneity by disease histotype. More than 90% of ovarian cancers are epithelial in origin,1 with the major histotypes exhibiting varied risk profiles29 and likely having distinct etiologic pathways. Therefore, we evaluated associations between breastfeeding and epithelial ovarian cancer risk overall and by histotype using data from 13 case-control studies participating in the Ovarian Cancer Association Consortium.

    Methods
    Study Population

    The Ovarian Cancer Association Consortium was established in 2005 to promote collaborative research on epidemiologic factors associated with ovarian cancer. Our analysis includes data from 13 Ovarian Cancer Association Consortium studies32-44 with information on breastfeeding history (eTable 1 in Supplement). All studies are population-based and used in-person interviews for data collection except the Australian Ovarian Cancer Study37 and the German Ovarian Cancer Study,41 which used self-administered questionnaire for data collection. All studies frequency matched by age categories. The Hawaii Ovarian Cancer Case-Control Study,34 Family Registry for Ovarian Cancer and Genetic Epidemiology of Ovarian Cancer study,36 and University of Southern California Study of Lifestyle and Women’s Health43 additionally matched for race. The New Jersey Ovarian Cancer Study32 did not have any matching variables. All participants provided informed consent, and participating institutions obtained approval from relevant ethics committees. We excluded women who were nulliparous (n = 6309), missing parity information (n = 233), missing breastfeeding status (n = 480), and had nonepithelial tumors (n = 115). All data were collected from individual sites from November 1989 to December 2009.

    Study Variables

    Detailed information on breastfeeding history for each pregnancy lasting 6 months or longer, including ever breastfeeding (yes/no), breastfeeding duration (months), and age at each pregnancy was self-reported. Ever breastfeeding was defined as any breastfeeding, regardless of duration. A single breastfeeding episode refers to breastfeeding offspring from a given pregnancy (including twins and multiples). Total duration of breastfeeding was calculated by summing durations of individual breastfeeding episodes. If duration of any breastfeeding episode was unknown, total duration was considered unknown (n = 51). Mean breastfeeding duration per episode was obtained by dividing total duration by number of breastfeeding episodes. Timing of supplementation by formula, milk, or other foods was assessed in 5 studies (Connecticut Ovarian Cancer Study,38 Diseases of the Ovary and their Evaluation,40 Hawaii Ovarian Cancer Case-Control Study,34 North Carolina Ovarian Cancer Study,44 and University of Southern California Study of Lifestyle and Women’s Health43), although specific wording varied by sites. To define the duration of exclusive breastfeeding consistently across studies, we calculated the duration as the time between birth and initial supplementation based on these questions. Analyses of ages at first and last breastfeeding episode were restricted to girls and women 15 years or older at first or last breastfeeding episode. Other relevant variables include age at diagnosis/interview, decade of participant’s birth, self-reported race, attained education, total duration of OC use, parity, history of endometriosis, tubal ligation, menopausal status, young adult body mass index (calculated as weight in kilograms divided by height in meters squared), and family history of ovarian cancer.

    Statistical Analyses

    We used unconditional logistic regression to estimate the odds ratios (ORs) and 95% CIs for associations between breastfeeding and ovarian cancer risk for each site. We used indicator variables to account for missing data (race/ethnicity, n = 881; OC use, n = 264). In the main multivariate model, we adjusted for age (continuous), race/ethnicity (white, black, Asian, other/unknown), OC use (never, <1 year, 1 to <5 years, 5 to <10 years, ≥10 years, unknown), parity (continuous), and decade of birth (to account for possible changes in breastfeeding practices over time). We also considered adjustments for additional ovarian cancer risk factors including education (>high school, high school, some college, college, unknown), tubal ligation (no, yes, unknown), endometriosis (no, yes, unknown), body mass index at young adulthood (<20, 20 to <25, 25 to <30, ≥30, unknown), and family history of ovarian cancer (no, yes, unknown). However, these factors did not change the association between breastfeeding and ovarian cancer risk more than 10% and were not included in final models. We used random-effects meta-analyses of invasive cancers and borderline tumors and likelihood ratio tests to assess heterogeneity of the associations between study sites. Because we observed no significant heterogeneity, we used the pooled data set for all analyses adjusted for study site. We performed polytomous logistic regression to evaluate the associations between breastfeeding and cancer risk by invasive (low-grade serous, high-grade serous, mucinous, endometrioid, clear cell, other) and borderline (serous, mucinous) histotypes and likelihood ratio tests to evaluate differences in the associations by histotype. Among invasive serous tumors, low grade was defined as grade of 1 and high grade as grade of 2 or higher.

    Because parity and breastfeeding are highly correlated, we created variables to evaluate each possible combination of parity and breastfeeding (eg, 1 liveborn with no breastfeeding, 1 liveborn with breastfeeding) to evaluate the independent association of breastfeeding with outcomes. We performed stratified analyses by age (≤50 years, >50 years), body mass index at young adulthood (<25, 25 to <30, ≥30), history of endometriosis, family history of ovarian cancer, and race/ethnicity. To evaluate interactions, we created crossproduct terms involving breastfeeding and the potential effect modifier and calculated likelihood-ratio statistics comparing models with and without the interaction terms. We tested for trend using Wald tests of continuous variables (months of breastfeeding, number of breastfeeding episodes, ages at first and last breastfeeding episodes, time since last breastfeeding episode) among women who reported ever having breastfed. Additionally, we conducted a sensitivity analysis using residuals to examine the association of breastfeeding patterns independent of parity. We computed residuals from a linear regression model with parity as the independent variable and number of breastfeeding episodes/total duration of breastfeeding as dependent variables. Residuals of breastfeeding episodes or total breastfeeding duration were next grouped into quintiles and used as the exposure of interest in multivariate models. To address potential confounding by parity, we restricted the analysis to women with exactly 2 births and examined whether breastfeeding both vs 1 child was associated with differential risk, adjusting for total duration of breastfeeding.

    When examining the associations between ages at first and last breastfeeding episodes and ovarian cancer risk, we additionally adjusted for total breastfeeding duration and ages at first or last birth, respectively. We examined whether ages at first and last breastfeeding were independently associated with risk by simultaneously including both variables in the model. We additionally adjusted for age at last birth when examining the association between time since last breastfeeding and ovarian cancer risk, and we performed the duration and timing analyses restricted to high-grade serous histotype.

    We used SAS version 9.4 (SAS Institute) for logistic regression analyses. For polytomous logistic regression, we used Stata/IC, version 15.1 (StataCorp). All P values are 2-sided, with .05 as the significance threshold. Analysis was performed from September 2017 to July 2019.

    Results

    A total of 9973 women with ovarian cancer and 13 843 controls were included in the analysis. Among parous controls, the prevalence of ever having breastfed ranged from 41% to 93% across studies, and mean breastfeeding duration per episode ranged from 3.4 to 8.7 months (eTable 1 in the Supplement). The mean (SD) age was 57.4 (11.1) years for women with ovarian cancer and 56.4 (11.7) years for controls, and 21 103 participants (89%) identified as white (eTable 2 in the Supplement). Compared with controls, those with ovarian cancer were older, more likely to be postmenopausal, primiparous, have never used OCs, have a history of endometriosis, and have a family history of ovarian cancer.

    After multivariable adjustment, ever having breastfed was inversely associated with risks of both invasive (OR, 0.76; 95% CI, 0.71-0.80) and borderline (OR, 0.72; 95% CI, 0.64-0.81) tumors compared with never breastfeeding (Table 1). Associations were consistent across study sites for both invasive and borderline tumors (Figure). Among invasive tumors, the association was statistically significant for high-grade serous (OR, 0.75; 95% CI, 0.70-0.81), endometrioid (OR, 0.73; 95% CI, 0.64-0.84), and clear cell tumors (OR, 0.78; 95% CI, 0.64-0.96). We observed similar, although not statistically significant, associations for low-grade serous and no significant inverse association for mucinous tumors. For borderline tumors, there was a statistically significant inverse association for both mucinous (OR, 0.68; 95% CI, 0.57-0.82) and serous tumors (OR, 0.77; 95% CI, 0.66-0.89). In the 5 studies34,38,40,43,44 with data on exclusive breastfeeding, we observed a similar inverse association with ovarian cancer risk for women who breastfed exclusively for at least 3 months (OR, 0.81; 95% CI, 0.72-0.92) and breastfed but not exclusively for 3 months (OR, 0.70; 95% CI, 0.62-0.79) compared with women who never breastfed.

    To examine the association between breastfeeding and ovarian cancer risk within parity strata, we created a crossclassified variable of parity and breastfeeding (eFigure in the Supplement). Among primiparous women, ever breastfeeding was associated with 14% lower risk of all invasive disease (OR, 0.86; 95% CI, 0.75-0.99) and 16% lower risk of high-grade serous tumors (OR, 0.84; 95% CI, 0.71-0.99) compared with never breastfeeding. For multiparous women, we observed a similar inverse association for both all invasive and high-grade serous tumors.

    In stratified analyses, we observed no statistically significant effect modification by age, body mass index at young adulthood, history of endometriosis, and family history of ovarian cancer (eTable 3 in the Supplement). Furthermore, we observed significant interaction by race/ethnicity (P for interaction = .01), with the strongest association in white women (OR, 0.73; 95% CI, 0.69-0.79) and no significant association among black women (OR, 0.92; 95% CI, 0.66-1.29) or Asian women (OR, 0.81; 95% CI, 0.58-1.12).

    Compared with women who never breastfed, longer mean duration of breastfeeding per episode was inversely associated with invasive ovarian cancer risk (Table 2). Mean breastfeeding duration of less than 3 months per child was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88) while mean breastfeeding duration of more than 12 months per child was associated with 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75; P for trend = .001). Similar associations were observed in analyses restricted to high-grade serous tumors (Table 2) and in regression analyses of residuals controlled for parity (data not shown). In addition, we stratified mean breastfeeding duration per episode by parity (1, 2, and ≥3 live births) and observed associations similar in magnitude (Table 2). Similarly, total breastfeeding duration was significantly associated with reduced ovarian cancer risk (P for trend <.001 among women who breastfed; data not shown).

    Among women who breastfed, older ages at first (OR, 0.90; 95% CI, 0.85-0.96, per 5 years of age increase at first breastfeeding; P for trend = .001) and last breastfeeding episode (OR, 0.94; 95% CI, 0.89-0.99, per 5 years of age increase at last breastfeeding; P for trend = .02) were associated with lower risk of invasive ovarian cancer (eTable 4 in the Supplement). When adjusted for ages at first and last birth together, both associations were attenuated. Breastfeeding was associated with a substantial reduction in ovarian cancer risk for decades after the last breastfeeding episode, although the magnitude of risk reduction attenuated over time. Compared with women who never breastfed, time since last breastfeeding episode of less than 10 years was associated with 44% lower risk (OR, 0.56; 95% CI, 0.47-0.66), while time since last breastfeeding episode of 30 years or less was associated with 17% lower risk (OR, 0.83; 95% CI, 0.77-0.90; P for trend = .02). Associations for age at breastfeeding and timing of breastfeeding were similar for high-grade serous tumors (eTable 4 in the Supplement) and when restricted to women with 2 births (eTable 5 in the Supplement).

    Discussion

    In this largest study of breastfeeding and ovarian cancer risk to date and to our knowledge, including 9973 parous women with ovarian cancer from 13 studies, a history of breastfeeding was associated with 24% decrease in invasive cancer risk and 28% decrease in borderline tumor risk, with consistent risk reduction across study sites. Furthermore, mean breastfeeding duration per episode was inversely associated with risk, with 18% reduction in risk for women who breastfed less than 3 months per live birth and 34% reduction for women who breastfed 12 months or longer per live birth. Similar associations were observed for high-grade serous tumors, the deadliest ovarian cancer histotype.

    Consistent with some but not all prior studies,3-15,17,20,22,24,26,27,29,30,44-55 we observed an inverse association between mean breastfeeding duration per episode and risk of invasive and borderline ovarian tumors. Statistically significant risk reduction associated with a mean breastfeeding duration of less than 3 months per episode suggests even a short duration of breastfeeding is beneficial. We did not observe a statistically significant difference in risk associated with nonexclusive breastfeeding compared with exclusive breastfeeding; however, sample size was limited and exclusive breastfeeding definitions varied between studies.56 Associations between breastfeeding and ovarian cancer risk were stronger with older ages at first and last breastfeeding episodes, consistent with previous reports.57-59 However, these associations were attenuated after mutual adjustment for ages at first and last breastfeeding. While risk reduction was greatest for women who had breastfed within the past 10 years, the association persisted more than 30 years, a pattern also seen with time since last OC use and last birth.59

    Our findings indicate that breastfeeding is associated with lower risk of high-grade serous cancers, the most common and fatal subtype. While previous studies4,5,29,46,47 reported inconsistent findings for serous histotypes, most did not separate low- from high-grade serous tumors, which are thought to have separate etiologic pathways.29,60 The Million Women Study5 separately analyzed low- and high-grade serous tumors and reported a lower risk of both histotypes with longer total and mean duration per episode of breastfeeding. However, the associations did not reach statistical significance. Similar to ovarian cancer overall, we observed a reduced risk of high-grade serous tumors with as little as 3 months’ mean breastfeeding duration per episode and greater risk reduction with longer breastfeeding duration, older ages at first and last breastfeeding episodes, and recent (<10 years) breastfeeding. The inverse association with time since last breastfeeding persisted for more than 30 years. While we observed similar associations with breastfeeding patterns and endometrioid ovarian cancers, fewer cases of other invasive histotypes limited our ability to evaluate them with the same level of detail.

    Biological mechanisms through which breastfeeding could reduce ovarian cancer risk are not well understood. To date, the leading hypothesis has been that ovulation suppression during breastfeeding inhibits epithelial cell division and proliferation, thereby reducing the opportunity to initiate or promote carcinogenesis. This may especially be pertinent in the first few months post partum when immune function and tumor surveillance mechanisms remain suppressed.61 However, we observed a stronger inverse association with longer breastfeeding duration, suggesting anovulation cannot entirely explain the association because ovulation typically returns once solids are introduced. Several lines of evidence suggest that breastfeeding may also be associated with long-term modulation of inflammatory, immune, or metabolic pathways, which could influence ovarian cancer risk.62,63

    Strengths and Limitations

    Important strengths of this study include detailed data on breastfeeding patterns, including information on duration and timing of each breastfeeding episode. We included a large number of women with ovarian cancer and controls from established studies with geographic diversity and extensive data on demographic, reproductive, and lifestyle variables. The large sample size enabled us to examine breastfeeding patterns in detail and specifically to assess high-grade serous tumors, the most common and fatal histotype. In addition, our pooled analysis allowed us to harmonize variables for consistency across the 13 studies, adjust for a single set of confounders, evaluate histotype-specific associations, and assess potential effect modification in stratified analyses. Importantly, we were also able to disentangle the association between breastfeeding and ovarian cancer risk from that of parity.

    Our study has some limitations, including the potential for differential self-reporting of breastfeeding information by disease status, which could distort the magnitude of associations. Our results may also be influenced by selection bias as controls participating in these studies may differ from women with ovarian cancer by factors influencing breastfeeding or ovarian cancer risk, including unknown factors that could not be accounted for in the analysis. Despite adjustment for potential confounders, unmeasured confounding may persist but is unlikely to substantively alter our findings given our robust associations. Validation in prospective cohorts is needed to address these concerns. Finally, because our study population included predominantly white women, we could not sufficiently evaluate details of breastfeeding patterns in black women, Asian women, and less common racial and ethnic groups.20 The association between breastfeeding and ovarian cancer needs to be investigated in large populations of other races and ethnicities.

    Conclusions

    In conclusion, breastfeeding is associated with a significant decrease in ovarian cancer risk overall and for high-grade serous tumors, the most lethal subtype. The World Health Organization recommends exclusive breastfeeding for at least 6 months and continued breastfeeding with complementary foods for 2 or more years.2,64 Our results support these recommendations, while noting that breastfeeding fewer than 3 months per child is still associated with significant ovarian cancer risk reduction.

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    Article Information

    Corresponding Author: Naoko Sasamoto, MD, MPH, Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115 (nsasamoto@bwh.harvard.edu).

    Accepted for Publication: February 6, 2020.

    Published Online: April 2, 2020. doi:10.1001/jamaoncol.2020.0421

    Author Contributions: Dr Terry had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Babic and Sasamoto contributed equally as co–first authors, and

    Drs Modugno and Terry contributed equally as co–senior authors to this work.

    Concept and design: Babic, Sasamoto, Moysich, Ness, McGuire, Webb, Modugno, Terry.

    Acquisition, analysis, or interpretation of data: Babic, Sasamoto, Rosner, Tworoger, Jordan, Risch, Harris, Rossing, Doherty, Fortner, Chang-Claude, Goodman, Thompson, Moysich, Ness, Kjaer, Jensen, Schildkraut, Titus, Cramer, Bandera, Qin, Sieh, Sutphen, Pearce, Wu, Pike, Webb, Modugno, Terry.

    Drafting of the manuscript: Babic, Sasamoto, Jordan, Pike, Modugno, Terry.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Babic, Sasamoto, Rosner, Tworoger, Jordan, Risch, Harris, Schildkraut, Pike, Modugno.

    Obtained funding: Risch, Rossing, Doherty, Goodman, Ness, Kjaer, Schildkraut, Titus, Sutphen, Modugno, Terry.

    Administrative, technical, or material support: Risch, Harris, Rossing, Fortner, Thompson, Jensen, Titus, Cramer, Sieh, Sutphen, Pearce, Wu, Webb, Modugno.

    Supervision: Ness, Webb, Modugno, Terry.

    Conflict of Interest Disclosures: Drs Babic, Sasamoto, Rosner, Tworoger, Cramer, Qin, Schildkraut, Titus, Pearce, Pike, Terry, and Modugno report grants from the National Institutes of Health during the conduct of the study. Dr Jordan reports grants from the National Health and Medical Research Council of Australia during the conduct of the study. Dr Fortner reports grants from the Federal Ministry of Education and Research of Germany during the conduct of the study. Dr Kjaer reports grants from the Danish Cancer Society and The Mermaid I Project during the conduct of the study. Drs Pearce, Webb, and Modugno report grants from Congressionally Directed Medical Research Programs and National Institutes of Health during the conduct of the study. No other disclosures were reported.

    Funding/Support: The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (grant U19-CA148112).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We thank all of the members of the Ovarian Cancer Association Consortium for their support of this collaborative network and are grateful to the family and friends of Kathryn Sladek Smith for their generous support of the Ovarian Cancer Association Consortium through their donations to the Ovarian Cancer Research Fund. We also thank the funders for the individual studies analyzed in this article: The Australian Ovarian Cancer Study Group was supported by the Army Medical Research and Materiel Command, National Health and Medical Research Council of Australia, Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, and Cancer Foundation of Western Australia. The Connecticut Ovarian Cancer Study, the Diseases of the Ovary and their Evaluation study, Hawaii Ovarian Cancer Case-Control Study, and Family Registry for Ovarian Cancer and Genetic Epidemiology of Ovarian Cancer study were supported by the National Institutes of Health. The German Ovarian Cancer Study was supported by the German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research and the German Cancer Research Center. The Hormones and Ovarian Cancer Prediction Study was supported by the University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award (Dr Modugno), US Department of Defense, and National Institutes of Health. The Malignant Ovarian Cancer Study was supported by the National Institutes of Health, Danish Cancer Society; and the Mermaid I Project. The North Carolina Ovarian Cancer Study was supported by the National Cancer Institute and US Department of Defense. The New England Case Control Study was supported by the National Institutes of Health and US Department of Defense. The New Jersey Ovarian Cancer Study was supported by the National Institutes of Health and the Rutgers Cancer Institute of New Jersey. The Southern Ontario Ovarian Cancer Study was supported by the National Health Research and Development Program, Canada. The University of Southern California Study of Lifestyle and Women’s Health study was supported by the National Institutes of Health and California Cancer Research Program.

    References
    1.
    American Cancer Society.  Cancer Facts & Figures 2019. American Cancer Society; 2019.
    2.
    World Cancer Research Fund/ American Institute for Cancer Research.  Diet, Nutrition, Physical Activity and Cancer: a Global Perspective. World Cancer Research Fund International; 2018.
    3.
    Chiaffarino  F, Pelucchi  C, Negri  E,  et al.  Breastfeeding and the risk of epithelial ovarian cancer in an Italian population.   Gynecol Oncol. 2005;98(2):304-308. doi:10.1016/j.ygyno.2005.05.006 PubMedGoogle ScholarCrossref
    4.
    Danforth  KN, Tworoger  SS, Hecht  JL, Rosner  BA, Colditz  GA, Hankinson  SE.  Breastfeeding and risk of ovarian cancer in two prospective cohorts.   Cancer Causes Control. 2007;18(5):517-523. doi:10.1007/s10552-007-0130-2 PubMedGoogle ScholarCrossref
    5.
    Gaitskell  K, Green  J, Pirie  K,  et al; Million Women Study Collaborators.  Histological subtypes of ovarian cancer associated with parity and breastfeeding in the prospective Million Women Study.   Int J Cancer. 2018;142(2):281-289. doi:10.1002/ijc.31063 PubMedGoogle ScholarCrossref
    6.
    Greggi  S, Parazzini  F, Paratore  MP,  et al.  Risk factors for ovarian cancer in central Italy.   Gynecol Oncol. 2000;79(1):50-54. doi:10.1006/gyno.2000.5909 PubMedGoogle ScholarCrossref
    7.
    Gronwald  J, Byrski  T, Huzarski  T,  et al.  Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland.   Breast Cancer Res Treat. 2006;95(2):105-109. doi:10.1007/s10549-005-9051-5 PubMedGoogle ScholarCrossref
    8.
    Gwinn  ML, Lee  NC, Rhodes  PH, Layde  PM, Rubin  GL.  Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer.   J Clin Epidemiol. 1990;43(6):559-568. doi:10.1016/0895-4356(90)90160-Q PubMedGoogle ScholarCrossref
    9.
    Harlow  BL, Weiss  NS, Roth  GJ, Chu  J, Daling  JR.  Case-control study of borderline ovarian tumors: reproductive history and exposure to exogenous female hormones.   Cancer Res. 1988;48(20):5849-5852.PubMedGoogle Scholar
    10.
    Harris  R, Whittemore  AS, Itnyre  J; Collaborative Ovarian Cancer Group.  Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III: epithelial tumors of low malignant potential in white women.   Am J Epidemiol. 1992;136(10):1204-1211. doi:10.1093/oxfordjournals.aje.a116428 PubMedGoogle ScholarCrossref
    11.
    Hartge  P, Schiffman  MH, Hoover  R, McGowan  L, Lesher  L, Norris  HJ.  A case-control study of epithelial ovarian cancer.   Am J Obstet Gynecol. 1989;161(1):10-16. doi:10.1016/0002-9378(89)90221-4 PubMedGoogle ScholarCrossref
    12.
    Hirose  K, Tajima  K, Hamajima  N,  et al.  Comparative case-referent study of risk factors among hormone-related female cancers in Japan.   Jpn J Cancer Res. 1999;90(3):255-261. doi:10.1111/j.1349-7006.1999.tb00741.x PubMedGoogle ScholarCrossref
    13.
    Huusom  LD, Frederiksen  K, Høgdall  EV,  et al.  Association of reproductive factors, oral contraceptive use and selected lifestyle factors with the risk of ovarian borderline tumors: a Danish case-control study.   Cancer Causes Control. 2006;17(6):821-829. doi:10.1007/s10552-006-0022-x PubMedGoogle ScholarCrossref
    14.
    Jordan  SJ, Green  AC, Whiteman  DC, Webb  PM; Australian Ovarian Cancer Study Group.  Risk factors for benign, borderline and invasive mucinous ovarian tumors: epidemiological evidence of a neoplastic continuum?   Gynecol Oncol. 2007;107(2):223-230. doi:10.1016/j.ygyno.2007.06.006 PubMedGoogle ScholarCrossref
    15.
    Kurta  ML, Moysich  KB, Weissfeld  JL,  et al.  Use of fertility drugs and risk of ovarian cancer: results from a U.S.-based case-control study.   Cancer Epidemiol Biomarkers Prev. 2012;21(8):1282-1292. doi:10.1158/1055-9965.EPI-12-0426 PubMedGoogle ScholarCrossref
    16.
    Le  DC, Kubo  T, Fujino  Y,  et al.  Reproductive factors in relation to ovarian cancer: a case-control study in Northern Vietnam.   Contraception. 2012;86(5):494-499. doi:10.1016/j.contraception.2012.02.019 PubMedGoogle ScholarCrossref
    17.
    McLaughlin  JR, Risch  HA, Lubinski  J,  et al; Hereditary Ovarian Cancer Clinical Study Group.  Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study.   Lancet Oncol. 2007;8(1):26-34. doi:10.1016/S1470-2045(06)70983-4 PubMedGoogle ScholarCrossref
    18.
    Mink  PJ, Folsom  AR, Sellers  TA, Kushi  LH.  Physical activity, waist-to-hip ratio, and other risk factors for ovarian cancer: a follow-up study of older women.   Epidemiology. 1996;7(1):38-45. doi:10.1097/00001648-199601000-00008 PubMedGoogle ScholarCrossref
    19.
    Modugno  F, Goughnour  SL, Wallack  D,  et al.  Breastfeeding factors and risk of epithelial ovarian cancer.   Gynecol Oncol. 2019;153(1):116-122. doi:10.1016/j.ygyno.2019.01.017 PubMedGoogle ScholarCrossref
    20.
    Moorman  PG, Alberg  AJ, Bandera  EV,  et al.  Reproductive factors and ovarian cancer risk in African-American women.   Ann Epidemiol. 2016;26(9):654-662. doi:10.1016/j.annepidem.2016.07.004 PubMedGoogle ScholarCrossref
    21.
    Mori  M, Harabuchi  I, Miyake  H, Casagrande  JT, Henderson  BE, Ross  RK.  Reproductive, genetic, and dietary risk factors for ovarian cancer.   Am J Epidemiol. 1988;128(4):771-777. doi:10.1093/oxfordjournals.aje.a115030 PubMedGoogle ScholarCrossref
    22.
    Mori  M, Nishida  T, Sugiyama  T,  et al.  Anthropometric and other risk factors for ovarian cancer in a case-control study.   Jpn J Cancer Res. 1998;89(3):246-253. doi:10.1111/j.1349-7006.1998.tb00555.x PubMedGoogle ScholarCrossref
    23.
    Pięta  B, Chmaj-Wierzchowska  K, Opala  T.  Past obstetric history and risk of ovarian cancer.   Ann Agric Environ Med. 2012;19(3):385-388.PubMedGoogle Scholar
    24.
    Salazar-Martinez  E, Lazcano-Ponce  EC, Gonzalez Lira-Lira  G, Escudero-De los Rios  P, Salmeron-Castro  J, Hernandez-Avila  M.  Reproductive factors of ovarian and endometrial cancer risk in a high fertility population in Mexico.   Cancer Res. 1999;59(15):3658-3662.PubMedGoogle Scholar
    25.
    Titus-Ernstoff  L, Rees  JR, Terry  KL, Cramer  DW.  Breast-feeding the last born child and risk of ovarian cancer.   Cancer Causes Control. 2010;21(2):201-207. doi:10.1007/s10552-009-9450-8 PubMedGoogle Scholar
    26.
    Tsilidis  KK, Allen  NE, Key  TJ,  et al.  Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition.   Br J Cancer. 2011;105(9):1436-1442. doi:10.1038/bjc.2011.371 PubMedGoogle Scholar
    27.
    Tung  KH, Goodman  MT, Wu  AH,  et al.  Reproductive factors and epithelial ovarian cancer risk by histologic type: a multiethnic case-control study.   Am J Epidemiol. 2003;158(7):629-638. doi:10.1093/aje/kwg177 PubMedGoogle Scholar
    28.
    Weiderpass  E, Sandin  S, Inoue  M,  et al.  Risk factors for epithelial ovarian cancer in Japan: results from the Japan Public Health Center-based Prospective Study cohort.   Int J Oncol. 2012;40(1):21-30.PubMedGoogle Scholar
    29.
    Wentzensen  N, Poole  EM, Trabert  B,  et al.  Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium.   J Clin Oncol. 2016;34(24):2888-2898. doi:10.1200/JCO.2016.66.8178 PubMedGoogle Scholar
    30.
    Whittemore  AS, Harris  R, Itnyre  J; Collaborative Ovarian Cancer Group.  Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II: invasive epithelial ovarian cancers in white women.   Am J Epidemiol. 1992;136(10):1184-1203. doi:10.1093/oxfordjournals.aje.a116427 PubMedGoogle Scholar
    31.
    Wilailak  S, Vipupinyo  C, Suraseranivong  V,  et al.  Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case-control study.   BJOG. 2012;119(6):672-677. doi:10.1111/j.1471-0528.2012.03298.x PubMedGoogle Scholar
    32.
    Bandera  EV, King  M, Chandran  U, Paddock  LE, Rodriguez-Rodriguez  L, Olson  SH.  Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study.   BMC Womens Health. 2011;11:40. doi:10.1186/1472-6874-11-40 PubMedGoogle Scholar
    33.
    Glud  E, Kjaer  SK, Thomsen  BL,  et al.  Hormone therapy and the impact of estrogen intake on the risk of ovarian cancer.   Arch Intern Med. 2004;164(20):2253-2259. doi:10.1001/archinte.164.20.2253 PubMedGoogle Scholar
    34.
    Goodman  MT, Lurie  G, Thompson  PJ, McDuffie  KE, Carney  ME.  Association of two common single-nucleotide polymorphisms in the CYP19A1 locus and ovarian cancer risk.   Endocr Relat Cancer. 2008;15(4):1055-1060. doi:10.1677/ERC-08-0104 PubMedGoogle Scholar
    35.
    Lo-Ciganic  WH, Zgibor  JC, Bunker  CH, Moysich  KB, Edwards  RP, Ness  RB.  Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, or acetaminophen and risk of ovarian cancer.   Epidemiology. 2012;23(2):311-319. doi:10.1097/EDE.0b013e3182456ad3 PubMedGoogle Scholar
    36.
    McGuire  V, Felberg  A, Mills  M,  et al.  Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations.   Am J Epidemiol. 2004;160(7):613-618. doi:10.1093/aje/kwh284 PubMedGoogle Scholar
    37.
    Merritt  MA, Green  AC, Nagle  CM, Webb  PM; Australian Cancer Study (Ovarian Cancer); Australian Ovarian Cancer Study Group.  Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer.   Int J Cancer. 2008;122(1):170-176. doi:10.1002/ijc.23017 PubMedGoogle Scholar
    38.
    Risch  HA, Bale  AE, Beck  PA, Zheng  W.  PGR +331 A/G and increased risk of epithelial ovarian cancer.   Cancer Epidemiol Biomarkers Prev. 2006;15(9):1738-1741. doi:10.1158/1055-9965.EPI-06-0272 PubMedGoogle Scholar
    39.
    Risch  HA, Marrett  LD, Howe  GR.  Parity, contraception, infertility, and the risk of epithelial ovarian cancer.   Am J Epidemiol. 1994;140(7):585-597. doi:10.1093/oxfordjournals.aje.a117296PubMedGoogle Scholar
    40.
    Bodelon  C, Cushing-Haugen  KL, Wicklund  KG, Doherty  JA, Rossing  MA.  Sun exposure and risk of epithelial ovarian cancer.   Cancer Causes Control. 2012;23(12):1985-1994. doi:10.1007/s10552-012-0076-xPubMedGoogle Scholar
    41.
    Royar  J, Becher  H, Chang-Claude  J.  Low-dose oral contraceptives: protective effect on ovarian cancer risk.   Int J Cancer. 2001;95(6):370-374. doi:10.1002/1097-0215(20011120)95:6<370::AID-IJC1065>3.0.CO;2-T PubMedGoogle Scholar
    42.
    Terry  KL, De Vivo  I, Titus-Ernstoff  L, Shih  MC, Cramer  DW.  Androgen receptor cytosine, adenine, guanine repeats, and haplotypes in relation to ovarian cancer risk.   Cancer Res. 2005;65(13):5974-5981. doi:10.1158/0008-5472.CAN-04-3885 PubMedGoogle Scholar
    43.
    Wu  AH, Pearce  CL, Tseng  CC, Templeman  C, Pike  MC.  Markers of inflammation and risk of ovarian cancer in Los Angeles County.   Int J Cancer. 2009;124(6):1409-1415. doi:10.1002/ijc.24091 PubMedGoogle Scholar
    44.
    Moorman  PG, Calingaert  B, Palmieri  RT,  et al.  Hormonal risk factors for ovarian cancer in premenopausal and postmenopausal women.   Am J Epidemiol. 2008;167(9):1059-1069. doi:10.1093/aje/kwn006 PubMedGoogle Scholar
    45.
    Booth  M, Beral  V, Smith  P.  Risk factors for ovarian cancer: a case-control study.   Br J Cancer. 1989;60(4):592-598. doi:10.1038/bjc.1989.320 PubMedGoogle Scholar
    46.
    Jordan  SJ, Cushing-Haugen  KL, Wicklund  KG, Doherty  JA, Rossing  MA.  Breast-feeding and risk of epithelial ovarian cancer.   Cancer Causes Control. 2012;23(6):919-927. doi:10.1007/s10552-012-9963-4 PubMedGoogle Scholar
    47.
    Modugno  F, Ness  RB, Wheeler  JE.  Reproductive risk factors for epithelial ovarian cancer according to histologic type and invasiveness.   Ann Epidemiol. 2001;11(8):568-574. doi:10.1016/S1047-2797(01)00213-7 PubMedGoogle Scholar
    48.
    Chen  Y, Wu  PC, Lang  JH, Ge  WJ, Hartge  P, Brinton  LA.  Risk factors for epithelial ovarian cancer in Beijing, China.   Int J Epidemiol. 1992;21(1):23-29. doi:10.1093/ije/21.1.23 PubMedGoogle Scholar
    49.
    Mills  PK, Riordan  DG, Cress  RD.  Epithelial ovarian cancer risk by invasiveness and cell type in the Central Valley of California.   Gynecol Oncol. 2004;95(1):215-225. doi:10.1016/j.ygyno.2004.07.012 PubMedGoogle Scholar
    50.
    Ness  RB, Grisso  JA, Klapper  J,  et al; SHARE Study Group.  Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives.   Am J Epidemiol. 2000;152(3):233-241. doi:10.1093/aje/152.3.233 PubMedGoogle Scholar
    51.
    Riman  T, Dickman  PW, Nilsson  S,  et al.  Risk factors for epithelial borderline ovarian tumors: results of a Swedish case-control study.   Gynecol Oncol. 2001;83(3):575-585. doi:10.1006/gyno.2001.6451 PubMedGoogle Scholar
    52.
    Risch  HA, Weiss  NS, Lyon  JL, Daling  JR, Liff  JM.  Events of reproductive life and the incidence of epithelial ovarian cancer.   Am J Epidemiol. 1983;117(2):128-139. doi:10.1093/oxfordjournals.aje.a113523 PubMedGoogle Scholar
    53.
    Rosenblatt  KA, Thomas  DB; The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.  Lactation and the risk of epithelial ovarian cancer.   Int J Epidemiol. 1993;22(2):192-197. doi:10.1093/ije/22.2.192 PubMedGoogle Scholar
    54.
    Yen  ML, Yen  BL, Bai  CH, Lin  RS.  Risk factors for ovarian cancer in Taiwan: a case-control study in a low-incidence population.   Gynecol Oncol. 2003;89(2):318-324. doi:10.1016/S0090-8258(03)00088-X PubMedGoogle Scholar
    55.
    Zhang  M, Xie  X, Lee  AH, Binns  CW.  Prolonged lactation reduces ovarian cancer risk in Chinese women.   Eur J Cancer Prev. 2004;13(6):499-502. doi:10.1097/00008469-200412000-00006PubMedGoogle Scholar
    56.
    Perez  A, Vela  P, Masnick  GS, Potter  RG.  First ovulation after childbirth: the effect of breast-feeding.   Am J Obstet Gynecol. 1972;114(8):1041-1047. doi:10.1016/0002-9378(72)90866-6 PubMedGoogle Scholar
    57.
    Adami  HO, Hsieh  CC, Lambe  M,  et al.  Parity, age at first childbirth, and risk of ovarian cancer.   Lancet. 1994;344(8932):1250-1254. doi:10.1016/S0140-6736(94)90749-8 PubMedGoogle Scholar
    58.
    Whiteman  DC, Siskind  V, Purdie  DM, Green  AC.  Timing of pregnancy and the risk of epithelial ovarian cancer.   Cancer Epidemiol Biomarkers Prev. 2003;12(1):42-46.PubMedGoogle Scholar
    59.
    Wu  AH, Pearce  CL, Lee  AW,  et al.  Timing of births and oral contraceptive use influences ovarian cancer risk.   Int J Cancer. 2017;141(12):2392-2399. doi:10.1002/ijc.30910 PubMedGoogle Scholar
    60.
    Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine.  Ovarian Cancers: Evolving Paradigms in Research and Care. National Academies Press;2016.
    61.
    Groer  MW, El-Badri  N, Djeu  J, Williams  SN, Kane  B, Szekeres  K.  Suppression of natural killer cell cytotoxicity in postpartum women: time course and potential mechanisms.   Biol Res Nurs. 2014;16(3):320-326. doi:10.1177/1099800413498927 PubMedGoogle Scholar
    62.
    Stuebe  AM, Rich-Edwards  JW.  The reset hypothesis: lactation and maternal metabolism.   Am J Perinatol. 2009;26(1):81-88. doi:10.1055/s-0028-1103034 PubMedGoogle Scholar
    63.
    Zhang  D, Li  N, Xi  Y, Zhao  Y, Wang  T.  Diabetes mellitus and risk of ovarian cancer: a systematic review and meta-analysis of 15 cohort studies.   Diabetes Res Clin Pract. 2017;130:43-52. doi:10.1016/j.diabres.2017.04.005 PubMedGoogle Scholar
    64.
    World Health Organization. Maternal, newborn, child and adolescent health. Accessed February 27, 2020. https://www.who.int/maternal_child_adolescent/topics/child/nutrition/breastfeeding/en/
    ×