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Infertility and risk of postmenopausal breast cancer in the women’s health initiative

  • Epidemiology
  • Published:
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Abstract

Purpose

Although infertility (i.e., failure to conceive after ≥ 12 months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women’s Health Initiative (analytic sample = 131,784; > 25 years of follow-up).

Methods

At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy.

Results

We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02–1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2–84.3%).

Conclusion

These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

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Data and material availability

Data is available through the WHI online resource, https://www.whi.org/datasets, while the WHI remains funded and indefinitely through BioLINCC, https://biolincc.nhlbi.nih.gov/studies/whi_ctos/. Eligible researchers may download the data directly at the WHI online resource. Other researchers may download the publicly available data through BioLINCC, in accordance with NHLBI's BioLINCC guidelines.

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Funding

The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Funding for this project was supported by NICHD R03 HD102403 (Farland).

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, 1295 N Martin Ave, Tucson, AZ, 85724, USA

    Leslie V. Farland & Denise J. Roe

  2. Department of Obstetrics and Gynecology, College of Medicine - Tucson, University of Arizona, Tucson, AZ, USA

    Leslie V. Farland

  3. Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA

    Kimberly E. Lind & Cynthia A. Thomson

  4. College of Medicine, Sulaiman Al Rajhi University, Al Bukayriyah, Kingdom of Saudi Arabia

    Nazmus Saquib

  5. Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, CA, USA

    Aladdin H. Shadyab

  6. Departments of Obstetrics and Gynecology and Internal Medicine, Reading Hospital and Drexel University, Reading, PA, USA

    Peter F. Schnatz

  7. Clinical and Translational Sciences, College of Medicine - Tucson, University of Arizona, Tucson, AZ, USA

    Rogelio Robles-Morales

  8. Department of Public Health Sciences, School of Medicine, University of California, Davis, Davis, CA, USA

    Lihong Qi

  9. Department of Epidemiology and Biostatistics, Albert Einstein College of Medicine, Bronx, NY, USA

    Howard Strickler

  10. Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Dorothy S. Lane

  11. Spring Fertility, San Francisco, CA, USA

    Gayathree Murugappan

  12. University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    Denise J. Roe

  13. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Holly R. Harris

  14. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA

    Holly R. Harris

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  1. Leslie V. Farland
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  2. Kimberly E. Lind
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  3. Cynthia A. Thomson
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  5. Aladdin H. Shadyab
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  6. Peter F. Schnatz
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  9. Howard Strickler
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  11. Gayathree Murugappan
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  12. Denise J. Roe
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  13. Holly R. Harris
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Contributions

LF, HH conceived of the idea. KL conducted the statistical analyses and prepared the figures. LF wrote the main manuscript text. All authors critically reviewed the manuscript.

Corresponding author

Correspondence to Leslie V. Farland.

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Conflict of interest

The authors have no conflict of interests to disclose.

Ethical approval consent to participate

This study was reviewed and approved by the IRB of the Fred Hutchinson Cancer Center in accordance with U.S. Department of Health and Human Services regulations at 45 CFR 46 (approval number: 3467-EXT) and this analysis was approved by the University of Arizona IRB (Protocol number: 2011237760). Participants provided written informed consent to participate. Additional consent to review medical records was obtained through signed written consent.

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Farland, L.V., Lind, K.E., Thomson, C.A. et al. Infertility and risk of postmenopausal breast cancer in the women’s health initiative. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07257-2

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