January 13, 2025

Cervical Health Awareness Month

Cervical Cancer and Hormonal Contraceptives A Review of Research

By: Abbygail Munsterteiger, MD

Editor’s NoteThis week, we continue to explore the crucial role of the cervix on fertility and women’s health. While on the FACTS elective, Dr. Abbygail Munsterteiger summarized a systematic review published by Smith et al in Lancet in 2003. [1] The research evaluated the relationship between duration of hormonal contraceptive use and cervical cancer while considering the presence or absence of human papillomavirus (HPV). Although the causal role of HPV in cervical cancer was discovered more than forty years ago, studies into the intricacies of this relationship continue to this day. Learn more about this and the exciting role of fertility awareness-based methods in women’s health in one of our thirteen FACTS CME courses!

Introduction

Cervical cancer is the fourth most common cancer that affects women globally. [2] The majority of cervical cancer is caused by human papillomavirus (HPV), specifically high-risk strains. Other factors may also contribute to an increased risk of cervical cancer. Some studies suggest long-duration use of oral contraceptives increases the risk of cervical cancer in women who test positive for HPV. [3] This review takes into account HPV status and presents results of cervical cancer risk based on both duration of use and time since ceasing use of hormonal contraceptives. [1]

“Some studies suggest long-duration use of oral contraceptives increases the risk of cervical cancer in women who test positive for HPV.”

Methodology

The search identified 28 eligible studies from numerous countries. Published between 1986 and 2002, these studies included 12,531 women with cervical cancer. The search was limited to human studies and peer reviewed articles. Study designs included cohort and case-control studies. All studies had an outcome of invasive cervical cancer, carcinoma in situ, or cervical intraepithelial neoplasia 3 (CIN3), with the exception of one study that also included CIN2. Hormonal contraceptives included oral and injectable treatments. Most studies used the term “oral contraceptive” without defining formulation or dose.

The results from each study were grouped into categories of duration of use of hormonal contraceptives: never, short (<5 years), medium (5-9 years), and long duration (≥10 years). Grouping also included the time since ceasing use: current use, <8 years, and >8 years since discontinuation. For studies that included HPV status, separate analyses were performed for HPV+ and HPV- groups. Analysis was performed using relative risk (RR) and their corresponding 95% confidence intervals (CI).

Results

The first main result was the association between cervical cancer and duration of oral contraceptive use. When the 28 studies were combined, the relative risk of cervical cancer increased with increasing duration of use. The relative risk of cervical cancer associated with short, medium, and long duration of use was 1.1 (CI 1.1-1.2), 1.6 (CI 1.4-1.7), and 2.2 (CI 1.9-2.4), respectively. Three studies presented results on duration of use of injectable contraceptives. Use of injectable contraceptives for more than 5 years showed a relative risk of 1.1 (CI 1.0-1.6). Relative risk was consistently higher in the cohort studies compared to the case-control studies, and there is evidence of statistical heterogeneity between studies.

Separate analyses were performed for HPV+ and HPV- groups. Twelve studies including 3,000 cases recorded HPV status. In HPV+ women, the RR of cervical cancer associated with short, medium, and long duration of use was 0.9 (CI 0.7-1.2), 1.3 (CI 1-1.9), and 2.5 (CI 1.6-3.9), respectively. The RR of HPV- women showed a similar trend but to a lesser degree. Yet, the results for HPV- women are difficult to interpret because if HPV is the cause of the majority of cervical cancers, it is possible the tests were false positives.

The second main result was the association between cervical cancer risk and time since ceasing use of oral contraceptives. Twenty studies included this data which showed RR decreases with increasing time since last use.

Discussion

The results of this systematic review show the relative risk of cervical cancer increases with increasing duration of oral contraceptive use. This study has relevance to women’s health because of the association of a common prescription (hormonal contraceptives) with a potentially life-threatening disease (cervical cancer). Given that cervical cancer is one of the few cancers for which screening is available, this has public health implications in terms of educating all women, especially those who take hormonal contraceptives, on the importance of screening for cervical changes that may lead to or signal cancer.

“The results of this systematic review show the relative risk of cervical cancer increases with increasing duration of oral contraceptive use.”

Strengths of the review include its size (over 12,000 women), publications form a variety of countries, analyzing HPV status, and investigating the association between cervical cancer risk and time since ceasing contraceptives. Limitations include the lack of specification of drug formulation and dose, making it impossible to distinguish between combined and progestin-only formulations. Another limitation is the statistical heterogeneity between studies. The source of variation seemed to be present between the case-control and cohort studies.

A question remains regarding the HPV- statistics and whether HPV infection in general is a confounding variable. Cervical cancer and HPV are so exquisitely linked that more data are needed, especially in HPV- women. Perhaps for women with confirmed cervical cancer but a negative HPV test, multiple HPV tests separated in time would shed light on the HPV- cases, as some may initially be false negative results.

Another question that remains concerns the time since ceasing hormonal contraception and baseline risk of cervical cancer. The review suggests the RR of cervical cancer decreases with increasing time since ceasing hormonal contraceptive use. It would be valuable to study how long after ceasing use the RR of cervical cancer returns to that of a ‘never’ user, if it ever does. Lastly, a systematic review published in 2022 looked at the relationship between hormonal contraception and cervical cancer when HPV was controlled for; the study found inconsistent evidence that oral contraceptive use is associated with increased risk of cervical cancer. [4]  Further studies are needed to continue investigating this complex relationship.

“This study by Smith et al (shows) how a widely used treatment—hormonal birth control—for a handful of women’s health issues continues to show potentially negative outcomes.”

Impact of the FACTS Elective

Throughout the FACTS course, I gained insight on various aspects of women’s health. First, the sheer importance of the ovarian-menstrual cycle, which I am now convinced is truly a fifth vital sign. Second, the benefits of cycle charting for both patient and medical professional to observe patterns and choose targeted interventions to restore a woman’s cycle back to a healthy state. Third, through evidence shown in this study by Smith et al, we learned how a widely used treatment—hormonal birth control—for a handful of women’s health issues continues to show potentially negative outcomes. I am grateful for this course that goes beyond the surface of the female cycle to impart a deeper understanding of the complex female reproductive and endocrine systems. This knowledge will expand what I can offer in patient care and education in my future family medicine practice!

 

Editor’s Note: Follow the links below to learn more about the key role of the cervix and cervical fluid on fertility and women’s health.

References

[1] Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet. 2003;361(9364):1159-1167. doi:10.1016/s0140-6736(03)12949-2

[2] World Health Organization. Cervical cancer. https://www.who.int/news-room/fact-sheets/detail/cervical-cancer. Published 17 Nov 2023. Accessed 28 Nov 2023.

[3] Moreno V, Bosch FX, Muñoz N, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet. 2002;359(9312):1085-1092. doi:10.1016/S0140-6736(02)08150-3

[4]  Anastasiou E, McCarthy KJ, Gollub EL, Ralph L, van de Wijgert JHHM, Jones HE. The relationship between hormonal contraception and cervical dysplasia/cancer controlling for human papillomavirus infection: A systematic review. Contraception. 2022;107:1-9. doi:10.1016/j.contraception.2021.10.018

ABOUT THE AUTHOR

Abbygail Munsterteiger, MD

Abbygail Munsterteiger, MD is a recent graduate of the University of Minnesota Medical School. She completed her undergraduate education at the University of Minnesota, Duluth. Dr. Munsterteiger plans to complete residency in family medicine and is interested in rural medicine and nutrition. She enrolled in the FACTS elective to learn more about fertility awareness-based methods and plans to empower her patients in their health and reproductive decisions by sharing these methods.

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