Hormonal contraceptives and adverse effects: What’s the evidence?

Nathorn Chaiyakunapruk, PhD, of the department of pharmacotherapy at the College of Pharmacy, University of Utah, Salt Lake City, Utah and of the School of Pharmacy, University of Wisconsin, Madison, Utah and colleagues conducted the umbrella review.

Researchers reported contraceptive use is increasing worldwide, with about 1.1 billion women in need of services.1 Fifty percent of those women use hormonal contraceptives, which include skin patches, intravaginal rings, intramuscular injections, IUDs, implants, and tablets.¹ These methods use either progesterone alone or a combination of estrogen and progesterone and are available in different doses. Are there risks involved for women who choose this family planning method?

Some meta-analyses have found major adverse health effects for women on hormonal contraceptives, including cancer, cardiovascular, gastrointestinal, and metabolic issues, as well as fractures, while others report hormonal contraceptives reduce certain risks.^1-3 Study authors sought to evaluate the quality of evidence in meta-analysis studies to clarify this conflicting information.

Researchers collected cohort studies and randomized clinical trials (RCTs) that looked at adverse health outcomes from hormonal contraceptives in women. The authors used the Cochrane Database of Systematic Reviews, Medline, and Embase, from inception through August 2020. They searched for terms such as meta-analysis and systematic review with terms including “hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel.”¹

After screening 2996 studies, researchers evaluated 310 full-text articles. Of these, 58 were selected for evidence analysis: 45 meta-analyses of cohort studies and 13 of RCTs. The authors used the Assessment of Multiple Systematic Reviews, version 2, to grade studies’ methodologies; results were categorized as high, moderate, low, and critically low.¹ “The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high,” researchers reported.1 Cohort study evidence association quality evaluated criteria as being convincing, highly suggestive, suggestive, weak, and nonsignificant.¹

Researchers found 60 associations between hormonal contraceptive use and adverse outcomes described in meta-analyses of RCTs, and 96 associations described in meta-analyses of cohort studies.¹ They reported that none of the associations were supported by high-quality evidence. Out of the 60 associations described in RCTs, researchers said only 14 were nominally statistically significant, but none of these were supported by strong evidence.¹

“The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis,” study authors reported.¹ Of the 96 associations described in cohort studies, 40 were nominally statistically significant, but none were supported by convincing evidence in the primary or subgroup analyses, researchers said.¹ The risk of venous thromboembolism among those using oral contraceptives was initially supported by highly suggestive evidence. However, this was downgraded to weak in the sensitivity analysis, researchers said.¹

Study authors reported several limitations. First, the quality of the primary studies used in each meta-analysis depended on the assessment reported by the meta-analysis.¹ Next, most reviews focused on estrogen-containing combined oral contraceptives. Researchers said progestin-only methods, such as tablets, depot medroxyprogesterone acetate injections, progesterone implants, and levonorgestrel-releasing intrauterine systems did not have meaningful clinical representation.¹

“The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use,” researchers said. They concluded that meta-analysis studies associating major adverse health outcomes such as cancer and increased cardiovascular events linked to hormonal contraceptives did not have high-quality evidence.¹

References

1. Brabaharan S, Veettil SK, Kaiser JE, et al. Association of hormonal contraceptive use with adverse health outcomes: an umbrella review of meta-analyses of randomized clinical trials and cohort studies. JAMA Netw Open. 2022;5(1):e2143730. Published 2022 Jan 4. doi:10.1001/jamanetworkopen.2021.43730
2. Roe A, Bartz DA, DouglasPS. Combined estrogen-progestin contraception: side effects and health concerns. UpToDate. Updated October 20, 2021. Accessed August 7, 2020. https://www.uptodate.com/contents/combined-estrogen-progestin-contraception-side-effects-and-health-concerns
3. Lopez LM, GrimesDA, GalloMF, StocktonLL, SchulzKF.Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev. 2013;2013(4):CD003552. doi:10.1002/14651858.CD003552.pub4