Associations between hormonal contraception and adverse health outcomes not supported by high-quality evidence

1. Among 156 associations described in 58 meta-analyses of randomized clinical trials and cohort studies reviewed by this study, none of the associations between hormonal contraception and adverse health outcomes were supported by high-quality evidence.

2. The association between the use of a levonorgestrel releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use was graded as having high-quality evidence.

Evidence Rating Level: 1 (Excellent)

Study Rundown: When prescribed and used appropriately, hormonal contraceptive agents are safe and effective forms of contraception. However, contradictory findings have been reported from several meta-analyses on the associations between hormonal contraceptive use and adverse health outcomes, without examination in aggregate. This umbrella review systematically identified relevant meta-analyses of randomized clinical trials (RCTs) and cohort studies of hormonal contraceptive agents, summarized the findings, and graded the evidence to provide a comprehensive understanding of the associations between hormonal contraception and adverse health outcomes. Among 58 meta-analyses of RCTs and cohort studies, 156 associations were described and examined between hormonal contraception and adverse health outcomes. None of the associations with adverse outcomes, including cardiovascular and cancer risk, were supported by high-quality evidence. Of note, the association between the use of a levonorgestrel releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use was graded as having high-quality evidence. These findings confirmed preexisting understandings of the risks and benefits associated with hormonal contraceptive agents. A limitation of this study was that only adverse outcomes included in the selected meta-analyses and subsequent RCTs and cohort studies were cross-examined, precluding the study from other potential adverse outcomes and a complete evaluation of safety aspects of hormonal contraceptive agents.

Click to read the study in JAMA Network Open

Relevant Reading: Risks and mechanisms of cardiovascular events in users of oral contraceptives

In-Depth [systematic review and meta-analysis]: This umbrella review of 58 studies included 13 meta-analyses of RCTs and 45 meta-analyses of cohort studies from MEDLINE, Embase, and the Cochrane Database of Systematic Reviews, searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis. The Assessment of Multiple Systematic Reviews and Grading of Recommendation, Assessment, Development and Evaluations were used to assess the quality of the methodology and evidence presented in each of the selected meta-analyses. In total, 60 associations (14 statistically significant; P ≤.05) were described in meta-analyses of RCTs and 96 associations (40 statistically significant; P ≤.05) from meta-analyses of cohort studies. Among meta-analyses of RCTs, no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. During primary analysis, the association between use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (OR, 0.22; 95%CI, 0.13-0.38) was graded as high-quality evidence and subsequently retained in the subgroup analysis. Among meta-analyses of cohort studies, no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence.

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