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Association of Hormonal Contraceptive Use With Adverse Health Outcomes

An Umbrella Review of Meta-analyses of Randomized Clinical Trials and Cohort Studies

Sharmila Brabaharan, BPharm1; Sajesh K. Veettil, PhD2; Jennifer E. Kaiser, MD, MSCI3; et al Vrosha Rau Raja Rao, BPharm4; Rujira Wattanayingcharoenchai, MD5; Marikannan Maharajan, PhD6; Putsarat Insin, MD7; Pattarawalai Talungchit, PhD8; Thunyarat Anothaisintawee, PhD9,10; Ammarin Thakkinstian, PhD10; Nathorn Chaiyakunapruk, PhD2,11Author Affiliations Article Information

Key Points

Question What are the quality and certainty of evidence for an association between hormonal contraceptive use and the risk of adverse health outcomes in meta-analyses of randomized clinical trials and cohort studies?

Findings In this umbrella review of 58 meta-analyses of randomized clinical trials and cohort studies describing 156 associations between hormonal contraceptive use and adverse health outcomes among women, no associations with adverse outcomes, including cardiovascular and cancer risk, were supported by high-quality evidence. However, the association between the use of a levonorgestrel-releasing intrauterine system and
reductions in endometrial polyps associated with tamoxifen use was graded as having highquality evidence.

Meaning The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use, suggesting that the associations between hormonal contraceptive use and adverse health outcomes are not supported by high-quality evidence.

Abstract
Importance Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate.

Objective To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women.

Data Sources MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were 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.

Evidence Review The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. 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. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing.

Results A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. 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 evedence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 assocoations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1./&-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis.

Conclusions And Relevance The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence.

Fazit Regen:

Die Studien der Metaanalysen sind sehr inhomogen, unterschiedliche Laufzeit, in der Regel nicht wirklich gute Evidenz.
Es fehlen tatsächlich gute Studien.

Die Thrombosegefahr ist unserer Meinung bei Minipillen (3.+4. Generation) real.