Relationship between caffeine intake and infertility: a systematic review of controlled clinical studies.

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Background: For a long time, the relationship between caffeine consumption and infertility in the general population is unclear, this study is aimed to systematically review the evidence from any type of controlled clinical studies to explore whether caffeine intake is a risk factor for human infertility.Methods: Seven databases were searched from inception to May 2019. We included women/men without a history of infertility but were willing to have children in prospective studies and women/men who were diagnosed with infertility in retrospective studies. The observed exposure factor should be caffeine or caffeine containing beverage. Diagnosis of infertility or not for participants was the key outcome. The Newcastle-Ottawa scale (NOS) or Cochrane risk of bias tool were used to assess the methodological quality of included studies. Meta-analysis was conducted if there were acceptable clinical and statistical heterogeneity among studies. The GRADE method was used to assess the certainty of the evidence.Results: Four studies (one cohort study and three case-control studies) involving 12,912 participants were included. According NOS, the average score of case-control studies was 6, and the cohort study achieved 9. Meta-analysis and subgroup analysis were conducted. The results showed that low (OR 0.95, 95%CI 0.78-1.16), medium (OR 1.14, 95%CI 0.69-1.86) and high doses (OR 1.86, 95%CI 0.28-12.22) of caffeine intake may not increase the risk of infertility. The quality of the current evidence bodies were all low.Conclusion: Our study provides low quality evidence that regardless of low, medium and high doses of caffeine intake do not appear increase the risk of infertility. But the conclusion should be treated with caution.