Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children. (November 2017)

• Record Type: Journal Article
• Authors: Wikoff, Daniele; Welsh, Brian T.; Henderson, Rayetta; Brorby, Gregory P.; Britt, Janice; Myers, Esther; Goldberger, Jeffrey; Lieberman, Harris R.; O'Brien, Charles; Peck, Jennifer; Tenenbein, Milton; Weaver, Connie; Harvey, Seneca; Urban, Jonathan; Doepker, Candace
• Is Part Of: Food and chemical toxicology. Volume 109:Part 1(2017)
• Page Start: 585
• Page End: 648
• Publication Date: 2017-11
• Subjects: Caffeine -- Systematic review -- Safety -- Pregnancy -- Coffee -- Behavior; ADHD attention deficit hyperactivity disorder -- AHRQ Agency for Healthcare Research and Quality -- BMC bone mineral content -- BMD bone mineral density -- BMI body mass index -- CDC US Centers for Disease Control and Prevention -- CDH chronic daily headache -- CI confidence interval -- CNS central nervous system -- COI conflict of interest -- COMT catechol-O-methyl transferase -- CVD cardiovascular disease -- CVM cardiovascular malformation -- DGAC US Dietary Guidelines Advisory Committee -- DSM Diagnostic and Statistical Manual of Mental Disorders -- ED emergency department -- ESCALE Epidemiological Study on Childhood Cancer and Leukemia -- FDA US Food and Drug Administration -- HDL high-density lipoprotein -- HF high frequency -- ICD International Classification of Diseases -- ILSI North America North American Branch of the International Life Sciences Institute -- IOM Institute of Medicine -- IUGR intrauterine growth restriction -- LD limb defect -- LDL low-density lipoprotein -- LF low frequency -- LOEL lowest observed effect level -- NOEL no observed effect level -- NTD neural tube defect -- OHAT National Toxicology Program's Office of Health Assessment and Translation -- OR odds ratio -- OTC over-the-counter -- PD pharmacodynamics -- PECO population, exposure, comparator, and outcome -- PK pharmacokinetics -- POMS Profile of Mood States -- RCT randomized controlled trial -- RR relative risk -- SAB scientific advisory board -- SDNN standard deviation of NN intervals -- SGA small for gestational age -- SR systematic review -- SRDR AHRQ Systematic Review Database Repository -- VAS visual analogue scale; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2017.04.002
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10, 000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field. Graphical abstract: Highlights: Conducted systematic review of the potential adverse effects of caffeine consumption in healthy populations. Included evaluation of cardiovascular, behavioral, reproductive & developmental, bone & calcium, and acute effects. Evidence supported consumption of ≤400 mg/day in adults is not associated with overt, adverse effects. Intakes of ≤300 mg/day in pregnant women and ≤2.5 mg/kg-day in children and adolescents remain acceptable. Findings support shift in future research to unhealthy populations, sensitive populations and interindividual variability.