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Project: Systematic review of the adverse reproductive and developmental effects of caffeine consumption in healthy adults and pregnant women

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Title Systematic review of the adverse reproductive and developmental effects of caffeine consumption in healthy adults and pregnant women
Description 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.
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Methodology Problem formulation was based on providing an update of Nawrot et al. (2003), “Effects of caffeine on human health,” [PMID 12519715]. No comprehensive studies of similar scope have been published in the peer-reviewed literature, and thus the overall objective is to conduct an update to Nawrot et al. that applies the rigor of a systematic review. This review is one of five systematic reviews being conducted simultaneously (other endpoints include acute toxicity and adverse effects on reproduction/development, cardiovascular, and bone and calcium balance outcomes. Exposure and comparators were thus based on levels determined by Nawrot et al., (2003). Searches: The searches were conducted using: PubMed, EMBASE, and the Cochrane Database of Systematic Review. The restrictions will be articles published in English between 2001 and June 8, 2015. EMBASE searches were exclusive of MEDLINE and restricted to selected journals (430 journals were selected based on relevance). The Cochrane library was searched between Jan 2001 and June 2015 for review articles. Search strategies were informed and reviewed by a librarian. Types of studies included: All study types (excluding case studies) characterizing a quantitative exposure to caffeine and an adverse bone and calcium balance endpoint will be included. Both exposure and response must be evaluated at the individual level. Reviews will not be included in the systematic assessment (unless original data, such as a meta analysis, were conducted), but selected reviews will be consulted for context. Include: studies reporting parameters or effects associated with adverse effects within a benefit/therapy study. Exclude: Studies assessing only beneficial or therapeutic endpoints or outcomes following exposure to caffeine. Participants/ population: Populations: healthy adults, healthy pregnant women, healthy adolescents (aged 12-19), healthy children (aged 3-12). Exposure: = 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). Comparator: < 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). *Applies to both adolescents and children. Include: Studies evaluating a healthy population; this will include athletes, military, and pregnant women, unless otherwise noted as unhealthy. Healthy in this context was defined as subjects who were not specifically described as hospitalized, diagnosed with disease, and/or receiving medical treatment for a disease at the time of the study. Include: Studies that evaluate the effects of caffeine exposure in humans. This included studies in which healthy individuals were included as a control group (or similar) as part of a study on unhealthy populations (only information from the healthy individuals would be carried forward). Include: crossover balance studies could with a control period rather than a control group. Exclude: Studies evaluating unhealthy populations with no healthy control arm; this includes asthmatics and smoking populations. Exclude: Studies that describe effects of caffeine exposure in animal species or in vitro studies. Exclude: Case studies with no comparison group. Intervention(s), exposure(s) Exposure to caffeine: = 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). *Applies to both adolescents and children. Include: Studies that provide a quantitative exposure to a caffeine source associated with an adverse effect. Acceptable forms of caffeine are coffee, tea, chocolate, cola-type beverages, energy drinks (e.g. Monster, Red Bull, Rockstar), supplements, medicines, energy shots, caffeinated chewing gum, caffeinated sport gel, and caffeinated sport bars. Include: Studies evaluating the effects of caffeine alone, in one of the aforementioned forms, or in combination with one or more compounds occurring in the approved sources at levels designed to match constituents of valid sources (e.g., caffeine and green tea extract). Exclude: Studies that do not provide a quantitative exposure to an acceptable caffeine source associated with an adverse effect. This includes studies that evaluate only decaffeinated coffee/tea and caffeine placebo exposures (i.e. exposures where participants were expecting caffeine but did not receive the drug), Yerba mate, guarana, damiana and/or contaminants of caffeine or caffeine metabolites. Exclude: Studies that evaluate the effects of caffeine in combination with another pharmacologically active compound in an OTC medicine such as Excedrin (acetaminophen + caffeine) or in a prescribed drug, alcohol, or nicotine. Exclude: Studies less than six months in duration. Six months is the minimum time needed to see bone outcome endpoint effects on most any intervention (this does not include balance studies). Comparator(s)/ control: Comparator: < 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population) *Applies to both adolescents and children Outcome(s): Primary outcomes Adverse bone and calcium balance effects include, effects on bone fracture, bone mineral density, calcium absorption and any other adverse bone and calcium balance effects reported (inclusive investigation). Exclude: Studies assessing hypertension and menopausal symptoms (not considered adverse). Studies addressing rare bone disorders like Paget’s disease, Osteoporosis Imperfecta, etc. Secondary outcomes Pharmacokinetic data that could be used to interpret the primary outcome (e.g., contextual information). Risk of bias (quality) assessment: Risk of bias will be evaluated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal studies (2015). Study reliability will also be characterized using the systematic approach for evaluating and scoring human data proposed by Money et al (2013) [PMID 23579077] Strategy for data synthesis: The body of evidence was evaluated and integrated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review an Evidence Integration (2015). The process will involve generation of evidence tables and a qualitative synthesis of the available data. Evidence analysts will use a weight of evidence approach incorporating concepts such as consistency, dose response, imprecision, indirectness, magnitude of effect, confounding, and risk of bias to determine conclusions regarding levels of caffeine associated with acute adverse effects. Analytical tools, such as forest plots and descriptive statistical parameters, were used to aid in the weight of evidence assessment. Based on the availability of data, considerations were also be made regarding the severity of the outcome as well as the event(s) relative to the progression of the outcome.
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Funding Source The systematic review of the adverse bone and calcium balance effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children is sponsored by the North American Branch of the International Life Sciences Institute (ILSI) Caffeine Working Group. Unrestricted grants from the American Beverage Association (ABA) and the National Coffee Association (NCA) were also received.
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Key Questions

1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on reproductive and developmental outcomes?
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Associated Extraction Forms

Title Created by Key Questions Addressed Form Notes
Reproductive Toxicity - Design Details Ray DeVirgiliis 1

Associated Studies (each link opens a new tab)

Title Author Year
Coffee Consumption During Pregnancy and Birth Weight: Does Smoking Modify the Association? B. H. Bech, M. Frydenberg, T. B. Henriksen, C. Obel and J. Olsen 2015
The associations of maternal caffeine consumption and nausea with spontaneous abortion. W Wen,XO Shu,DR Jacobs,JE Brown, 2001
Maternal caffeine intake and intrauterine growth retardation. LM Grosso,KD Rosenberg,K Belanger,AF Saftlas,B Leaderer,MB Bracken, 2001
Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. LB Signorello,A Nordmark,F Granath,WJ Blot,JK McLaughlin,G Annerén,S Lundgren,A Ekbom,A Rane,S Cnattingius, 2001
Effect of caffeine exposure during pregnancy on birth weight and gestational age. B Clausson,F Granath,A Ekbom,S Lundgren,A Nordmark,LB Signorello,S Cnattingius, 2002
Association of maternal caffeine consumption with decrements in fetal growth. MB Bracken,EW Triche,K Belanger,K Hellenbrand,BP Leaderer, 2003
Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion. V Rasch, 2003
The effect of smoking and caffeine on the fetus and placenta in pregnancy. O Balat,A Balat,MG Ugur,S Pençe, 2003
Maternal characteristics and lifestyle factors and the risk of delivering high birth weight infants. J Ørskou,TB Henriksen,U Kesmodel,NJ Secher, 2003
The effect of caffeine consumption and nausea on the risk of miscarriage. M Giannelli,P Doyle,E Roman,M Pelerin,C Hermon, 2003
High caffeine consumption in the third trimester of pregnancy: gender-specific effects on fetal growth. T Vik,LS Bakketeig,KU Trygg,K Lund-Larsen,G Jacobsen, 2003
Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. F Sata,H Yamada,K Suzuki,Y Saijo,EH Kato,M Morikawa,H Minakami,R Kishi, 2005
Coffee and fetal death: a cohort study with prospective data. BH Bech,EA Nohr,M Vaeth,TB Henriksen,J Olsen, 2005
Effect of coffee intake on blood flow and maternal stress during the third trimester of pregnancy. H Tsubouchi,K Shimoya,S Hayashi,M Toda,K Morimoto,Y Murata, 2006
Alcohol, caffeine and smoking in relation to age at menopause. A Kinney,J Kline,B Levin, 2006
Semen analysis in fertile patients undergoing vasectomy: reference values and variations according to age, length of sexual abstinence, seasonality, smoking habits and caffeine intake. BP Sobreiro,AM Lucon,FF Pasqualotto,J Hallak,KS Athayde,S Arap, 2005
Maternal caffeine consumption and fetal death: a case-control study in Uruguay. A Matijasevich,FC Barros,IS Santos,A Yemini, 2006
Risks of repeated miscarriage. L George,F Granath,AL Johansson,B Olander,S Cnattingius, 2006
Stillbirth and slow metabolizers of caffeine: comparison by genotypes. BH Bech,H Autrup,EA Nohr,TB Henriksen,J Olsen, 2006
Association of cytochrome P450 1B1 polymorphism with first-trimester miscarriage. AH Karypidis,T Söderström,A Nordmark,F Granath,S Cnattingius,A Rane, 2006
The effects of male age on sperm DNA damage in healthy non-smokers. TE Schmid,B Eskenazi,A Baumgartner,F Marchetti,S Young,R Weldon,D Anderson,AJ Wyrobek, 2007
Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial. BH Bech,C Obel,TB Henriksen,J Olsen, 2007
Risk factors for first trimester miscarriage--results from a UK-population-based case-control study. N Maconochie,P Doyle,S Prior,R Simmons, 2007
Maternal caffeine consumption and risk of cardiovascular malformations. ML Browne,EM Bell,CM Druschel,LJ Gensburg,AA Mitchell,AE Lin,PA Romitti,A Correa, , 2007
Maternal alcohol and coffee drinking, parental smoking and childhood leukaemia: a French population-based case-control study. F Menegaux,M Ripert,D Hémon,J Clavel, 2007
Caffeine intake and small-for-gestational-age birth: modifying effects of xenobiotic-metabolising genes and smoking. C Infante-Rivard, 2007
Maternal smoking, alcohol consumption, and caffeine consumption during pregnancy in relation to a son's risk of persistent cryptorchidism: a prospective study in the Child Health and Development Studies cohort, 1959-1967. ML Mongraw-Chaffin,BA Cohn,RD Cohen,RE Christianson, 2008
Caffeine and miscarriage risk. DA Savitz,RL Chan,AH Herring,PP Howards,KE Hartmann, 2008
Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. X Weng,R Odouli,DK Li, 2008
Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy and childhood malignant central nervous system tumours: the ESCALE study (SFCE). M Plichart,F Menegaux,B Lacour,O Hartmann,D Frappaz,F Doz,AI Bertozzi,AS Defaschelles,A Pierre-Kahn,C Icher,P Chastagner,D Plantaz,X Rialland,D Hémon,J Clavel, 2008
Coffee consumption during pregnancy and the risk of hyperkinetic disorder and ADHD: a prospective cohort study. KM Linnet,K Wisborg,NJ Secher,PH Thomsen,C Obel,S Dalsgaard,TB Henriksen, 2009
Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. , 2008
Maternal exposure to tobacco smoke, alcohol and caffeine, and risk of anorectal atresia: National Birth Defects Prevention Study 1997-2003. EA Miller,SE Manning,SA Rasmussen,J Reefhuis,MA Honein, , 2009
Caffeinated and alcoholic beverage intake in relation to ovulatory disorder infertility. JE Chavarro,JW Rich-Edwards,BA Rosner,WC Willett, 2009
Maternal consumption of coffee and caffeine-containing beverages and oral clefts: a population-based case-control study in Norway. AM Johansen,AJ Wilcox,RT Lie,LF Andersen,CA Drevon, 2009
Maternal caffeine intake during pregnancy and orofacial clefts. SA Collier,ML Browne,SA Rasmussen,MA Honein, , 2009
Maternal caffeine consumption and risk of neural tube defects. RJ Schmidt,PA Romitti,TL Burns,ML Browne,CM Druschel,RS Olney, , 2009
Risk factors for unexplained recurrent spontaneous abortion in a population from southern China. BY Zhang,YS Wei,JM Niu,Y Li,ZL Miao,ZN Wang, 2010
Caffeine intake during pregnancy, late miscarriage and stillbirth. DC Greenwood,N Alwan,S Boylan,JE Cade,J Charvill,KC Chipps,MS Cooke,VA Dolby,AW Hay,S Kassam,SF Kirk,JC Konje,N Potdar,S Shires,N Simpson,N Taub,JD Thomas,J Walker,KL White,CP Wild, 2010
Caffeine intake and semen quality in a population of 2,554 young Danish men. TK Jensen,SH Swan,NE Skakkebaek,S Rasmussen,N Jørgensen, 2010
Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: the Generation R Study. R Bakker,EA Steegers,A Obradov,H Raat,A Hofman,VW Jaddoe, 2010
Caffeinated chewing gum increases repeated sprint performance and augments increases in testosterone in competitive cyclists. CD Paton,T Lowe,A Irvine, 2010
Caffeine consumption during pregnancy and risk of preterm birth: a meta-analysis. E Maslova,S Bhattacharya,SW Lin,KB Michels, 2010
Maternal caffeine intake, blood pressure, and the risk of hypertensive complications during pregnancy. The Generation R Study. R Bakker,EA Steegers,H Raat,A Hofman,VW Jaddoe, 2011
Maternal periconceptional factors affect the risk of spina bifida-affected pregnancies: an Italian case-control study. P De Marco,E Merello,MG Calevo,S Mascelli,D Pastorino,L Crocetti,P De Biasio,G Piatelli,A Cama,V Capra, 2011
Maternal caffeine intake and risk of selected birth defects in the National Birth Defects Prevention Study. ML Browne,AT Hoyt,ML Feldkamp,SA Rasmussen,EG Marshall,CM Druschel,PA Romitti, 2011
Maternal caffeine consumption and sine causa recurrent miscarriage. EM Stefanidou,L Caramellino,A Patriarca,G Menato, 2011
alcohol, smoking, and caffeine in relation to fecundability, with effect modification by NAT2. KC Taylor,CM Small,CE Dominguez,LE Murray,W Tang,MM Wilson,M Bouzyk,M Marcus, 2011
Caffeinated beverage and soda consumption and time to pregnancy. EE Hatch,LA Wise,EM Mikkelsen,T Christensen,AH Riis,HT Sørensen,KJ Rothman, 2012
Maternal caffeine consumption and infant nighttime waking: prospective cohort study. IS Santos,A Matijasevich,MR Domingues, 2012
Caffeine intake during pregnancy and risk of problem behavior in 5- to 6-year-old children. EM Loomans,L Hofland,O van der Stelt,MF van der Wal,HM Koot,BR Van den Bergh,TG Vrijkotte, 2012
Maternal caffeine consumption and risk of congenital limb deficiencies. L Chen,EM Bell,ML Browne,CM Druschel,PA Romitti,RJ Schmidt,TL Burns,R Moslehi,RS Olney, , 2012
Childhood acute leukemia, maternal beverage intake during pregnancy, and metabolic polymorphisms. A Bonaventure,J Rudant,S Goujon-Bellec,L Orsi,G Leverger,A Baruchel,Y Bertrand,B Nelken,M Pasquet,G Michel,N Sirvent,P Bordigoni,S Ducassou,X Rialland,D Zelenika,D Hémon,J Clavel, 2013
Maternal caffeine intake during pregnancy is associated with birth weight but not with gestational length: results from a large prospective observational cohort study. V Sengpiel,E Elind,J Bacelis,S Nilsson,J Grove,R Myhre,M Haugen,HM Meltzer,J Alexander,B Jacobsson,AL Brantsaeter, 2013
Risk of spina bifida and maternal cigarette, alcohol, and coffee use during the first month of pregnancy. CM Benedum,MM Yazdy,AA Mitchell,MM Werler, 2013
Maternal caffeine consumption and small for gestational age births: results from a population-based case-control study. AT Hoyt,M Browne,S Richardson,P Romitti,C Druschel, , 2014
Descriptive and risk factor analysis for choanal atresia: The National Birth Defects Prevention Study, 1997-2007. V Kancherla,PA Romitti,L Sun,JC Carey,TL Burns,AM Siega-Riz,CM Druschel,AE Lin,RS Olney, , 2014
Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis. LW Chen,Y Wu,N Neelakantan,MF Chong,A Pan,RM van Dam, 2014

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