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Study Title and Description

Maternal caffeine consumption and risk of cardiovascular malformations.



Key Questions Addressed
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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Primary Publication Information
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TitleData
Title Maternal caffeine consumption and risk of cardiovascular malformations.
Author ML Browne,EM Bell,CM Druschel,LJ Gensburg,AA Mitchell,AE Lin,PA Romitti,A Correa, ,
Country
Year 2007
Numbers

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Reproductive Toxicity - Design Details
Arms
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 17405163
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What outcome is being evaluated in this paper? Reproductive and Development
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What is the objective of the study (as reported by the authors)? Many epidemiologic studies of caffeine exposure and malformations have either grouped etiologically different malformations or have compared broad categories of exposure as ‘‘any versus none.’’ Such groupings of heterogeneous categories can obscure potential associations. In addition, failure to include all major sources of caffeine can result in underestimation of total caffeine intake and further misclassification of caffeine exposure (Brown et al., 2001). In this study, we analyze maternal caffeine consumption and the risk of specific CVM subgroups among subjects in the National Birth Defects Prevention Study (NBDPS) and attempt to address some of these limitations. We hypothesized that any associations between caffeine exposure and risk of CVMs would exist for specific case subgroups and possibly only for exposure to caffeine in combination with other exposures such as smoking, alcohol use, or vasoactive medication use.
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Provide a general description of the methods as reported by the authors. Information should be extracted based on relevance to the SR (i.e., caffeine related methods) Large sample size from the National Birth Defects Prevention Study allowed us to examine caffeine consumption and specific cardiovascular malformation (CVM) case groups. We studied consumption of caffeinated coffee, tea, soda, and chocolate to estimate total caffeine intake and separately examined exposure to each caffeinated beverage. Smoking, alcohol, vasoactive medications, folic acid supplement use, and infant gender were evaluated for effect modification. Maternal interview reports for 4,196 CVM case infants overall and 3,957 control infants were analyzed. Caffeine intake was assessed by telephone interview; the interval between birth (or estimated date of delivery for pregnancies not resulting in a live birth) and interview varies by outcome category, with average intervals ranging from 8 to 12 months among cases and approximately 8 months for controls. Caffeine exposure was estimated at 100 mg for a cup of coffee and 37 mg for a cup of tea. The caffeine contents of various soda types and brands were obtained from websites sponsored by the American Beverage Association (2005) and various soft drink manufacturers. Chocolate was assigned a value of 10 mg per ounce based on a weighted average taking into account milk chocolate versus dark chocolate preference. Exposure to caffeine in medications was evaluated separately from caffeine in beverages and chocolate but determined not to be common and so not further examined. Logistic regression models were constructed to estimate prevalence ORs and 95% CIs for the association between maternal exposure to caffeine and CVMs, while controlling for confounding variables.
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How many outcome-specific endpoints are evaluated? 1
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What is the (or one of the) endpoint(s) evaluated? (Each endpoint listed separately) cardiovascular malformation (CVM) birth defects (including subgroups: conotruncal, septal, left obstructive, right obstructive, and other)
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes
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Clinical Clinical
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Physiological
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Other
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What is the study design? Case-Control
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Randomized or Non-Randomized?
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What were the diagnostics or methods used to measure the outcome? Objective
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Optional: Name of Method or short description ascertained through birth defects surveillance registries in eight states (AR, CA, GA, IA, MA, NJ, NY, and TX)
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Caffeine (general) Caffeine (general)
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Coffee Coffee
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Chocolate Chocolate
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Energy drinks
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Gum
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Medicine/Supplement Medicine/Supplement
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Soda Soda
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Tea Tea
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Measured
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Self-report Self-report
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Children
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Adolescents
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Adults
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Pregnant Women Pregnant Women
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Caffeine: <10, 10- <100, 100-<200, 200- <300, >/=300 mg/day
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What were the listed confounders or modifying factors as stated by the authors? (e.g. multi-variable components of models.  Copy from methods) Variables examined as covariates included the following maternal characteristics: age at delivery, parity, race/ ethnicity, education, prepregnancy BMI (weight in kg/ height in m2), gestational diabetes, nausea or vomiting during month 1 of the index pregnancy, and fever during the first trimester. Also examined were the following maternal exposures during the periconceptional period (defined as 1 month before pregnancy through the third month of pregnancy unless otherwise specified): cigarette smoking; maximum number of alcoholic drinks on one occasion; use of vasoconstrictive drugs including antihypertensives, decongestants, bronchodilators, antiseizure medications, antimigraine medications, and cocaine; use of any vasoactive medications including salicylates and nonsteroidal anti-inflammatory drugs as well as vasoconstrictive agents; and use of a folic acid–containing vitamin supplement (any use during the period 1 month before pregnancy through the first month of pregnancy). Family history of a CVM, infant sex, season of birth, and mother’s state of residence at the time of birth were also considered.
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Provide a general description of results (as reported by the authors). 4,196 cases with a CVM and 3,957 controls in final analyses. Risk estimates for isolated ASD were decreased for high total caffeine intake (OR . 0.65; 95% CI . 0.41–1.05) and for coffee intake (OR . 0.46; 95% CI . 0.28–0.75), with an inverse dose-response trend (p < .001) for coffee intake. No other patterns of association were observed between total caffeine or caffeinated beverage intake and CVMs (tetralogy of Fallot, transposition of the great arteries, hypoplastic left heart syndrome, coarctation of the aorta, atrial septal defect, perimembranous ventricular septal defect, pulmonary valve stenosis). When caffeine consumption was cross-classified by smoking status, small nonsignificant increases in the risk of tetralogy of Fallot, dTGA, and CVM with MCA were observed for low to moderate caffeine intake alone (ORs of 1.3 to 1.5 among nonsmokers) and modest increases in risk were observed for smoking alone but risk estimates for both smoking and caffeine were less than the excess risk for smoking alone. No obvious patterns of association were observed between total caffeine and any of the CVM case subgroups with <150 cases (muscular VSD, aortic valve stenosis, pulmonary atresia, tricuspid atresia, Ebstein’s anomaly, anomalous pulmonary venous return, atrioventricular septal defect, double-outlet right ventricle, heterotaxy, or other complex CVM) based on crude risk estimates (data not shown).
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Did the authors perform a dose-response analysis (or trend/related analysis)? Yes
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What were the authors's observations re: trend analysis? In beverage-specific analyses, which were a secondary (exploratory) aim of this study, an inverse trend was observed between coffee intake and isolated ASDs.
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What were the author's conclusions? In summary, the large sample size and precise case classification of the NBDPS allowed us to evaluate the relationship between maternal caffeine consumption and CVM for specific, well-defined case groups, overall and stratified by selected potential effect modifiers. This level of analytic detail has not been reported in previous studies of this topic. Among the many comparisons conducted, we observed only a modest nonsignificant positive association between moderate (but not high) total caffeine intake and the risk of isolated tetralogy of Fallot and a significant inverse trend between coffee intake and risk of ASDs. We also observed decreased risks for the highest caffeine exposure category and less-than-additive risks for total caffeine and smoking for certain CVM subgroups, which are difficult to interpret. Possible unmeasured confounding related to habits that involve consumption of various caffeinated beverages complicates evaluation of risks due to maternal caffeine exposure, but the available data suggest there is little evidence for an appreciable teratogenic effect of caffeine with regard to CVMs.
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What were the sources of funding? Grant sponsor: Centers for Disease Control and Prevention; Grant number: Centers of Excellence Award No. U50/CCU0223184.Coding of drug information in the NBDPS utilized the Slone Epidemiology Center Drug Dictionary, under license from the Slone Epidemiology Center at Boston University
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What conflicts of interest were reported? This article is a US Government work and, as such, is in the public domain in the United States of America.
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Does the exposure (dose) need to be standardized to the SR? No
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Provide calculations/conversions for the exposure based on the decision tree in the guide (for all endpoints/exposure levels of interest).
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List all the endpoint(s) followed by the dose (mg) which will be used in comparison to Nawrot.  Characterize value as LOAEL/NOAEL, etc. if possible.  cardiovascular malformation (CVM) NOAEL = >/=300 mg/day
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. Although individual defects and subgroups of defects were also analyzed, no significant findings were observed for these or for CVM when analyzed overall - therefore, CVM was selected as a class.
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What is the importance of the study with respect to the adverseness of the outcome? Critcal
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Baseline Characteristics
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