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Study Title and Description

Maternal caffeine consumption and risk of congenital limb deficiencies.



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 congenital limb deficiencies.
Author L Chen,EM Bell,ML Browne,CM Druschel,PA Romitti,RJ Schmidt,TL Burns,R Moslehi,RS Olney, ,
Country
Year 2012
Numbers

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


Extraction Form: Reproductive Toxicity - Design Details
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 22903936
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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)? This study attempts to address these limitations by measuring maternal caffeine intake from caffeinated coffee, tea, soda, and chocolate and by exploring the effect of caffeine exposure on the etiologically different subtypes of LDs using the National Birth Defects Prevention Study (NBDPS) data. Analyses previously conducted using NBPDS data examined associations between maternal dietary caffeine consumption and congenital heart defects (Browne et al., 2007), orofacial defects (Collier et al., 2009), NTDs (Schmidt et al., 2009), anorectal atresia (Miller et al., 2009), and bilateral renal agenesis or hypoplasia (Slickers et al., 2008), as well as other birth defect groups (Browne et al., 2011). The accumulated number of cases from NBDPS is now sufficient to examine subtypes of LDs. Potential effect modification by maternal smoking, alcohol consumption, and use of vasoconstrictive medication was also evaluated
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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) This case-control study assessed associations between maternal dietary caffeine and congenital LDs using data from the National Birth Defects Prevention Study (NBDPS), with 844 LD cases and 8069 controls from 1997 to 2007. The study included LD cases with and without an additional major nonlimb anomaly. Controls were live born infants without birth defects randomly selected from birth certificates from the same time period and geographic region as case infants. Interviews were completed between 6 weeks and 24 months after EDD of the LD case or control infant. Caffeine intakes from beverages (coffee, tea, and soda) and chocolate combined and by beverage type were examined – for the year before pregnancy. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for subtypes of isolated LDs (no additional major anomalies) and LDs with other major anomalies separately.
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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) Congenital limb deficiencies (all, longitudinal, longitudinal preaxial, transverse)
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes Eligible LDs were (1) absent or partially absent bony elements of the extremities, diagnosed by radiography or reliable physical examination or (2) diagnoses of split hand/split foot if there was a ‘‘deep cleft’’ in the hand or foot. Ineligible LD diagnoses were: (1) generalized limb shortening without confirmation or absent bones; (2) brachydactyly types A–E; (3) known or strongly suspected single gene conditions or chromosome abnormalities; (4) unconfirmed LD diagnoses; (5) deficiencies related to twinning such as acephalus-acardia; (6) sirenomelia; and (7) limb-body wall and amniotic band phenotypes.
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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 Cases are identified by the existing birth defect surveillance system of each participating site and must have been diagnosed with at least one major, eligible birth defect within the first year of life, as described elsewhere.
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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
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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 mg/day: 0-<10, 10-<100, 100-<200, 200-<300, >/=300
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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) Maternal characteristics examined were: age at conception (<20 years, 20–34 years, or _x0002_35 years), race/ethnicity (non- Hispanic white, non-Hispanic black, Hispanic, or other), education (_x0003_12 years or >12 years), body mass index (<18.5, 18.5–<25, or _x0002_25), parity (0 or _x0002_1 live births), initiation of prenatal care (first trimester, second trimester, or third trimester), gestational diabetes (yes or no), nausea or vomiting during the first month of pregnancy (yes or no), fever in the first trimester (yes or no), and study site. Periconceptional exposures examined for the period 1 month before pregnancy through the first trimester included: cigarette smoking (none, environmental smoking exposure only, or active smoking with or without environmental smoking exposure), smoking frequency (none, <1 pack/day, or _x0002_1 pack/day), alcohol consumption (yes or no), alcohol consumption frequency (none, <1 drink/day, or _x0002_1 drink/day), binge drinking (no drinking, drink but not binge drinking, or _x0002_4 drinks/ occasion), oral contraception use (yes or no), use of vasoconstrictive medicine including decongestants, ergot antimigraine medications, amphetamines, and cocaine (yes or no), and use of folic acid-containing supplements during 1 month before pregnancy through the first month of gestation was also considered (yes or no). Illicit drug use was not analyzed separately because <1% of study participants reported any maternal use during 1 month before pregnancy through the first trimester.
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Provide a general description of results (as reported by the authors). Increased odds for all isolated LDs combined and for isolated transverse LDs were observed for all total dietary caffeine intake categories compared to the referent Increased odds for all isolated LDs combined and for isolated transverse LDs were observed for all total dietary caffeine intake categories compared to the referent category. ORs were weakly to moderately elevated for all total daily dietary caffeine categories and isolated longitudinal LDs. Odds of isolated preaxial LDs were not associated with any caffeine consumption category compared to the no to low consumption category. No pattern of dose response was observed for any isolated LD subtype. Coffee and tea consumptions were not associated with increased odds of any isolated LD subtype. Tea consumption at 1 cup/month to 6 cups/week and 1 to 2 cups/day were inversely related to the odds of isolated longitudinal LDs (adjusted odds ratios [ORs], 0.6). Soda consumption was moderately associated with all isolated LDs (aORs, 1.2–1.4). The OR was marginally statistically significantly elevated for the association between isolated longitudinal LDs (aOR, 1.6; 95% CI, 1.0–2.5) and three or more servings of soda per day.
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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? We did not observe a pattern of dose response for total dietary caffeine intake for any LD type.
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What were the author's conclusions? In conclusion, the current study explored the effect of maternal dietary caffeine on the risk of congenital limb deficiencies overall, as well as in subtypes including longitudinal, preaxial longitudinal, and transverse limb deficiencies. We observed a moderate increase in the risk for limb deficiencies overall and for transverse LDs with maternal dietary caffeine consumption. Maternal soda consumption of one to two servings per day was associated with an elevated risk of MCA preaxial longitudinal LDs, and soda consumption of three or more servings per day was associated with elevated risk of isolated longitudinal LDs. No dose-response pattern was observed and no risk increase was observed for maternal coffee or tea consumption. Risk of isolated LDs overall, isolated transverse LD subtype, and MCA LDs overall associated with caffeine consumption above the lowest intake level among active tobacco smokers did not differ from that among nonsmokers. Future studies might improve exposure assessment by collecting more detailed information on change in consumption in early pregnancy, more accurately measuring caffeine contents in beverages, and measuring energy drink intake in addition to intake of soda and other soft drinks. Genetic epidemiologic studies including gene-caffeine and gene-gene interaction in the CYP1A2 and NAT2 genes would be of interest to further explore any relationship between caffeine and LDs.
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What were the sources of funding? This study was supported by a cooperative agreement from the Centers for Disease Control and Prevention, Centers of Excellence Award No. U01/ DD00048702.
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What conflicts of interest were reported? None reported
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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.  Isolated LDs All: LOAEL = 10-<100 mg/day Longitudinal: NOAEL = >/=300 mg/day Longitudinal preaxial: NOAEL = >/=300 mg/day Transverse: LOAEL = 10-<100 mg/day Multiple congenital anomaly with LDs All subgroups NOAEL = >/=300 mg/day
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. Isolated LDs: ORs for each dose vs. 0-<10 mg/day All: 1.5 (1.2-2.0), 1.7 (1.3-2.3), 1.5 (1.1-2.1), 1.4 (1.0-2.0) Longitudinal: all CIs crossed unity Longitudinal preaxial: all CIs crossed unity Transverse: 1.5 (1.1-2.1), 1.8 (1.3-2.5), 1.5 (1.0-2.2), 1.3 (0.9-2.0) Multiple congenital anomaly with LDs – all or specific, no significant ORs at any intake level For isolated LDs, all or transverse, the LOAEL was determined to be the lowest significant effect level. However, the response was similar across all dose groups and no dose-response was observed. The study used the estimate from Bracken (Bracken et al., 2002) of 100 mg caffeine for a cup of coffee and 37 mg caffeine for each cup of tea. Brand-specific caffeine contents for soda were based on the caffeine content per 12 ounce serving obtained from soda manufacturers (Schmidt, 2007; Schmidt et al., 2009). An average value of 37 mg was assigned to caffeinated soda for which caffeine was an ingredient but the amount could not be determined, based on a review of manufacturers provided information (Schmidt, 2007). A weighted average of 10 mg per ounce was used for chocolate (National Confectioners Association, 2009).
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What is the importance of the study with respect to the adverseness of the outcome? Critcal
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