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Study Title and Description

Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses.



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 Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses.
Author LB Signorello,A Nordmark,F Granath,WJ Blot,JK McLaughlin,G Annerén,S Lundgren,A Ekbom,A Rane,S Cnattingius,
Country
Year 2001
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 11755554
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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)? We measured caffeine metabolites in the urine to arrive at an index of CYP1A2 activity (CYP1A2 phenotype) and also identified allelic variants of the NAT2 gene (NAT2 genotype). Both served as surrogate markers of caffeine clearance capacity. Our aim was to investigate whether these metabolic indices were themselves risk factors for normal karyotype spontaneous abortion and also whether they modified the effect of caffeine on abortion risk. Our a priori hypothesis was that slow metabolizers of caffeine (by either the CYP1A2 or NAT2 pathway) have a higher risk of spontaneous abortion and/or exhibit a stronger association between caffeine and spontaneous abortion.
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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) Cases were women identified (1996-1998) presenting at the Uppsala University Hospital in Uppsala, Sweden, with a spontaneous abortion at 6–12 completed weeks’ gestation. Karyotyping revealed 101 fetuses (58 male, 43 female) to be chromosomally normal, and these cases were used for the present analysis. Controls were randomly selected from pregnant women who were between 6–12 completed gestational weeks and were seeking prenatal care in Uppsala county. Controls were frequency matched to the 562 women in the case group by gestational week and area of residence. Specially trained midwives conducted in-person interviews using a structured questionnaire, and 90% of the cases were interviewed within 2 weeks after their spontaneous abortion diagnosis. All cases were interviewed within 7 weeks, whereas all subjects in the control group were interviewed within 6 days after enrolling in the study. Subjects were asked to report specific sources of caffeine intake on a week-by-week basis, starting 4 weeks before their last menstrual period and ending in the last completed gestational week before they were identified. For coffee, tea, and cocoa, respondents were offered five frequency categories (none, one to two cups/day, three to four cups/day, five to six cups/day, and seven or more cups/day) and for coffee and tea, they were offered four cup sizes (1 dL, 1.5 dL, 2 dL, and 3 dL) from which to choose. Weekly soft drink intake was estimated by the women in cL. Urine samples were analyzed by a high performance liquid chromatography method as previously described. Concentrations of the following four caffeine metabolites were measured: 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methyluric acid (1U), 1-methylxanthine (1X), and 1,7-dimethyluric acid (1,7U). Genotyping was performed after extraction of genomic DNA from whole blood according to standard procedures. Women who had two slow acetylator alleles (ie, homozygousmutated NAT2 genes by PCR) were classified as slow acetylators, and those who did not (ie, either heterozygous wild type or homozygous wild type) were classified as fast acetylators. Caffeine intake was estimated using the following conversion factors: 150 mL of coffee: brewed 115 mg, boiled 90 mg, and instant 60 mg; 150 mL of loose tea or tea bag: 39 mg (herbal tea 0 mg); 150 mL of soft (cola) drinks: 15 mg; 150 mL of cocoa: 4 mg; 1 g of chocolate bar: 0.3 mg; and a few drugs included 50–100 mg of caffeine per tablet. Total pregnancy caffeine intake was calculated as the sum of weekly caffeine intake from the time of estimated conception (ie, 2 weeks after the last menstrual period) through the last completed gestational week before enrollment. Mean daily caffeine intake during pregnancy was calculated as: (total pregnancy caffeine intake [mg])/(number of completed gestational weeks x 7 [days]). The CYP1A2 phenotype was determined by using the concentrations of the four measured urinary metabolites of caffeine in the following equation: (AFMU + 1U + 1X)/(1,7U). Low CYP1A2 activity was defined as having a log-transformed CYP1A2 index below the median value among the controls (0.73), and high CYP1A2 activity as being above the median. Unconditional logistic regression models were constructed to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metabolic indices and spontaneous abortion risk and between caffeine and spontaneous abortion risk, while adjusting for potential confounders.
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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) Spontaneous abortion
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes The relationship between caffeine and SA without stratification by metabolism was not evaluated.
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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 Patients presented at hospital with SA, confirmatory pregnancy tests were performed
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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.) Mean daily caffeine intake (mg/day): 0-99, 100-299, >/=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) Adjusted for maternal age, gestational week, smoking, and nausea score
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Provide a general description of results (as reported by the authors). Women with low CYP1A2 activity had a significant 65% reduction in risk (OR 0.35, 95% CI 0.20, 0.63). This association was attenuated (OR 0.78, 95% CI 0.27, 2.29) when we changed the outcome of interest to recurrent spontaneous abortion (data not shown). In contrast, women who were slow acetylators had a nonsignificantly increased risk of spontaneous abortion (OR 1.36, 95% CI 0.84, 2.21). A positive association between slow acetylation and recurrent spontaneous abortion was also observed, but again was not statistically significant (OR 2.51, 95% CI 0.81, 7.76) (data not shown). A dose-related effect of caffeine intake on spontaneous abortion risk was evident among women with CYP1A2 activity above the median, but not below. Caffeine intake over 300 mg/day was associated with a three-fold increase in spontaneous abortion risk among women with high CYP1A2 activity (OR 3.17, 95% CI 1.22, 8.22), but with a nonsignificant deficit in risk among women with low CYP1A2 activity (OR 0.46, 95% CI 0.12, 1.73). Caffeine intake was positively associated with spontaneous abortion among both slow and fast acetylators. A significant effect of caffeine at the level of 100–299 mg/day was found for slow acetylators (OR 2.38, 95% CI 1.04, 5.49), but higher exposure (300 mg/day or more) was associated with a lower and nonsignificant OR (OR 1.65, 95% CI 0.67, 4.06).
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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? A dose-related effect of caffeine intake on spontaneous abortion risk was evident among women with CYP1A2 activity above the median (p=.03), but not below. No significant trend related to acetylator status.
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What were the author's conclusions? The findings indicate that high CYP1A2 activity may increase the risk of spontaneous abortion, independently or by modifying the effect of caffeine. The results regarding NAT2 are less conclusive but suggest that slow acetylators may be at elevated risk of spontaneous abortion. We found that caffeine intake as low as 100–299 mg/ day was associated with a doubled risk for spontaneous abortion among slow acetylators, but among fast acetylators, no association with caffeine was observed below an exposure of 300 mg/day. The higher OR at 100–299 mg/day than at 300 mg/day or more among slow acetylators is likely a chance finding, but given the high prevalence of slow acetylators (ranging from 25% in Asian populations to 70% in white populations13,15,27), the public health importance of any effect at doses below 300 mg/day could be considerable.
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What were the sources of funding? Funding was provided by the International Epidemiology Institute through a grant from the National Soft Drink Association, and by the Swedish Medical Research Council (04496) (AR).
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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.  Adjusted OR for SA and Caffeine Intake Stratified by Indices of Caffeine Metabolism CYP1A2 index below median: NOAEL = 300 mg/day Caffeine (mg/day); OR (95% CI) 0-99; 1.00 (Referent) 100-299; 0.32 (0.08-1.23) >/=300; 0.46 (0.12-1.73) CYP1A2 index above median: LOAEL = 100-299 mg/day Caffeine (mg/day); OR (95% CI) 0-99; 1.00 (Referent) 100-299; 2.42 (1.01-5.80) >/=300; 3.17 (1.22-8.22) Slow acetylators: LOAEL = 100-299 mg/day - note lack of dose response Caffeine (mg/day); OR (95% CI) 0-99; 1.00 (Referent) 100-299; 2.38 (1.04-5.49) >/=300; 1.65 (0.67-4.06) Fast acetylators: NOAEL = >/=300 mg/day Caffeine (mg/day); OR (95% CI) 0-99; 1.00 (Referent) 100-299; 1.07 (0.39-2.95) >/=300; 1.93 (0.67-5.51)
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. affeine intake was estimated using the following conversion factors: 150 mL of coffee: brewed 115 mg, boiled 90 mg, and instant 60 mg; 150 mL of loose tea or tea bag: 39 mg (herbal tea 0 mg); 150 mL of soft (cola) drinks: 15 mg; 150 mL of cocoa: 4 mg; 1 g of chocolate bar: 0.3 mg; and a few drugs included 50–100 mg of caffeine per tablet. The relationship between caffeine and SA without stratification by metabolism was not evaluated.
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What is the importance of the study with respect to the adverseness of the outcome? Critcal
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