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Study Title and Description

Stillbirth and slow metabolizers of caffeine: comparison by genotypes.



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 Stillbirth and slow metabolizers of caffeine: comparison by genotypes.
Author BH Bech,H Autrup,EA Nohr,TB Henriksen,J Olsen,
Country
Year 2006
Numbers

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


Extraction Form: Reproductive Toxicity - Design Details
Arms
No arms have been defined in this extraction form.

Design Details
Question... Follow Up Answer Follow-up Answer
Refid 16782969
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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)? Our aim was to determine whether genotypes related to caffeine metabolism and oxidative stress were associated with the risk of stillbirth. Second, we wanted to see whether slow caffeine metabolizers had a higher risk of stillbirth, taking the external coffee intake into account.
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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) We conducted a nested case non-case control study within the Danish National Birth Cohort. Information on pregnancy outcomes was obtained from the Civil Registration System and the Danish National Discharge Register. Stillbirth was defined as the delivery of a dead infant at 28 completed weeks of gestation or later; excluded intrapartum deaths. Pregnancy interview at ~16 weeks of gestation. Cases and controls were frequency-matched on parity. Blood samples were missing for 12.3% of cases (n 5 20) and 12.3% of controls (n 5 22). The final study population consisted of 142 cases and 157 controls. Genotyping using PCR methods. Unconditional logistic regression models were constructed to estimate odds ratios (OR) and 95% confidence intervals (95% CIs) for the association between maternal characteristics and genotype, and the risk of stillbirth. We stratified the analysis of genotypes on coffee intake to see whether the association between genotype and stillbirth was modified by coffee intake. The interaction was evaluated by a likelihood ratio test.
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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) Stillbirth
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes tillbirth was defined as the delivery of a dead infant at 28 completed weeks of gestation or later; excluded intrapartum deaths.
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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 Civil Registration System and the Danish National Discharge Register
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Caffeine (general)
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Coffee Coffee
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Chocolate
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Energy drinks
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Gum
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Medicine/Supplement
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Soda
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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.) Coffee: 0, 0.5-3, and >/=4 cups/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) Authors report in text an adjusted OR but do not specify covariates; unadjusted ORs are the only values reported in table
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Provide a general description of results (as reported by the authors). Women with a consumption of four or more cups of coffee per day had no higher risk of stillbirth compared with non-consumers (adjusted OR 5 1.04, 95% CI 0.47–2.30). [REVIEWER NOTE: The adjusted analysis is not presented or discussed elsewhere in the paper beyond this one sentence). Unadjusted analysis gives an OR = 1.12, CI 0.61,2.08. Slow oxidizer status (CYP1A2), slow acetylator status (NAT2), and low activity of GSTA1 were not individually associated with the risk of stillbirth [odds ratio (OR) 5 1.06, 95% confidence interval (95% CI) 0.67–1.67, OR 5 0.95, 95% CI 0.60–1.51, and OR 5 1.42, 95% CI 0.88–2.28, respectively]. We did, however, observe that subjects with a combination of slow CYP1A2, slow NAT2, and low GSTA1 genes had almost a 2-fold risk of stillbirth compared with subjects with other combinations of genotypes.
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Did the authors perform a dose-response analysis (or trend/related analysis)? No
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What were the authors's observations re: trend analysis?
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What were the author's conclusions? We found no association between coffee intake and stillbirth in our data, but this may be due to random variation in selecting controls.
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What were the sources of funding? This work was supported by a grant from the Danish Centre for Environmental Health, Danish Ministry of the Interior and Health. The Danish National Research Foundation established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is, furthermore, a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, and the Agustinus Foundation.
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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? Yes
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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). NOAEL = >/= 4 cups/day 4 cups/day x 95 mg/cup = 380 mg/day
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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.  NOAEL = >/= 380 mg/day
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. Although the authors discuss adjusted analysis in the text but not unadjusted, and present only the unadjusted in the table, the outcome is the same regarding the NOAEL.
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What is the importance of the study with respect to the adverseness of the outcome? Critcal
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