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Study Title and Description

Association of cytochrome P450 1B1 polymorphism with first-trimester miscarriage.



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 Association of cytochrome P450 1B1 polymorphism with first-trimester miscarriage.
Author AH Karypidis,T Söderström,A Nordmark,F Granath,S Cnattingius,A Rane,
Country
Year 2006
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 16978616
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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 have demonstrated that high intake of caffeine is associated with increased risk of first-trimester miscarriage (24). Since in vitro data indicated a role for CYP1B1 in the caffeine metabolism and in vivo and in vitro studies have shown an effect of the CYP1B1 Val432Leu genotype on sex steroid metabolism, we have investigated whether the CYP1B1 Val432Leu polymorphism is related to the risk of miscarriage of human pregnancy in the first trimester. We used large population- based clinical material that was previously studied with respect to environmental risk factors for miscarriage
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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) Main Outcome Measure(s): CYP1B1 Val432Leu genotype frequencies in cases and controls. The population-based case-control study included 507 women with miscarriage in the first trimester of pregnancy and 908 controls with a normal first-trimester pregnancy. The cases were women with miscarriage in the first trimester of pregnancy (6–12 completed weeks of gestation). The controls were frequency matched to cases. Three midwives conducted in-person interviews with the women, using a structured questionnaire. All women were asked to report specific sources of caffeine ingested daily on a week-by-week basis, starting 4 weeks before the last menstrual period and ending in the most recently completed week of gestation. Sources of caffeine included coffee, tea, cocoa, chocolate, soft drinks, and caffeine-containing medications. Women reported consumption of coffee, tea, and cocoa by number of cups per day, and were offered four cup sizes from which to choose (1.0, 1.5, 2.0, and 3.0). Genotypes analyzed by PCR. The material was analyzed taking maternal age, smoking habits, alcohol intake, caffeine intake, fetal karyotype, nausea, and vomiting into consideration. Odds ratios (OR) were used as an approximation of relative risks, using 95% confidence intervals (CI).
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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) SA (miscarriage)
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes Miscarriage in the first trimester of pregnancy (6–12 completed weeks of gestation).
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Clinical Clinical
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Physiological
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Other 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 Not specified. Cases were recruited - assumed to be from medical facilities.
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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 mg/day: <100, 100-299, 300-499, >500
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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 age, daily smoking, alcohol intake, earlier miscarriages, parity, and pregnancy symptoms.
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Provide a general description of results (as reported by the authors). We found a significant interaction between genotype and caffeine intake (P=.04 in test of deviation from multiplicative effect of caffeine intake and genotype). We therefore stratified the analyses of genotype by average intake of caffeine during pregnancy. In crude analyses, caffeine consumption of at least 300 mg/day was, irrespective of genotype, associated with increased risk of spontaneous abortion. In the adjusted analyses, risks related to high caffeine exposure decreased, which mainly was an effect of adjusting for pregnancy symptoms. In the adjusted analyses, the effect of caffeine on risk of spontaneous abortion was strongest among women who were homozygous for Val. In contrast, among heterozygous women (Leu/Val), there was virtually no effect of caffeine on risk of spontaneous abortion
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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? Our findings of an association of CYP1B1 genotype with first-trimester miscarriage may add to the understanding of the biological background of miscarriage. Detecting genotype-environmental interactions is of vital importance because environmental factors can be intervened at the individual level. The interaction observed with caffeine may prove helpful for clinicians when counseling couples affected, since women with the Val/Val genotype probably have more to gain by avoiding caffeine. In summary, CYP1B1 Val432Leu polymorphism is associated with first-trimester miscarriage possibly through the involvement of CYP1B1 in the metabolism of E2 and T. This polymorphism may also modify the risk among coffee drinkers. Since CYP1B1 has numerous substrates, there may be other metabolic pathways that contribute to the increased risk of miscarriage. The Val432Leu polymorphism is rather common, and therefore its role in the mechanisms that lead to first-trimester miscarriage may be clinically significant.
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What were the sources of funding? Supported by grants from the Swedish Foundation for Strategic Research, the Swedish Cancer Society, and the International Epidemiology Institute.
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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.  SA: LOAEL = 500 mg/day for Val/Val
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. No significant effects in Leu/Leu or Leu/Val genotypes
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What is the importance of the study with respect to the adverseness of the outcome? Critcal
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