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Study Title and Description

Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study.



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 intake during pregnancy and risk of fetal growth restriction: a large prospective observational study.
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Year 2008
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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 18981029
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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)? In order to examine the association of maternal caffeine intake on fetal growth, we used a validated, robust caffeine assessment tool to quantify total caffeine intake, from all possible sources, throughout pregnancy. Using these data, and taking into account individual variation in caffeine metabolism, we aimed to establish the safe upper limit of caffeine consumption with respect to adverse pregnancy outcome (specifically fetal growth restriction).
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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) Prospective longitudinal observational study. Quantification of total caffeine intake from 4 weeks before conception and throughout pregnancy was undertaken with a validated caffeine assessment tool. Caffeine intake was estimated with a validated caffeine assessment tool, a questionnaire designed at the University of Leeds, to record habitual caffeine intake before and during pregnancy. Information in the questionnaire included estimates of caffeine content from all potential dietary sources and over the counter drugs and details of potential confounders such as smoking, alcohol intake, and nausea. We recorded specific brand names, portion sizes, methods of preparation, and quantity and frequency of intake for different gestational periods. We also obtained details of caffeine content for each item from published reports, manufacturers, and coffee houses, and, from these, we estimated precise caffeine intakes using an SPSSv14 program developed in-house. Three caffeine assessment tools were administered by the clinical research fellow and research midwives to determine caffeine intake in pregnancy—the first, administered at recruitment by the researcher, included aspects of recall of caffeine intake from four weeks before pregnancy until recruitment into the study at 8-12 weeks of pregnancy; the second covered the period 13-28 weeks; and the third included the period 29-40 weeks of pregnancy. Caffeine half life (proxy for clearance) was determined by measuring caffeine in saliva after a caffeine challenge using HPLC. Participants were provided with appropriate materials and instructions to perform the test at home, and the samples were then returned in a prepaid envelope. The test involved overnight fasting, followed by the challenge (a drink of 500 ml diet cola containing 63.5 mg caffeine ingested over a period of 20 minutes) with no other caffeine consumed during the challenge. Participants then collected saliva samples about one and five hours after the challenge. The primary outcome measure was fetal growth restriction defined as birth weight <10th centile on a customized centile chart which takes into account maternal height, weight, ethnicity, and parity and neonatal birth weight and sex – weight attained from maternity databases. In addition, we assessed the association of maternal caffeine intake with birth weight. Other pregnancy outcomes studied were late miscarriage (spontaneous pregnancy loss between 12 and 24 weeks), preterm delivery (delivery at <37 completed weeks), gestational hypertension (blood pressure ≥140/90 mmHg on more than one occasion 4 hours apart after >20 weeks of pregnancy), proteinuric hypertension (gestational hypertension and proteinuria of ≥300 mg protein in 24 hours, based on the International Society for the Study of Hypertension in Pregnancy), and stillbirth (delivery ≥24 weeks with no signs of life at birth). Statistics set up to give 80% power to detect an odds ratio for fetal growth restriction of 1.4 between high and low caffeine consumers (defined as being above or below the median caffeine intake). We performed unconditional logistic regression modelling for fetal growth restriction and general linear modelling for birth weight. We also assessed the relation between the risk of fetal growth restriction and maternal caffeine intake during pregnancy by considering caffeine intake as a continuous variable. Caffeine half life as assessed by the caffeine challenge test was not normally distributed. We therefore categorized women in relation to the median value as having a shorter half life (faster caffeine clearance from the circulation) or longer half life (slower clearance).
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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) SGA/IUGR; birthweight
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes Fetal growth restriction defined as birth weight <10th centile on a customized centile chart which takes into account maternal height, weight, ethnicity, and parity and neonatal birth weight and sex.
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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? Cohort
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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 Birth weight from maternal database records. Fetal growth restriction defined as birth weight <10th centile on a customized centile chart which takes into account maternal height, weight, ethnicity, and parity and neonatal birth weight and sex.
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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 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, 100-199, 200-299, >/=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) Unadjusted odds ratios take account of maternal age, weight, height, ethnicity, and parity and neonatal gestational age at delivery and sex. Adjusted odds ratios are also adjusted for smoking status (salivary cotinine concentration) and alcohol intake.
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Provide a general description of results (as reported by the authors). The relation between total caffeine intake in pregnancy and fetal growth restriction showed a significant trend with increasing caffeine intake (test for trend P=0.02). Compared with caffeine intake of <100 mg/ day, the odds ratio of having a growth restricted baby increased to 1.2 (95% confidence interval 0.9 to 1.6) for intakes of 100-199 mg/day, to 1.5 (1.1 to 2.1) for intakes of 200-299 mg/day, and to 1.4 (1.0 to 2.0) for intakes of ≥300 mg/day. This relation was consistent across all three trimesters. Caffeine consumption of >200 mg/day during pregnancy was associated with a reduction in birth weight of about 60-70 g, with a significant trend for greater reduction in birth weight with higher caffeine intake (P=0.004). This relation was consistent across all three trimesters. To examine possible threshold effects, we analyzed the relation between the estimated risk of delivering a growth restricted fetus and maternal caffeine intake during pregnancy measured as a continuous variable. At no point did the estimated risk cease to increase with increasing caffeine intake. There was no observed plateau effect. Using maternal caffeine half life as a proxy for clearance rate, we found some evidence that the association between caffeine intake and fetal growth restriction was stronger in women with a faster caffeine clearance than in those with slower clearance (test for interaction, P=0.06).
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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? The relation between total caffeine intake in pregnancy and fetal growth restriction showed a significant trend with increasing caffeine intake (test for trend P=0.02). Caffeine consumption of >200 mg/day during pregnancy was associated with a reduction in birth weight of about 60-70 g, with a significant trend for greater reduction in birth weight with higher caffeine intake (P=0.004).
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What were the author's conclusions? This large prospective cohort study has demonstrated that maternal caffeine intake is associated with an increased risk of fetal growth restriction. The threshold at which this risk is significantly higher is not well characterized, but our data confirm that the association of fetal growth restriction with caffeine is reduced for those consuming <100 mg/day. We suggest that sensible advice for women contemplating pregnancy is to reduce their caffeine intake from all sources before conception. Once pregnancy is confirmed, they should make every effort to stop or markedly reduce caffeine consumption.
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What were the sources of funding? Food Standards Agency, United Kingdom, Grant contract No T01032/33.
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What conflicts of interest were reported? None declared
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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.  SGA/IUGR (fetal growth restriction) LOAEL = 200-299 mg/day caffeine
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. ORs = 1.2 (95% CI 0.9 to 1.6) for 100-199 mg/day 1.5 (1.1 to 2.1) for 200-299 mg/day 1.4 (1.0 to 2.0) for >300mg/day test for trend P=0.02 (Based on adjusted analysis; note, include p value for unadjusted (p<0.001) in the abstract, appears to be a mistake.) Note that only regression analysis was performed for birthweight (no value to compare to PECO), and no data were presented on other outcomes of interest.
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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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