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Study Title and Description

Caffeine intake during pregnancy, late miscarriage and stillbirth.



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 intake during pregnancy, late miscarriage and stillbirth.
Author DC Greenwood,N Alwan,S Boylan,JE Cade,J Charvill,KC Chipps,MS Cooke,VA Dolby,AW Hay,S Kassam,SF Kirk,JC Konje,N Potdar,S Shires,N Simpson,N Taub,JD Thomas,J Walker,KL White,CP Wild,
Country
Year 2010
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 20306287
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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)? To contribute to understanding the role of caffeine during pregnancy, using improved methodology, we examined the association of maternal caffeine intake with late miscarriage and intrauterine fetal death (stillbirth), using a highly detailed caffeine assessment tool, previously validated against both a food and drink diary and repeated biomarkers of caffeine intake (salivary caffeine and paraxanthine), to prospectively quantify total caffeine intake, from all possible sources, in the first trimester and throughout pregnancy [20]. We aimed to adequately correct for potentially important confounding from alcohol intake and most importantly from smoking using cotinine as a biomarker in a large cohort of pregnant women.
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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) Recruited a cohort of 2,643 pregnant women, aged 18–45 years, attending two UK maternity units. We used a validated tool to assess caffeine intake at different stages of pregnancy and related this to late miscarriage and stillbirth, adjusting for confounders, including salivary cotinine as a biomarker of smoking status. Information regarding antenatal pregnancy complications and delivery details were obtained from the electronic maternity databases. This paper presents outcome measure of late miscarriage (spontaneous pregnancy loss between 12 and 24 weeks) and stillbirth (delivery C 24 weeks with no signs of life at birth). A validated caffeine assessment tool completed during initial hospital registration at 8–12 weeks recorded habitual caffeine intake, repeated again for weeks 13–28, and again for weeks 28–36 weeks or end of pregnancy. The questionnaire covered all potential dietary sources of caffeine, both food and drink, and over the counter medications. Specific brand names, portion sizes, methods of preparation, quantity and frequency of intake were collected for different gestational periods. Precise caffeine intakes were then estimated based on the published caffeine content for each item, and information provided by manufacturers and coffee houses. Numbers were too small to investigate associations with intake in the second and third trimesters. Unconditional logistic regression modelling was used to predict late miscarriage or stillbirth; tests for linear trend over the continuous measure of caffeine exposure were conducted.
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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 + late miscarriage (combined)
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes late miscarriage (spontaneous pregnancy loss between 12 and 24 weeks) and stillbirth (delivery C 24 weeks with no signs of life at birth).
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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 Information regarding antenatal pregnancy complications and delivery details were obtained from the electronic maternity databases.
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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 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) Adjusted odds ratios take account of maternal age, parity, amount smoked (cotinine concentration as a continuous variable, ng/ml) and alcohol intake (categorized as 0,\0.25, 0.25–0.5, 0.5–1 and 1? units/day). Further adjusted for nausea.
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Provide a general description of results (as reported by the authors). A total of 13,071 eligible women were invited to participate and 2,643 (20%) consented. Of the remaining 2,635 pregnancies, 19 resulted in late miscarriage and 9 in stillbirth. There was a strong association between caffeine intake in the first trimester and subsequent late miscarriage between 12 and 24 weeks or stillbirth after 24 weeks adjusting for maternal age, parity, alcohol intake and amount smoked measured by salivary cotinine. Compared to those consuming <100 mg/day, the odds ratio for late miscarriage or stillbirth increased to 2.2 (95% CI: 0.7–7.1) for intakes between 100 and 199 mg/day, to 1.7 (0.4–7.1) for those taking between 200 and 299 mg/day and to 5.1 (1.6–16.4) for those consuming over 300 mg/day (Ptrend = 0.004). There were insufficient events to present these separately for late miscarriage and stillbirth. This relationship appeared strongest in relation to caffeine consumption in the first few weeks of pregnancy, though confidence intervals are wide
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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? P for trend = 0.0004
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What were the author's conclusions? Our study identified only small numbers of late miscarriages and stillbirths, limiting power to detect small associations, and resulting in very wide confidence intervals. Therefore, although reaching statistical significance, there is considerable uncertainty in the size of the association. However, given the careful methodology employed, and the advances over some earlier studies, our findings make a valuable contribution to the literature in this field. Given also the paucity of randomised controlled trials in this area, and the practical and ethical difficulties in conducting them, our study strengthens the observational evidence base on which current guidance is founded.
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What were the sources of funding? This research was funded by the Food Standards Agency (Contract T01032/33).
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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.  Stillbirth + miscarriage (combined) LOAEL = >/=300 mg/day
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. There were insufficient events to present these separately for late miscarriage and stillbirth. Compared to those consuming <100 mg/day, the odds ratio for late miscarriage or stillbirth increased to 2.2 (95% CI: 0.7–7.1) for intakes between 100 and 199 mg/day, to 1.7 (0.4–7.1) for those taking between 200 and 299 mg/day and to 5.1 (1.6–16.4) for those consuming over 300 mg/day (Ptrend = 0.004).
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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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