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Study Title and Description

Maternal caffeine intake during pregnancy and orofacial clefts.



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 orofacial clefts.
Author SA Collier,ML Browne,SA Rasmussen,MA Honein, ,
Country
Year 2009
Numbers

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


Extraction Form: Reproductive Toxicity - Design Details
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 19591116
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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)? The National Birth Defects Prevention Study (NBDPS)—an ongoing, population-based case-control study of risk factors for major birth defects, including orofacial clefts— presents an opportunity for a detailed analysis of maternal caffeine intake and the occurrence of orofacial clefts.
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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) The National Birth Defects Prevention Study is a population based, case-control study of major birth defects, excluding infants with single-gene disorders and chromosomal abnormalities. This analysis includes infants with cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), excluding infants whose cleft was secondary to holoprosencephaly or amniotic band sequence. In addition to the routine case review by clinical geneticists at each site, clinical information on all infants with a diagnosis of an orofacial cleft underwent a second review by a clinical geneticist. Control-infants are live-born infants without major birth defects randomly selected from birth certificate files or hospital delivery logs and from the same geographical areas as the case infants. Trained NBDPS interviewers conduct standardized telephone interviews with case and control mothers between 6 weeks and 24 months after the estimated date of their delivery. Mothers reported dietary caffeine intake from coffee, tea, sodas, and chocolate in the year before pregnancy and reported intake of medications containing caffeine during pregnancy. An estimate of total dietary caffeine intake per day was calculated using responses to questions about usual consumption of caffeinated coffee, tea, soda or soft drinks, and chocolate during the year before pregnancy. The portion size was specified as cups for coffee and tea; cans, glasses, or bottles for soda; and 1 ounce for chocolate. Sixteen response categories were provided, ranging from ‘‘never or less than once per month’’ to ‘‘six or more servings per day.’’ An estimate of total dietary caffeine intake per day was calculated using responses to these questions. Estimated average caffeine values for coffee, tea, soda, and chocolate intake were used to produce an index representing daily total caffeine exposure from beverages and chocolate. Caffeine intake from medications was also examined. Our initial full logistic regression model included: maternal age, maternal race or ethnicity (non-Hispanic white, other), maternal education (</=12 years, >12 years), periconceptional maternal smoking (any smoking from 1 month before pregnancy through the end of the first trimester, no smoking), periconceptional maternal alcohol consumption (any alcohol use from 1 month before pregnancy through the end of the first trimester, no use), periconceptional maternal binge drinking (more than four drinks on one occasion from 1 month before pregnancy through the end of the first trimester, no use), periconceptional maternal folic acid consumption (any use in the month before pregnancy or the first month of pregnancy, no use), maternal body mass index before pregnancy (calculated as weight in kilograms divided by height in meters squared), gravidity at time of conception (primigravid, multigravid), parity at time of conception (nulliparous, parous), plurality (singleton, twins, or higher order multiples), the infant’s family history of a parent or sibling with a cleft (yes, no), and gestational diabetes diagnosed during the index pregnancy (yes, no). We removed one variable at a time from the model and replaced it if its removal caused effect estimates (odds ratios [ORs]) to change by >10%.
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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) orofacial clefts - cleft lip with or without cleft palate; cleft palate only
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes
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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? Both
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Optional: Name of Method or short description In addition to the routine case review by clinical geneticists at each site, clinical information on all infants with a diagnosis of an orofacial cleft underwent a second review by a clinical geneticist.
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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: <10, 10–99, 100–199, 200–299, >/=300 mg/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) Our initial full logistic regression model included: maternal age, maternal race or ethnicity (non-Hispanic white, other), maternal education (</=12 years, >12 years), periconceptional maternal smoking (any smoking from 1 month before pregnancy through the end of the first trimester, no smoking), periconceptional maternal alcohol consumption (any alcohol use from 1 month before pregnancy through the end of the first trimester, no use), periconceptional maternal binge drinking (more than four drinks on one occasion from 1 month before pregnancy through the end of the first trimester, no use), periconceptional maternal folic acid consumption (any use in the month before pregnancy or the first month of pregnancy, no use), maternal body mass index before pregnancy (calculated as weight in kilograms divided by height in meters squared), gravidity at time of conception (primigravid, multigravid), parity at time of conception (nulliparous, parous), plurality (singleton, twins, or higher order multiples), the infant’s family history of a parent or sibling with a cleft (yes, no), and gestational diabetes diagnosed during the index pregnancy (yes, no). We removed one variable at a time from the model and replaced it if its removal caused effect estimates (odds ratios [ORs]) to change by >10%.
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Provide a general description of results (as reported by the authors). While some effect estimates were elevated for moderate levels of caffeine intake (100–199 mg/day), estimates were closer to the null for high levels of caffeine). Mostly null associations were observed for consumption of <3 servings per day of coffee, tea, or soda. For high-level coffee consumption, the only statistically significant result was a protective effect for CPO with multiple defects (aOR: 0.3; 95% CI: 0.1–0.9). High-level tea consumption was associated with CPO with multiple defects (aOR: 2.4; 95% CI: 1.3–4.6). Because of the small number of subjects who consumed caffeine-containing medications, we were able to evaluate only the risk for the isolated case groups. Women who reported taking medication that contained at least 100 mg of caffeine per dose were at increased risk of having an infant with isolated CL/P (aOR: 2.3; 95% CI: 1.3–4.0), but did not have an increased risk of having an infant with isolated CPO (aOR: 0.5; 95% CI: 0.1–2.0).
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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 data do not suggest an association between maternal caffeine intake and CL/P or CPO. Although some effect estimates were elevated for moderate levels of caffeine intake (100–199 mg/day), estimates were closer to the null for high levels of caffeine. Mostly null associations were observed for consumption of fewer than 3 cups per day of coffee, tea, or soda when assessed individually. Use of medications containing at least 100 mg of caffeine per recommended dose periconceptionally was significantly associated with isolated CL/P, but this exposure was reported by 0.7% of control- mothers and less than 2% of mothers of infants with isolated CL/P. Our data do not suggest an association between maternal dietary caffeine intake and orofacial clefts, but caffeine-containing medications merit further study
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What were the sources of funding? This project was supported in part by an appointment to the Research Participation Program for the CDC administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and the CDC.
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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.  orofacial clefts - cleft lip with or without cleft palate; cleft palate only NOAEL = >/=300 mg/day
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. No significant associations found with multiple cases. Borderline significant associations observed for both isolated cleft lip (with or without palate) and cleft palate at the two lower dose levels (10-100 and 100-<200 mg/day); however, the authors only make note of findings at 100-<200 mg/day. The adjusted ORs were 1.2 (95% CI 1.0-.4) and 1.2 (95% CI 1.0-1.6), respectively. No associations observed for higher intakes levels (200-<300 and >/=300 mg/day). Given the borderline significance (CI starting at 1.0) at the lower levels and no significant findings at higher levels, the reviewer concurs with the authors that the data to not suggest an association, and as such, a NOAEL = 10-<100 mg/day is selected.
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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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Results & Comparisons

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