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Study Title and Description

Maternal caffeine intake and risk of selected birth defects in the National Birth Defects Prevention 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 and risk of selected birth defects in the National Birth Defects Prevention Study.
Author ML Browne,AT Hoyt,ML Feldkamp,SA Rasmussen,EG Marshall,CM Druschel,PA Romitti,
Country
Year 2011
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 21254365
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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)? As the NBDPS continues to accrue case and control infants, there are sufficient numbers to examine maternal caffeine exposure and the risks of additional types of birth defects. In this study, we analyzed a number of birth defect types for which there were 200 or more case infants in the NBDPS (excluding those birth defect types already analyzed and published as noted above): anotia/ microtia, esophageal atresia, small intestinal atresia, craniosynostosis, diaphragmatic hernia, omphalocele, and gastroschisis. Few previous studies have examined the influence of maternal caffeine consumption on the risk of any of these specific birth defects; none has evaluated additive interaction with potential effect modifiers. We hypothesized that any causal associations between caffeine exposure and risk of birth defects would exist for certain types of birth defects, given the etiologic and pathogenetic heterogeneity of birth defects, and possibly only for exposure to caffeine in combination with other exposures. We evaluated additive interaction with maternal smoking; use of folic acid-containing vitamin supplements, alcohol, and vasoconstrictive medications; and infant sex. We considered folic acid supplementation because it is known to reduce the risk of neural tube defects (MRC Vitamin Study Research Group, 1991) and may reduce the risk of other birth defects (Goh et al., 2006) and modify the effects of environmental teratogens (Acs et al., 2005). Because the effects of other risk factors for gastroschisis have varied by maternal age (Werler et al., 2009), we also evaluated effect modification by maternal age for caffeine exposure and gastroschisis.
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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 NBDPS is a multi-site population-based case-control study. The present analysis included 3,346 case infants and 6,642 control infants born from October 1997 through December 2005. Clinical geneticists reviewed and classified each case infant as isolated or multiple birth defects (two or more major unrelated defects. Maternal telephone interview reports of demographic characteristics and conditions and exposures before and during pregnancy were collected. The interviews were conducted by trained interviewers between 6 weeks and 24 months after the EDD. Briefly, mothers were asked about their usual intake of coffee, tea, soda, and chocolate during the year before they became pregnant. Frequency categories ranged from none or less than once per month to six or more times per day. Caffeine exposure was estimated at 100 mg for a cup of coffee, 37 mg for a cup of tea (Bracken et al., 2002), 10 mg per ounce of chocolate, and according to the manufacturer or published caffeine contents for soda and other soft drinks by brand and variety. Exposure to caffeine in medications was evaluated separately. Odds ratios and 95% confidence intervals, adjusted for relevant covariates, were calculated to estimate the associations between maternal dietary caffeine intake (coffee, tea, soda, and chocolate) and maternal use of caffeine-containing medications and each defect.
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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) Birth defects - anotia/microtia, esophageal atresia, small intestinal atresia, craniosynostosis, diaphragmatic hernia, omphalocele, and gastroschisis
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes Microtia included dysplastic ear pinna and stenosis or atresia of the external auditory canal. Infants with intestinal atresia limited to the duodenum were not counted as small intestinal atresias for this analysis; only ileal, jejunal, and multiple intestinal atresias or stenoses were included. Infants with esophageal or small intestinal atresia that occurred as a component of VATER or VACTERL association of defects were included in the study and were classified as having multiple defects. To reduce etiologic heterogeneity within case groups, we excluded infants classified as having a complex sequence (a group of defects that are believed to be pathogenetically related, but for which the primary defect is not apparent), for example, infants with a diaphragmatic hernia identified as part of Pentalogy of Cantrell or with a limb-body wall defect.
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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 Clinical geneticists reviewed and classified each case infant as isolated or multiple birth defects (two or more major unrelated defects.
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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-<100, 100-<200, 200- <300 , >/=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) Covariates included the following maternal characteristics: age at delivery (<20, 20–24, 25–29, 30–34, or 351), parity (primiparous, multiparous), race/ethnicity (white non-Hispanic, black non-Hispanic, Hispanic, other), education (less than high school, high school, college), prepregnancy body mass index (weight in kg/height in m2; <18.5, 18.5–<25, 25–<30, or 301), the mother’s state of residence at the time of the infant’s birth, and dichotomous variables for: gestational diabetes, use of fertility medications or procedures, fever during the first trimester, and nausea or vomiting during month one of the index pregnancy. We also considered folic acid-containing vitamin supplement use (any use during one month before pregnancy through month one, any during month two or three, later in pregnancy, or none) and periconceptional exposure to the following: cigarette smoking (yes, no), maximum number of alcoholic drinks on one occasion (none, 1–3, or 41), and use of vasoconstrictive medications (yes, no; including decongestants, ergot antimigraine medications, amphetamines, and cocaine). The influence of family history of a defect of the same organ system and multiple gestation pregnancies were assessed by conducting additional analyses that excluded case and control infants with these characteristics.
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Provide a general description of results (as reported by the authors). Elevated aORs ranging from 1.3 to 1.8 were observed for associations between dietary caffeine consumption and anotia/microtia, small intestinal atresia, craniosynostosis, omphalocele, and gastroschisis. Statistically significant associations were observed between both low (10–<100 mg/day) and moderate (200–<300 mg/day) total caffeine intake and small intestinal atresia and between high (300+ mg/day) dietary caffeine consumption and craniosynostosis. Consistent increases were generally not observed across increasing caffeine categories. Although the aOR for the association between high dietary caffeine intake and gastroschisis was 1.26 (95% CI, 0.90–1.78), in analyses stratified by maternal age, the aORs for high dietary caffeine intake increased as maternal age increased. The aORs increased from 0.99 (0.66–1.48) for age <25 years to 1.93 (95% CI, 0.77–4.87) and 2.90 (95% CI, 0.86–9.79) for 25 to <30 years and 301 years, respectively (data not shown). The analysis of caffeine-containing medications was based on relatively small numbers of exposed case infants. Elevated aORs ranging from 1.6 to 2.6 were observed for periconceptional use of medications with 1001 mg caffeine/dose and anotia/microtia, esophageal atresia, craniosynostosis, diaphragmatic hernia, omphalocele, and gastroschisis. The estimates for anotia/microtia and esophageal atresia were statistically significant (aOR, 2.60; 95% CI, 1.00–6.73 and aOR, 2.33; 95% CI, 1.03–5.28, respectively). When separate analyses of total dietary caffeine were conducted for infants with isolated defects, risk estimates were similar to those for all case infants with only a few exceptions.
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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? No actual analysis but authors state, "No dose-response relation was apparent for any birth defect studied."
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What were the author's conclusions? In summary, we observed relatively small elevations in effect estimates for total dietary caffeine or specific types of caffeinated beverages and anotia/microtia, esophageal atresia, small intestinal atresia, and craniosynostosis; however, dose-response patterns were absent. Periconceptional use of caffeine-containing medications was infrequent and estimates were imprecise. Thus, we did not find convincing evidence of an association between maternal caffeine consumption and the birth defects included in this study. The increasing popularity of caffeine- containing energy drinks and other caffeinated products may result in higher caffeine intake among women of childbearing age. Future studies should consider more detailed evaluation of such products.
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What were the sources of funding? This study was supported by a cooperative agreement from the Centers for Disease Control and Prevention, Centers of Excellence Award No. U01/DD00048702. Coding of drug information in the NBDPS used the Slone Epidemiology Center Drug Dictionary, under license from the Slone Epidemiology Center at Boston University.
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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.  anotia/microtia, esophageal atresia, small intestinal atresia, craniosynostosis, diaphragmatic hernia, omphalocele, or gastroschisis 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 were noted for any caffeine level and anotia/microtia, esophageal atresia, diaphragmatic hermia, omphalocele, or gastroschisis. Statistically significant associations were observed between both low (10–<100 mg/day; OR = 1.54, 95% CI 1.02-2.33) and moderate (200–<300 mg/day; OR = 1.79, 1.09-2.93) total caffeine intake and small intestinal atresia but not at other intake levels. High (300+ mg/day) dietary caffeine consumption and craniosynostosis were significantly associated (OR = 1.34, 1.01-1.77); but no dose response was observed and the authors conclude there was not overall association. No dose response was seen for any birth defects studied.
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What is the importance of the study with respect to the adverseness of the outcome? Critcal
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