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Study Title and Description

Maternal caffeine consumption and risk of neural tube defects.



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 consumption and risk of neural tube defects.
Author RJ Schmidt,PA Romitti,TL Burns,ML Browne,CM Druschel,RS Olney, ,
Country
Year 2009
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 19711421
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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 date, human studies of the association between maternal caffeine consumption and congenital defects have been inconclusive (Nelson and Forfar, 1971; Fedrick, 1974; Heinonen et al., 1977; Borlee et al., 1978; Lechat et al., 1980; Jacobson et al., 1981; Linn et al., 1982; Rosenberg et al., 1982; Kurppa et al., 1983; Furuhashi et al., 1985; Kline et al., 1991; Olsen et al., 1991; McDonald et al., 1992;). Few of these studies examined NTDs separately from other congenital defects (Fedrick, 1974; Heinonen et al., 1977; Linn et al., 1982; Rosenberg et al., 1982; Kurppa et al., 1983; McDonald et al., 1992), and even fewer examined NTDs by case type (Fedrick, 1974; Furuhashi et al., 1985); grouping etiologically heterogeneous malformations together could have obscured potential associations with caffeine consumption. Folic acid was not considered in previous studies on maternal caffeine consumption because its relation to NTDs was unknown at the time the studies were conducted. The small sample size of many of these studies also limited their power to detect small effects and to stratify analyses. We overcame these limitations by using data from a large collaborative study, the National Birth Defects Prevention Study (NBDPS), to examine whether maternal caffeine consumption was associated with an increased risk of NTDs and whether associations differed by the caffeine source or by type of NTD.
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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) Associations between maternal caffeine consumption and neural tube defects (NTDs) by type of NTD (anencephaly, spina bifida, or encephalocele) were examined using data from the National Birth Defects Prevention Study (NBDPS). Eligible case-infants were live births, stillbirths, or elective terminations. Systematic clinical criteria were used to define NTD diagnoses and to classify cases as isolated (NTD and no other unrelated, major, structural birth defect) or as multiple (NTD and one or more additional unrelated, major, structural birth defects). Clinical geneticists at each site reviewed abstracted medical records before including them in the NBDPS, and each case was independently selected and classified for these analyses by one of two clinical geneticists. Eligible control-infants were a random sample of unaffected, liveborn infants identified from birth certificates or birth hospital records within the same geographical region. Computer-assisted telephone interviews were administered within 24 months of birth/delivery date. Total average daily caffeine from coffee, tea, soda, and chocolate consumption during the year before pregnancy was estimated for 768 mothers of infants with NTDs and 4143 mothers of infants without birth defects. The caffeine content of coffee was based on the average caffeine amount found in a 10-ounce serving and estimated as 100 mg of caffeine per cup, each cup of tea 37 mg of caffeine as an average amount derived from different brew times, soda a 12-ounce serving of each reported brand consumed, . We assigned an average value of 37 mg to brands that contained caffeine as an ingredient but in which the amount of caffeine was unknown. Each ounce of chocolate was assigned a value of 10 mg of caffeine. Use of caffeine-containing medications was evaluated separately. Adjusted odds ratios (OR) and 95% confidence intervals (CI) associated with consumption of total caffeine and each caffeine source were estimated from logistic regression models. A number of risk factors for NTDs were assessed as covariates: maternal age at conception; race/ethnicity; education level; prepregnancy body mass index (BMI); Type 1 and Type 2 diabetes; gravidity; parity; history of miscarriage; nausea or vomiting during the first month of pregnancy (yes or no); timing of pregnancy confirmation; timing of first prenatal care visit; periconceptional alcohol consumption (yes or no, maximum consumption, average frequency of consumption); cigarette smoking (ever smoked, smoked during periconceptional period, yes or no); oral contraceptive use; diet soda consumption; and average folic acid, vitamin B6, vitamin B12, dietary fat, calcium, sugar, and total caloric intake for the year before pregnancy. Use of any vasoconstrictive drugs including antihypertensives, decongestants, bronchodilators, antiseizure medications (including valproic acid), antimigraine medications, and cocaine and use of any vasoactive medications including salicylates, and nonsteroidal antiinflammatory drugs during the period one month before pregnancy through the first three months of pregnancy were examined as potential confounders and effect modifiers. Study center, household income, family history of NTDs, infant live status, and sex of infant were also evaluated.
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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) Neural tube defects - NTD, spina bifida, anencephaly, encephalocele
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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 Clinical geneticists at each site reviewed abstracted medical records before including them in the NBDPS, and each case was independently selected and classified for these analyses by one of two clinical geneticists
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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: 1) 0-9 (none) vs. >/=10; 0-9 (none) 2) 10-99, 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) A number of risk factors for NTDs were assessed as covariates: maternal age at conception; race/ethnicity; education level; prepregnancy body mass index (BMI); Type 1 and Type 2 diabetes; gravidity; parity; history of miscarriage; nausea or vomiting during the first month of pregnancy (yes or no); timing of pregnancy confirmation; timing of first prenatal care visit; periconceptional alcohol consumption (yes or no, maximum consumption, average frequency of consumption); cigarette smoking (ever smoked, smoked during periconceptional period, yes or no); oral contraceptive use; diet soda consumption; and average folic acid, vitamin B6, vitamin B12, dietary fat, calcium, sugar, and total caloric intake for the year before pregnancy. Use of any vasoconstrictive drugs including antihypertensives, decongestants, bronchodilators, antiseizure medications (including valproic acid), antimigraine medications, and cocaine and use of any vasoactive medications including salicylates, and nonsteroidal antiinflammatory drugs during the period one month before pregnancy through the first three months of pregnancy were examined as potential confounders and effect modifiers. Study center, household income, family history of NTDs, infant live status, and sex of infant were also evaluated
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Provide a general description of results (as reported by the authors). Odds ratios were increased for total caffeine consumption at or above 10 mg per day for NTDs combined, spina bifida, and encephalocele, but not for anencephaly. Caffeinated coffee was associated with increased risk of spina bifida and encephalocele. Tea consumption was associated with decreased risk of spina bifida, but an increased risk of encephalocele. Adjusted ORs for caffeinated soda were slightly increased for NTDs combined and spina bifida. Associations were not observed between spina bifida and consumption of caffeine-free soda (OR 0.9; 95% CI: 0.6–1.3) or diet soda (OR 0.9; 95% CI: 0.6–1.3). A nonsignificant increased risk was observed for caffeine-containing medications and spina bifida; this association was similar when mothers who reported use ‘‘as needed’’ were included in addition to those reporting specific timing of use. Little indication of a dose effect existed for any caffeine source or case group
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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 trend analysis was done but the authors state: "Little indication of a dose effect existed for any caffeine source or case group...Although the lack of a dose effect is evidence against a causal association and could indicate bias, persons who regularly consume caffeine develop a tolerance to the effects of caffeine within certain levels of consumption (Robertson et al., 1981; Evans and Griffith, 1992; Shi et al., 1993), which could have minimized a dose effect. Because of this tolerance effect, women who do not consume caffeine regularly but who happen to ingest moderate to large amounts of caffeine during the critical period of neural tube development may be at greatest risk for the effects of caffeine. The questionnaire used in our study asked about ‘average intake’ and did not allow identification of these women. However, these women would be expected to be the women who reported consuming coffee or soda only occasionally, fewer cups on average, and low to moderate average total caffeine amounts, the women associated with the greatest risk in our study."
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What were the author's conclusions? The findings from this population-based case-control study indicate that women who report drinking caffeinated beverages in the year before pregnancy may be at modestly increased risk for a pregnancy affected by an NTD. Reported consumption of caffeinated beverages for this period is likely to be similar to women’s consumption during early pregnancy before their pregnancies were confirmed, which corresponds to the time of neural tube development.
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What were the sources of funding? This work was supported by a grant from the Centers for Disease Control and Prevention (U50/CCU 713238).
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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.  NTD, Spina bifida, Anencephaly, or Encephalocele: NOAEL = >/=300 mg/day
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. ALL NTD: The adjusted OR for all NTDs at >/=10 mg/day was 1.3 (95% CI 1.0, 1.6) – the authors conclude this to be "modestly increased risk" but do not conclude it to be significant. In addition, there was no dose response when broken into quartiles (Cis start at 1.0 for 2 lower groups but 2 higher groups start at 0.9 and 0.8). To be consistent with other developmental studies, we would consider it the LOAEL. However, with the lack of dose-response and borderline CI, which is consistent with other paper clefts endpoints (Collier et al.) – we could consider no effect. However, Collier et al. did not do a separate analysis for all vs. none. Selected LOAEL as >/=10 mg/day. SPINA BIFIDA: Same issue as NTD, OR = 1.4 (CI 1.1, 1.9) for >/=10mg/day The caffeine content of coffee was based on the average caffeine amount found in a 10-ounce serving and estimated as 100 mg of caffeine per cup, each cup of tea 37 mg of caffeine as an average amount derived from different brew times, soda a 12-ounce serving of each reported brand consumed, . We assigned an average value of 37 mg to brands that contained caffeine as an ingredient but in which the amount of caffeine was unknown. Each ounce of chocolate was assigned a value of 10 mg of caffeine.
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What is the importance of the study with respect to the adverseness of the outcome? Critcal
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