American Journal of Epidemiology ª The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: [email protected]. Vol. 169, No. 10 DOI: 10.1093/aje/kwp040 Advance Access publication April 2, 2009 Original Contribution Maternal Consumption of Coffee and Caffeine-containing Beverages and Oral Clefts: A Population-based Case-Control Study in Norway Anne Marte W. Johansen, Allen J. Wilcox, Rolv T. Lie, Lene F. Andersen, and Christian A. Drevon Initially submitted August 11, 2008; accepted for publication February 2, 2009. A large, population-based case-control study of facial clefts was carried out in Norway between 1996 and 2001. The study included 573 cases—377 with cleft lip with or without cleft palate and 196 with cleft palate only—and 763 randomly selected controls. Maternal consumption of coffee and other caffeine-containing beverages in early pregnancy was recorded shortly after birth. Compared with that for no coffee consumption, the adjusted odds ratios for cleft lip with or without cleft palate were 1.39 (95% confidence interval: 1.01, 1.92) for less than 3 cups a day and 1.59 (95% confidence interval: 1.05, 2.39) for 3 cups or more. Coffee consumption was not associated with risk of cleft palate only (for 3 cups vs. none, adjusted odds ratio ¼ 0.96, 95% confidence interval: 0.55, 1.67). Tea consumption was associated with a reduced odds ratio of both cleft lip with or without cleft palate and cleft palate only. There was little evidence of an association between caffeine exposure and clefts when all sources of caffeine were considered. Adjustment for known confounding factors in general had minor effects on risk estimates. Still, the authors could not rule out the possibility of uncontrolled confounding by factors associated with the habit of drinking coffee. caffeine; cleft lip; cleft palate; coffee; pregnancy Abbreviations: CI, confidence interval; CLP, cleft lip with or without cleft palate; CPO, cleft palate only. Orofacial clefts are among the most common birth defects, and the prevalence in Norway (2.2 per 1,000 livebirths) is particularly high. The etiology of clefts is complex and largely unknown. The high risk of recurrence of clefts among first-degree relatives (as much as 56 times the background prevalence) suggests a strong genetic component (1). However, environmental factors such as maternal nutrition (2–4), vitamin supplements (5), smoking (6), and binge alcohol consumption (7) also appear to contribute. Coffee consumption is relatively high in Norway. In the latest nationwide study, average coffee intake was half a liter a day, with peak intake among those aged 40–60 years (8). Data from animal studies suggest that large single doses of caffeine may cause palatal clefts as well as other birth defects (9), although studies of coffee consumption in humans have provided little evidence of teratogenic effects (10). In a systematic review of 3 studies of orofacial clefts and caffeine, high coffee intake was associated with a slight in- crease in risk (11). According to a recently published article, maternal caffeine intake during pregnancy was associated with fetal growth restriction (12). Coffee is a commonly consumed beverage among pregnant women, and even a small increase in malformation risk could be a matter of concern. We used data from a populationbased case-control study to evaluate the association of maternal consumption of coffee and caffeinated beverages in early pregnancy with the risk of delivering an infant with an orofacial cleft. MATERIALS AND METHODS All infants born with facial clefts in Norway are treated at government expense in surgical centers at university hospitals located in Oslo and Bergen. In collaboration with these 2 centers, we identified all babies born from 1996 to 2001 who were referred for treatment for either cleft lip with or Correspondence to Anne Marte Wetting Johansen, Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1046, 0316 Oslo, Norway (e-mail: [email protected]). 1216 Am J Epidemiol 2009;169:1216–1222 Maternal Caffeine Consumption and Oral Clefts without cleft palate (CLP) or cleft palate only (CPO). Controls were recruited during the same period by randomly selecting approximately 4 births per 1,000 from the National Medical Birth Registry (which includes all births in the country). These births served as controls for both case groups, with the target of 2 controls per case of CLP (nearly 4 controls for each case of CPO). Both cases and controls were recruited during their first weeks of life. Our present study was approved by the regional ethics review board, the Norwegian Data Inspectorate, and the US National Institute of Environmental Health Sciences Review Board. All participating mothers provided informed consent. Participants There were 676 women in Norway who delivered infants requiring surgery for orofacial clefts during 1996–2001. We excluded 24 mothers who did not speak Norwegian or whose infant died after birth, leaving 652 eligible mothers. Of these, 88% (n ¼ 573) agreed to participate. We randomly selected 1,022 control mothers of livebirths via the national Medical Birth Registry within 6 weeks of delivery. After excluding 16 who were not Norwegian speakers or whose infant died, 1,006 mothers of controls were eligible, of whom 76% (n ¼ 763) agreed to participate. Data on intake of coffee and other caffeinated beverages were available for all participating mothers of cases and controls. We identified other birth defects among the cleft cases by using 3 data sources: the Medical Birth Registry (based on delivery records and hospital records from the first week of life), medical records at the hospital performing the corrective surgery, and mother’s questionnaire. Accompanying defects were reported for 17% of CLP cases and 40% of CPO cases. Cases of clefts without accompanying defects have been categorized as isolated clefts. Data collection Mothers completed a 32-page questionnaire covering demographic characteristics, reproductive history, and exposures during pregnancy (including smoking, alcohol consumption, coffee intake, medication use, and occupational and household exposures). Median time from delivery to completion of the questionnaire was 14 weeks for cases and 15 weeks for controls. The questionnaire included items on maternal consumption of caffeine-containing beverages (coffee, tea, and soft drinks) during the first 3 months of pregnancy. For each beverage, there was 1 question with 5 response categories: none, number of cups per day, number of cups per week, number of cups per month, and number of cups per year (without specifying the size of the cup). An English translation of the questionnaire is available online (http://www.niehs.nih.gov/research/atniehs/labs/epi/ studies/ncl/ncl_pregnancy_en.pdf). Statistical methods The risk of delivering offspring with an orofacial cleft was estimated by odds ratios with 95% confidence intervals Am J Epidemiol 2009;169:1216–1222 1217 in unconditional logistic regression models. All beverages were summarized and were analyzed in the same way, as follows. ‘‘Cups per day’’ was computed from reported number of cups consumed per day, per week (divided by 7), or per month (divided by 30). Women who reported consuming less than 1 cup per month were categorized as consuming zero. The cups-per-day variable was analyzed as a continuous variable. Finally, a 3-category variable was created: 0 cups per day (reference category), more than 0 but less than 3 cups per day, and 3 or more cups per day. Trends across the categories were evaluated, with zero as the reference. An estimate of caffeine from all sources was computed from the data on coffee, tea, and caffeinated soft drinks. Caffeine content was estimated as 100 mg per cup of coffee, 40 mg per cup of tea, and 20 mg per cup of caffeinated soft drink based on values from the Norwegian Health Authorities Web page (http://www.matportalen.no/Emner/Gravide (in Norwegian)). Risk of clefts was evaluated per 100-mg increase in caffeine intake (continuous variable) and for the categories >100–<500 mg and 500 mg of caffeine relative to 0–100 mg. Adjustments were made for potential confounders (factors associated with clefts in other studies, most of which were also associated in our study), namely, dietary vitamin A (quartiles), dietary folate (quartiles), folic acid supplement (400 lg/day, yes or no), vitamin supplement use (yes or no), consumption of alcohol in early pregnancy (number of drinks per sitting), smoking (ordinal linear with 5 categories: none; passive only; and 1–5, 6–10, and 11 cigarettes a day), nausea during the first trimester (yes or no), employment in early pregnancy (yes or no), education (ordinal linear with 6 categories), father’s income (ordinal linear with 3 categories), and year of birth. Evaluations of possible interactions with coffee intake were carried out for use of folic acid supplements and smoking. In evaluating the effects of coffee or tea separately, we adjusted for the other (categorized as number of cups per day). Because CLP and CPO are considered etiologically distinct outcomes, we conducted separate analyses for each (1). Separate analyses were also performed for isolated clefts (i.e., excluding those with accompanying defects). Because oral clefts are relatively rare birth defects, odds ratios are close approximations of relative risks. All statistical analyses were performed by using SPSS 14.0 software (SPSS Inc., Chicago, Illinois). RESULTS Women who gave birth to infants with CLP were taller, less educated, and less likely to work during the first trimester compared with mothers who gave birth to healthy controls (Table 1). Compared with mothers of controls, fewer mothers of CLP cases used a folic acid supplement, and they were more often coffee consumers and smokers. Fewer mothers of CLP and CPO cases drank tea compared with mothers of controls (Table 1). Maternal coffee consumption was associated with an increased risk of CLP. In the adjusted analyses, the odds ratio 1218 Johansen et al. Table 1. Demographic and Other Characteristics of Participants in the Case-Control Study of Maternal Consumption of Caffeine-containing Beverages and Oral Clefts, Norway, 1996–2001 Cleft Lip With or Without Cleft Palate (n 5 377) Median (25th, 75th percentile)a % Mean (SD) Cleft Palate Only (n 5 196) Median (25th, 75th percentile)a % Control Group (n 5 763) Mean (SD) Median (25th, 75th percentile)a % Mean (SD) Mother’s characteristics Coffee consumption before pregnancy, cups/day 3.0 (1.0, 4.1) 3.0 (1.0, 5.0) 3.0 (1.0, 4.3) Coffee consumption during the first trimester, cups/day 2.0 (0.7, 4.0) 2.0 (0.4, 3.0) 2.0 (0.7, 3.0) Coffee consumers during the first trimester Tea consumption during the first trimester, cups/day 56.0 1.0 (0.4, 2.0) Tea consumers during the first trimester Soft drink consumption in the first trimester, cups/day 49.0 45.7 1.0 (0.3, 2.0) 62.1 1.0 (0.4, 2.0) 62.2 0.6 (0.3, 2.0) 71.7 0.6 (0.3, 1.0) 0.6 (0.3,1.5) Soft drink consumers during the first trimester 77.1 70.9 73.1 Folic acid supplement use during the first trimester (400 lg) 13.1 15.8 19.0 Multivitamin use during the first trimester 32.6 36.2 36.6 Smoking during the first trimesterb 44.1 36.8 31.9 Alcohol consumption, drinks/sitting 2.0 (1.0, 2.0) 1.0 (1.0, 2.0) Age at delivery, years Height, cm 1.0 (1.0, 2.0) 28.9 (4.9) 28.9 (5.1) 29.2 (4.8) 168.6 (5.7) 166.9 (6.6) 167.7 (6.0) Prepregnancy weight, kg 67.2 (12.9) 66.2 (13.6) Body mass index, kg/m2 23.6 (4.3) 23.8 (4.5) 66.0 (11.3) 23.4 (3.7) Education less than high school 18.8 11.2 11.0 Working during the first trimester 76.3 79.5 83.1 Father’s income <250,000 Norwegian kroner 52.6 54.5 47.3 Other birth defects 16.7 39.8 5.0 Abbreviation: SD, standard deviation. Intake among consumers only. b All levels of active smoking versus nonsmoking and passive smoking. a of CLP increased by 7% per-cup increase in daily coffee intake (adjusted odds ratio ¼ 1.07, 95% confidence interval (CI): 1.00, 1.16). Compared with those for women with zero coffee consumption, the adjusted odds ratios of CLP were 1.39 (95% CI: 1.01, 1.92) for daily coffee consumption of less than 3 cups a day and 1.59 (95% CI: 1.05, 2.39) for consumption of 3 or more cups a day (Table 2), and inspection of categories of coffee intake confirmed that there was a trend in risk by dose (Ptrend ¼ 0.013 in the adjusted analyses). The association between coffee consumption and CLP persisted among nonsmokers (among whom there would presumably be no residual confounding by smoking) and among mothers of isolated cleft cases (Table 2). We found no evidence of an association between maternal coffee consumption during the first trimester and the risk of CPO (Table 2). Consumption of caffeine-containing tea was associated with a decrease in the odds ratio of both CLP and CPO (Table 2). Compared with no tea intake, daily tea intake of 3 or more cups gave adjusted odds ratios of 0.55 (95% CI: 0.32, 0.95) for CLP and 0.58 (95% CI: 0.31, 1.07) for CPO. Soft drinks that contain caffeine were positively associated with both types of facial clefts, although with confidence intervals that did not exclude 1 (Table 2). Table 3 shows maternal intake of caffeine from all beverages in relation to cleft risk. Although there was Am J Epidemiol 2009;169:1216–1222 Am J Epidemiol 2009;169:1216–1222 Table 2. Maternal Consumption of Caffeine-containing Coffee, Tea, and Soft Drinks During the First Trimester and Odds Ratios of Cleft Lip With or Without Cleft Palate and Cleft Palate Only, Norway, 1996–2001 Cleft Lip With or Without Cleft Palate Crude Analysis (n 5 377/763)b Coffee, per-cup increase Cleft Palate Only Isolateda Cases All Cases Adjustedc Analysis (n 5 318/653) Crude Analysis (n 5 314/763) Isolateda Cases All Cases Adjustedc Analysis (n 5 263/653) Crude Analysis (n 5 196/763) Adjustedc Analysis (n 5 178/653) Crude Analysis (n 5 118/763) Adjustedc Analysis (n 5 108/653) Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI 1.11 1.04, 1.18 1.07 1.00, 1.16 1.09 1.00, 1.17 1.09 1.00, 1.17 1.00 0.92, 1.09 0.98 0.88, 1.09 0.95 0.84, 1.07 0.94 0.82, 1.09 Coffee, categoricald >0–<3 cups/day 1.37 1.03, 1.81 1.39 1.01, 1.92 1.41 1.05, 1.90 1.47 1.05, 2.07 1.17 0.83, 1.66 1.26 0.85, 1.86 1.11 0.72, 1.70 1.24 0.77, 1.99 3 cups/day 1.80 1.29, 2.53 1.59 1.05, 2.39 1.85 1.29, 2.64 1.67 1.08, 2.58 1.07 0.68, 1.70 0.96 0.55, 1.67 0.88 0.48, 1.61 0.91 0.45, 1.85 P for trend 0.013 <0.001 Tea, per-cup increase 0.85 0.76, 0.94 0.86 0.76, 0.98 <0.001 1.01 0.97, 1.05 0.566 <0.001 1.01 0.97, 1.05 0.86 0.75, 0.99 0.760 0.82 0.70, 0.96 0.879 0.81 0.67, 0.98 0.877 0.79 0.64, 0.97 d Tea, categorical >0–<3 cups/day 0.68 0.52, 0.88 0.74 0.55, 1.01 0.65 0.49, 0.86 0.72 0.52, 0.99 0.65 0.46, 0.91 0.66 0.45, 0.95 0.64 0.43, 0.97 0.64 0.41, 1.01 3 cups/day 0.50 0.31, 0.80 0.55 0.32, 0.95 0.49 0.30, 0.82 0.53 0.30, 0.94 0.68 0.39, 1.18 0.58 0.31, 1.07 0.49 0.23, 1.05 0.45 0.20, 1.01 Soft drinks, per-cup increase 0.001 1.04 0.97, 1.11 0.014 1.05 0.96, 1.14 0.001 1.04 0.97, 1.11 0.011 1.04 0.95, 1.14 0.033 1.03 0.96, 1.12 0.025 1.05 0.95, 1.15 0.018 1.06 0.97, 1.15 0.020 1.06 0.96, 1.18 Soft drinks, categoricald >0–<3 cups/day 1.20 0.90, 1.62 1.16 0.84, 1.62 1.23 0.90, 1.69 1.17 0.82, 1.67 0.85 0.60, 1.22 0.84 0.56, 1.24 1.15 0.72, 1.83 1.14 0.69, 1.89 3 cups/day 1.44 0.93, 2.23 1.48 0.88, 2.49 1.43 0.90, 2.27 1.44 0.82, 2.51 1.15 0.68, 1.96 1.30 0.70, 2.40 1.36 0.69, 2.67 1.43 0.65, 3.13 P for trend 0.086 0.144 0.107 0.193 0.928 0.788 0.371 0.384 Abbreviation: CI, confidence interval. No accompanying malformations. b All parenthetical information is expressed as number of mothers of cases/number of mothers of controls. c Odds ratios were adjusted for maternal nausea, smoking, alcohol consumption, folic acid supplement use, multivitamin supplement use, coffee consumption (in the analysis of tea and soft drinks), tea consumption (in the analysis of coffee and soft drinks), dietary folate, dietary vitamin A, work status during the first trimester, educational level, income level (father), and year of birth. d Reference category: 0 cups/day. a Maternal Caffeine Consumption and Oral Clefts P for trend 1219 Abbreviation: CI, confidence interval. No accompanying malformations. b All parenthetical information is expressed as number of mothers of cases/number of mothers of controls. c Odds ratios were adjusted for maternal nausea, smoking, alcohol consumption, folic acid supplement use, multivitamin supplement use, dietary folate, dietary vitamin A, work status during the first trimester, educational level, income level (father), and year of birth. d Reference category: 0–100 mg. a 0.297 0.32, 2.11 0.83 0.40, 1.93 0.299 0.88 0.54, 2.16 0.475 1.08 0.70, 2.25 0.863 1.26 0.62, 2.02 0.851 1.12 0.96, 2.54 0.138 1.56 0.66, 2.04 0.834 1.16 0.122 1.00, 2.50 1.58 500 mg P for trend 0.48, 1.18 0.76 0.51, 1.14 1.05 >100–<500 mg 0.81, 1.36 0.97 0.72, 1.30 1.07 0.82, 1.42 0.99 0.72, 1.36 0.82 0.59, 1.15 0.77 0.53, 1.11 0.76 0.80, 1.05 0.92 0.82, 1.04 1.08 Caffeine, per 100-mg increased 1.02, 1.15 1.05 0.98, 1.13 1.08 1.02, 1.16 1.05 0.97, 1.14 0.98 0.90, 1.07 0.95 0.86, 1.06 0.92 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio Adjustedc Analysis (n 5 108/653) Crude Analysis (n 5 118/763) Adjustedc Analysis (n 5 178/653) Crude Analysis (n 5 196/763) Adjustedc Analysis (n 5 262/653) Crude Analysis (n 5 313/763) Adjustedc Analysis (n 5 318/653) Crude Analysis (n 5 375/763)b Isolated Casesa Cleft Palate Only All Cases Isolateda Cases Cleft Lip With or Without Cleft Palate All Cases Table 3. Maternal Consumption of Caffeine During the First Trimester and Odds Ratios of Cleft Lip With or Without Cleft Palate and Cleft Palate Only, Norway, 1996–2001 1220 Johansen et al. a positive association in the crude analysis, the association was reduced after adjustment. We also considered mothers who reported drinking coffee during the year before pregnancy but not during the first trimester. There was only a weak, positive association with risk of CLP in this group (adjusted odds ratio ¼ 1.21, 95% CI: 0.80, 1.85) (Table 4). DISCUSSION Maternal intake of coffee during the first 3 months of the pregnancy was associated in a dose-response manner with risk of delivering an infant with CLP. In contrast, we found no evidence of an association between coffee intake and risk of CPO. The association between coffee and CLP was only slightly decreased by adjustments for confounders, and it persisted for nonsmokers and the subset of infants with isolated CLP. There is no known mechanism by which coffee intake might increase the risk of CLP. Effects on homocysteine is one potential pathway. Evidence suggests that maternal hyperhomocysteinemia may be linked to increased risk of CLP (13). Coffee intake increases the plasma concentration of homocysteine (14–16), as does smoking (15), a well-established risk factor for CLP (17). Folic acid supplements are consistently associated with reduced risk of CLP (18), and such supplements reduce plasma homocysteine (15). In the present study, the association between high coffee intake and CLP was slightly stronger for women who did not take a folic acid supplement (crude odds ratio ¼ 1.99, 95% CI: 1.30, 3.04), although this interaction did not approach statistical significance (P for interaction ¼ 0.89). Consumption of caffeine-containing tea was strongly associated with a reduced risk of both CLP and CPO. Potential health benefits of tea have been linked to its high content of antioxidants (19). This is not a likely explanation for the reduced cleft risk, however, because coffee has an even higher total content of antioxidants than tea does (20). The association of tea with lower risk of both types of clefts may reflect the presence of unmeasured confounding factors. Tea drinkers may have more healthy habits; consumers of high quantities of tea in our study were older, more educated, and drank less alcohol per sitting compared with nonconsumers. Furthermore, the diet of consumers of high quantities of tea contained more of every macronutrient and almost every micronutrient compared with the diet of nonconsumers (data not shown). The association of coffee with CLP appears to be independent of the role of caffeine. We found no association between total caffeine intake and risk of CLP (reflecting the combination of the positive association with coffee and the negative association with tea). Only 5 women drank decaffeinated coffee exclusively, too few for a separate analysis. When we combined data on decaffeinated coffee with those on caffeinated coffee, the odds ratios for CLP were slightly increased, consistent with the association of coffee and CLP being unrelated to caffeine intake (data not shown). Am J Epidemiol 2009;169:1216–1222 Maternal Caffeine Consumption and Oral Clefts 1221 Table 4. Maternal Coffee Consumption Before and During Pregnancy and Odds Ratios of Cleft Lip With or Without Cleft Palate, Norway, 1996– 2001 Crude Odds Ratio 95% CI Adjusteda Odds Ratio 95% CI Quitters (cases/controls ¼ 57/135): consumed coffee the year before pregnancy but not during the first trimester 1.06 0.72, 1.54 1.21 0.80, 1.85 Stable consumers (cases/controls ¼ 208/348): consumed coffee both the year before pregnancy and during the first trimester 1.49 1.13, 1.97 1.53 1.10, 2.12 Stable high consumers (cases/controls ¼ 78/110): consumed 3 cups of coffee/day both the year before pregnancy and during the first trimester 1.77 1.23, 2.55 1.61 1.04, 2.49 b Never consumers (cases/controls ¼ 112/280 ): did not consume coffee before pregnancy or during the first trimesterc Abbreviation: CI, confidence interval. Adjusted for maternal nausea, smoking, alcohol consumption, folic acid supplement use, multivitamin supplement use, dietary folate, dietary vitamin A, tea consumption, work status during the first trimester, educational level, income level (father), and year of birth. b All parenthetical information is expressed as number of mothers of cases/number of mothers of controls. c Reference category. a By the same token, high-quantity coffee consumers (>3 cups/day) were older, less educated, smoked more, and drank more alcohol per sitting compared with nonconsumers. Even though we adjusted for possible confounding factors, we cannot rule out the possibility of residual confounding by known factors such as smoking or confounding by unmeasured factors. Although we did not control for diet, there was no evidence of a poorer diet among consumers of high quantities of coffee, who actually reported eating more vegetables, less sugar, and more of many essential nutrients (data not shown). Another potential source of bias in this study comes from possible selective participation of controls. While participation was relatively high (88% for cases and 76% for controls), the lower participation of controls leaves room for differential participation by coffee drinking. However, it is unlikely that such selection would occur for one type of facial cleft and not the other. Coffee was strongly associated with CLP but not with CPO in our data. This specificity has been found for other factors associated with facial clefts (6). By the same argument, the lack of specificity for the tea association (which was protective for both types of facial clefts) raises the question of whether this association might be due to some unmeasured bias. Women may reduce their coffee consumption as they develop pregnancy symptoms of nausea and vomiting. Given that closure of the lip and palate occurs relatively late in the first trimester (8–12 weeks after the last menstrual period) (1), it is possible that reported coffee intake is greater than actual consumption at the crucial stage of embryonic development. This bias would tend to weaken the observed association. Our study had the advantage of enrolling mothers soon (an average of 15 weeks) after delivery. In addition, questions on coffee and other caffeinated beverages constituted only a small part of the questionnaire, with no specific emphasis on these beverages that would be expected to bias reporting. Another strength of the study was collection of extensive data on potential confounders such as folic acid supplement use, alcohol consumption, and smoking. Confounders were adjusted for as continuous variables in our Am J Epidemiol 2009;169:1216–1222 analyses, but adjustment using categorized variables did not alter the results. A meta-analysis of 3 studies on maternal coffee consumption and orofacial clefts found a slight increase in the risk of clefts (11). All 3 studies used 0 cups as the reference category. When high coffee intake was compared with low intake, the pooled odds ratio was 1.2 (95% CI: 0.9, 1.6). One of the studies provided results for CLP separately, with an adjusted odds ratio for CLP of 1.3 (95% CI: 0.9, 1.9) associated with more than 3 cups of coffee a day (11). The 2 other studies combined both types of clefts in their analyses. In the report by Kurppa et al. (21), drinking more than 4 cups of coffee a day had no association with risk of clefts (unadjusted odds ratio ¼ 1.0, 95% CI: 0.6, 1.6), whereas, according to McDonald et al. (22), more than 3 cups of coffee daily resulted in an adjusted odds ratio of 1.4 (95% CI: 0.7, 2.7). A recent cohort study from Denmark found that coffee intake was associated with a reduced risk of CLP (23). The authors observed an odds ratio of 0.66 (95% CI: 0.27, 1.62) when comparing daily intake of more than 5 cups of coffee with no intake. The Danish study had the advantage of a prospective design, although one cost of this design was a relatively small number of cases (134 with CLP). In summary, results from our study showed a dosedependent association between coffee consumption during the first trimester and increased risk of CLP. This association was specific to CLP, with no association found between coffee consumption and risk of CPO. There was little or no evidence for an association between caffeine from other types of beverages and CLP. Even with extensive adjustments for confounders, we cannot eliminate the possibility that the associations between coffee consumption and risk of CLP are due to uncontrolled confounding by factors associated with the habit of drinking coffee. Still, considering our results and the prior mixed evidence for a coffee effect on clefts, women cannot be assured that maternal coffee consumption is entirely benign for the developing fetus. Other clefts studies now in progress should give close attention to a possible association of coffee consumption with facial clefts. 1222 Johansen et al. ACKNOWLEDGMENTS Author affiliations: Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway (Anne Marte W. Johansen, Lene F. Andersen, Christian A. Drevon); Epidemiology Branch, National Institute of Environmental Health Sciences/National Institutes of Health, Durham, North Carolina (Allen J. Wilcox); Section for Epidemiology and Medical Statistics, Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway (Rolv T. Lie); and Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway (Rolv T. Lie). This work was supported by the Research Council of Norway (grant 166026/V50); the Freia Medical Foundation; the Throne-Holst Foundation for Nutrition Research; the thematic area of perinatal nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway; and Nutrigenomics, Network of Excellence, FP6, Food Quality and Safety (NuGO FP6-506360). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Conflict of interest: none declared. REFERENCES 1. Sivertsen A, Wilcox AJ, Skjaerven R, et al. Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives. BMJ. 2008; 336(7641):432–434. 2. Johansen AM, Lie RT, Wilcox AJ, et al. Maternal dietary intake of vitamin A and risk of orofacial clefts: a populationbased case-control study in Norway. Am J Epidemiol. 2008; 167(10):1164–1170. 3. Shaw GM, Carmichael SL, Laurent C, et al. Maternal nutrient intakes and risk of orofacial clefts. Epidemiology. 2006;17(3): 285–291. 4. Krapels IP, Vermeij-Keers C, Muller M, et al. Nutrition and genes in the development of orofacial clefting. Nutr Rev. 2006; 64(6):280–288. 5. Wilcox AJ, Lie RT, Solvoll K, et al. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ. 2007;334(7591):464. 6. Lie RT, Wilcox AJ, Taylor J, et al. Maternal smoking and oral clefts: the role of detoxification pathway genes. Epidemiology. 2008;19(4):606–615. 7. Deroo LA, Wilcox AJ, Drevon CA, et al. First-trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: a population-based case-control study. Am J Epidemiol. 2008;168(6):638–646. 8. Norwegian Directorate of Health. Norkost 1997 Nationwide Dietary Survey Among Women and Men Aged 16–79 Years [in Norwegian]. Oslo, Norway: Norwegian Directorate of Health. (Report no. 2/1999). (http://www.helsedirektoratet.no/vp/ multimedia/archive/00003/IS-0168_3745a.pdf). 9. Nehlig A, Debry G. Effects of coffee and caffeine on fertility, reproduction, lactation, and development. Review of human and animal data [in French]. J Gynecol Obstet Biol Reprod (Paris). 1994;23(3):241–256. 10. Nehlig A, Debry G. Consequences on the newborn of chronic maternal consumption of coffee during gestation and lactation: a review. J Am Coll Nutr. 1994;13(1):6–21. 11. Browne ML. Maternal exposure to caffeine and risk of congenital anomalies: a systematic review. Epidemiology. 2006; 17(3):324–331. 12. CARE Study Group. Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ. 2008;337:a2332. 13. Verkleij-Hagoort A, Bliek J, Sayed-Tabatabaei F, et al. Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis. Am J Med Genet A. 2007;143(9):952–960. 14. Grubben MJ, Boers GH, Blom HJ, et al. Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial. Am J Clin Nutr. 2000;71(2): 480–484. 15. Refsum H, Nurk E, Smith AD, et al. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006; 136(6 suppl):1731S–1740S. 16. Urgert R, van Vliet T, Zock PL, et al. Heavy coffee consumption and plasma homocysteine: a randomized controlled trial in healthy volunteers. Am J Clin Nutr. 2000;72(5): 1107–1110. 17. Little J, Cardy A, Munger RG. Tobacco smoking and oral clefts: a meta-analysis. Bull World Health Organ. 2004; 82(3):213–218. 18. Johnson CY, Little J. Folate intake, markers of folate status and oral clefts: is the evidence converging? Int J Epidemiol. 2008; 37(5):1041–1058. 19. Mukhtar H, Ahmad N. Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr. 2000;71(6 suppl): 1698S–1702S. 20. Halvorsen BL, Carlsen MH, Phillips KM, et al. Content of redox-active compounds (ie, antioxidants) in foods consumed in the United States. Am J Clin Nutr. 2006;84(1):95–135. 21. Kurppa K, Holmberg PC, Kuosma E, et al. Coffee consumption during pregnancy and selected congenital malformations: a nationwide case-control study. Am J Public Health. 1983; 73(12):1397–1399. 22. McDonald AD, Armstrong BG, Sloan M. Cigarette, alcohol, and coffee consumption and congenital defects. Am J Public Health. 1992;82(1):91–93. 23. Bille C, Olsen J, Vach W, et al. Oral clefts and life style factors—a case-cohort study based on prospective Danish data. Eur J Epidemiol. 2007;22(3):173–181. Am J Epidemiol 2009;169:1216–1222
