First-trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: a population-based case-control study

Although alcohol is a recognized teratogen, evidence is limited on alcohol intake and oral cleft risk. The authors examined the association between maternal alcohol consumption and oral clefts in a national, population-based case-control study of infants born in 1996-2001 in Norway. Participants were 377 infants with cleft lip with or without cleft palate, 196 with cleft palate only, and 763 controls. Mothers reported first-trimester alcohol consumption in self-administered questionnaires completed within a few months after delivery. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusting for confounders. Compared with nondrinkers, women who reported binge-level drinking (>or=5 drinks per sitting) were more likely to have an infant with cleft lip with or without cleft palate (odds ratio = 2.2, 95% confidence interval: 1.1, 4.2) and cleft palate only (odds ratio = 2.6, 95% confidence interval: 1.2, 5.6). Odds ratios were higher among women who binged on three or more occasions: odds ratio = 3.2 for cleft lip with or without cleft palate (95% confidence interval: 1.0, 10.2) and odds ratio = 3.0 for cleft palate only (95% confidence interval: 0.7, 13.0). Maternal binge-level drinking may increase the risk of infant clefts.     

Tobacco smoking and oral clefts: a meta-analysis

OBJECTIVE: To examine the association between maternal smoking and non-syndromic orofacial clefts in infants. METHODS: A meta-analysis of the association between maternal smoking during pregnancy was carried out using data from 24 case-control and cohort studies. FINDINGS: Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35). There was evidence of a modest dose-response effect for cleft lip with or without cleft palate. CONCLUSION: The evidence of an association between maternal tobacco smoking and orofacial clefts is strong enough to justify its use in anti-smoking campaigns.     

Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns.

The results of previous epidemiologic research on the possible association between maternal smoking during pregnancy and risk of oral clefts in offspring have been inconsistent. This may be due in part to methodological limitations, including imprecise measurement of tobacco use, failure to consider etiologic heterogeneity among types of oral clefts, and confounding. This analysis, based on a large case-control study, further evaluated the effect of first trimester maternal smoking on oral facial cleft risk by examining the dose-response relationship according to specific cleft type and according to whether or not additional malformations were present. A number of factors, including dietary and supplemental folate intake and family history of clefts, were evaluated as potential confounders and effect modifiers. Data on 3,774 mothers interviewed between 1976 and 1992 by the Slone Epidemiology Unit Birth Defects Study were used. Study subjects were actively ascertained from sites in areas around Boston, Massachusetts and Philadelphia, Pennsylvania; the state of Iowa; and southeastern Ontario, Canada. Cases were infants with isolated defects--cleft lip alone (n = 334), cleft lip and palate (n = 494), or cleft palate alone (n = 244)--and infants with clefts plus (+) additional malformations: cleft lip+ (n = 58), cleft lip and palate+ (n = 140), or cleft palate+ (n = 209). Controls were infants with defects other than clefts, excluding defects possibly associated with maternal cigarette use. There were no associations with maternal smoking for any oral cleft group, except for a positive dose response among infants with cleft lip and palate+ (for light smokers, odds ratio (OR) = 1.09 (95% confidence interval (CI): 0.6, 1.9); for moderate smokers, OR = 1.84 (95% CI: 1.2, 2.9); and for heavy smokers, OR = 1.85 (95% CI: 1.0, 3.5), relative to nonsmokers). This finding may be related to the additional malformations rather than to the cleft itself.     

Parent's occupation and isolated orofacial clefts in Norway: a population-based case-control study

PURPOSE: Occupational factors have been associated with risk of orofacial clefts in offspring, although data are limited. We explored associations between parent's occupation and isolated orofacial clefts using a population-based case-control study. METHODS: Cases were restricted to infants born with an isolated orofacial cleft in Norway during the period 1996 to 2001 (314 with cleft lip with or without palate [CLP] and 118 with cleft palate only [CPO]). Controls (n = 763) were chosen randomly from all Norwegian live births. We considered full-time employment during the first 3 months of pregnancy. RESULTS: Several maternal occupations previously associated with clefts showed some evidence of association, including hairdressers (CLP; adjusted odds ratio = 4.8; 95% confidence interval [CI]: 0.99-23). Mothers working in manufacturing and in food production had increased odds for babies with CPO (3.8; 1.3-11, and 7.1; 1.5-33, respectively). Among fathers' occupations previously associated with clefts, an association was suggested for woodworking both for CLP (1.7; 0.85-3.2) and for CPO (2.0; 0.82-4.7). Fathers working as professional housekeepers showed substantial increased odds of CPO (12; 3.3-46). CONCLUSIONS: Taken together with previous studies, these results suggest that exposures in certain occupations may influence the risk of orofacial clefting in offspring. Specific exposures accompanying these occupations warrant exploration.     

Interaction between smoking and body mass index and risk of oral clefts

PurposeTo examine maternal smoking and body mass index (BMI) interactions in contributing to risk of oral clefts.MethodsWe studied 4935 cases and 10,557 controls from six population-based studies and estimated a pooled logistic regression of individual-level data, controlling for study fixed effects and individual-level risk factors.ResultsWe found a significant negative smoking–BMI interaction, with cleft risk with smoking generally declining with higher BMI. For all clefts combined, the odds ratio for smoking was 1.61 (95% confidence interval [CI]: 1.39–1.86) at BMI 17 (underweight), 1.47 (95% CI: 1.34–1.62) at BMI 22 (normal weight), 1.35 (95% CI: 1.22–1.48) at BMI 27 (overweight), 1.21 (95% CI: 1.04–1.41) at BMI 33 (obese), and 1.13 (95% CI: 0.92–1.38) at BMI 37 (very obese). A negative interaction was also observed for isolated clefts and across cleft types but was more pronounced for cleft lip only and cleft palate only.ConclusionsOur findings suggest that the risk of oral clefts associated with maternal smoking is largest among underweight mothers, although the smoking–BMI interaction is strongest for cleft lip only and cleft palate only. BMI was not protective for the effects of smoking; a clinically relevant increase in smoking-related cleft risk was still present among heavier women.     

Smoking and the risk of oral clefts: exploring the impact of study designs

BACKGROUND: Maternal cigarette smoking is a suspected cause of oral clefts, although this association has not been firmly established. We used case-crossover, case-time-control, and bidirectional case-crossover designs to supplement findings from a case-control study of maternal smoking and oral clefts among offspring in a large birth registry. METHODS: Data are from the Swedish Medical Birth Registry. From 1983 through 1997 there were 678 recorded cases of cleft palate and 1175 cases of cleft lip with or without palate. Maternal smoking status was ascertained in early pregnancy. Controls for the case-control study were a random sample of infants born without a cleft; controls for the case-crossover designs were nonmalformed infants born to case mothers. RESULTS: Cleft palate was positively associated with maternal smoking in all study designs, whereas cleft lip with or without cleft palate was associated with smoking only in the case-control design. In the case-control design, the odds ratios for cleft palate were 1.2 (95% confidence interval = 1.0-1.5) for women who smoked 1 to 9 cigarettes per day and 1.4 (1.1-1.8) for women who smoked 10+ cigarettes per day. In the case-time-control analysis, the odds ratio for cleft palate with maternal smoking was 3.2 (1.3-7.4) and in the bidirectional case-crossover design, the odds ratio was 2.2 (1.1-4.1). CONCLUSIONS: An association between smoking and cleft palate was supported by all designs, whereas that between smoking and cleft lip with or without cleft palate was not. Case-only designs are a viable option in birth registries and may yield more information than a case-control design alone.     

Risk of oral clefts in relation to prepregnancy weight change and interpregnancy interval

Epidemiologic evidence regarding the influence of maternal obesity on the risk of oral clefts is inconsistent. It is unknown whether increases in maternal weight before pregnancy are related to the risk of these malformations. The authors conducted a population-based cohort study in Sweden among 220,328 women who had their first two pregnancies between 1992 and 2004. The risk of oral clefts during the second pregnancy was estimated in relation to maternal change in body mass index (BMI; weight (kg)/height (m)(2)) from the beginning of the first pregnancy to the beginning of the second pregnancy. Among women whose second-pregnancy BMI was > or =3 units higher than their first-pregnancy BMI, the adjusted risk of isolated cleft palate was 2.3 times higher (95% confidence interval: 1.4, 4.0) as compared with women whose BMI did not change substantially. BMI change was not related to the risk of cleft lip. Unexpectedly, the birth prevalence of isolated cleft palate per 1,000 livebirths increased linearly with the length of the interpregnancy interval, from 0.3 in women with intervals of <12 months to 0.9 in women with intervals of > pr =48 months (adjusted p for trend = 0.002). High prepregnancy maternal weight gain and long interpregnancy intervals appear to be associated with increased risk of cleft palate.     

Maternal reproductive history and the risk of isolated congenital malformations

We examined the relationship between maternal reproductive history and the newborn's risk of isolated congenital malformations in a large case-control cohort from the Polish Registry of Congenital Malformations. Congenital malformations were classified into four categories: isolated congenital heart defects (n=1673), isolated cleft palate (n=255), cleft lip with or without cleft palate (n=448) and renal agenesis (n=103). The case groups were compared with a shared group of 2068 controls recruited in the same time period and geographic area. Multivariable logistic regression was used to assess the risk associated with maternal gravidity and of previous miscarriages after accounting for maternal age and other potential risk factors. In unadjusted analyses, maternal gravidity was significantly associated with increased risk of all four classes of congenital malformations. After adjustment, a significant association persisted for congenital heart defects [odds ratio (OR)=1.22, [95% confidence interval (CI) 1.09, 1.36], P=0.0007] and cleft lip with or without cleft palate (OR=1.21, [95% CI 1.09, 1.36], P=0.0005). A similar trend existed for isolated cleft palate (OR=1.18, [95% CI 1.02, 1.37], P=0.03). There was no appreciable increase in the risk of congenital malformations associated with a maternal history of miscarriages, but a trend for a protective effect on the occurrence of cleft lip with or without cleft palate was observed (OR=0.72, [95% CI 0.52, 0.99], P=0.045). Based on our data, maternal gravidity represents a significant risk factor for congenital heart defects and cleft lip with or without cleft palate in the newborn infant. Our data do not support an increase in risk because of past history of miscarriages.     

Parental occupational pesticide exposure and nonsyndromic orofacial clefts

Nonsyndromic orofacial clefts are common birth defects. Reported risks for orofacial clefts associated with parental occupational pesticide exposure are mixed. To examine the role of parental pesticide exposure in orofacial cleft development in offspring, this study compared population-based case-control data for parental occupational exposures to insecticides, herbicides, and fungicides, alone or in combinations, during maternal (1 month before through 3 months after conception) and paternal (3 months before through 3 months after conception) critical exposure periods between orofacial cleft cases and unaffected controls. Multivariable logistic regression was used to estimate odds ratios, adjusted for relevant covariables, and 95% confidence intervals for any (yes, no) and cumulative (none, low [相似文献   

Tobacco and alcohol use during pregnancy and risk of oral clefts. Occupational Exposure and Congenital Malformation Working Group

OBJECTIVES: This study examined the relationship between maternal tobacco and alcohol consumption during the first trimester of pregnancy and oral clefts. METHODS: Data were derived from a European multicenter case-control study including 161 infants with oral clefts and 1134 control infants. RESULTS: Multivariate analyses showed an increased risk of cleft lip with or without cleft palate associated with smoking (odds ratio [OR] = 1.79, 95% confidence interval [CI] = 1.07, 3.04) and an increased risk of cleft palate associated with alcohol consumption (OR = 2.28, 95% CI = 1.02, 5.09). The former risk increased with the number of cigarettes smoked. CONCLUSIONS: This study provides further evidence of the possible role of prevalent environmental exposures such as tobacco and alcohol in the etiology of oral clefts.     

Maternal nutrient intakes and risk of orofacial clefts

BACKGROUND: Information about nutritional factors as potential risks of orofacial clefts is limited. METHODS: In this population-based case-control study, we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, and several other nutrients were associated with orofacial clefts. We included data on deliveries from 1997 through 2000 in the National Birth Defects Prevention Study. Orofacial cleft cases were infants or fetuses born with cleft palate (CP) or with cleft lip with or without cleft palate (CLP). Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. Interviews were completed for 704 CLP cases, 404 CP cases, and 2594 controls. RESULTS: The odds ratio (OR) for CLP associated with use of vitamin supplements containing folic acid was 0.88 (95% confidence interval = 0.73-1.07) and for CP was 1.09 (0.84-1.40). Adjusting for maternal race/ethnicity, age, and education produced an OR of 1.01 (0.82-1.24) for CLP and 1.02 (0.77-1.34) for CP. We found some evidence for decreased CLP risks (>or=30% reduction in risk) with increasing intakes of total protein, choline, and methionine. Decreased CP risk was associated with increased intake of cysteine. Intakes of only 2 micronutrients, iron and riboflavin, were found to reduce CLP risk when adjusted for other nutrients. CONCLUSION: Our observations contribute to the limited body of evidence suggesting a woman's periconceptional diet may influence clefting risks in her offspring. Our finding of no reduction in clefting risk with periconceptional use of supplements containing folic acid is inconsistent with many previous observations but not all.     

Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts

BACKGROUND: Smoking during pregnancy has been associated with orofacial clefts in numerous studies. However, most previous studies have not been able to assess the relation between maternal smoking and specific phenotypes (eg, bilateral clefts). METHODS: We examined the association between periconceptional maternal smoking, environmental tobacco smoke (ETS) exposure, and cleft lip with or without cleft palate (CLP) (n = 933) and cleft palate only (CPO) (n = 528) compared with infants with no major birth defects (n = 3390). Infants were born between 1 October 1997 and 31 December 2001, and exposures were ascertained from maternal telephone interviews for the National Birth Defects Prevention Study. We excluded infants who had a first-degree relative with an orofacial cleft. Effect estimates were adjusted for folic acid use, study site, prepregnancy obesity, alcohol use, gravidity, and maternal age, education, and race/ethnicity. RESULTS: Periconceptional smoking was associated with CLP (odds ratio = 1.3; 95% confidence interval = 1.0-1.6), and more strongly associated with bilateral CLP (1.7; 1.2-2.6), with a weaker association observed for CPO. Heavy maternal smoking (25+ cigarettes/day) was associated with CLP (1.8; 1.0-3.2), bilateral CLP (4.2; 1.7-10.3), and CPO with Pierre Robin sequence (2.5; 0.9-7.0). ETS exposure was not associated with CLP or CPO. CONCLUSIONS: This study confirmed the modest association between smoking and orofacial clefts that has been consistently reported, and identified specific phenotypes most strongly affected.     

Periconceptional folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate

BACKGROUND: Inadequate maternal vitamin intake during pregnancy has been suggested as a risk factor for cleft lip with or without cleft palate (CLP). The independent role of folate has not been clarified. METHODS: To investigate the association between maternal folate intake by supplement and food and the risk of CLP offspring, a case-control study was conducted in the Netherlands (1998-2000) among 174 mothers of a child with nonsyndromic CLP and 203 mothers of a child without congenital malformations. RESULTS: Daily use of a folic acid supplement by mothers starting from 4 weeks before until 8 weeks after conception gave a 47% CLP risk reduction compared to mothers who did not use these supplements [odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33, 0.85]. Ninety-three percent of the users took a supplement containing folic acid only. Dietary folate intake reduced CLP risk independently in a dose-response manner. The largest risk reductions were found on those mothers who had a diet of more than 200 microg folate per day in combination with a folic acid supplement (OR: 0.26, 95% CI: 0.09, 0.72). CONCLUSIONS: We demonstrated that periconceptional maternal folic acid supplement use was beneficial to reduce the risk for CLP. An additional effect of food folate was shown.     

Maternal alcohol binge-drinking in the first trimester and the risk of orofacial clefts in offspring: a large population-based pooling study

Using individual participant data from six population-based case–control studies, we conducted pooled analyses to examine maternal alcohol consumption and the risk of clefts among >4600 infants with cleft lip only, cleft lip with cleft palate, or cleft palate only and >10,000 unaffected controls. We examined two first-trimester alcohol measures: average number of drinks/sitting and maximum number of drinks/sitting, with five studies contributing to each analysis. Study-specific odds ratios (ORs) were estimated using logistic regression and pooled to generate adjusted summary ORs. Across studies, 0.9–3.2 % of control mothers reported drinking an average of 5+ drinks/sitting, while 1.4–23.5 % reported drinking a maximum of 5+ drinks/sitting. Compared with non-drinkers, mothers who drank an average of 5+ drinks/sitting were more likely to deliver an infant with cleft lip only (pooled OR 1.48; 95 % confidence intervals 1.01, 2.18). The estimate was higher among women who drank at this level 3+ times (pooled OR 1.95; 1.23, 3.11). Ever drinking a maximum of 5+ drinks/sitting and non-binge drinking were not associated with cleft risk. Repeated heavy maternal alcohol consumption was associated with an increased risk of cleft lip only in offspring. There was little evidence of increased risk for other cleft types or alcohol measures.     

Retinoic acid receptor alpha gene variants,multivitamin use,and liver intake as risk factors for oral clefts: a population-based case-control study in Denmark, 1991-1994

Previous studies suggest that the risks of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate are influenced by variation at several loci and that these loci interact with environmental factors to determine disease risk. One putative genetic risk factor for these conditions is the retinoic acid receptor alpha (RARA) locus, which is involved in cell-specific responses to retinoic acid. Hence, RARA may influence disease risk via an interaction with vitamin A and related compounds. Data from a Danish case-control study (1991-1994) were used to evaluate the relations between oral clefts, RARA, and maternal vitamin A exposure from multivitamins and liver. Analyses provided no compelling evidence that the risks of CL+/-P or isolated cleft palate are related to the RARA variant analyzed. Consistent with several previous studies, the authors' analyses indicated that maternal multivitamin supplement use protects against CL+/-P. Within the range observed in this population, higher levels of vitamin A intake from multivitamins and liver sources also seemed to protect against CL+/-P. Exploratory analyses suggested that the latter association was not entirely explained by the association between CL+/-P and multivitamin use, indicating that adequate levels of vitamin A may be required for normal development of the primary palate.     

Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts

Orofacial clefts have been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial nitric oxide synthase (NOS3) activity influences homocysteine concentration and because smoking compromises NOS3 activity, genetic variation in NOS3 might interact with smoking and folic acid use in clefting risk. The authors genotyped 244 infants with isolated cleft lip with or without cleft palate (CL/P), 99 with isolated cleft palate, and 588 controls from a California population-based case-control study (1987-1989 birth cohort) for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each polymorphism revealed a 60% increased risk of CL/P among NOS3 A(-922)G homozygotes (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.6). There was some evidence for higher risk of CL/P with maternal periconceptional smoking in infants with an NOS3 -922G allele (for homozygotes, OR = 2.5, 95% CI: 1.2, 5.6) but not in those with an 894T allele. For CL/P risk, odds ratios were over 4 among mothers who smoked, who did not use vitamins, and whose infants had at least one variant allele for each NOS3 polymorphism (for A(-922)G, OR = 4.6, 95% CI: 2.1, 10.2; for 894T, OR = 4.4, 95% CI: 1.8, 10.7). No similar patterns were observed for risk of cleft palate.     

Maternal smoking and the risk of orofacial clefts: Susceptibility with NAT1 and NAT2 polymorphisms

BACKGROUND: Orofacial clefts are etiologically heterogeneous malformations. One probable cause is maternal smoking during pregnancy. The effect of maternal smoking may be modified by genes involved in biotransformation of toxic compounds derived from tobacco. We investigated whether polymorphic variants of fetal acetyl-N-transferases 1 (NAT1) and 2 (NAT2) interact with maternal cigarette smoking during early pregnancy to increase the risk of delivering an infant with an orofacial cleft. METHODS: In a California population-based case-control study, we genotyped 421 infants born with an isolated cleft and 299 nonmal-formed controls for 2 NAT1 and 3 NAT2 single nucleotide polymorphisms RESULTS: Although smoking was independently associated with increased risks for both isolated cleft lip +/- cleft palate and isolated cleft palate, no independent associations were found for NAT1 1088 or 1095 genotypes or for NAT2 acetylator status. However, the infant NAT1 1088 and 1095 polymorphisms were strongly associated with the risk of clefts among smoking mothers; infants with NAT1 1088 genotype AA versus TT (odds ratio [OR] = 3.9; 95% confidence interval = 1.1-17.2) and with NAT1 1095 genotype AA versus CC (OR = 4.2; 1.2-18.0). Infant NAT2 acetylator status did not appreciably affect susceptibility of the fetus to the teratogenic effects of maternal smoking. CONCLUSIONS: Our results suggest that maternal smoking during pregnancy may increase risk for orofacial clefts particularly among smokers whose fetuses have polymorphic variants of NAT1, an enzyme involved in phase II detoxification of tobacco smoke constituents.     

Maternal periconceptional alcohol consumption and risk of orofacial clefts

Using data from the National Birth Defects Prevention Study, the authors investigated the association between maternal reports of periconceptional alcohol consumption and clefting. Cases with a cleft lip, cleft palate, or both and unaffected controls delivered from 1997 through 2002 were ascertained. Interview reports of alcohol consumption were obtained from 1,749 (75.1%) case and 4,094 (68.2%) control mothers. Adjusted odds ratios and 95% confidence intervals were calculated to assess associations. Compared with odds ratios for mothers with no reported consumption, those for mothers who consumed alcohol tended to be near to (cleft lip, cleft lip with cleft palate) or to exceed (cleft palate) unity. The odds ratios associated with binge drinking were elevated but did not demonstrate significantly increased risk for any phenotype; however, the odds ratios differed by the type of alcohol consumed, particularly for cleft palate (distilled spirits > wine > beer). These odds ratios were further increased among mothers with no reported folic acid intake. Although these findings suggest that the association between alcohol consumption and clefting might be most influenced by the type of beverage consumed and folic acid intake, they are preliminary and might reflect chance associations. Such findings need exploration in additional, large studies.     

Maternal cigarette smoking during pregnancy in relation to oral clefts

Studies on maternal smoking in relation to oral cleft defects have yielded inconsistent findings, with results ranging from no association to sixfold increases in risk. The authors examined this relation in a case-control study conducted in Boston, Massachusetts, Philadelphia, Pennsylvania, Toronto, Ontario, Canada, and the state of Iowa during the years 1983-1987, in which mothers of malformed infants were interviewed within 6 months after delivery about prenatal events and exposures. Maternal cigarette smoking during pregnancy for 400 infants with cleft lip with or without cleft palate and for 215 infants with cleft palate alone was compared with that for 2,710 infants with other malformations (controls). Relative risks (and 95% confidence intervals) were estimated for smokers of 1-14, 15-24, and greater than or equal to 25 cigarettes per day relative to never smokers; the respective estimates for cleft lip with or without cleft palate were 1.2 (95% confidence interval (CI) 0.9-1.6), 1.4 (95% CI 1.0-2.1), and 0.7 (95% CI 0.3-1.6), and for cleft palate alone, estimates were 1.0 (95% CI 0.7-1.5), 0.9 (95% CI 0.5-1.5), and 0.8 (95% CI 0.3-2.2). Relative risks were also close to unity for case subgroups divided according to the presence or absence of an associated malformation. Multivariate control of several potential confounders did not alter these estimates. Based on this large series of cases, maternal smoking during pregnancy does not appear to increase the risk of oral clefts.     

Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects

How folate reduces the risks of congenital anomalies is unknown. The authors focused on a gene involved in folate transport-reduced folate carrier-1 gene (RFC1). Using data from a California case-control study (1987-1989 births), the authors investigated whether the risks of orofacial clefts or conotruncal heart defects were influenced by a polymorphism of infant RFC1 or by an interaction between the RFC1 gene and maternal periconceptional use of vitamins containing folic acid. A total of 305 liveborn infants with cleft lip with or without cleft palate, 123 with cleft palate, 163 with conotruncal heart defects, and 364 nonmalformed controls were genotyped. Odds ratios of 1.6 (95% confidence interval: 0.9, 2.8) for the G80/G80 genotype and of 2.3 (95% confidence interval: 1.3, 3.9) for the G80/A80 genotype were observed relative to the A80/A80 genotype for conotruncal defects. Among mothers who did not use vitamins, the risk of conotruncal defects was 2.1 (95% confidence interval: 0.7, 5.9) for infants with genotype G80/G80 compared with those with the A80/A80 genotype. Among mothers who did use vitamins, the risk was 1.3 (95% confidence interval: 0.7, 2.7). Substantially elevated risks for either cleft group were not observed irrespective of genotype and use/nonuse of vitamins. Thus, this study found modest evidence for a gene-nutrient interaction between infant RFC1 genotype and periconceptional intake of vitamins on the risk of conotruncal defects.