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.     

A case-control study of nonsyndromic oral clefts in Maryland.

PURPOSE: Isolated, nonsyndromic oral clefts cases (n = 171) and unaffected controls (n = 182) were used to identify both genetic and environmental risk factors. METHODS: Infants born in Maryland between 1992 to 1998 with an isolated, nonsyndromic oral cleft [cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP)] were recruited and exposure plus family history data were collected. Controls were unaffected infants. DNA was collected from all cases and their parents, plus controls. RESULTS: No statistically significant association was found between any of the following: maternal smoking, vitamin use, urinary tract infection, or recreational drug use in either univariate analysis or after adjusting for maternal age and education. More control mothers reported alcohol use during the critical time period of pregnancy (one month before conception through the first trimester) as compared to case mothers. There was a 10-fold increase in risk to siblings of cases as compared to siblings of controls. Markers at four candidate genes were examined: transforming growth factor alpha (TGF alpha), transforming growth factor beta 3 (TGF beta 3), MSX1, and BCL3. Only MSX1 showed significant differences in allele frequencies between CP cases and controls. MSX1 also showed significant evidence of linkage disequilibrium with a susceptibility gene controlling risk for CP. CONCLUSION: Most environmental risk factors examined here gave little evidence of association with risk to isolated, nonsyndromic oral clefts, although any alcohol consumption seemed protective. MSX1 showed evidence of linkage disequilibrium in both case-control and case-parent trio analysis.     

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.     

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.     

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 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.     

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.     

First-trimester nonsystemic corticosteroid use and the risk of oral clefts in Norway

PurposeExposure of pregnant mice to corticosteroids can produce oral clefts in offspring. Although data in humans are more mixed, recent reports have suggested that dermatologic steroids are associated with oral clefts.MethodsWe investigated maternal first-trimester exposure to corticosteroids (focusing on dermatologic uses) and oral clefts in offspring using two population-based studies. The Norway Cleft Study (1996–2001) is a national case-control study including 377 infants with cleft lip ± palate (CLP), 196 infants with cleft palate only (CPO), and 763 controls. The Norwegian Mother and Child Cohort Study (MoBa, 1998–2008) is a national birth cohort including 123 infants with CLP, 61 infants with CPO, and 551 controls.ResultsIn the case-control study, there was the suggestion of an association of dermatologic corticosteroids with both CLP (adjusted OR [aOR], 2.3; 95% confidence interval [CI], 0.71–7.7) and CPO (aOR, 3.4; CI, 0.87–13). There was no evidence of this association in the cohort data (odds ratio for CLP, 1.2; CI, 0.50–2.8 and odds ratio for CPO, 1.0; CI, 0.30–3.4), although exposure to dermatologic steroids was less specifically ascertained. There were no associations with other types of corticosteroids.ConclusionsOur data add to the suggestive but inconsistent findings for this association.     

Risk factors for oral clefts: a population-based case-control study in Shenyang, China

Shenyang in Northern China has one of the highest reported prevalence rates of oral clefts in the world. To explore the risk factors for oral clefts in Shenyang, we carried out a population-based case-control study. A total of 360 990 births in 2000 to 2007 were screened for oral clefts; the overall prevalence was 1.76 per 1000. The ratio of cleft lip with or without cleft palate (CL ± P) : cleft palate only (CP) was 5.60:1. The overall male : female ratio was 2.02:1. CLP and CL were more common in males than in females with a sex ratio (SR) of 2.88:1 and 1.86:1 respectively, whereas CP was more common in females with an SR of 0.71:1.
Using a multivariable conditional logistic regression model, 586 oral clefts cases were compared with 1172 control mothers. Maternal factors significantly associated with increased risk for oral clefts were history of a fever or cold (adjusted OR 2.34, 95% CI 1.06, 5.60); use of analgesic and antipyretic drugs (adjusted OR 3.10, 95% CI 1.41, 6.86); poor ventilation during heating (adjusted OR 2.25, 95% CI 1.10, 4.60); and consumption of pickled vegetables >6 per week (adjusted OR 3.86, 95% CI 1.11, 13.47) during pregnancy. Factors which appeared to be protective were meat consumption ≥4 times per week (adjusted OR 0.43, 95% CI 0.28, 0.67); and legume consumption >6 times per week (adjusted OR 0.60, 95% CI 0.41, 0.89). Differences in risk were found between the two most common phenotypes, CL ± P and CP only. Most of the environmental factors had stronger associations with risk for CL ± P rather than CP, whereas history of oral clefts, as well as legume consumption, were more strongly associated with the risk for CP than for CL ± P. The findings suggest that aetiological heterogeneity may exist between CL ± P and CP.     

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.     

Lower Respiratory Tract Infections and Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children’s Study

BackgroundLower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs.MethodsThis prospective cohort study used data from the Japan Environment and Children’s Study, for which baseline recruitment was conducted during 2011–2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months’ age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as a potential mediator.ResultsThe incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP, 2.38; 95% confidence interval [CI], 1.30–4.36 and IRR of CL, 2.73; 95% CI, 1.40–5.33), but not ones with CP (IRR 1.08; 95% CI, 0.28–4.15). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP, 2.16; 95% CI, 1.19–3.93).ConclusionInfants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.Key words: cohort study, orofacial clefts, respiratory tract infection     

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 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.     

766 cases of oral cleft in Italy

Epidemiological and genetic variables for oral clefts were analysed for the years 1981–1989 in a case-control study of congenital malformations in the Emilia Romagna, Veneto, and Friuli regions, and in the Trento and Bolzano hospitals. Birth prevalence for all cases of cleft lip with or without cleft palate (CL(P)) was 8.2 per 10,000 births, and that for cleft palate only (CP) was 6.1 per 10,000. Coexisting abnormalities were found in 23% of CL(P) cases and in 43% of CP. No clusters in time or space were detected. For isolated clefts, a predominance of males among CL(P) and of females among CP was found; epilepsy was the only maternal risk factor correlated with clefts, and an association between clefting and consanguinity was found. Empirical recurrence risks were calculated in both isolated CL(P) and CP.     

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.     

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 dietary intake of vitamin A and risk of orofacial clefts: a population-based case-control study in Norway

A population-based case-control study was carried out in Norway between 1996 and 2001. The aim was to evaluate the association between maternal intake of vitamin A from diet and supplements and risk of having a baby with an orofacial cleft. Data on maternal dietary intake were available from 535 cases (188 with cleft palate only and 347 with cleft lip with or without cleft palate) and 693 controls. The adjusted odds ratio for isolated cleft palate only was 0.47 (95% confidence interval: 0.24, 0.94) when comparing the fourth and first quartiles of maternal intake of total vitamin A. In contrast, there was no appreciable association of total vitamin A with isolated cleft lip with or without cleft palate. An intake of vitamin A above the 95th percentile was associated with a lower estimated risk of all isolated clefts compared with the 40th-60th percentile (adjusted odds ratio = 0.48, 95% confidence interval: 0.20, 1.14). Maternal intake of vitamin A is associated with reduced risk of cleft palate only, and there is no evidence of increased risk of clefts among women in our study with the highest 5% of vitamin A intake.     

Maternal smoking, genetic variation of glutathione s-transferases, and risk for orofacial clefts

BACKGROUND: Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke. METHODS: Using a population-based case-control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1. RESULTS: If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2-7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked >/=20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82-57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3-42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1. CONCLUSIONS: Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.     

Parent's age and the risk of oral clefts

BACKGROUND: Some malformations are clearly associated with older maternal age, but the effect of older age of the father is less certain. The aim of this study is to determine the degree to which maternal age and paternal age independently influence the risk of having a child with oral clefts. METHODS: Among the 1,489,014 live births in Denmark during 1973-1996, there were 1920 children with nonsyndromic cleft lip with or without cleft palate and 956 children with nonsyndromic cleft palate. We used logistic regression to assess the impact of parental age on the occurrence of cleft lip with or without cleft palate and cleft palate. Interaction between mother's and father's age was included in the analysis. RESULTS: Separate analyses of mother's and father's age showed that older age was associated with increased risk of both cleft lip with or without cleft palate and cleft palate only. In a joint analysis, both maternal and paternal ages were associated with the risk of cleft lip with or without cleft palate, but the contribution of each was dependent on the age of the other parent. In the analysis of cleft palate only, the effect of maternal age disappeared, leaving only paternal age as a risk factor. CONCLUSION: Both high maternal age and high paternal age were associated with cleft lip with or without cleft palate. Higher paternal age but not maternal age increased the risk of cleft palate only.