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 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, 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.     

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 employment status and isolated orofacial clefts in Hungary

AIMS: To study the role of maternal employment status as indicator of socioeconomic status in the origin of isolated orofacial clefts (OFC) and in the use of periconceptional folic acid/multivitamin supplementation. METHODS: 1,975 cases with OFC (1,374 cases with cleft lip +/- palate and 601 cases with posterior cleft palate), 38,151 population controls without any defects and 20,868 patient controls with other isolated defects were compared in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996. RESULTS: The proportion of professionals and managerials was lower, while the proportion of unskilled workers, housewives and others was higher in the mothers of cases with OFC compared with the population control group. However, the comparison of OFC and patient control groups did not show any difference in the employment status of mothers. A lower level of folic acid supplementation occurred in the professional and skilled worker mothers of cases with OFC compared with the population control group. This difference was confirmed by the comparison of folic acid used by mothers of cases with OFC compared with patient controls. An infrequent multivitamin use was displayed in the studied groups. CONCLUSIONS: The prevalence of OFC at birth shows a slightly lower maternal employment status as indicator of socioeconomic status than in the population control group. The higher level of maternal education does not imply a higher rate of folic acid supplementation in the group of OFC.     

Genes as instruments for studying risk behavior effects: an application to maternal smoking and orofacial clefts

This study uses instrumental variable (IV) models with genetic instruments to assess the effects of maternal smoking on the child's risk of orofacial clefts (OFC), a common birth defect. The study uses genotypic variants in neurotransmitter and detoxification genes relateded to smoking as instruments for cigarette smoking before and during pregnancy. Conditional maximum likelihood and two-stage IV probit models are used to estimate the IV model. The data are from a population-level sample of affected and unaffected children in Norway. The selected genetic instruments generally fit the IV assumptions but may be considered "weak" in predicting cigarette smoking. We find that smoking before and during pregnancy increases OFC risk substantially under the IV model (by about 4-5 times at the sample average smoking rate). This effect is greater than that found with classical analytic models. This may be because the usual models are not able to consider self-selection into smoking based on unobserved confounders, or it may to some degree reflect limitations of the instruments. Inference based on weak-instrument robust confidence bounds is consistent with standard inference. Genetic instruments may provide a valuable approach to estimate the "causal" effects of risk behaviors with genetic-predisposing factors (such as smoking) on health and socioeconomic outcomes.     

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 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.     

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.     

Maternal cigarette smoking and oral clefts: a population-based study.

Analyses of 1984 data from the Maryland Birth Defects Reporting and Information System indicate that mothers of infants with oral clefts (cleft lip with or without cleft palate; and cleft palate) smoked more during pregnancy than mothers of infants with other defects (odds ratio OR of 2.56 and 2.39, respectively). There was a dose-response relation between the daily amount smoked and the risk of clefting. Adjustment for available confounding variables did not account for the association between smoking and oral clefts.     

Socio-economic status and risk of conotruncal heart defects and orofacial clefts

Studies of socio-economic status (SES) have figured prominently in research related to a variety of health outcomes, although the question remains as to whether SES contributes to the aetiologies of congenital anomalies. This study examines the association of SES with risks of conotruncal heart defects and orofacial clefts, using interview data from 696 case mothers (86% of eligible) and 734 (78%) control mothers from a population-based case-control study. Socio-economic measures from maternal interview included mother's education and employment. Reported addresses were linked with the US census to characterise six measures of neighbourhood SES (education, poverty, unemployment, occupation, crowding and rental occupancy). Results were adjusted for race-ethnicity, multivitamin/mineral supplement intake, cigarette smoking and binge drinking. Results for individual and neighbourhood measures suggested that low SES was associated with increased risk of d-transposition of the great arteries (dTGA), reduced risk of tetralogy of Fallot (TOF), but was not associated with risk of orofacial clefts. For example, when examining odds ratios (OR) that compared risks among women whose neighbourhoods were in the lowest vs. highest quartile of the census-based SES measures, ORs for five of the six measures were> 1.4 for dTGA, and ORs for all six measures were < 0.7 for TOF. ORs for clefts tended to be closer to 1. This study suggests that SES risks are birth defect specific.     

Maternal smoking and the risk of polyhydramnios.

BACKGROUND. Washington State birth certificates were used to conduct a population-based case-control study to assess the possible association of maternal smoking with polyhydramnios. METHODS. All singleton births complicated by polyhydramnios (n = 557) were identified from the vital records for the years 1984 to 1987. For comparison, 1671 records were randomly selected for the same years from singleton births uncomplicated by polyhydramnios. RESULTS. Women who reportedly smoked prenatally were found to be at increased risk for polyhydramnios (relative risk [RR] = 1.7, 95% confidence interval [CI] = 1.5-2.1, adjusted for marital status, maternal age, and parity). When women with conditions known to be associated with polyhydramnios were excluded, the risk for those who smoked prenatally remained elevated (RR = 1.8, 95% CI = 1.1-2.3). CONCLUSION. Overdistention of the uterus from polyhydramnios may cause a variety of pregnancy complications. The observed association of smoking with polyhydramnios may be a further indication for public health interventions aimed at preventing smoking during pregnancy.     

Maternal smoking and the risk of early weaning: a meta-analysis

OBJECTIVES: This study reviewed evidence on the effect of maternal smoking on early weaning. METHODS: The following databases and journals were searched: Medline, Scientific Citation Index, Pediatrics, Journal of Pediatrics, New England Journal of Medicine, and Lancet. Analysis was restricted to studies in which infants who had never been breastfed were excluded or the prevalence of breastfeeding initiation was more than 90%. RESULTS: In smoking vs nonsmoking mothers, the random effects odds ratio for weaning before 3 months was 1.93 (95% confidence interval [CI] = 1.55, 2.40). An adjusted odds ratio of 1.50 (95% CI = 1.34, 1.68) was shown in studies that had lost-to-follow-up rates below 15% and included adequate adjustment for confounding. CONCLUSIONS: Maternal smoking increases the risk of early weaning.     

Incidence of orofacial clefts in the Slovak Republic

Orofacial clefts (OC) are quite common congenital defects. Retrospective active survey collecting clinical data of children with OC examined and operated on in the three main specialized departments of plastic surgery in the Slovak Republic over 16 years (1985-2000) revealed total incidence of 1.61/10(3) live births (LB). 1,849 children suffering from OC were recognised out of 1,147,236 live births. Total incidence (TI) of OC per 1,000 live births was determined by types, gender, regions, districts and seasonal variation. The highest rate, 40.5% of clefts, affected the primary and secondary palate (CLP), more than 32% were of cleft palate type (CP), about 26% cleft lip (CL) and about 1% of associated malformations (AM). Clefts in males (1.71/10(3) LB) were significantly more common than in females (1.50/10(3) LB), sex ratio 1.14:1. Morbidity rates (TI) varies from 1.29/10(3) LB in the east Slovakia to the highest incidence of 1.93/10(3) LB in the middle Slovakia with wide range by district. Comparing data from the study and from the national register, 17% of children with OC were missed. Presented survey assessed risk of OC in Slovakia at the rate 1 newborn with OC per 620 LB compared with notified frequency of 1 OC per 745 LB.     

Maternal nutritional status and the risk for orofacial cleft offspring in humans

Periconceptional folate and folic acid intake prevents orofacial clefts (OFC) in the offspring. It has been suggested that other nutrients also play a role. We investigated the preconceptional intake of macronutrients (protein, fat, carbohydrate, fiber, and cholesterol), vitamins (vitamin A, retinol, beta-carotene, ascorbic acid, and alpha-tocopherol), minerals (calcium, phosphorus, iron, magnesium, and zinc) and food groups in mothers of OFC children and controls. At approximately 14 mo after the index pregnancy, 206 mothers of a child with a nonsyndromic OFC and 203 control mothers completed a FFQ on current food intake and a general questionnaire. After exclusion of pregnant and lactating mothers, mothers who reported a change in diet compared with the preconceptional period, and those for whom periconceptional folic acid supplement use was unclear, 182 OFC mothers and 173 control mothers were evaluated. Macronutrient, vitamin, mineral, and food group intakes were compared. After adjustment for energy, quintiles of dietary nutrient intake and odds ratios with 95% CI were calculated. The preconceptional intake of all macronutrients, vitamins, minerals, and food groups with the exception of milk (products), potatoes, pies/cookies were lower in OFC mothers than in controls. The energy-adjusted intakes of vegetable protein, fiber, beta-carotene, ascorbic acid, alpha-tocopherol, iron, and magnesium were significantly lower in cases compared with controls. Increasing intakes of vegetable protein, fiber, ascorbic acid, iron, and magnesium decreased OFC risk. In conclusion, a higher preconceptional intake of nutrients predominantly present in fruits and vegetables reduces the risk of offspring affected by OFC.     

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.