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.     

Congenital defects and electric bed heating in New York State: a register-based case-control study.

Exposure to 60-cycle electromagnetic fields has been hypothesized to be a cause of childhood cancer and congenital defects. Because electric bed heaters are a major source of variation in electromagnetic field exposure in the population, the authors conducted a case-control study in 1988-1989 to examine the relations between congenital defects and the use of electric blankets and heated waterbeds. Cases were identified by the New York State Congenital Malformations Registry as babies with cleft palate (n = 121), cleft lip with or without cleft palate (n = 197), born in 1983-1984, and anencephalus and spina bifida (n = 224), born in 1983-1986, all to upstate New York residents. Controls were selected at random from birth registrations individually matched to cases by maternal race, age, home county, month of last menses, and child's sex. Information on periconceptional electric blanket and heated waterbed use as well as known and suspected risk factors for defects was obtained from questionnaires mailed to the mothers. Matched odds ratio estimates and 95% confidence intervals (CIs) for electric blanket use relative to nonuse were 0.8 (95% CI 0.3-2.1) for cleft palate, 0.7 (95% CI 0.3-1.3) for cleft lip, and 0.9 (95% CI 0.5-1.6) for neural tube defects. The respective odds ratios for heated waterbed use were nearly identical to these. Adjustment for potential confounding factors (maternal education, vitamin use, smoking) and stratification by season of conception and bed heat control setting had no meaningful effect on odds ratios. These results suggest that 60-cycle fields do not cause neural tube and oral cleft defects.     

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 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.     

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.     

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.     

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.     

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.     

Maternal occupational risk factors for oral clefts. Occupational Exposure and Congenital Malformation Working Group

OBJECTIVES: This study investigated the role of maternal exposures at work during pregnancy in the occurrence of oral clefts. METHODS: The occupational exposures of 851 women (100 mothers of babies with oral clefts and 751 mothers of healthy referents) who worked during the first trimester of pregnancy were studied. All the women were part of a multicenter European case-referent study conducted using 6 congenital malformation registers between 1989 and 1992. In each center, the mother's occupational history, obtained from an interview, was reviewed by industrial hygienists who were blinded to the subject's status and who assessed the presence of chemicals and the probability of exposure. Odds ratios (OR) were estimated by a multivariate analysis including maternal occupation or occupational exposures during the first trimester of pregnancy and possible confounding factors such as center of recruitment, maternal age, urbanization, socioeconomic status, and country of origin. RESULTS: After adjustment for confounding factors, cleft palate only was significantly associated with maternal occupation in services such as hairdressing [OR 5.1, 95% confidence interval (95% CI) 1.0-26.0] and housekeeping (OR 2.8, 95% CI 1.1-7.2). The analysis suggests that the following occupational exposures are associated with orofacial clefts: aliphatic aldehydes (OR 2.1, 95% CI 0.8-5.9) and glycol ethers (OR 1.7, 95% CI 0.9-3.3) for cleft lip with or without cleft palate and lead compounds (OR 4.0, 95% CI 1.3-12.2), biocides (OR 2.5, 95% CI 1.0-6.0), antineoplastic drugs (OR 5.0, 95% CI 0.8-34.0), trichloroethylene (OR 6.7, 95% CI 0.9-49.7), and aliphatic acids (OR 6.0, 95% CI 1.5-22.8) for cleft palate only. CONCLUSIONS: Due to the limited number of subjects, these results must be interpreted with caution. However, they point out some chemicals already known or suspected as reproductive toxins.     

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.     

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.     

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.     

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 birth defects: validity of birth certificate data for effect estimation

OBJECTIVES: The authors sought to assess the validity of birth certificate data for estimating the association between maternal smoking and birth defects. The US standard birth certificate includes check boxes for maternal smoking and for 21 congenital anomalies. The sensitivity and specificity of birth certificate data have been studied, but previous studies have not addressed the validity of these data for estimating the association between birth defects and maternal smoking or other risk factors. METHODS: US public-use natality data (1997-1998) were used to calculate the prevalence ratio (adjusted for maternal age, race/ethnicity, and education) for the association between maternal smoking and 13 defects/defect categories. All analyses were restricted to 45 states, New York City, and the District of Columbia because they collect both maternal smoking and birth defect data. RESULTS: Maternal smoking was associated with an increased prevalence of hydrocephaly (adjusted prevalence ratio [PR] = 1.24; 95% confidence interval [CI] = 1.08, 1.43), microcephaly (PR 1.47; 95% CI 1.15, 1.88), omphalocele/gastroschisis (PR 1.37; 95% CI 1.22, 1.53), cleft lip/palate (PR 1.35; 95% CI 1.25, 1.45), clubfoot (PR 1.62; 95% CI 1.49, 1.75), and polydactyly/syndactyly/adactyly (PR 1.33; 95% CI 1.23, 1.43 ). Previous studies have indicated an association between maternal smoking and gastroschisis, oral clefts, and clubfoot with effect estimates of similar magnitude to this study. CONCLUSIONS: These findings suggest that birth certificate data may be useful for exploratory or corroborative studies estimating the association between birth defects and some risk factors recorded on birth certificates.     

孕早期感冒或发热与常见体表出生缺陷关系的病例对照研究

一些研究表明孕早期感冒或发热与某些出生缺陷的发生有关[1~6]。中国北方地区是体表重大出生缺陷高发的地区,同时由于气候寒冷,也是感冒或发热高发的地区。因此,研究感冒或发热与出生缺陷危险性的关系,对于有效预防和控制出生缺陷具有重要意义。山西省属于我国乃至世界上体表出     

Selection bias and the use of controls with malformations in case-control studies of birth defects

We compared four methods of control selection to assess the effect of using infants with malformations as controls in case-control studies of birth defects. We identified cases and controls using data from the Slone Epidemiology Unit Births Defect Study for the years 1976-1992. Cases were defined as infants with cleft lip and palate and no other malformations (N = 494). Controls (N = 8356) were chosen from infants with other malformations, excluding other oral cleft conditions or syndromes associated with clefts. Maternal smoking during the first 13 weeks of pregnancy was the exposure of interest. We then assessed the measures of association resulting from using controls with varying restrictions. When we excluded all defects potentially associated with maternal smoking (based on reports in the literature), the crude odds ratio for smoking and oral cleft risk was 1.6 (1.3-1.9). When we eliminated all defect groups with a smoking prevalence that was one or more standard deviations above or below the total control group mean, the odds ratio was 1.5 (1.2-1.8); with controls restricted to infants with Mendelian-inherited disorders (with presumably no causal effect of smoking), the odds ratio was 1.6 (1.1-2.7); and when selection was unrestricted, the crude odds ratio was 1.5 (1.2-1.8). When used selectively, infants with malformations other than the anomaly of interest can be a suitable source of controls.     

Cleft lip and palate versus cleft lip only: are they distinct defects?

Cleft lip defects are usually regarded as a single entity, with the assumption that an accompanying cleft palate represents the more severe form. The authors linked data from the Medical Birth Registry of Norway with medical records from two centralized centers to provide a population-based data set. They assessed the distribution of cleft lip only and cleft lip with cleft palate by covariate. Among 1.8 million Norwegian livebirths between 1967 and 1998, there were 1,572 cases of cleft lip with cleft palate and 1,122 cases with cleft lip only. Seventeen percent of those with cleft lip and palate had another defect compared with 9% of those with cleft lip only. For boys, the risk was greater for cleft lip and palate than for cleft lip only (odds ratio=2.4 vs. 1.8, p<0.001 for difference). The risk of cleft lip only, but not of cleft lip and palate, was increased for twins (odds ratio=1.6 vs. 1.1, p=0.11) and infants whose parents were first cousins (odds ratio=2.7 vs. 0.7, p=0.07). Although cleft lip with cleft palate may simply represent a more severe form of the defect, epidemiologic assessments of cleft lip should, when possible, include separate analyses of these two groups.     

A case-control study of maternal smoking and congenital malformations

We conducted a population-based case-control study to assess the association between maternal smoking during pregnancy and the risk of giving birth to a child with a congenital malformation. Cases were all singleton livebirths with a congenital malformation recorded on the 1984-1986 Washington State Birth Records (n = 3284). The smoking histories of these mothers were compared to a randomly selected group of mothers with a singleton livebirth of a child without a malformation during these same years (n = 4500). When all malformations were taken as a group, there was no association with maternal smoking (relative risk (RR) = 1.0, 95% CI 0.9-1.1). However, increased risks were observed for a number of specific malformations, including microcephalus (RR = 2.0, 95% CI 1.0-4.0), cleft defects (RR = 1.4, 95% CI 1.0-2.0), and club foot (RR = 1.4, 95% CI 1.0-2.0). We did not find any association with Down's syndrome (RR = 0.8 95% CI 0.5-1.3) or any other malformation. We conclude that maternal smoking during pregnancy may be associated with an increased risk for some malformations.     

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.     

The contribution of maternal epilepsy and its treatment to the etiology of oral clefts: A population based case-control study

The associations between maternal epilepsy and anticonvulsant drug therapy with the risk of oral clefts in the offspring were investigated using data from a population-based case-control study. Cases included 238 infants with cleft lip ± cleft palate (CLP) and 107 infants with cleft palate (CP) ascertained through the Metropolitan Atlanta Congenital Defects Program (MACDP) between 1968 and 1980. Controls included 3029 population-based normal infants. Histories of maternal epilepsy and drug therapy during pregnancy were compared between cases and controls using maternal interviews and reviews of hospital medical records. Maternal epilepsy was associated with increased risk of nonsyndromic CLP (OR = 3.78, 95% C.I. 1.65–7.88), and less with CP (OR = 1.75, 95% C.I. 0.20–6.99). Therapy during pregnancy was associated with the greatest excess risk (CLP OR = 7.77, C.I. 2.02–26.0; CP OR = 3.61, C.I. 0.08–26.5). The use of polytherapy was associated with the highest risk (CLP OR = 10.5, C.I. 1.52–59.9). Adjustment for potential confounding variables in the study did not change these findings. In this well-defined population, maternal epilepsy and its treatment account for a small proportion of nonsyndromic oral clefts (attributable fraction CLP = 3.3%, CP = 0.9%). © 1994 Wiley-Liss, Inc.