Is there a relationship between risk factors for oral clefts?

Oral clefts include cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP) and collectively these constitute a heterogeneous group of nonfatal birth defects known to be multifactorial in origin, in that both genes and environmental factors contribute to their etiology (Mitchell et al., ’02). The incidence of oral clefting varies from 0.6 to 1.7 per 1,000 Caucasian births. African Americans show a lower incidence (0.4/ 1,000) and Japanese have a higher frequency (1.7/ 1,000). Cleft lip with cleft palate comprise about 45% of all cleft cases, cleft palate only about 30%, and cleft lip only about 25% (Gorlin et al., ’90). Identification of modifiable risk factors for oral clefts is the first step toward primary prevention. A few such risk factors have been described. Maternal smoking (Kallen, ’97; Chung et al., ’00) and folic acid deficiency are two factors that have been associated with increased risk for oral clefts (Khoury et al., ’87; Shaw et al., ’95). Factoring in genetic information complicates matters further, as gene-environment interaction seems to play a role in the etiology of clefts (Hwang et al., ’94; Shaw et al., ’98; Romitti et al., ’99). In this issue, Vieira and Orioli present a metaanalysis of eight studies where another possible risk factor for oral clefts is described, increasing birth order. When considering isolated cleft cases only, the highest risk was seen in the “four or more” birth order category; however, risk was also increased in the second and third birth order category. Interestingly, when multiple anomaly cases were included in the analysis, these risks were even greater. As the authors point out, adjustment for maternal age was not possible. Maternal smoking status and folate levels were not included as well; birth order could be a surrogate for these factors. Meta-analysis can be a useful tool to untangle the often disparate results from several small studies, especially when studying rare diseases such as birth defects. It is difficult for any one study to recruit enough subjects to obtain sufficient power to detect a modest association. It is also important to realize that detecting a statistical association between a risk factor and a disease does not automatically represent a biological mechanism. The association could arise from the risk factor playing a direct role in disease etiology; an indirect association between the risk factor and another risk factor; and confounding due to population stratification (Hwang et al., ’94). In 1987, Khoury et al. (’87) found a positive relationship between smoking and cleft lip and palate (OR 3.33; 95% CI 1.3– 8.4). Wyszynski et al. (’97) performed a meta-analysis utilizing the results from 11 studies and found an overall odds ratio of 1.29 (95% CI 1.18 –1.42) for oral clefts in children of women who smoked and calculated an attributable risk of 11%, suggesting that smoking is a general risk factor for all oral clefts. Lieff et al. (’99) found a positive dose-response relationship between CLP and smoking (light smokers: OR 1.09, 95% CI 0.6 –1.9; moderate smokers: OR 1.84, 95% CI 1.2–2.9; heavy smokers: OR 1.85, 95% CI 1.0 – 3.5). In a large study, Chung et al. (’00) found an adjusted odds ratio for smokers versus nonsmokers of 1.34 (95% CI 1.16 –1.54). Honein et al. (’01) found that cigarette smoking increased the risk for several birth defects, including oral clefts. Folic acid has been recognized as an important component of early fetal development. In 1952, Theirsch suggested an association between neural tube defects (NTDs) and low maternal folate levels (SteegersTheunissen, ’95). Case control studies (Werler et al., ’93), randomized trials (MRC Vitamin Research Group, ’91; Czeizel and Duda, ’92), and observational studies (Milunsky et al., ’89) have shown that periconceptual use of folic acid (doses ranged from 0.35 to 5 mg/d) reduces the occurrence and recurrence of NTDs from 60% to 100%. A recent meta-analysis of four clinical trials in which women were supplemented with folic acid periconceptually found a significant reduction in the incidence of NTDs (Lumley et al., ’02). Folic acid is thought to play an important role in the prevention of clefts. Tolorova and Harris (’95) found a