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The two main types of oral clefts are cleft lip and cleft palate. Cleft lip is the congenital failure of the maxillary and median nasal processes to fuse, forming a groove or fissure in the lip. Cleft palate is the congenital failure of the palate to fuse properly, forming a grooved depression or fissure in the roof of the mouth. Clefts of the lip and palate can occur individually, together, or in conjunction with other defects. For etiologic reasons, cleft lip with cleft palate and cleft lip without cleft palate are often grouped together. Cleft palate without cleft lip is classified as a separate defect.
Oral clefts frequently occur in combination with a wide range of chromosomal abnormalities and syndromes (trisomy 13, amniotic band anomalad, Fryns syndrome, Meckel syndrome, Stickler syndrome, Treacher Collins syndrome, van der Woude syndrome, Velocardiofacial syndrome, etc.).
DEMOGRAPHIC AND REPRODUCTIVE FACTORS
Several studies have reported increased risk of oral clefts with increased maternal age (Shaw 1991). However, larger studies failed to identify advanced maternal age as a risk factor for oral clefts (Abramowicz 2003, Baird 1994, Vieira 2002b, Vallino-Napoli 2004). Conversely, another study found a greater risk for cleft lip among younger mothers (DeRoo 2003, Reefhuis, 2004).
There are racial/ethnic differences in risk for oral clefts. Asians have the highest risk (14:10,000 births), followed by whites (10:10,000 births) and African Americans (4:10,000 births) (Das 1995). Among Asians, the risk for oral clefts is higher among Far East Asians (Japanese, Chinese, Korean) and Filipinos than Pacific Islanders (Yoon 1997). Amerindian populations in South America have been found to have higher rates than other “mixed“ populations (Vieira 2002a).
Genetic factors are believed to account for some defects, often in combination with one or more environmental factors. Several loci have been identified for cleft lip with or without cleft palate, and, in one case, a specific gene has also been found. In cleft palate alone, one gene has been identified, but many more are probably involved (Carinci 2003). There is evidence of two main types of cleft lip and palate in whites (Ardinger 1989, Chung 1986, Johnston 1989). The first type is controlled by a single gene, which may code for a transforming growth factor‑alpha (TGF-alpha) variant. The second type is multifactorial in nature. Asians, however, do not appear to have a major gene etiology for oral clefts (Ardinger 1989, Chung 1986, Chung 1987, Johnston 1989). There is also some evidence that maternal and/or infant gene variations in conjunction with maternal smoking may lead to oral clefts in the infant (Hwang 1995, Shaw 1996, Fallin 2003, Lammer 2004). In addition to these factors, there is some evidence that indicates that a defect in the maternal metabolism of specific dietary elements may also be a contributing factor in producing an affected child (Prescott 2002, van Rooj 2003). In this instance, the presence of a gene identified as MTHFR 677TT in conjunction with a low folate diet may lead to increased orofacial clefting (van Rooj 2003). There is also an indication that even with adequate folate intake, these clefts may still occur in some cases (Lammer 2004, Prescott 2002). Other genetic factors that may affect the presence of orofacial clefts include maternal ability to maintain red blood cell zinc concentrations and myo-inositol concentrations (a hexahydrocycyclohexane sugar alcohol) (Krapels 2004). Maternal ability to maintain adequate levels of Vitamins B6 and B12 and fetal ability to utilize these nutrients are also seen as a factor in the development of oral clefts (van Rooj 2004). When these nutrients are not metabolized properly, errors in DNA synthesis and transcription may occur (van Rooj 2004).
Demographic factors not considered to affect risk for oral clefts include season, geographic location(Christensen 1995), social class, parity (Shaw 1991), and paternal age. However, higher birth order has been associated with increased risk (Vieira 2002c).
Low socioeconomic status, when adjusted for adjusting for race-ethnicity, multivitamin/mineral supplement intake, cigarette smoking and binge drinking, was not associated with increased risk of orofacial clefts. (Carmichael 2003). However, a Scottish study did find a link with socioeconomic deprivation (not adjusted for other factors) (Clark 2003).
Infant sex influences the risk for oral clefts. Males are more likely than females to have a cleft lip with or without cleft palate, while females are at slightly greater risk for cleft palate alone (Blanco-Davila 2003, Das 1995, Owens 1985, Shaw 1991). One study indicated that family history of clefts, birth order, maternal age at birth, first-trimester maternal smoking, and alcohol consumption during pregnancy did not explain the sex difference (Abramowicz 2003). Infants born with other malformations such as those involving the respiratory system, eyes, ears, upper alimentary tract and other musculoskeletal anomalies are at increased risk for having cleft lip and/or cleft palate (Shaw 2002). Additionally, infants with oral clefts were more likely to have congenital heart disease; however, these diseases were more likely to be associated with a syndrome than with an isolated cleft (Barbosa 2003). Other malformations associated with clefting include respiratory system defects (Shaw 2003).
FACTORS IN LIFESTYLE OR ENVIRONMENT
Overall, environmental factors are considered much less important than genetic factors in the etiology of oral clefts (Christensen 1995, Fraser 1970).
Maternal intake of vasoactive drugs, which include pseudoephedrine, aspirin, ibuprofen, amphetamine, cocaine, or ecstasy, as well as cigarette smoking, have been associated with higher risk for oral clefts (Beaty 1997, Erikson 1979, Khaoury 1989, Lammer 2004, Munger 1996, Rosenburg 1982). Anticonvulsant medications such as phenobarbital, trimethadione, valproate, and dilantin have been documented to increase incidence of cleft lip and/or cleft palate (Ardinger 1988, Feldman 1977, Hanson 1976, Hanson 1984, Holmes 2004, Kallen 2003, Meadow 1970, Wyszynski 1996, Zackai 1975). However, there is some question as to whether this increase is due to the medications or the underlying epilepsy (Wyszynski 1996). Isotretinoin (Accutane) has been identified as potential causative factors for oral clefts (Benke 1984, Lammer 1985). Diazepam (Valium) and Bendectin have not been found to increase the rate of oral clefts (Mitchell 1981, Rosenberg 1983). An association between maternal intake of sulfasalazine, naproxen, and glucocortisoids during the first trimester has been suggested (Kallen 2003). Aminopterin (a cancer drug) has also been linked to the development of oral clefts (Warkany 1978).
Children born to mothers with ulcerative colitis were not found to be at higher risk for oral clefts (Norgard 2003).
Maternal smoking has been linked to cleft lip and palate in offspring (Little 2004, Little 2004, Lorente 2000, Christianson 1980, Erikson 1979, Higgins 2002, Khoury 1987, Khoury 1989, Lieff 1999, Shiono 1986, Van Den Eeden 1990, van Rooij 2003, Werler 1990, Werler 1997, Wyszynski 2002). A different study indicated that smoking during pregnancy was a minor risk factor in oral clefting, and was dose related (Wyszynski 2002). Other research indicated an association between maternal smoking and cleft palate, but not maternal smoking and cleft lip, with or without cleft palate (Meyer 2004). In addition, there is evidence that there may be a strong interaction between certain maternal and/or infant gene variations and smoking leading to oral clefts in the infant (Hwang 1995, Shaw 1996, Fallin 2003, Lammer 2004).
Alcohol may increase the risk of oral clefts (Lorente 2000, Clarren 1978, Hassler 1986, Munger 1996, Shaw 1999a, Streissguth 1980, Werler 1991). However, another researcher did not find this association (Meyer 2003).
Corticosteroids, either used topically or systemically have a slight association with an increased risk of orofacial clefting (Edwards 2003, Pradat 2003).
One study found that the use of dimenhydrinate (an anti-nausea or vomiting drug) was more common among mothers of subjects with cleft palate, whereas iron seemed to have a protective effect against this condition (Czeizel 2003). One study found a lower rate of oral clefts among the offspring of women who had experienced hyperemesis gravidarum (severe “morning sickness” with vomiting) (Czeizel 2003).
Caffeine has not been linked to oral cleft risk (Rosenberg 1982).
Maternal occupational exposure to glycol ethers, a chemical found in a variety of domestic and industrial products, has been reported to increase the rate of cleft lip (Cordier 1997). Exposure to organic solvents such as xylene, toluene, and acetone has also been reported to increase the rate of this defect (Holmberg 1982, Wyszynski 1996). Maternal occupationsincluding services such as hairdressing, agriculture, and leather or shoe manufacturing as well as exposure to pesticides, lead, and aliphatic acids have been reported to increase rates of oral clefts (Bianchi 1997, Garcia 1998, Lorente 2000, Wyszynski 1996); however, other studies failed to find a link between pesticides and oral cleft risk (Shaw 1995a, Wyszynski 1996). One study failed to find any link betweenparental occupational exposure to lead and oral cleft risk. However, the number of cases in the study was small, and the measure of lead exposure was based on census records (Irgens 1998). Maternal exposure to general laboratory chemicals was not seen as a significant, however exposure to organic solvents, specifically benzene, was seen as a contributing factor to an increase in neural crest malformations in offspring, including orofacial clefting (Wennborg 2005).
Living in proximity to hazardous waste sites does not appear to increase risk for cleft lip and palate (Croen 1997), nor does parental occupational exposure to 50 Hz magnetic fields (Blaasaas 2002). Studies have been unable to find conclusive evidence of an effect of exposure to water chlorination and chlorination byproducts (Hwang 2002 and 2003).
One study (Shaw 1999b) found that periconceptional use of electric bed-heating devices (electric blankets, bed warmers, and heated waterbeds) did not appear to affect risk for oral clefts. Maternal fever was associated with increased risk, but multivitamin supplements appeared to lower this risk. (Botto 2002).
It has been suggested that nutrition plays a role in the manifestation of oral clefts. Maternal periconceptional use of folic acid has been found to reduce the risk of neural tube defects. As a result, the question has been raised about whether there is a similar protective effect for other birth defects, including oral clefts. Maternal multivitamin use has been found to result in a significant reduction in cleft palate risk and a nonsignificant reduction in cleft lip risk (Werler 1999). Several studies have reported decreased rates of cleft lip and palate with folic acid use (Czeizel 1996, Malek 2003, Mulinare 1995, Munger 1997, Shaw 1995b, Shaw 2002, Tolarova 1995), while other studies have failed to find such an effect (Hays 1996). Some ambiguity of the studies may be explained by a recent study that found oral cleft risk can be reduced only by high doses of folic acid consumed at the time of lip and palate formation (Czeizel 1999). B vitamins and zinc have also been reported to reduce risk of oral clefts (Munger 1997, Munger 2004, Krapels 2004), as well as vitamin A (Mitchell 2003). In addition, mothers with the MTHFR 677TT or MTHFR 1298CC genotype and low periconceptional folate intake were found to have an increased risk for cleft lip with or without cleft palate among their offspring (Jugessur 2003, van Rooij 2003).
Birth prevalence in the United States for cleft lip with or without cleft palate ranges between 4.80 and 17.47 per 10,000 live births, and the range of rates for cleft palate without cleft lip ranges from 2.80 to 13.45 (National Birth Defects Prevention Network 2005). The rate in Texas for 1999-2002 deliveries was 10.78 cases of cleft lip with or without cleft palate per 10,000 live births and 5.87 for cleft palate alone (Texas Department of State Health Services 2005). Differences in prevalence may be due to differences in case inclusion criteria
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