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Title Prevention Of Orofacial Clefts
Clinical Question Is smoking cessation or increased dietary folic acid intake associated with prevention of orofacial clefts?
Clinical Bottom Line Increased folic acid intake and cessation of smoking before and during pregnancy may reduce the incidence of cleft lip with or without cleft palate. (See Comments on the CAT below)
Best Evidence (you may view more info by clicking on the PubMed ID link)
PubMed ID Author / Year Patient Group Study type
(level of evidence)
#1) 17259187Wilcox AJ 2007Infants born in Norway between 1996 and 2001 who had been referred for surgical treatment of a cleft lip or palate which consisted of 377 infants with cleft lip with or without cleft palate and 196 infants with cleft palate alone. 763 infants born in Norway during the same time were also selected as controls.National population based case-control study
Key resultsFolic acid intake of 400 μg or more a day during early pregnancy was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors [odds ratio 0.61, 95% confidence interval 0.39 to 0.96]. Diets with high folate containing foods such as fruits and vegetables reduced the risk somewhat [odds ratio 0.75, 0.50 to 1.11]. Lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins [0.36, 0.17 to 0.77]. No protection against cleft palate alone was noted [1.07, 0.56 to 2.03].
#2) 17133404Badovinac, RL 2006Studies included into this meta-anaylsis were five prospective intervention trial and cohort studies along with 12 case control studies that looked at the association between the effect of folic acid supplementation on the prevalence of oral facial clefts.Meta-analysis
Key resultsWhen reviewing the five prospective trials included in the analysis, the combined results gave the relative risk for all clefts as 0.55 [95% confidence interval; 0.39, 0.95], combined results for relative risk for cleft lip was 0.51 [95% confidence interval; 0.26, 0.98] and combined results for relative risk for cleft palate was 1.19 [95% confidence interval; 0.43,3,28]. Examining the 12 case control studies gave a relative risk for all clefts was 0.77 [95% confidence interval; 0.65, 0.90], combined relative risk for cleft lip was 0.72 [95% confidence interval; 0.58, 0.87] and combined relative risk for cleft palate was 0.80 [95% confidence interval; 0.69,0.93]. After examination of all relative risks it was found that supplementing with folic acid during pregnancy might protect against oral clefts and discussed the importance of taking a multivitamin during pregnancy.
#3) 10697150Chung KC 20002207 newborns with cleft lip/palate without other associated congenital anomalies and 4414 controls, those with no congenital disabilities, were randomly selected from newborns from the National Center for Health Statistics 1996 Natality database. Study subjects without smoking history were excluded; therefore all cases and controls contained history of smoking. Retrospective Cohort Study
Key resultsSignificant association was found between any amount of maternal cigarette use during pregnancy and having a child with cleft lip/palate, unadjusted odds ratio 1.55 (1.36, 1.76), p < 0.001. After adjusting for confounders, such as maternal education level, age, race, and maternal medical conditions, the odds ratio remained significant, odds ratio 1.34 (1.16, 1.54), p < 0.001. Dose response of cigarette smoking during pregnancy divided into three groups based on consumption with their associated dose-response relationships when comparing smoking category to the non-smoking control group: 1 to 10 cigarettes per day [1.50 (1.28, 1.76)], 11 to 20 cigarettes per day [1.55 (1.23, 1.95)], and 21 or more cigarettes per day [1.78 (1.22, 2.59)].
Evidence Search ("smoking"[MeSH Terms] OR "smoking"[All Fields]) AND ("cleft lip"[MeSH Terms] OR ("cleft"[All Fields] AND "lip"[All Fields]) OR "cleft lip"[All Fields]) AND ("palate"[MeSH Terms] OR "palate"[All Fields]) (“cleft palate” [MeSH Terms] ("folic acid"[MeSH Terms] OR ("folic"[All Fields] AND "acid"[All Fields]) OR "folic acid"[All Fields]) AND supplements[All Fields] AND ("risk"[MeSH Terms] OR "risk"[All Fields] OR "risk of"[All Fields]) AND ("face"[MeSH Terms] OR "face"[All Fields] OR "facial"[All Fields]) AND clefts[All Fields]
Comments on
The Evidence
When looking at the risk factors associated with orofacial clefts, case controlled studies, such as the study by Wilcox, found that the intake of 400 μg or more a day of folic acid before and during the early stages of pregnancy seems to reduce the risk of isolated cleft lip with or without cleft palate by about a third. This study had a small number of subjects and there were many confounding variables, such as multivitamins and diets rich in fruits and vegetables, which are believed to reduce the risks. The meta-analysis by Badovinac also discussed the importance of folic acid but revealed the high potential for bias and uncontrolled confounding when reviewing the results of the studies with regards to folic acid intake and the risk associated with development of oral facial clefts. Retrospective cohort studies, such as Chung’s have found that after adjusting for confounding variables cigarette smoking during pregnancy was significantly associated with a risk of having a newborn with cleft lip/palate and that there was a dose response curve. While this study is weak in that it is a retrospective cohort, they did examine over 2200 cases, they adjusted for confounds and excluded patients without a smoking history. From the evidence presented it could be stated that increases in folic acid intake and a cessation of smoking before and during pregnancy may reduce the incidence of cleft lip with or without cleft palate.
Applicability Target population is women who are of child bearing age and are considering having children.
Specialty/Discipline (Public Health) (General Dentistry) (Pediatric Dentistry)
Keywords orofacial clefts, cleft lip, cleft palate, smoking, folic acid
ID# 879
Date of submission: 05/05/2011spacer
E-mail meisterj@uthscsa.edu
Author David Meister
Co-author(s) e-mail
Faculty mentor/Co-author Peter T. Gakunga, BDS, MS, PhD
Faculty mentor/Co-author e-mail GAKUNGA@uthscsa.edu
Basic Science Rationale
(Mechanisms that may account for and/or explain the clinical question, i.e. is the answer to the clinical question consistent with basic biological, physical and/or behavioral science principles, laws and research?)
post a rationale
None available
Comments on the CAT
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by Nancy Quach & Brandon Pitcher (San Antonio, TX) on 10/03/2014
A PubMed search conducted in Sept 2014 found more recent evidence on the subject. Butali (2013) (PMID: 23670871) conducted a case control study on the genetic level. Individual participant data meta-analysis was used to give the findings greater statistical power. The findings concur with previous studies suggesting that folic acid and smoking influence oral facial cleft outcomes.

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