Oral and maxillofacial surgery| Volume 122, ISSUE 6, P680-690, December 2016

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Maternal active smoking and risk of oral clefts: a meta-analysis

Published:August 18, 2016DOI:


      To assess the association between maternal active cigarette smoking and the risk of oral clefts in the offspring.

      Study Design

      Oral clefts are divided into three subgroups: total clefts, cleft lip with or without cleft palate (CL ± P), and cleft palate only (CP). Data from studies on different levels of smoking were gathered to examine the dose–response effect.


      The present meta-analysis included 29 case-control and cohort studies through Cochrane, PubMed, and Ovid Medline searches. A modest but statistically significant association was found between maternal active smoking and CL ± P (odds ratio [OR] 1.368; 95% confidence interval [CI] 1.259-1.486) as well as CP (OR 1.241; 95% CI 1.117-1.378). Half the studies showed positive dose–response effect for each subgroup (test for linear trend, P < .05).


      There is a moderate risk for having a child with a CL ± P or CP in women who smoke during pregnancy. We could not confirm whether there was a positive dose–response effect between maternal smoking and clefts.
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        • Derijcke A.
        • Eerens A.
        • Carels C.
        The incidence of oral clefts: a review.
        Br J Oral Max Surg. 1996; 34: 488-494
        • Vanderas A.P.
        Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review.
        Cleft Palate J. 1987; 24: 216-225
        • Trasler D.G.
        • Fraser F.C.
        Role of the tongue in producing cleft palate in mice with spontaneous cleft lip.
        Dev Biol. 1963; 6: 45-60
        • Fraser F.C.
        The genetics of cleft lip and cleft palate.
        Am J Hum Genet. 1970; 22: 336-352
        • DeRoo L.A.
        • Gaudino J.A.
        • Edmonds L.D.
        Orofacial cleft malformations: associations with maternal and infant characteristics in Washington State.
        Birth Defects Res A Clin Mol Teratol. 2003; 67: 637-642
        • Khoury M.J.
        • Gomez-Farias M.
        • Mulinare J.
        Does maternal cigarette smoking during pregnancy cause cleft lip and palate in offspring?.
        Am J Dis Child. 1989; 143: 333-337
        • Wong F.K.
        • Hagg U.
        An update on the aetiology of orofacial clefts.
        Hong Kong Med J. 2004; 10: 331-336
        • Bailey L.J.
        • Johnston M.C.
        • Billet J.
        Effects of carbon monoxide and hypoxia on cleft lip in A/J mice.
        Cleft Palate Craniofac J. 1995; 32: 14-19
        • Meng T.
        • Shi B.
        • Zheng Q.
        Clinical and epidemiologic studies of nonsyndromic cleft lip and palate in China: analysis of 4268 cases.
        Ann Plast Surg. 2006; 57: 264-269
        • Wyszynski D.F.
        • Duffy D.L.
        • Beaty T.H.
        Maternal cigarette smoking and oral clefts: a meta-analysis.
        Cleft Palate Craniofac J. 1997; 34: 206-210
        • Little J.
        • Cardy A.
        • Munger R.G.
        Tobacco smoking and oral clefts: a meta-analysis.
        B World Health Organ. 2004; 82: 213-218
        • Kelsey J.L.
        • Dwyer T.
        • Holford T.R.
        Maternal smoking and congenital malformations: an epidemiological study.
        J Epidemiol Commun H. 1978; 32: 102-107
        • van Rooij I.A.
        • Wegerif M.J.
        • Roelofs H.M.
        Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene-environment interaction.
        Epidemiology. 2001; 12: 502-507
        • Chung K.C.
        • Kowalski C.P.
        • Kim H.M.
        Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate.
        Plas Reconstr Surg. 2000; 105: 485-491
        • Leite I.C.
        • Koifman S.
        Oral clefts, consanguinity, parental tobacco and alcohol use: a case-control study in Rio de Janeiro.
        Brazil Braz Oral Res. 2009; 23: 31-37
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Egger M.
        • Smith G.D.
        • Schneider M.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Khoury M.J.
        • Weinstein A.
        • Panny S.
        Maternal cigarette smoking and oral clefts: a population-based study.
        Am J Public Health. 1987; 77: 623-625
        • Malloy M.H.
        • Kleinman J.C.
        • Bakewell J.M.
        Maternal smoking during pregnancy: no association with congenital malformations in Missouri 1980-83.
        Am J Public Health. 1989; 79: 1243-1246
        • Werler M.M.
        • Lammer E.J.
        • Rosenberg L.
        Maternal cigarette smoking during pregnancy in relation to oral clefts.
        Am J Epidemiol. 1990; 132: 926-932
        • Eeden S.K.
        • Karagas M.R.
        • Daling J.R.
        A case-control study of maternal smoking and congenital malformations.
        Paediatr Perinat Ep. 1990; 4: 147-155
        • Seidman D.S.
        • Ever-Hadani P.
        • Gale R.
        Effect of maternal smoking and age on congenital anomalies.
        Obstet Gynecol. 1990; 76: 1046-1050
        • Van Rooij I.A.
        • Groenen P.M.
        • van Drongelen M.
        Orofacial clefts and spina bifida: N-acetyltransferase phenotype, maternal smoking, and medication use.
        Teratology. 2002; 66: 260-266
        • Shaw G.M.
        • Iovannisci D.M.
        • Yang W.
        Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts.
        Am J Epidemiol. 2005; 162: 1207-1214
        • Honein M.A.
        • Rasmussen S.A.
        • Reefhuis J.
        Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts.
        Epidemiology. 2007; 18: 226-233
        • Lie R.T.
        • Wilcox A.J.
        • Taylor J.
        Maternal smoking and oral clefts: the role of detoxification pathway genes.
        Epidemiology. 2008; 19: 606-615
        • Carmichael S.L.
        • Yang W.
        • Feldkamp M.L.
        Reduced risks of neural tube defects and orofacial clefts with higher diet quality.
        Arch Pediatr Adolesc Med. 2012; 166: 121-126
        • Shi M.
        • Christensen K.
        • Weinberg C.R.
        Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.
        Am J Hum Genet. 2007; 80: 76-90
        • Saxén I.
        Cleft lip and palate in Finland: parental histories, course of pregnancy and selected environmental factors.
        Int J Epidemiol. 1974; 3: 263-270
        • Evans D.R.
        • Newcombe R.G.
        • Campbell H.
        Maternal smoking habits and congenital malformations: a population study.
        BMJ. 1979; 2: 171
        • Ericson A.
        • Kallen B.
        • Westerholm P.
        Cigarette smoking as an etiologic factor in cleft lip and palate.
        Am J Obstet Gynecol. 1979; 135: 348-351
        • Shiono P.H.
        • Klebanoff M.A.
        • Berendes H.W.
        Congenital malformations and maternal smoking during pregnancy.
        Teratology. 1986; 34: 65-71
        • McDonald A.D.
        • Armstrong B.G.
        • Sloan M.
        Cigarette, alcohol, and coffee consumption and congenital defects.
        Am J Public Health. 1992; 82: 91-93
        • Hwang S.J.
        • Beaty T.H.
        • Panny S.R.
        Association study of transforming growth factor alpha (TGFα) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants with birth defects.
        Am J Epidemiol. 1995; 141: 629-636
        • Shaw G.M.
        • Wasserman C.R.
        • Lammer E.J.
        Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants.
        Am J Hum Genet. 1996; 58: 551-561
        • Källén K.
        Maternal smoking and orofacial clefts.
        Cleft Palate Craniofac J. 1997; 34: 11-16
        • Lieff S.
        • Olshan A.F.
        • Werler M.
        Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns.
        Am J Epidemiol. 1999; 150: 683-694
        • Romitti P.A.
        • Lidral A.C.
        • Munger R.G.
        Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts.
        Teratology. 1999; 59: 39-50
        • Lorente C.
        • Cordier S.
        • Goujard J.
        Tobacco and alcohol use during pregnancy and risk of oral clefts. Occupational Exposure and Congenital Malformation Working Group.
        Am J Public Health. 2000; 90: 415
        • Beaty T.H.
        • Wang H.
        • Hetmanski J.B.
        A case-control study of nonsyndromic oral clefts in Maryland.
        Ann Epidemiol. 2001; 11: 434-442
        • Wyszynski D.F.
        • Wu T.
        Use of US birth certificate data to estimate the risk of maternal cigarette smoking for oral clefting.
        Cleft Palate-Cran J. 2002; 39: 188-192
        • Meyer K.A.
        • Williams P.
        • Hernandez-Diaz S.
        Smoking and the risk of oral clefts: exploring the impact of study designs.
        Epidemiology. 2004; 15: 671-678
        • Bille C.
        • Olsen J.
        • Vach W.
        Oral clefts and life style factors—a case-cohort study based on prospective Danish data.
        Eur J Epidemiol. 2007; 22: 173-181
        • Chevrier C.
        • Bahuau M.
        • Perret C.
        Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft.
        Am J Med Genet A. 2008; 146: 2396-2406
        • Grewal J.
        • Carmichael S.L.
        • Ma C.
        Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies.
        Birth Defects Res A Clin Mol Teratol. 2008; 82: 519-526
        • Krapels I.P.
        • Raijmakers-Eichhorn J.
        • Peters W.H.
        The I105 V polymorphism in glutathione S-transferase P1, parental smoking and the risk for nonsyndromic cleft lip with or without cleft palate.
        Eur J Hum Genet. 2008; 16: 358-366
        • MacLehose R.F.
        • Olshan A.F.
        • Herring A.H.
        Bayesian methods for correcting misclassification: an example from birth defects epidemiology.
        Epidemiology. 2009; 20: 27-35
        • Lebby K.D.
        • Tan F.
        • Brown C.P.
        Maternal factors and disparities associated with oral clefts.
        Ethnic Dis. 2010; 20 (S1-146-9)
        • Marshall E.G.
        • Harris G.
        • Wartenberg D.
        Oral cleft defects and maternal exposure to ambient air pollutants in New Jersey.
        Birth Defects Res A Clin Mol Teratol. 2010; 88: 205-215
        • Zhang B.
        • Jiao X.H.
        • Mao L.M.
        Cigarette smoke exposure before pregnancy and the associated risk of having a child with orofacial clefts in China: a case-control study.
        Plast Reconstr Surg. 2011; 127: 61e-62e
        • Chenevix-Trench G.
        • Jones K.
        • Green A.C.
        Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci.
        Am J Hum Genet. 1992; 51: 1377-1385
        • Lidral A.C.
        • Romitti P.A.
        • Basart A.M.
        Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.
        Am J Hum Genet. 1998; 63: 557-568
        • Jianyan L.
        • Zeqiang G.
        • Yongjuan C.
        Analysis of interactions between genetic variants of BMP4 and environmental factors with nonsyndromic cleft lip with or without cleft palate susceptibility.
        Int J Oral Max Surg. 2010; 39: 50-56
        • Savitz D.A.
        • Schwingl P.J.
        • Keels M.A.
        Influence of paternal age, smoking, and alcohol consumption on congenital anomalies.
        Teratology. 1991; 44: 429-440
        • Li Z.
        • Liu J.
        • Ye R.
        Maternal passive smoking and risk of cleft lip with or without cleft palate.
        Epidemiology. 2010; 21: 240-242
        • Jia Z.L.
        • Li Y.
        • Li L.
        Association among IRF6 polymorphism, environmental factors, and nonsyndromic orofacial clefts in western China.
        DNA Cell Biol. 2009; 28: 249-257
        • Guo Z.
        • Huang C.
        • Ding K.
        Transforming growth factor beta-3 and environmental factors and cleft lip with/without cleft palate.
        DNA Cell Biol. 2010; 29: 375-380
        • Sabbaqh H.J.
        • Hassan M.H.
        • Innes N.P.
        Passive smoking in the etiology of non-syndromic orofacial clefts: a systematic review and meta-analysis.
        PLoS One. 2015; 10: e0116963