The aim of this study was to investigate the effect of environmental factors, such as tobacco, alcohol and folic acid intake, obesity, stressful events, low blood levels of zinc and fever during pregnancy, on the incidence of cleft lip and/or palate (CL ± P). An electronic search was performed in the Cochrane Reviews, the ISI Web of Knowledge, PubMed and Scopus, along with a manual search to identify other relevant case–control and cohort studies. Quality assessments and an evaluation of publication bias were undertaken. Statistical heterogeneity was examined, and odds ratios (ORs) and 95% confidence intervals (CI) estimated using the random effects model. Of 372 articles initially retrieved, 28 studies were selected as eligible for meta-analysis. No evidence of publication bias was found using funnel plot analysis and the Egger linear regression method. Many studies were classified as low quality due to inadequate case–control data. On the basis of this research, maternal factors most associated with CL ± P were: tobacco (OR 1.48), alcohol (OR 1.28), folic acid intake (OR 0.77), obesity (OR 1.26), stressful events (OR 1.41), low blood zinc levels (OR 1.82), and fever during pregnancy (OR 1.30). Folic acid intake by the mother reduced the risk of CL ± P in offspring (OR 0.77).
Cleft lip and/or palate (CL ± P) is a frequent congenital malformation of the head and neck. It results from non-closure of specific facial structures implicated in lip and palate formation during weeks 5–9 of pregnancy. Affected infants require multidisciplinary surgical and non-surgical care, including that of psychologists, speech therapists, oral and maxillofacial surgeons, paediatric dentists, ear, nose and throat specialists and orthodontists, from birth until adulthood. Dental anomalies are frequently found in CL ± P subjects. Abnormal dental conditions include tooth agenesis, supernumerary teeth, microdontia, fused teeth, ectopic eruptions and taurodontism. In orthodontic terms, patients with oral clefts present problems of growth, with the maxilla being recessive relative to the jaw. Such patients require orthodontic treatment, and possibly orthognathic surgery, when growth stops.
The aetiology of oral clefts is not fully understood, but the best evidence today suggests a multifactorial origin for this type of birth defect, with both genetic and environmental causal factors. The first term in pregnancy is the most sensitive period in the aetiology of this malformation. At this early stage, interaction with teratogens can lead to alterations in embryogenesis. The worldwide prevalence of the anomaly at birth is high, and depends on ethnic factors and geographic origin. Previous studies have identified a number of factors associated with orofacial clefts, including alcohol, tobacco, stress, obesity, low zinc concentrations, folic acid intake and fever during pregnancy. Owing to the high incidence of this disfiguring craniofacial anomaly, even the slightest reduction in environmental risk factors can lead to significant benefits to public health. The aim of this meta-analysis was to critically evaluate the various environmental factors that the literature suggests are associated with CL ± P.
Material and methods
The first phase of the meta-analysis was to develop a specific protocol. The MOOSE guidelines for reporting meta-analyses formed the basis of data presentation. To minimize bias in locating studies, a detailed search of appropriate electronic database citations of potentially relevant trials published in journals, dissertations, and conference proceedings was carried out. The authors also searched databases in the research register to identify unpublished or ongoing studies that might also be of relevance. The search ended in January 2011 and included computerized bibliographic searches of the Cochrane Controlled Trials Register, MEDLINE (1966 to January 2011), PubMed (1966 to January 2011), EMBASE (1974 to January), and ISI proceedings (from inception to January 2011). Search terms were: “cleft lip” [mh] OR “cleft palate” [mh] AND (“aetiology” OR “causality” OR “risk factor” OR “tobacco” OR “alcohol” OR “obesity” OR “maternal age” OR “zinc” OR “folic acid” OR “stress” OR “illness”). A manual search was also carried out to identify other relevant studies. No restrictions were placed on the year, publication status or language of the retrieved trials. In order to be included in the study, every article had to fulfil the selection criteria, which are detailed in Table 1 . Articles were not selected if they failed to meet the inclusion criteria, did not relate to this topic, or were related but had a different aim. Other criteria for exclusion were: small sample size; case reports or reports of cases; case series; authors’ replies; studies of genetic aetiology; studies that used animals; insufficient or unclear data.