Meta Analysis Cleft Lip and Palate Maternal biomarkers of methylation status and non- syndromic orofacial cleft risk: a meta-analysis R. Blanco, A. Colombo, R. Pardo, J. Suazo: Maternal biomarkers of methylation status and non-syndromic orofacial cleft risk: a meta-analysis. Int. J. Oral Maxillofac. Surg. 2016; 45: 1323–1332. # 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. R. Blanco 1 , A. Colombo 2 , R. Pardo 3,4,5 , J. Suazo 6 1 Program of Human Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile; 2 Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile; 3 Seccio ´n de Gene ´ tica, Hospital Clı ´nico Universidad de Chile, Santiago, Chile; 4 Unidad de Neonatologı ´a, Hospital Clı ´nico Universidad de Chile, Santiago, Chile; 5 Unidad de Gene ´ tica, Hospital Dr. So ´tero del Rı ´o, Santiago, Chile; 6 Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile Abstract. Animal models have shown evidence of the role of maternal methyl donor status and its metabolism (one-carbon metabolism) in normal embryonic maxillofacial development. Nevertheless, studies in humans have shown conflicting results for the association of maternal methylation status biomarkers in the aetiology of the main craniofacial birth defects: non-syndromic orofacial clefts (NSOFCs). The aim of this study was to perform a meta-analysis assessing the relationship between maternal levels of methylation status biomarkers (plasma and erythrocyte folates and plasma vitamin B12 and homocysteine) and the risk of NSOFCs. A literature search of the conventional and grey medical–scientific databases identified 12 studies considering these variables. Based on standardized differences between means among cases and controls (Cohen’s d test), evidence was found of an association only with high plasma homocysteine (d = 0.37; P = 0.026) when single effects were pooled. In addition to its usefulness as a marker of poor methyl- donor intake and/or metabolism, homocysteine appears to have a teratogenic effect. Although the results are based on a relatively small number of reports and/or studies of small sample sizes showing between-study heterogeneity, these problems were resolved by including an additional analysis. Therefore these findings constitute a real contribution towards explaining the complex aetiology of orofacial clefts. Key words: orofacial clefts; folate; vitamin B12; homocysteine; meta-analysis. Accepted for publication 14 June 2016 Available online 27 June 2016 Orofacial clefts (OFCs) are the most common birth defects affecting the cra- niofacial structures. The average preva- lence of OFCs varies according to ethnic origin, geographic location, and socio- economic status, among other factors. 1 OFCs are generally classified as cleft palate only (CPO), cleft lip only (CL), or cleft lip with cleft palate (CLP). The latter two categories are historically re- ferred to as cleft lip with or without cleft palate (CL/P). 2 Approximately 70% of OFCs are non-syndromic (NSOFCs), oc- curring as isolated conditions without any other apparently structural or cogni- tive abnormality. The remaining 30% are defects found as part of more than 300 recognizable genetic syndromes. 1,2 The Int. J. Oral Maxillofac. Surg. 2016; 45: 1323–1332 http://dx.doi.org/10.1016/j.ijom.2016.06.011, available online at http://www.sciencedirect.com 0901-5027/01101323 + 010 # 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.