Oxidative balance scores and neural crest cell-related congenital anomalies.

Oxidative stress and redox imbalance adversely affect embryonic development. We developed two oxidative balance scores (OBS) that include dietary and nondietary exposures. We hypothesized that higher scores (i.e., lower oxidative stress) would be associated with lower risk of neural tube defects, orofacial clefts, conotruncal heart defects, and limb deficiencies. We used data from the National Birth Defects Prevention Study to create a dietary OBS based on intake of 13 nutrients and an overall OBS that included the 13 nutrients and eight additional nondietary factors related to oxidative balance (e.g., smoking). We used logistic regression to examine odds ratios associated with having low or high scores (i.e., <10th or >90th percentiles). Continuous models indicated reduced odds associated with high versus low scores (i.e., comparing odds at the 90th versus 10th percentile values of the distribution) on the overall OBS for cleft lip with or without cleft palate [adjusted odds ratio (aOR) 0.72, 95% confidence interval (CI) 0.63-0.82], longitudinal limb deficiency (aOR 0.73, CI 0.54-0.99), and transverse limb deficiency (aOR 0.74, CI 0.58-0.95); increased odds for anencephaly (aOR 1.40, CI 1.07-1.84); and primarily nonsignificant associations with conotruncal heart defects. Results for the dietary OBS were similar. This study provides some evidence that oxidative stress contributes to congenital anomalies related to neural crest cell development.

Health outcomes of smoking during pregnancy and the postpartum period: an umbrella review.

BACKGROUND: Smoking during pregnancy (SDP) and the postpartum period has serious health outcomes for the mother and infant. Although some systematic reviews have shown the impact of maternal SDP on particular conditions, a systematic review examining the overall health outcomes has not been published. Hence, this paper aimed to conduct an umbrella review on this issue. METHODS: A systematic review of systematic reviews (umbrella review) was conducted according to a protocol submitted to PROSPERO ( CRD42018086350 ). CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science, CRD Database and HMIC databases were searched to include all studies published in English by 31 December 2017, except those focusing exclusively on low-income countries. Two researchers conducted the study selection and quality assessment independently. RESULTS: The review included 64 studies analysing the relationship between maternal SDP and 46 health conditions. The highest increase in risks was found for sudden infant death syndrome, asthma, stillbirth, low birth weight and obesity amongst infants. The impact of SDP was associated with the number of cigarettes consumed. According to the causal link analysis, five mother-related and ten infant-related conditions had a causal link with SDP. In addition, some studies reported protective impacts of SDP on pre-eclampsia, hyperemesis gravidarum and skin defects on infants. The review identified important gaps in the literature regarding the dose-response association, exposure window, postnatal smoking. CONCLUSIONS: The review shows that maternal SDP is not only associated with short-term health conditions (e.g. preterm birth, oral clefts) but also some which can have life-long detrimental impacts (e.g. obesity, intellectual impairment). IMPLICATIONS: This umbrella review provides a comprehensive analysis of the overall health impacts of SDP. The study findings indicate that while estimating health and cost outcomes of SDP, long-term health impacts should be considered as well as short-term effects since studies not including the long-term outcomes would underestimate the magnitude of the issue. Also, interventions for pregnant women who smoke should consider the impact of reducing smoking due to health benefits on mothers and infants, and not solely cessation.

[Pharmacovigilance update]. / Pharmacovigilance.

The main pharmacovigilance updates in 2020 are reviewed. Remdesivir in COVID-19: relatively safe but turns out to be less effective than expected. Hydroxychloroquine in COVID-19 : lack of efficacy and risk of arrhythmias. Cytokines storm in COVID-19: may impact pharmacokinetics. VEGF inhibitors: risk of aneurysm and artery dissection. Tofacitinib: dose-dependant risk of venous thromboembolic events. Ondansetron in the first trimester of pregnancy : a highly debated risk of orofacial cleft defects. Fingolimod : contraindicated during pregnancy due to suspected risk of congenital malformations. Ranitidine: global market withdrawal due to contamination with nitrosamines. Ulipristal for uterine fibroids : market withdrawal due to risk of severe liver injury. Ingenol mebutate : market withdrawal due to paradoxical risk of skin cancers.

Les principales actualités de pharmacovigilance 2020 sont passées en revue. Remdésivir et Covid-19 : moins efficace qu'attendu mais assez sûr. Hydroxychloroquine et Covid-19 : absence d'efficacité et risque d'arythmies. Orage cytokinique et Covid-19 : impact possible sur les paramètres pharmacocinétiques. Inhibiteurs du VEGF : risque d'anévrisme artériel et de dissection. Tofacitinib : risque d'événements thromboemboliques. Ondansétron au 1er trimestre de grossesse : risque controversé de fentes palatines. Fingolimod : contre-indiqué dans la grossesse pour possible risque malformatif. Ranitidine : retrait du marché mondial pour contamination par des nitrosamines. Ulipristal et fibromyomes utérins : retrait du marché pour risque d'atteinte hépatique grave. Mébutate d'ingénol : retrait du marché pour risque paradoxal de cancers cutanés.

Determinants and seasonality of major structural birth defects among newborns delivered at primary and referral hospital of East and West Gojjam zones, Northwest Ethiopia 2017-2018: case-control study.

OBJECTIVE: Although infant mortality because of birth defect has increased in both developed and developing countries, had not got attention like other health issues at national, regional, or local levels. Documenting the risk factors that influence the occurrence of birth defects and its seasonality will help to inform the community and to develop preventive strategies for the country. RESULTS: Factors associated with higher likelihood of a major structural birth defects included maternal age; neonates born from women living in urban; and in Dega; history of fever during pregnancy; intake of herbal medicine; and drinking alcohol. Counselling for pregnancy preparation and folic acid supplementation was found protective for the likelihood of birth defect.

Can contamination of the environment by dioxins cause craniofacial defects?

Cleft lip and cleft palate also known as orofacial cleft is a congenital malformation involving the partial or total lack of anatomical continuity of craniofacial tissue. The most common environmental factors that may cause orofacial clefts include pharmaceuticals, alcohol, addictive drugs, and tobacco smoke. Living in the area of industrial factories, garbage, ironworks, crematoria, wastewater treatment plants, and plastic waste landfills also has a significant impact on the development of the craniofacial defects. Some of the main factors causing the formation of congenital craniofacial defects are dioxins, of which emission to the environment is an important environmental and health problem. Dioxins are a diverse group of organic chemical compounds, derivatives of oxanthrene and fumarates, which are organoleptically imperceptible. Acting mainly through induction of inflammation, they influence a number of metabolic processes, including the process of bone mineralization and embryonic development. In this work, we highlight the problem of orofacial cleft including the impact of dioxin on development of this defect and the recommended prevention.

New molecular aspects in the mechanism of oromaxillofacial cleft prevention by B-vitamins.

Clinical and experimental studies show a clear positive effect of B-vitamins in the prevention of oromaxillofacial clefts, especially cleft lip and palate (CL/P). Hereby the local effect of thiamin (B1) in the amniotic fluid is very important for the embryonic facial development as seen in palatal organ models stimulated by topical B-vitamin application (Scheller et al., 2013a). Moreover a low B1 concentration in the serum and amniotic fluid was found in pregnant mice with clefts in their offspring (Scheller et al., 2013b). Immunochemical analyses of midface sections (ThTr-1 transporter) and the placenta (ThTr-2 transporter) of cleft fetuses with orofacial clefts showed an atypical cytoplasmatic localization (Scheller et al., 2017). mRNA nalyses of different B-vitamin transporters (B1, B2, B5, B7, B9) were performed and showed ThTr2 transporter in a short splice variant in all cleft fetuses. This splice variant may cause a functional loss of the transport capacity through the placenta barrier and result in a low amniotic fluid concentration of vitamin B1. All other analyzed transport proteins showed no functional change. These findings confirm the hypothesis that cleft prevention by high vitamin B1 substitution fails in genetically determined cleft mice, caused by an insufficient B1 uptake and missing local effect.

Impacto del Ácido Fólico en la Incidencia de Fisuras Labiopalatinas de la Población Occidente de la Región Metropolitana, Chile / Impact of Folic Acid on the Incidence of Cleft Lip and Palate of the Western Population of the Metropolitan Region, Chile

RESUMEN: La fisura labiopalatina ha tenido una alta frecuencia en la población chilena. A partir del 2000 se inició el programa de fortificación de la harina con ácido fólico a fin de disminuir los defectos del tubo neural. El objetivo de este estudio fue determinar el impacto que presenta la incorporación del ácido fólico en la incidencia de fisuras labiopalatinas de la población del área occidente de la Región Metropolitana. Se recopiló información a partir de las fichas clínicas de la Fundación Gantz seleccionando a los recién nacidos entre 1990 y 2009, correspondientes a las comunas del Servicio de Salud Occidente de la Región Metropolitana. Desde el 2000 hasta el 2004 se observó una disminución importante en las tasas de fisura labiopalatina, con una tasa de 0,88 fisurados por 1000 recién nacidos vivos. Posteriormente se observó un incremento a partir del 2005 hasta el 2009 llegando a una tasa de 1,52 fisurados por 1000 recién nacidos vivos. En conclusión, el efecto protector del ácido fólico se evidencia en la disminución de las tasas de los recién nacidos con fisuras durante los primeros años de su implementación. Sin embargo, posteriormente se observó un aumento de dichas tasas, lo cual podría deberse al incumplimiento de la norma.

ABSTRACT: Cleft lip and palate has had a high frequency in the Chilean population. From the year 2000 a flour fortification program with folic acid was initiated in order to reduce the defects of the neural tube. The objective of this study was to determine the impact of the incorporation of folic acid in the incidence of cleft lip and palate of the population of the western area of the Metropolitan Region. Information was collected from clinical records of the Gantz Foundation, selecting newborns from 1990 to 2009, corresponding to the districts of the western sector of the Metropolitan Region. From 2000 to 2004 there was a significant decrease in cleft lip and palate rates, with a rate of 0.88 cases per 1000 live births. Subsequently, an increase was observed from 2005 to 2009, reaching a rate of 1.52 cases per 1000 live births. In conclusion, the protective effect of folic acid is evidenced in the reduction of the rates of newborns with cleft palate during the first years of its implementation. However, an increase in these rates was subsequently observed, which could be due to noncompliance with the standard.

Oral vitamin B1-substitution does not decrease genetically determined cleft rate in mice (A/WySn).

PURPOSE: Cleft lip and palate (CL/P) are one of the most common human birth defects. Animal experiments and clinical investigations show a clear reduction of teratogenic clefts by a high-dose vitamin B supplementation during early pregnancy, especially in families at risk (reduction of recurrence). The aim of this work was to examine the influence of thiamine (vitamin B1) on CL/P appearance in genetically determined A/WySn mice within different supplementation starting points. MATERIALS AND METHODS: A total of 24 A/WySn female mice were orally supplemented with high doses (80 mg/kg) of thiamine at different times of pregnancy (5 groups, n = 90). The influence of thiamine on the abortion rate and CL/P appearance in the offspring was analyzed with respect to the concentration of thiamine in the serum and amniotic fluid (HPLC-chromatography). Immunochemical analyses of the ThTr-1 und ThTr-2 receptor-status were performed in midface sections of A/WySn-fetuses and the corresponding placenta, with and without CL/P. RESULTS: High doses of orally supplemented thiamine did not reduce the CL/P appearance in A/WySn mice. However, the different starting points of vitamin B1 substitution had some influence. Additionally, an obvious decrease in aborted fetuses was noticed in all supplemented groups. The oral substitution caused a clear increase of the serum concentration in all mothers, but showed no increase of the amniotic fluid concentration. Then immunohistochemistry detected an overexpression of ThTr-1 in the midface and an irregular localization of ThTr-2 in the placenta of fetuses with clefts. CONCLUSION: Our results suggest a time-dependent influence of thiamine on CL/P appearance in female mice. The prophylactic/periconceptional, but not the therapeutic supplementation, starting point can be proposed as a crucial step for regular facial and palatal fusion in embryonic development. The absolute rate of CL/P was not reduced, and the concentration of the water-soluble thiamine could not increase in the amniotic fluid. Thus the proposed local effect of thiamine failed in the development of genetically determined mice.

[Cleft lip/palate and flour fortification with folic acid in Chile]. / Fisuras labio-palatinas y fortificación de la harina con ácido fólico en Chile: An exploratory study.

BACKGROUND: The effect of food fortification with folic acid on the incidence of lip-palate fissures (FLP) is under discussion. AIM: To calculate the rate of hospital discharges due to cleft lip and palate (CLP) and explore whether they decreased after the start of folic acid fortification in Chile. MATERIAL AND METHODS: The hospital discharge databases published by the Chilean Ministry of Health were analyzed. The trends of discharge rates due to CLP of children of less than one year of life (ICD-10 Q350-379 code) and live births (lb) were calculated from 1986 to 2012. Variables such as incidence of rubella, poverty rate, obesity in pregnant women, and percentage of women who smoked or drank alcohol in the last month were included. The relative risk (RR) of CLP pre-fortification (1986-1999) and post-fortification (2000-2010) was calculated. Mixed and Prais-Winsten models were used to adjust other variables. RESULTS: The hospital discharge rate due to CLP decreased from 1.88 x 1,000 lb during 1986-1996 to 1.68 x 1,000 lb (RR = 1.09 (95% CI 1.05-1.14, p < 0.001). Prais-Winsten and Mixed models, determined that folic acid fortification is the variable explaining this decrease. During 2004-2011, hospital discharge rates for cleft lip decreased but there was an increase in the figures for cleft lip and palate. CONCLUSIONS: The 9% decrease in hospital discharge rates for CLP is concomitant with wheat folic acid fortification.

Fisuras labio-palatinas y fortificación de la harina con ácido fólico en Chile: an exploratory study / Cleft lip/palate and flour fortification with folic acid in Chile

Background: The effect of food fortification with folic acid on the incidence of lip-palate fissures (FLP) is under discussion. Aim: To calculate the rate of hospital discharges due to cleft lip and palate (CLP) and explore whether they decreased after the start of folic acid fortification in Chile. Material and Methods: The hospital discharge databases published by the Chilean Ministry of Health were analyzed. The trends of discharge rates due to CLP of children of less than one year of life (ICD-10 Q350-379 code) and live births (lb) were calculated from 1986 to 2012. Variables such as incidence of rubella, poverty rate, obesity in pregnant women, and percentage of women who smoked or drank alcohol in the last month were included. The relative risk (RR) of CLP pre-fortification (1986-1999) and post-fortification (2000-2010) was calculated. Mixed and Prais-Winsten models were used to adjust other variables. Results: The hospital discharge rate due to CLP decreased from 1.88 x 1,000 lb during 1986-1996 to 1.68 x 1,000 lb (RR = 1.09 (95% CI 1.05-1.14, p < 0.001). Prais-Winsten and Mixed models, determined that folic acid fortification is the variable explaining this decrease. During 2004-2011, hospital discharge rates for cleft lip decreased but there was an increase in the figures for cleft lip and palate. Conclusions: The 9% decrease in hospital discharge rates for CLP is concomitant with wheat folic acid fortification.

Association of Parental Environmental Exposures and Supplementation Intake with Risk of Nonsyndromic Orofacial Clefts: A Case-Control Study in Heilongjiang Province, China.

The aim of present study was to check the possible association of potential parental environmental exposures and maternal supplementation intake with the risk of nonsyndromic orofacial clefting (NSOC). A retrospective study comprised 499 cases and 480 controls was conducted in Heilongjiang Province. Chi-square analysis and unconditional multiple logistic regression were used in the study. The results showed that maternal history of fever and the common cold without fever (ORCL/P = 3.11 and 5.56, 95%CI: 1.67-5.82 and 2.96-10.47, ORCPO = 3.31 and 8.23, 95%CI: 1.58-6.94 and 4.08-16.95), paternal smoking and alcohol consumption (ORCL/P = 2.15 and 5.04, 95%CI: 1.37-3.38 and 3.00-8.46, ORCPO = 1.82 and 4.40, 95%CI: 1.06-3.13 and 2.50-7.74), maternal exposure to organic solvents, heavy metals, or pesticides (ORCL/P = 6.07, 5.67 and 5.97, 95%CI: 1.49-24.76, 1.34-24.09 and 2.10-16.98, ORCPO = 10.65, 7.28 and 3.48, 95%CI: 2.54-44.67, 1.41-37.63 and 1.06-11.46) and multivitamin use during the preconception period (ORCL/P = 0.06, 95%CI: 0.02-0.23, ORCPO = 0.06, 95%CI: 0.01-0.30) were associated with cleft lip or without cleft palate (CL/P) and cleft palate only (CPO). Maternal history of skin disease and negative life events (ORCL/P = 12.07 and 1.67, 95%CI: 1.81-80.05 and 1.95-2.67) were associated with CL/P. Some potential parental hazardous exposures during the periconception period and maternal use of multivitamins during the preconception period were associated with risk of NSOC.

Prevention of orofacial clefts caused by smoking: implications of the Surgeon General's report.

BACKGROUND: According to the 2014 Surgeon General's Report, smoking in early pregnancy can cause orofacial clefts. We sought to examine the implications of this causal link for the potential prevention of orofacial clefts in the United States. METHODS: Using published data on the strength of the association between orofacial clefts and smoking in early pregnancy and the prevalence of smoking at the start of pregnancy, we estimated the attributable fraction for smoking as a cause of orofacial clefts. We then used the prevalence of orofacial clefts in the United States to estimate the number of orofacial clefts that could be prevented in the United States each year by eliminating exposure to smoking during early pregnancy. We also estimated the financial impact of preventing orofacial clefts caused by maternal smoking based on a published estimate of attributable healthcare costs through age 10 for orofacial clefts. RESULTS: The estimated attributable fraction of orofacial clefts caused by smoking in early pregnancy was 6.1% (95% uncertainty interval 4.4%, 7.7%). Complete elimination of smoking in early pregnancy could prevent orofacial clefts in approximately 430 infants per year in the United States, and could save an estimated $40.4 million in discounted healthcare costs through age 10 for each birth cohort. CONCLUSION: Understanding the magnitude of the preventable burden of orofacial clefts related to maternal smoking could help focus smoking cessation efforts on women who might become pregnant.

Risk factors and the prevention of oral clefts

This article presents general aspects of risk factors and particularities of the management of individuals with oral clefts (OCs). A practical manual of prevention and management of this congenital defect was prepared based on a review of the literature and using data from Brazilian multicenter studies. Since OCs require efforts from all levels of healthcare, the data herein presented permits appropriate follow-up for affected individuals and their families. Also, the recognition of risk factors is crucial for planning and implementing preventive measures at the individual and population levels.

Screening for maternal coeliac disease as a potential risk factor for orofacial clefts--a pilot study.

There is increasing evidence that dietary folic acid deficiency in utero may increase the risk of developing the 'cleft lip with or without cleft palate' (CL±P) variant of orofacial cleft. Coeliac disease is a common cause of folic acid malabsorption, and in the majority of cases remains undiagnosed. This pilot study assessed the seroprevalence of undiagnosed coeliac disease in a cohort of mothers of infants with CL±P in the Hyderabad area of India. The seroprevalence of coeliac disease of 1.15% (95% confidence interval 0.37-2.66%) was little different from the expected figure based on published population studies, making a clinically significant association unlikely.

Maternal dietary intake of nitrates, nitrites and nitrosamines and selected birth defects in offspring: a case-control study.

BACKGROUND: Dietary intake of nitrates, nitrites, and nitrosamines can increase the endogenous formation of N-nitroso compounds in the stomach. Results from animal studies suggest that these compounds might be teratogenic. We examined the relationship between maternal dietary intake of nitrates, nitrites (including plant and animal sources as separate groups), and nitrosamines and several types of birth defects in offspring. METHODS: For this population-based case-control study, data from a 58-question food frequency questionnaire, adapted from the short Willett Food Frequency Questionnaire and administered as part of the National Birth Defects Prevention Study (NBDPS), were used to estimate daily intake of dietary nitrates, nitrites, and nitrosamines in a sample of 6544 mothers of infants with neural tube defects (NTD)s, oral clefts (OC)s, or limb deficiencies (LD)s and 6807 mothers of unaffected control infants. Total daily intake of these compounds was divided into quartiles based on the control mother distributions. Odds ratios (OR)s and 95% confidence intervals (CI)s were estimated using logistic regression; estimates were adjusted for maternal daily caloric intake, maternal race-ethnicity, education, dietary folate intake, high fat diet (>30% of calories from fat), and state of residence. RESULTS: While some unadjusted ORs for NTDS had 95% (CI)s that excluded the null value, none remained significant after adjustment for covariates, and the effect sizes were small (adjusted odds ratios [aOR]<1.12). Similar results were found for OCs and LDs with the exception of animal nitrites and cleft lip with/without cleft palate (aORs and CIs for quartile 4 compared to quartile 1 =1.24; CI=1.05-1.48), animal nitrites and cleft lip (4th quartile aOR=1.32; CI=1.01-1.72), and total nitrite and intercalary LD (4th quartile aOR=4.70; CI=1.23-17.93). CONCLUSIONS: Overall, odds of NTDs, OCs or LDs did not appear to be significantly associated with estimated dietary intake of nitrate, nitrite, and nitrosamines.

Diagnostic/genetic sreening - approach for genetic diagnoses and prevention of cleft lip and/or palate.

The treatment, research and volunteer work for cleft lip and/or palate (CL/P) has been led for over 30 years by our team. Within this period, more than 4,000 cases of CL/P were treated and at the same time, and approximately 400 papers were published as the first or partner researcher in Nature Genetics, New England Journal of Medicine and others. In addition, with $20 million that was donated from companies and laypeople, and the grant from the Japanese government, CL/P centres in many countries and in Japan, the oral and craniofacial congenital anomaly gene bank in our CL/P centre was established by our leadership. In the bank there are genes from approximately more than 8,000 cases. The genes were mapped with Professor Jeffery Murray of Iowa University in the United States, the findings about genetic syndromes such as Van der Woude Syndrome and basal cell nevus syndrome were applied in clinical settings. The genetic counselling section that specialises in the oral and maxillofacial field was established by our effort for the first time in Japan. In this review, our clinical experience and approach for genetic diagnoses and prevention of cleft lip and/or palate will be discussed.

Folic acid in cleft lip, alveolus and palate prevention: awareness among dental professionals.

OBJECTIVES: To determine the awareness amongst dental students, practitioners and maxillofacial surgeons the role of folic acid in the prevention of CLAP and its clinical use. MATERIALS AND METHODS: Questionnaire based study involving a sample base of 1100, comprising of dental students, practitioners and specialist maxillofacial surgeons. RESULTS: hundred percent of the sample population were aware of CLAP disorders, of which 9.5 % believed that CLAP could be prevented. 3.8 % of the population were able to correlate folic acid to CLAP while a negligible 0.03 % could provide the dosage. CONCLUSION: Educating healthcare providers and, in turn, the prospective parents on benefits folic acid would not only help in reducing the incidence of CLAP but also significantly influence the economics of the patients afflicted with CLAP disorders.

Folic acid and orofacial clefts: a review of the evidence.

Orofacial clefts are common and burdensome birth defects with a complex genetic and environmental etiology. The contribution of nutritional factors and supplements to the etiology of orofacial clefts has long been theorized and studied. Multiple studies have evaluated the role of folic acid in the occurrence and recurrence of orofacial clefts, using observational and non-randomized interventional designs. While preventive effects of folic acid on orofacial clefts are commonly reported, the evidence remains generally inconsistent. This paper reviews the findings of the main studies of the effects of folic acid on orofacial clefts, summarizes study limitations, and discusses research needs with a focus on studying the effects of high dosage folic acid on the recurrence of oral clefts using a randomized clinical trial design. The role of folic acid in the prevention of neural tube defects is also briefly summarized and discussed as a reference model for orofacial clefts.

Association among polymorphisms at MYH9, environmental factors, and nonsyndromic orofacial clefts in western China.

Myosin heavy chain 9, nonmuscle (MYH9) and environmental factors have been shown to be associated with nonsyndromic cleft lip with or without cleft palate in several populations. Our study aimed to confirm the contribution of MYH9 and environmental factors to nonsyndromic orofacial cleft risk in western Han Chinese. Four single-nucleotide polymorphisms were investigated in 180 case trios and 224 normal peers in western China using transmission disequilibrium test, family-based association test analysis, and logistic regression models. Strong evidence of linkage disequilibrium was found between these markers and the disease by both single-nucleotide polymorphism analysis (G allele at rs2269529 and T allele at rs16996652) and haplotype analysis (G-T [for rs2269529 and rs16996652] and G-A-T [for rs2269529, rs3752462, and rs16996652] among others). Mothers' illness, medication, and passive smoking during the first trimester may increase the risk of nonsyndromic orofacial clefts, but mothers' vitamin (including folic acid) supplementation during the first trimester is a protective factor. Interactions between mothers' passive smoking during the first trimester and T/T genotype of rs16996652 had statistical significance. Risk factors identified in our study may provide a better understanding of the etiological role of MYH9 and influence of environmental factors in nonsyndromic orofacial cleft incidence.