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Orofacial clefts are among the most prevalent birth defects, with severe medical and psychosocial consequences. Cleft lip with or without cleft palate (CL ± P) and cleft palate only (CPO) affect on average nearly 1/700 births worldwide. The cause of most non-syndromic cases is unknown. Maternal factors and disorders are assumed to modify the risk of orofacial clefting. In the present study, we performed a systematic review and meta-analysis to analyze the effects of maternal underweight, obesity, hypertension, diabetes, as well as smoking, and alcohol consumption on the development of orofacial clefts. As CL ± CP and CPO have distinct pathogenetic backgrounds, these cleft subtypes were assessed separately. Altogether, 5,830 studies were identified and 64 of them met the inclusion and exclusion criteria. Obesity significantly elevated the odds of clefting (OR = 1.28, CI:1.08-1.51) (OR CL±CP  = 1.23, CI:1.01-1.50; OR CPO  = 1.31, CI:0.97-1.77). Maternal underweight also significantly increased the odds of clefting (OR = 1.21 CI:1.06-1.38). In mothers with type 1 diabetes, the odds of cleft development were significantly elevated (OR = 1,75, CI:1.45-2.12). Essential hypertension was also associated with higher odds of developing cleft (OR = 1.55, CI:1.18-2.03). Smoking during pregnancy significantly elevated the odds of cleft development (OR = 1.55, CI:1.34-1.79) (OR CL±CP  = 1.58, CI:1.36-1.83; OR CPO  = 1.50, CI:1.15-1.96). Passive smoking was even more damaging than active tobacco use, but alcohol consumption had no effect. In conclusion, this study clearly showed the importance of maintaining normal maternal body weight and emphasized the importance of hypertension and type 1 diabetes care in the first months of pregnancy. It also highlighted similarnegative effects of passive and active smoking, while alcohol consumption did not seem to be a significant risk factor for cleft development. However, there is a complete lack of available studies on the interactions of these factors, which is an essential direction for improving prevention., Competing Interests: Declarations Conflict of interest There is nothing to declare., (© 2024. The Author(s).)

Background: Orofacial clefts (OFC) are the most common congenital malformation of the craniofacial skeleton. Attempts have been made to correlate the components of maternal diet as triggers for the development or prevention of OFC., Objective: To analyze nutritional status as a predictive factor for the development of cleft lip and palate in an Amazonian population., Methods: A total of 152 mothers within 3 months of delivery were interviewed for comparison: 51 mothers of children with nonsyndromic cleft lip and palate (CLP) (study group) and 101 mothers of children without OFC (control group). A food frequency questionnaire was used to assess maternal nutrition and to analyze the influence of macro- and micronutrients on the possible predisposition or protection for CLP., Results: The study group showed higher percentage of lipid intake than did the control group (p = 0.01). Among the participants with no family history of OFC, the study group had a higher percentage of lipid intake (p = 0.002) and lower vegetable intake (p = 0.037). Maternal micronutrient intake among the participants with a positive family history was lower in the study group for vitamins B2 (p = 0.03), B5 (p = 0.036), E (p = 0.03), and folate (p = 0.022)., Conclusions: Nutritional analysis indicated that higher maternal lipid intake increased the likelihood of having offsprings with nonsyndromic CLP. Moreover, families with a history of OFC and low maternal folate intake showed heightened risk of nonsyndromic CLP in their offsprings., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Maternal cigarette use is associated with the fetal development of orofacial clefts. Air pollution should be investigated for similar causation. We hypothesize that the incidence of non-syndromic cleft lip with or without palate (NSCLP) and non-syndromic cleft palate (NSCP) would be positively correlated with air pollution concentration., Methods: The incidence of NSCLP and NSCP per 1000 live births from 2016 to 2020 was extracted from the Centers for Disease Control and Prevention Vital Statistics Database and merged with national reports on air pollution using the Environmental Protection Agency Air Quality Systems annual data. The most commonly reported pollutants were analyzed including benzene, sulfur dioxide (SO 2 ), particulate matter (PM) 2.5, PM 10, ozone (O 3 ), and carbon monoxide (CO). Multivariable negative binomial and Poisson log-linear regression models evaluated the incidence of NSCLP and NSCP as a function of the pollutants, adjusting for race. All p-values are reported with Bonferroni correction., Results: The median NSCLP incidence was 0.22/1000 births, and isolated NSCP incidence was 0.18/1000 births. For NSCLP, SO 2 had a coefficient estimate (CE) of 0.60 (95% CI [0.23, 0.98], p < 0.007) and PM 2.5 had a CE of 0.20 (95% CI [0.10, 0.31], p < 0.005). Among isolated NSCP, no pollutants were found to be significantly associated., Conclusion: SO 2 and PM 2.5 were significantly correlated with increased incidence of NSCLP. The American people and perinatal practitioners should be aware of the connection to allow for risk reduction and in utero screening., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: The occurrence of orofacial Clefts (OFCs) is a congenital disease caused by many factors. According to recent studies, air pollution has a strong correlation with the occurrence of OFCs. However, there are still some controversies about the current research results, and there is no relevant research to review the latest results in recent years., Objective: In this paper, the authors conducted a systematic review and meta-analysis to explore the correlation between ambient air pollution and the occurrence of neonatal OFCs deformity., Methods: We searched Pubmed, Web of science, and Embase databases from the establishment of the database to May 2023. We included observational studies on the relationship between prenatal exposure to fine particulate matter 2.5 (PM2.5), fine particulate matter 10 (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO) and the risk of cleft lip (CL), cleft palate (CP), cleft lip with or without palate (CL/P). the Newcastle-Ottawa quality assessment scale (NOS) was used to evaluate the quality of the literature. Funnel plot and Egger's regression were used to verify the publication bias. Random effect model or fixed effect model was used to estimate the combined relative risk (RR) and 95% confidence interval (95%CI)., Results: A total of eleven studies were included in this study, including four cohort studies and seven case-control studies, including 22,453 cases of OFCs. Ten studies had low risk of bias and only one study had high risk of bias. Three studies reported that PM 2.5 was positively correlated with CL and CP, with a combined RR and 95%CI of 1.287(1.174,1.411) and 1.267 (1.105,1.454). Two studies reported a positive correlation between O 3 and CL, with a combined RR and 95%CI of 1.132(1.047,1.225). Two studies reported a positive correlation between PM 10 and CL, with a combined RR and 95%CI of 1.108 (1.017,1.206). No association was found between SO 2 , CO, NO 2 exposure during pregnancy and the risk of OFCs., Conclusion: The results of this study showed that there was a significant statistical correlation between exposure to PM 10 , PM 2.5 , O 3 and the risk of OFCs in the second month of pregnancy. Exposure assessment, research methods and mechanisms need to be further explored., (© 2023. The Author(s).)

Objective: The aim of this case-control study was to investigate environmental factors, such as caffeine, folic acid, nutritional iron supplementation, multivitamin complexes, alcohol, and tobacco (second-hand smoking), which have been described as risk factors for the development of oral clefts., Methods: This case-control study employed convenience sampling and included 409 mothers: 132 with children with oral clefts (cases) and 277 with children without oral clefts (controls). The age range of the children in both groups was 0 to 2 years. A questionnaire was administered to each mother to inquire about their habits and food consumption during the first trimester of pregnancy., Results: Folic acid supplementation was observed in 116 (87.8%) of the case group (p < 0.001) and 271 (97.8%) of the control group. Regarding the use of ferrous sulfate, 114 (86.3%) of the case group and 271 (97.8%) of the control group reported using it. In the case group, 84 (63.6%) mothers reported being exposed to second-hand smoke, and 5 (3.7%) reported alcohol consumption (p = 0.797). In terms of caffeine consumption, 127 mothers (95.4%) in the case group consumed it (p = 0.13), while 247 (88.8%) reported consumption in the control group., Conclusions: The results suggest a direct relationship between secondhand smoke, alcohol consumption, and the lack of maternal supplementation with oral clefts., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

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., (© 2023 Wiley Periodicals LLC.)

Brazil has one of the largest forest areas on the planet and the potential for the emergence of new diseases. In turn, orofacial clefts, especially cleft lip and or palate (CL/P), are characterized as congenital malformations and may be associated with genetic and environmental factors. The present study aimed to investigate in silico the flavivirus's potential to emerge in Brazil as an etiology of CL/P. A scoring method was created based on literature and nucleotide similarity analysis. An integrative analysis of the literature was performed to answer the questions through the databases PubMed/MEDLINE, SciELO, LILACS, and Google Scholar to have a more significant number of results. The software Basic Local Alignment Search Tool-BLAST 2.12.0, through the Genomic + Transcript Databases (Human Genomic plus Transcript Human G+T), was selected to find similarities with human sequences associated with CL/P. The viral sequences used were obtained from the National Center for Biotechnology Information Virus-NCBI Virus, in which only complete and referential genomes were selected. The flavivirus that emerged in Brazil and presented a high potential to cause CL/P was the Iguape virus strain (species Aroa virus ), followed by the Cacipacore virus and the Rocio virus strain (species Ilheus virus ) with medium potential to cause CL/P. In conclusion, we suggest among the virus evaluated that the Iguape virus presented a high potential of causing CL/P. As prevention, the control of arthropods and the hospital diffusion on viral dynamics, mainly in the CL/P context and other congenital malformations, are indicated., Competing Interests: T.S.M. received a scholarship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior). The remaining authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

This in silico study aims to investigate flaviviruses as an environmental factor in the etiology of nonsyndromic cleft lip and/or palate (CL/P)., A scoring method with 7 topics-disease, transplacental passage, tropism, cellular damage, reported case, analysis of genome similarity, and transcriptome between virus and host, was created based on literature and in silico experimentation. Viral genomes of NCBI virus were obtained and BLAST 2.12.0 was applied for the similarity analysis, adjusted to search for only human sequences related to CL/P with the statistical threshold defined for E-value ≤1., Flaviviruses with high potential to cause CL/P were: serotypes 2, 3, and 4 of the Dengue virus and lineage 2 of the West Nile virus , while the Yellow Fever virus , Japanese encephalitis virus , Tick-borne encephalitis virus , and Saint Louis encephalitis virus presented with medium potential to cause CL/P. As for the Zika virus , even strains associated with microcephaly showed only medium potential., Dengue virus and West Nile virus presented with high potential to act as environmental factors in the etiology of CL/P.

Objective: To determine whether maternal smoking and/or alcohol consumption has an influence on lip morphology. Maternal smoking is a known risk factor for orofacial clefts; however, its influence on normal lip variation is unknown. Recent research regarding normal lip morphology has been contradictory., Design: Retrospective cohort study., Setting and Participants: A total of 4747 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) who each had 3D facial scans carried out at 15 years of age were included in the study., Methods: Each of the participants was automatically categorised regarding predetermined lip morphological traits. Questionnaires completed by their mothers identified smoking and alcohol habits during pregnancy. Logistic regression analyses were applied to determine the effect of maternal smoking and alcohol consumption on lip morphology., Results: Maternal smoking has significant effects on upper and lower lip contours, Cupid's bow, lower lip-chin shape and lower lip tone (all P < 0.05). There was also an indication of a potential epigenetic effect of smoking pre-pregnancy on upper lip contour ( P = 0.0573). Alcohol consumption is significantly associated with philtrum shape, particularly when >6 units of alcohol are consumed per week ( P = 0.0149, 32 weeks). Overall results suggest a deeply grooved philtrum is more likely if alcohol is consumed. Investigating the combined effect of smoking and alcohol consumption, lower lip contour ( P = 0.00923) and lower lip-chin shape ( P = 0.0171) are statistically significant, with lower lip contour more likely to be narrow in the midline, and lower lip-chin shape more likely to be an angular concavity., Conclusion: Maternal smoking influences a number of lip traits, including a possible epigenetic effect on upper lip contour. Maternal alcohol consumption, particularly at a high level, influences philtrum shape. Maternal smoking and alcohol consumption have a combined effect on lower lip contour and lower lip-chin shape.

Objective: To investigate the association between periconceptional environmental exposures and the occurrence of cleft lips and palates., Methods: This case-control study analyzed 150 mothers of children with cleft lips and palates living in the same city as 250 mothers whose children did not present with this malformation (controls). Environmental exposure data were gathered through a questionnaire (Latin American Collaborative Study of Congenital Malformations methodology)., Results: Multivariate analysis revealed that monthly income below minimum wage, having another malformed child, other diseases in the first gestational trimester (urinary infection), use of pesticides in home gardens, and pesticide use in farms close to the home were risk factors associated with the malformation, whereas taking vitamins was a protective factor., Conclusion: Maternal and paternal exposure to pesticides is associated with cleft lip and palate in Mato Grosso State, Brazil., Competing Interests: Conflict of interest: None declared., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Objective To investigate the multiple correspondence of genetic and environmental risk factors with abnormal birth history and provide a scientific basis for improving the birth defects surveillance system and reducing the incidence of birth defects. Methods Data were collected from all the perinatal infants from 28-week-old fetuses to 7-day-old infants born in all the hospitals with obstetrical department in Xi'an from 2003 to 2015. Results A total of 1 236 937 perinatal infants were surveyed,including 10 619 with birth defects.The average incidence rate of birth defects was 0.86% (0.70%-1.15%).Multiple correspondence analysis showed that the women who had had 1 or 2 children with birth defects were associated with the history of spontaneous abortion,family history of birth defects,and history of exposure to toxic and harmful substances.The women who had had 3 or more children with birth defects showed stronger association with family history of birth defects.The birth defects in women with history of spontaneous abortion (257/10 619) was ranked in the order of congenital heart disease,polydactyly,neural tube defects,congenital hydrocephalus,cleft lip with cleft palate,and simple cleft lip.The birth defects in women who had given birth to children with birth defects (135/10 619) followed the order of cleft lip with cleft palate,anencephaly,hydrocephalus,neural tube defects,cleft lip,and talipes equinovarus. Conclusions Abnormal birth history is associated with family history of birth defects and history of exposure to environmental risk factors.Giving birth to three or more children with birth defects is highly correlated with the family history of birth defects.

A systematic review and meta-analysis to determine the association between active maternal smoking and cleft lip and palate etiology., Medline, Embase, Web of Science and the Cochrane Library from inception to November, 2020., Observational studies of cigarette smoking habits in pregnant women. Outcomes included cleft lip and/or palate, cleft lip  ±  palate and cleft palate only., Publication bias analyses were performed and the Newcastle Ottawa scales were used to assess study quality. Fixed or random effect models were used in the meta-analysis, dependent on risk of statistical heterogeneity., Forty-five studies were eligible for inclusion of which 11 were cohort and 34 were case-control studies. Sixteen studies were of sufficient standard for inclusion in the meta-analysis. The summary odds ratio for the association between smoking and cleft lip and/or palate was 1.42 (95%CI 1.27-1.59) with a population attributable fraction of 4% (95%CI 3%-5%). There was limited evidence to show a dose-response effect of smoking., This review reports a moderate association between maternal smoking and orofacial cleft but the overall quality of the conventional observational studies included was poor. There is a need for high quality and novel research strategies to further define the role of smoking in the etiology of cleft lip and palate.

Background: We conducted a meta-analysis of observational epidemiological studies to evaluate the association between periconceptional use of vitamin A and the risk of giving birth to a child with nonsyndromic orofacial clefts (NSOFCs)., Methods: We carried out a systematic literature search of Embase, PubMed, Web of Science, Google Scholar, and OpenGrey from inception to June 30, 2021. Two reviewers independently evaluated the studies that met the inclusion criteria and filled out an abstraction form for each study. Study quality was assessed using the Newcastle-Ottawa Assessment Scale (NOS). Adjusted estimates were pooled with an inverse variance weighting using a random-effects model. Heterogeneity and publication bias were assessed using the Cochran's Q test and funnel plot, respectively., Results: A total of six case-control studies with moderate risk of bias were included. The pooled OR showed a 20% reduction in the risk of NSOFCs for periconceptional use of vitamin A which was not statistically significant (OR = .80; 95% CI .54-1.17, p = .25). For nonsyndromic cleft lip with or without cleft palate (NSCL/P), the studies were homogenous, and the pooled estimate showed a 13% risk reduction, which was significant (OR = .87; 95% CI .77-.99, p = .03). For nonsyndromic cleft palate only (NSCPO), the pooled estimate showed a 33% lower likelihood, which was not statistically significant (OR = .67; 95% CI .42-1.08, p = .10)., Conclusion: Our results suggest a possible protective effect for the periconceptional use of vitamin A on the risk of NSCL/P. This finding should be investigated further in prospective studies across multiple populations., (© 2022 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Background: Cleft lip and/or cleft palate (CLP) is a prevalent condition with a multifactorial etiology. An understanding of its etiologic factors discourages harmful habits and promotes societal acceptability., Objectives: To assess the knowledge of environmental and genetic risk factors of CLP and determine its effect on predisposing social habits in a suburban community in Nigeria., Methods: This was a descriptive cross-sectional study conducted at Ifo Local Government Area (LGA), Ogun state, Nigeria. Participants were adult residents of Ifo L.G.A. Knowledge of CLP categorized into description, environmental risk factors and genetic factors were assessed using a well structured interviewer administered questionnaire., Results: A total of 300 adults (104 males; 196 females) aged 44.3 + 13.17 years with predominantly secondary level education participated in the study. Majority of participants (89.7%) had low overall knowledge of CLP including low knowledge on description of CLP (81.7%), environmental factors of CLP (81.3%), and genetic factors of CLP (93.7%). High level of education was significantly associated with increased knowledge on description of CLP (P < 0.05). No other significant association was noted between sociodemographic factors and knowledge of CLP. Decreased smoking history was associated with high knowledge on description of CLP (P = 0.043)., Conclusion: Majority of the population had low knowledge of CLP which was to an extent influenced by their lack of high level of education. This low knowledge was significantly associated with increased practices of social habits such as cigarette smoking that predispose unborn children to CLP. The low knowledge of CLP shown in this study highlights the need for increased community education and health promotion to encourage avoidance of risk factors that predispose to the condition and promote societal acceptability and quest for treatment of the condition., Competing Interests: The Authors declare that no competing interest exists., (Copyright © 2022 by West African Journal of Medicine.)

Background: Cleft lip and palate (cleft L/P) is one of the most common congenital anomalies and its etiology is assumed to be multifactorial. Recent epidemiological data involving a small number of participants suggested an association between perinatal exposure to heavy metals and cleft L/P in affected children. However, this association requires further investigation in a large cohort., Methods: This nested case-control study used a dataset of The Japan Environment and Children's Study, which is an ongoing research project to investigate the association between environmental factors and mother-child health. Participants were enrolled between 2011 and 2014. From the records of fetuses/children, we extracted data of isolated cleft L/P cases and matched children without cleft L/P at a ratio of 1:10. The exposures of interest were in utero exposure to four metals (mercury [Hg], lead [Pb], cadmium [Cd], and manganese [Mn]), which were sampled from mothers in the second/third trimester. Conditional logistic regression was used to assess the association between heavy metal exposure and isolated cleft L/P. Three sensitivity analyses were conducted to test the robustness of the findings, including the change in case definition and statistical methods., Results: Of 104,062 fetal records involving both live-birth and stillbirth, we identified 192 children with isolated cleft L/P and 1,920 matched controls. Overall, the blood metal levels were low (for example, median Pb level was 5.85, 6.22, and 5.75 μg/L in the total cohort, cases, and controls, respectively). Univariate and multivariate analyses showed that levels of none of the four heavy metals in the mother's blood during pregnancy were associated with the risk of cleft L/P in offspring; the adjusted odds ratios (per 1 μg/L increase) with 95% intervals were 0.96 (0.91-1.03), 1.01 (0.94-1.08), 1.00 (0.61-1.63) and 1.00 (0.97-1.03) for Hg, Pb, Cd and Mn, respectively. The results were consistent in all sensitivity analyses., Conclusions: Exposure to these four metals during pregnancy was not associated with isolated cleft L/P at the low exposure level in our cohort., Competing Interests: None.

Non-syndromic orofacial clefts (NSOFCs) are prevalent birth defects with a complex etiology where several interacting genetic and environmental factors have been observed. This narrative review describes maternal exposures that have been significantly associated with protective effects or risk factors. The statistically significant information reported here was found in meta-analysis studies, taking advantage of their precision in defining intervention effects and their management of heterogeneity between studies. In addition, I propose a hypothesis explaining the biological basis for the results of the meta-analyses. This review aims to improve the evidence available in parent counseling, to prevent the occurrence of orofacial clefts by suggesting lifestyle changes., (© 2021 Wiley Periodicals LLC.)

Infant hemangioma is a relatively rare congenital disease. Ulcer and infection may occur in some cases. A few cases may develop into deformity and defect. Herein, we present a case of secondary cleft lip induced by congenital hemangioma and also our sequential treatment.

Background: Both active and passive cigarette smoking have previously been associated with orofacial cleft aetiology. We aimed to analyse the impact of declining active smoking prevalence and the implementation of smoke-free legislation on the incidence of children born with a cleft lip and/or palate within the United Kingdom., Methods and Findings: We conducted regression analysis using national administrative data in the United Kingdom between 2000-2018. The main outcome measure was orofacial cleft incidence, reported annually for England, Wales and Northern Ireland and separately for Scotland. First, we conducted an ecological study with longitudinal time-series analysis using smoking prevalence data for females over 16 years of age. Second, we used a natural experiment design with interrupted time-series analysis to assess the impact of smoke-free legislation. Over the study period, the annual incidence of orofacial cleft per 10,000 live births ranged from 14.2-16.2 in England, Wales and Northern Ireland and 13.4-18.8 in Scotland. The proportion of active smokers amongst females in the United Kingdom declined by 37% during the study period. Adjusted regression analysis did not show a correlation between the proportion of active smokers and orofacial cleft incidence in either dataset, although we were unable to exclude a modest effect of the magnitude seen in individual-level observational studies. The data in England, Wales and Northern Ireland suggested an 8% reduction in orofacial cleft incidence (RR 0.92, 95%CI 0.85 to 0.99; P = 0.024) following the implementation of smoke-free legislation. In Scotland, there was weak evidence for an increase in orofacial cleft incidence following smoke-free legislation (RR 1.16, 95%CI 0.94 to 1.44; P = 0.173)., Conclusions: These two ecological studies offer a novel insight into the influence of smoking in orofacial cleft aetiology, adding to the evidence base from individual-level studies. Our results suggest that smoke-free legislation may have reduced orofacial cleft incidence in England, Wales and Northern Ireland., Competing Interests: The authors have declared that no competing interests exist.

Background: The etiologies of major birth defects are still unclear and few spatial analyses have been conducted in the United States. Spatial analyses of individual-level data can help elucidate environmental and social risk factors., Methods: We used generalized additive models to analyze 52,955 cases of neural tube defects, congenital heart defects (CHDs), gastroschisis, and orofacial cleft defects, and sampled from 642,399 controls born between 1999 and 2011 in Texas. The effect of geographic location was measured using a bivariable smooth term of geocoded birth address within a logistic regression framework. We calculated and mapped odds ratios (ORs) and 95% confidence intervals (CIs) for birth defects subtypes across Texas, and adjusted for maternal characteristics, environmental indicators, and community-level covariates. We also performed time-stratified spatiotemporal analyses for more prevalent birth defects., Results: Location was significantly associated with crude odds of all birth defects except hypoplastic left heart syndrome. After adjusting for maternal characteristics, environmental indicators, and community-level factors, ORs in many geographic areas were no longer statistically significant for most defects, especially CHDs. However, areas of significant and insignificant elevated risk remained for defects in all groups in North and South Texas, with ORs for ventricular septal defects increasing over time. Low risk of birth defects was often present in the northern part of East Texas., Conclusion: Significant spatial patterns of birth defects were identified and varied depending on adjustment of different categories of covariates. Further investigation of areas with increased risks may aid in our understanding of birth defects., (© 2021 Wiley Periodicals LLC.)

(1) Background: The etiology of orofacial cleft (OC) is not completely known but several genetic and environmental risk factors have been identified. Moreover, a knowledge gap still persists regarding neonatal characteristics. This study evaluated the effect of parental age and mothers' body mass index on the risk of having an OC child, in a matched year and sex group (cleft/healthy control). Additionally, birth data were analyzed between groups. (2) Methods: 266 individuals born between 1995 to 2015 were evaluated: 133 OC individuals (85 males/48 females) and 133 control (85 males/48 females). A logistic model was used for the independent variables. ANOVA or Kruskal-Wallis tests were used for comparison between the OC phenotypes. (3) Results: Regarding statistically significant parental related factors, the probability of having a cleft child decreases for each maternal year increase (odds ratio = 0.903) and increases for each body mass index unit (kg/m 2 ) increase (odds ratio = 1.14). On the child data birth, for each mass unit (kg) increase, the probability of having a cleft child decrease (odds ratio = 0.435). (4) Conclusions: In this study, only maternal body mass index and maternal age found statistical differences in the risk of having a cleft child. In the children's initial data, the cleft group found a higher risk of having a lower birth weight but no relation was found regarding length and head circumference.

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.

Objective: To compare the incidence of right-sided versus left-sided, and unilateral versus bilateral, nonsyndromic clefting in the affected offspring of smoking and nonsmoking mothers., Design: Self-report data on periconceptual and first trimester smoking behavior were collected from 842 mothers of children with nonsyndromic orofacial clefting. Differences in the incidence of left- versus right-sided clefts, and of unilateral versus bilateral clefts, were analyzed between the children of smoking and nonsmoking mothers., Setting: Interviews and clinical examinations took place at 8 specialist centers in Germany., Patients and Participants: Children with nonsyndromic clefts were recruited during the course of surgical or orthodontic treatment, or within the context of the annual control consultation. Patients with cleft palate only or missing data were excluded. The final cohort comprised 842 patients (540 males and 302 females) with unilateral or bilateral clefts. The respective mothers were interviewed., Main Outcome Measure: Side and laterality of nonsyndromic clefts were the main outcome measures., Results: Children of smoking mothers more often had right-sided clefts than children of nonsmoking mothers (42% right-sided clefts in children of smoking mothers vs 31% of nonsmoking mothers). Children of smoking mothers more often had bilateral clefts than children of nonsmoking mothers (35% bilateral clefts in children of smoking mothers vs 29% of nonsmoking mothers). Sex-specific analyses confirmed substantially and statistically significant associations only for girls., Conclusions: The results suggest that maternal smoking is a sex-specific, exogenous determinant of laterality and side in nonsyndromic clefts.

Background: Causes of most birth defects are largely unknown. Genetics, maternal factors (e.g., age, smoking) and environmental exposures have all been linked to some birth defects, including neural tube, oral cleft, limb reduction, and gastroschisis; however, the contribution of cumulative exposures across several environmental domains in association with these defects is not well understood., Methods: The Environmental Quality Index (EQI) and its domains (air, water, land, sociodemographic, built) were used to estimate county-level cumulative environmental exposures from 2006-2010 and matched to birth defects identified from Texas Birth Defects Registry and live birth records from births in years 2007-2010 (N = 1,610,709). Poisson regression models estimated prevalence ratios (PR) and 95% confidence intervals (CI) for associations between 10 birth defects and the EQI., Results: We observed some positive associations between worst environmental quality and neural tube, anencephaly, spina bifida, oral cleft, cleft palate, cleft lip with and without cleft palate, and gastroschisis [PR range: 1.12-1.55], but near null associations with limb reduction defects. Among domain specific results, we observed the strongest positive associations with the sociodemographic domain across birth defects but varied positive associations among the air and water domains, and negative or null associations with the land and built domains. Overall, few exposure-response patterns were evident., Conclusions: Our results highlight the complexities of cumulative, simultaneous environmental exposures in the prevalence rates of 10 selected birth defects. We were able to explore the impact of overall and domain specific environmental quality on birth defects and identify potential domain specific drivers of these associations., (© 2020 Wiley Periodicals LLC.)

Cleft lip and palate are types of craniofacial birth defects that affect thousands of children worldwide each year. These conditions are sensitive topics of conversations, often affected by the stigma of physical birth deformities and cultural myths. This article reviews the pathophysiology of cleft lip and palate, and describes the traditional management of patients with oral-facial clefts, including the extensive supportive care and an interprofessional team or cleft team approach that extends beyond the surgical correction.

Orofacial clefts (OFCs) are among the most common birth defects and impart a significant burden on afflicted individuals and their families. It is increasingly understood that many nonsyndromic OFCs are a consequence of extrinsic factors, genetic susceptibilities, and interactions of the two. Therefore, understanding the environmental mechanisms of OFCs is important in the prevention of future cases. This review examines the molecular mechanisms associated with environmental factors that either protect against or increase the risk of OFCs. We focus on essential metabolic pathways, environmental signaling mechanisms, detoxification pathways, behavioral risk factors, and biological hazards that may disrupt orofacial development., (© 2020 Wiley Periodicals LLC.)

Coffin-Siris Syndrome (CSS) is a genetic syndrome associated with multiple congenital anomalies due to mutations in the BAF-complex or SOX gene. Although well characterized overall, the subunits of the BAF-complex or SOX gene affected demonstrate phenotypic differences which are continuing to be defined. Among the variants is the SMARCE1 mutation, the least common identified genotype. This case report presents a pediatric patient with SMARCE1-related CSS, the seventh case reported in the literature. The congenital anomalies are discussed and compared to the reported cases of SMARCE1-related CSS and CSS overall with an emphasis on otolaryngologic manifestations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Nonsyndromic orofacial clefts (NSOFCs) represent the most common congenital anomalies in the head and neck region. Multiple factors contribute to the occurrence of this anomaly. The etiology of NSOFCs in the Ethiopian population has not been investigated prior to this study., Aims of the Study: To assess the role of maternal environmental factors in the occurrence of NSOFCs in the Ethiopian Population., Methods: The authors used unmatched case control study design and evaluated the role of environmental factors to the occurrence of NSOFCs in the Ethiopian population. The participants were recruited from the same institution (Yekatit 12 Hospital Medical College). The authors studied 760 mothers (359 mothers of children born with NSOFCs and 401 mothers of children born without any congenital anomalies). Univariate and multivariate logistic regression analyses were used to calculate relative risk by odds ratio and 95% confidence interval., Results: Mothers who gave history of bronchial asthma and mothers who were admitted for threatened abortion had a higher risk of delivering a child with NSOFCS P value=0.013; AOR=0.194, 95% CI [0.053-0.712], P value <0.001; AOR= 0.179, 95% CI [0.091-0.352] respectively. Higher number of children with NSOFCs were born to mothers who were exposed to diagnostic X-ray investigation during early pregnancy than those who were not exposed P value 0.048; AOR=0.375, 95% CI [0.142-0.990]., Conclusion: Maternal exposure to diagnostic x-ray, maternal chronic illness like bronchial asthma and threatened abortion were found to be associated with the occurrence of NSOFCS in the studied population.

Our aim was to evaluate the possible correlation between maternal alcohol consumption during the first trimester and the risk of having an offspring with non-syndromic oral cleft. We electronically searched all published papers from 1950 to 2019 about maternal alcohol consumption and oral clefts in PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Institute for Scientific Information (ISI) databases. Descriptive and quantitative data were extracted from eligible studies for systemic evaluation and meta-analysis. A total of 12 publications met our inclusion criteria, and nine of them presented sufficient data for quantitative analyses. The overall odds ratio of the nine reports was 1.00 (95% CI 0.87 to 1.15) for cleft lip with or without cleft palate (CL/P) and 1.02 (95% CI 0.92 to 1.14) for cleft palate only, indicating no significant difference between drinking and non-drinking mothers in the risk of having a child with a non-syndromic oral cleft. We found no confirmatory evidence for the presence of a dose-response relation between alcohol consumption and increase in the risk of oral cleft. Nevertheless, four of the studies enrolled found significantly increased risk of CL/P among mothers in the groups that consumed the most alcohol. All but one of the four studies suggested a positive correlation between binge drinking and the occurrence of non-syndromic oral cleft. Although we found no concrete correlation between mild alcohol consumption during pregnancy and the occurrence of non-syndromic oral cleft, precautions should still be taken to avoid binge drinking during the first trimester., (Copyright © 2019 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

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.

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.

This study examines the spatial structure of children with cleft lip and palate (CLP) and its association with polluted areas in the Monterrey Metropolitan Area (MMA). The Nearest Neighbor Index (NNI) and the Spatial Statistical Scan (SaTScan) determined that the CLP cases are agglomerated in spatial clusters distributed in different areas of the city, some of them grouping up to 12 cases of CLP in a radius of 1.2 km. The application of the interpolation by empirical Bayesian kriging (EBK) and the inverse distance weighted (IDW) method showed that 95% of the cases have a spatial interaction with values of particulate matter (PM 10 ) of more than 50 points. The study also shows that 83% of the cases interacted with around 2000 annual tons of greenhouse gases. This study may contribute to other investigations applying techniques for the identification of environmental and genetic factors possibly associated with congenital malformations and for determining the influence of contaminating substances in the incidence of these diseases, particularly CLP.

Objective: To analyze clinical and genetic features of a family affected with Van der Woude syndrome., Methods: The umbilical cord blood of the proband and the peripheral blood of the parents were used for the whole exon sequencing to find the candidate gene.Peripheral blood of 9 members of the family were collected for Sanger sequencing verification, bioinformatics analysis and genotype-phenotype correlation analysis., Results: The proband was diagnosed with cleft lip and palate by ultrasound. His father and grandmother had hollow lower lip and all other family members did not have the similar phenotype. A missense c.263A>G (p.N88S) mutation was found in exon 4 of IRF6 gene in the proband, his father and his grandmother.The mutation was not found in other family members., Conclusions: A missense c.263A>G (p.N88S) mutation in IRF6 gene probably underlies the pathogenesis of Van der Woude syndrome in the family and the mutation has been firstly discovered in China.

Nonsyndromic cleft lip with or without cleft palate is the most common craniofacial anomaly affecting around 1 in 700 live births worldwide. Clefts of the human face can be classified anatomically as cleft palate only (CPO), cleft lip only (CLO), cleft lip and palate (CLP) or a combined group of cleft lip with or without cleft palate (CL/P), based on different in embryologic development. These malformations have some genetic origin, in fact several association studies have been performed to obtain important information about the candidate genes; but more important are gene-environment interactions that play an increasing role in its etiology. Epidemiological studies have shown how environmental factors (alcohol, smoking, drugs), as well as possible gene-environment interactions, play an important role in the onset of the malformation. On the contrary, folic acid intake seems to have a protective effect. In this review, we analyze the role of environmental factors related to onset of cleft., (Copyright 2019 Biolife Sas. www.biolifesas.org.)

Nonsyndromic oral clefting (NSOC) is although one of the most common congenital disorders worldwide, its underlying molecular basis remains elusive. This process has been hindered by the overwhelmingly high level of heterogeneity observed. Given that hitherto multiple loci and genes have been associated with NSOC, and that complex diseases are usually polygenic and show a considerable level of missing heritability, we used a systems genetics approach to reconstruct the NSOC network by integrating human-based physical and regulatory interactome with whole-transcriptome microarray data. We show that the network component contains 53% (23/43) of the curated NSOC-implicated gene set and displays a highly significant propinquity (P < 0.0001) between genes implicated at the genomic level and those differentially expressed at the transcriptome level. In addition, we identified bona fide candidate genes based on topological features and dysregulation (e.g. ANGPTL4), and similarly prioritised genes at GWA loci (e.g. MYC and CREBBP), thus providing further insight into the underlying heterogeneity of NSOC. Gene ontology analysis results were consistent with the NSOC network being associated with embryonic organ morphogenesis and also hinted at an aetiological overlap between NSOC and cancer. We therefore recommend this approach to be applied to other heterogeneous complex diseases to not only provide a molecular framework to unify genes which may seem as disparate entities linked to the same disease, but to also predict and prioritise candidate genes for further validation, thus addressing the missing heritability.

Background: Arsenic is widely distributed in the environment in both inorganic and organic forms. Evidence from animal studies suggests that maternal inorganic arsenic may lead to the development of orofacial clefts (OFC)s in offspring. This evidence, together with the limited epidemiologic data available, supports the need for a comprehensive examination of major sources of arsenic exposure and OFCs in humans., Methods: Using interview data collected in the National Birth Defects Prevention Study, public and well water arsenic sampling data, and dietary arsenic estimates, we compared expert-rater assessed occupational arsenic exposure, individual-level exposure to arsenic through drinking water, and dietary arsenic exposure between mothers of OFC cases (N = 435) and unaffected controls (N = 1267). Associations for each source of exposure were estimated for cleft lip ± palate (CL/P) and cleft palate (CP) using unconditional logistic regression analyses., Results: Associations for maternal drinking water arsenic exposure and CL/P were near or below unity, whereas those for dietary arsenic exposure tended to be positive. For CP, positive associations were observed for maternal occupational arsenic and inorganic arsenic exposures, with confidence intervals that excluded the null value, whereas those for drinking water or dietary arsenic exposures tended to be near or below unity., Conclusions: Positive associations were observed for maternal occupational arsenic exposure and CP and for maternal dietary arsenic exposure and CL/P; the remainder of associations estimated tended to be near or below unity. Given the exploratory nature of our study, the results should be interpreted cautiously, and continued research using improved exposure assessment methodologies is recommended., (© 2018 Wiley Periodicals, Inc.)

Background: Limited epidemiologic research exists on the association between weather-related extreme heat events (EHEs) and orofacial clefts (OFCs). We estimated the associations between maternal exposure to EHEs in the summer season and OFCs in offspring and investigated the potential modifying effect of body mass index on these associations., Methods: We conducted a population-based case-control study among mothers who participated in the National Birth Defects Prevention Study for whom at least 1 day of their first two post-conception months occurred during summer. Cases were live-born infants, stillbirths, and induced terminations with OFCs; controls were live-born infants without major birth defects. We defined EHEs using the 95th and the 90th percentiles of the daily maximum universal apparent temperature distribution. We used unconditional logistic regression with Firth's penalized likelihood method to estimate adjusted odds ratios and 95% confidence intervals, controlling for maternal sociodemographic and anthropometric variables., Results: We observed no association between maternal exposure to EHEs and OFCs overall, although prolonged duration of EHEs may increase the risk of OFCs in some study sites located in the Southeast climate region. Analyses by subtypes of OFCs revealed no associations with EHEs. Modifying effect by BMI was not observed., Conclusions: We did not find a significantly increased risk of OFCs associated with maternal exposure to EHEs during the relevant window of embryogenesis. Future studies should account for maternal indoor and outdoor activities and for characteristics such as hydration and use of air conditioning that could modify the effect of EHEs on pregnant women., (© 2018 Wiley Periodicals, Inc.)

Objective: To investigate parental age in relation to the severity of cleft diagnosis in a population-based consecutive sample of individuals with clefts., Setting/sample: Retrospective, consecutive., Material/methods: The sample comprised 545 consecutive cases with nonsyndromic clefts (437 individuals with cleft lip with/without cleft palate [CL ± P] and 106 individuals with isolated cleft palate [CP]) and parental ages recorded. The groups were subdivided according to the extent/severity of cleft. Unilateral clefts were divided according to left/right sidedness. Logistic regression was used to analyse the association between parental age and risk of severe cleft separately for CL ± P and CP, as well as between parental age and risk of right-sided cleft., Results: In CL ± P, the risk of a complete cleft in the offspring increases with maternal age when the paternal age exceeds approximately 29 years. Moreover, the risk is higher when both parents are old than when both parents are young. In CP, no statistically significant results were identified. However, there were clear trends that indicated a similar pattern as that for CL ± P. No association was identified between increased parental age and the sidedness of clefts., Conclusions: Parental age seems to contribute to cleft severity, as older parents showed a higher risk of having offspring with a complete cleft than younger parents., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gorlin-Goltz syndrome encompasses a variety of clinical signs and symptoms including important oral manifestations which general dental practitioners should be aware of. In light of the risk of malignancy it is important to be aware of this syndrome and recognise the need for early referral for multidisciplinary management. This paper aims to discuss Gorlin-Goltz syndrome, the pathophysiology of the condition and address the wide range of clinical manifestations. The author will pay particular attention to the oral manifestations of the condition and the management of such anomalies.

Introduction: There is controversial evidence from the literature regarding the protective effect of folic acid supplementation during pregnancy against orofacial clefts. The authors undertook this meta-analysis to assess whether folate supplementation during pregnancy can reduce the risk of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) in infants., Methods: Eligible articles were identified by searching databases, including PubMed, Medline, Scopus, ISI (Web of Knowledge) to September 2017. A meta-analysis was performed to evaluate the effects of maternal supplementation on oral clefts. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using Stata software. Publication bias was assessed by the Begg and Egger test. (Registration ID: CRD42018083922) RESULTS:: Out of the 1630 articles found in the authors' initial literature searches, 6 cohort studies, and 31 case-control studies were included in the authors' final meta-analysis. The results of the main analysis revealed that maternal folate supplementation was associated with a modest but statically significant decreased risk of all cleft subtypes (OR = 0.69, 95% CI: 0.60, 0.78). Folic acid intake alone was inversely associated with CL/P (OR = 0.73, 95% CI: 0.62-0.85,) but to a lesser extent than CPO (OR = 0.75, 95% CI = 053-1.04). Multivitamin intake had a significant protective effect for CL/P (OR = 0.65 95% CI = 0.55-0.80) as well as CPO (OR = 0.69, 95% CI = 0.53-0.90)., Conclusions: Our results indicate that maternal supplementation in early pregnancy reduces the risk of nonsyndromic CL/P and CPO in infants. These data can serve to reassure women planning a pregnancy to consume multivitamins during the periconception period to protect against oral clefts.

Purpose: Exposure misclassification, selection bias, and confounding are important biases in epidemiologic studies, yet only confounding is routinely addressed quantitatively. We describe how to combine two previously described methods and adjust for multiple biases using logistic regression., Methods: Weights were created from selection probabilities and predictive values for exposure classification and applied to multivariable logistic regression models in a case-control study of prepregnancy obesity (body mass index ≥30 vs. <30 kg/m 2 ) and cleft lip with or without cleft palate (CL/P) using data from the National Birth Defects Prevention Study (2523 cases, 10,605 controls)., Results: Adjusting for confounding by race/ethnicity, prepregnancy obesity, and CL/P were weakly associated (odds ratio [OR]: 1.10; 95% confidence interval: 0.98, 1.23). After weighting the data to account for exposure misclassification, missing exposure data, selection bias, and confounding, multiple bias-adjusted ORs ranged from 0.94 to 1.03 in nonprobabilistic bias analyses and median multiple bias-adjusted ORs ranged from 0.93 to 1.02 in probabilistic analyses., Conclusions: This approach, adjusting for multiple biases using a logistic regression model, suggested that the observed association between obesity and CL/P could be due to the presence of bias., (Published by Elsevier Inc.)

Background: Maternal exposure to drinking water disinfection byproducts (DBP)s may contribute to orofacial cleft (OFC) development, but studies are sparse and beset with limitations., Methods: Population-based, maternal interview reports of drinking water filtration and consumption for 680 OFC cases (535 isolated) and 1826 controls were linked with DBP concentration data using maternal residential addresses and public water system monitoring data. Maternal individual-level exposures to trihalomethanes (THM)s and haloacetic acids (HAA)s (µg/L of water consumed) were estimated from reported consumption at home, work, and school. Compared to no exposure, associations with multisource maternal exposure <1/2 or ≥1/2 the Maximum Contaminant Levels (MCL)s for total THMs (TTHM)s and HAAs (HAA5) or Maximum Contaminant Level Goals (MCLG)s for individual THMs and HAAs (if non-zero) were estimated for all OFCs and isolated OFCs, cleft palate (CP), and cleft lip ± cleft palate (CL/P) using logistic regression analyses., Results: Compared to controls, associations were near or below unity for maternal TTHM, HAA5, and individual THM exposures with all OFCs and isolated OFCs, CP, and CL/P. Associations also were near or below unity for individual HAAs with statistically significant, inverse associations observed with each OFC outcome group except CL/P., Conclusions: This study examined associations for maternal reports of drinking water filtration and consumption and maternal DBP exposure from drinking water with OFCs in offspring. Associations observed were near or below unity and mostly nonsignificant. Continued, improved research using maternal individual-level exposure data will be useful in better characterizing these associations., (© 2018 Wiley Periodicals, Inc.)

We describe a paramedian cleft of the lower lip that cannot be explained by embryological development in a child with only one predisposing factor, which was fetal reduction for a multiple pregnancy. To the best of our knowledge, there has been no report of a cleft that has been induced by the reduction of a multifetal pregnancy., (Copyright © 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Fistulas following cleft palate repair impair speech, health, and hygiene and occur in up to 35 percent of cases. The authors detail the evolution of a surgical approach to palatoplasty; assess the rates, causes, and predictive factors of fistulas; and examine the temporal association of modifications to fistula rates., Methods: Consecutive patients (n = 146) undergoing palatoplasty during the first 6 years of practice were included. The technique of repair was based on cleft type, and a common surgical approach was used for all repairs., Results: The fistula rate was 2.4 percent (n = 125) after primary repair and 0 percent (n = 21) after secondary repair. All complications occurred in patients with type III or IV clefts. Cleft width and cleft-to-total palatal width ratio were associated with fistulas, whereas syndromes, age, and adoption were not. Most complications could also be attributed to technical factors. During the first 2 years, modifications were made around specific anatomical features, including periarticular bony hillocks, maxillopalatine suture, velopalatine pits, and tensor insertion. The fistula rate declined by one-half in subsequent years., Conclusions: The authors describe a surgical approach to cleft palate repair, its evolution, and surgically relevant anatomy. Fistulas were associated with increasing cleft severity but could also be attributed to technical factors. A reduction in frequency and severity of fistulas was consistent with a learning curve and may in part be associated with modifications to the surgical approach., Clinical Question/level of Evidence: Therapeutic, IV.

Purpose: The etiology of the palatal cleft in Robin sequence (RS) is unknown. The purpose of this study was to assess the position of the fetal tongue at prenatal magnetic resonance imaging (MRI) and to suggest a potential relation between tongue position and development of the cleft palate seen in most patients with RS., Materials and Methods: This is a retrospective case-and-control study including fetuses with prenatal MRIs performed in the authors' center from 2002 to 2017. Inclusion criteria were 1) prenatal MRI of adequate quality, 2) liveborn infant, and 3) postnatal diagnosis of RS (Robin group) or cleft lip and palate (CLP group). Patients with postnatal RS without a palatal cleft were excluded. A control group with normal facial morphology was matched by gestational age. The outcome variable was tongue position at fetal MRI, described as within the cleft, along the floor of the mouth (normal), other, or indeterminate., Results: One hundred twenty-two patients with mean gestational age at MRI of 25.8 ± 4.9 weeks were included (Robin, n = 21 [17%]; CLP, n = 47 [39%]; control, n = 54 [44%]). The tongue was visualized within the palatal cleft in 76.2% of the Robin group and 4.3% of the CLP group. The tongue was found along the floor of the mouth (normal) in the remainder of the Robin and CLP groups and in 100% of the control group., Conclusion: These findings suggest a relation between in utero tongue position and the development of cleft palate in RS., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Oral clefts are among the most common congenital anomalies. Most studies on risk factors of oral clefts have been carried out in developed countries. We investigated the associations between maternal exposures in the first trimester and oral clefts in South Vietnam., Methods: We conducted a hospital-based case-control study during October 2014-November 2015. Cases included 170 patients with nonsyndromic cleft lip with or without cleft palate and those with cleft palate only. Controls were 170 children without oral clefts, matched to each case by age and gender. Mothers were interviewed using structured questionnaire. We performed conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Passive smoking was associated with increased risk of oral clefts in univariate analysis, but not in multivariable analysis (adjusted OR [aOR] = 1.68; 95% CI, 0.53-5.37). No association was observed between liver intake and oral clefts. Compared with nondrinkers, mothers who reported consumption of caffeine-containing beverages were more likely to have an infant with oral cleft (aOR = 5.89; 95% CI, 1.08-32.00). Periconceptional use of folic acid and multivitamins supplementation was associated with reduced risk of oral clefts (aOR = 0.01; 95% CI, 0.00-0.09 and aOR = 0.03; 95% CI, 0.01-0.13, respectively)., Conclusions: The results suggest no associations of maternal passive smoking or liver intake with oral clefts. Periconceptional use of folic acid or multivitamins may protect against oral clefts. Further studies are warranted to examine the roles of caffeine consumption in pregnant mothers on occurrence of oral clefts in offspring., (© 2018 Wiley Periodicals, Inc.)

Background: Cleft lip and/or cleft palate (CL ± P) are among the most common congenital anomalies. Nevertheless, their etiologies remain poorly understood. Several studies have demonstrated increased rates of cancer among patients with CL ± P and their relatives, as well as increased risk of CL ± P among family members of cancer survivors. In addition, a number of possible genetic associations between cancer and CL ± P have been identified. However, these studies are limited by confounding factors that may be prevalent in these patients, such as tobacco exposure and perinatal complications.The purpose of this study was to quantitatively evaluate the association between family history of cancer and development of CL ± P in the child., Methods: A case-control study was conducted at the Cleft Hospital and the Bashir Hospital in Gujrat, Pakistan from December 2015 to December 2016. All new cases of CL ± P at the Cleft Hospital were included. Sociodemographically similar patients without congenital malformations at the Bashir Hospital served as controls. Risk factors associated with CL ± P were identified through bivariate analyses. Multiple logistic regressions were performed to calculate adjusted odds ratios of developing CL ± P., Results: There were 137 patients with CL ± P and 147 controls in the study. The following factors were statistically significantly associated with development of cleft: history of cancer in the family (P < 0.001), complications during pregnancy (P = 0.02), maternal hypertension during pregnancy (P = 0.01), mother not on any medications (P < 0.001), consanguineous marriage (parents are first or second cousins) (P = 0.03), lower socioeconomic status (P < 0.001), having a parent who smokes (P = 0.001), and history of miscarriage (P = 0.01). After adjustment for these variables, having a history of cancer in the family was independently associated with a 5.19 times increased odds of the child being born with CL ± P (95% confidence interval [CI], 1.57-17.03). Middle-class socioeconomic status (compared with lower) (odds ratio [OR], 0.36; 95% CI, 0.16-0.83), having a smoking parent (OR, 2.12; 95% CI, 1.05-4.28), and history of miscarriage (OR, 4.60; 95% CI, 1.21-17.54) were also statistically significantly associated with CL ± P within this model., Conclusions: This study provides evidence for a relationship between CL ± P and cancer that has been adjusted for confounders traditionally associated with patients with CL ± P, thereby supporting the evidence of shared environmental and/or genetic etiologies.

Objectives To evaluate the association between hypoxia during embryo development and oral clefts in an animal model, and to evaluate the association between polymorphisms in the HIF-1A gene with oral clefts in human families. Material and Methods The study with the animal model used zebrafish embryos at 8 hours post-fertilization submitted to 30% and 50% hypoxia for 24 hours. At 5 days post-fertilization, the larvae were fixed. The cartilage structures were stained to evaluate craniofacial phenotypes. The family-based association study included 148 Brazilian nuclear families with oral clefts. The association between the genetic polymorphisms rs2301113 and rs2057482 in HIF-1A with oral clefts was tested. We used real time PCR genotyping approach. ANOVA with Tukey's post-test was used to compare means. The transmission/disequilibrium test was used to analyze the distortion of the inheritance of alleles from parents to their affected offspring. Results For the hypoxic animal model, the anterior portion of the ethmoid plate presented a gap in the anterior edge, forming a cleft. The hypoxia level was associated with the severity of the phenotype (p<0.0001). For the families, there was no under-transmitted allele among the affected progeny (p>0.05). Conclusion Hypoxia is involved in the oral cleft etiology, however, polymorphisms in HIF-1A are not associated with oral clefts in humans.

Objective: To determine the association between maternal tobacco use or exposure, presence of variant transforming growth factor alpha (TGFA) gene, and the occurrence of oral clefts., Methods: The present case control study was carried out for 5 months in three tertiary government hospitals in Chennai city with a sample of 100 children (50 children with non syndromic cleft and 50 control) aged 0-24 months. The details of maternal risk factors during the period of gestation were recorded from case and control parents through a pre-validated questionnaire, following which blood samples from 92 children (46 case and 46 controls) based on consent were obtained and evaluated for TGFA gene polymorphism., Results: A significant number of case mothers (48%) were exposed to secondhand smoke during the period of gestation than their control counterparts (24%) (P = 0.01) with an odds ratio of 2.46 (95% CI = 0.99-6.08). Electrophoresis of the restriction fragment length polymorphism (RFLP) product revealed the presence of the homozygous C1C1 allele in all the tested 92 samples with no homozygous C2C2 allele or heterozygous C1C2 allele., Conclusion: The present study has highlighted the role of passive smoking in the causation of non syndromic oral clefts in a developing country like India; however, the involvement of TGFA in causing the same disease in an ethnically Dravidian Indian population is uncertain., Clinical Significance: The study has brought into forth the role of passive smoking in the development of oral clefts thereby warranting an effective public health policy to tackle the same.

Considering that environmental risk factors substantially contribute to the etiology of orofacial clefts and that knowledge about the characteristics and comorbidities associated with oral clefts is fundamental to promoting better quality of life, this study aimed to describe the risk factors, main characteristics, and comorbidities of a group of patients with cleft lip and/or cleft palate (CL/P) from Rio Grande do Norte (RN), Brazil. Data were obtained from 173 patients with CL/P using a form from the Brazilian database on Orofacial Clefts. Most patients were male with cleft lip and palate and had a normal size and weight at birth; presented few neonatal intercurrent events; and had anemia and respiratory and cardiovascular diseases as main associated comorbidities. They also required timely surgical rehabilitation and multidisciplinary care to stimulate their neuropsychomotor development. In addition, a high frequency of familial recurrence and of parental consanguinity was evidenced in the studied population, especially for the cleft lip and cleft palate type. Other relevant findings were the considerable maternal exposure to alcohol, infections, smoking, and hypertension, as well as low supplementation with vitamins and minerals and deliberate consumption of analgesics, antibiotics, and antihypertensives during pregnancy. Characterization of the CL/P patient profile is essential for the planning of health services and integration among the health professionals involved in the diagnosis and treatment of these malformations. Our results reinforce the need for additional research to confirm the association between environmental factors and the development of orofacial clefts.