Prenatal incidence of cleft lip/palate and cocaine abuse in parents: a systematic review and meta-analysis.

BACKGROUND: The study aimed to investigate the association between maternal cocaine abuse during pregnancy and the prevalence of cleft lip/palate (CL/P) in offspring, synthesizing existing evidence through a systematic review and meta-analysis. CL/P is a congenital craniofacial anomaly with complex etiology, and prior research has suggested potential links between maternal cocaine use and CL/P. However, these associations remain inconclusive. METHODS: A comprehensive literature search was conducted to identify relevant studies published up to the study's cutoff date in September 2021. Several databases were systematically searched using predefined search terms. Inclusion criteria were set to encompass studies reporting on the prevalence of CL/P in infants born to mothers with a history of cocaine use during pregnancy, with a comparison group of non-cocaine-using mothers. Data were extracted, and a meta-analysis was performed using a random-effects model to calculate pooled odds ratios (OR) and relative risks (RR) with their respective 95% confidence intervals (CI). RESULTS: The review included data from 4 studies that met the inclusion criteria. The combined OR from two studies was 0.05 (95% CI: 0.00, 4.41), which does not suggest a statistically significant association between prenatal cocaine exposure and the incidence of CL/P due to the confidence interval crossing the null value. Additionally, the combined RR was 0.17 (95% CI: 0.04, 0.66), indicating a statistically significant decrease in the risk of CL/P associated with prenatal cocaine exposure. These results, with an OR that is not statistically significant and an RR suggesting decreased risk, should be interpreted with caution due to considerable heterogeneity and variability among the included studies' findings. Further research is needed to clarify these associations. CONCLUSION: The findings from this systematic review and meta-analysis suggest that maternal cocaine use during pregnancy is not a statistically significant independent risk factor for the development of CL/P in offspring. These results underscore the multifactorial nature of CL/P etiology and emphasize the importance of considering other genetic, environmental, and nutritional factors in understanding the condition's origins. While the study provides important insights, limitations such as data heterogeneity and potential confounders should be acknowledged. Future research should adopt rigorous study designs and explore a broader range of potential risk factors to comprehensively elucidate CL/P development.

US air pollution is associated with increased incidence of non-syndromic cleft lip/palate.

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 (SO2), particulate matter (PM) 2.5, PM 10, ozone (O3), 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, SO2 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: SO2 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.

Association between gestational exposure and risk of orofacial clefts: a systematic review and meta-analysis.

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 PM2.5 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 O3 and CL, with a combined RR and 95%CI of 1.132(1.047,1.225). Two studies reported a positive correlation between PM10 and CL, with a combined RR and 95%CI of 1.108 (1.017,1.206). No association was found between SO2, CO, NO2 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 PM10, PM2.5, O3 and the risk of OFCs in the second month of pregnancy. Exposure assessment, research methods and mechanisms need to be further explored.

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.

Displasia frontonasal / Frontonasal dysplasia

Los trastornos del desarrollo son aquellos padecimientos que se manifiestan por defectos en la embriogénesis de la región afectada. La cara del ser humano comienza su formación alrededor de la cuarta semana de vida intrauterina y se manifiesta gracias a la fusión de cinco prominencias: dos pares conocidas como maxilar y mandibular, y una impar conocida como frontonasal. Cuando esta fusión no se lleva a cabo de una forma óptima, aparecen numerosas alteraciones del desarrollo como el labio y paladar hendido, y la displasia frontonasal. La displasia frontonasal produce frecuentemente afecciones oculares, nasales y orales. Dentro de las manifestaciones orales destacan una forma atípica de hendidura labial o palatina, afecciones dentales y alteraciones en el crecimiento de la cara. Dada la gran relación que este padecimiento tiene con la cavidad oral resulta importante que el odontólogo conozca la etiología y las características clínicas de este trastorno (AU)

Developmental disorders are those conditions that are manifested by defects in the embryogenesis of the affected region. The human face begins its formation around the fourth week of intrauterine life and is manifested thanks to the fusion of five prominences: two pairs known as maxillary and mandibular and odd one known as frontonasal. When this fusion is not carried out in an optimal way, numerous developmental alterations appear, such as cleft lip and palate and frontonasal dysplasia. Frontonasal dysplasia frequently produces ocular, nasal and oral affections. Among the oral manifestations, and atypical form of clef lip and/or palate, dental affections and alterations in the growth of the face stand out. Given the great relationship that this condition has with the oral cavity, it is important for the dentist to know the etiology and clinical characteristics of this disorder (AU)

Investigation of Flaviviruses Emerging in Brazil as Etiology Factor in Nonsyndromic Orofacial Cleft.

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.

Gene-environment interactions in the pathogenesis of common craniofacial anomalies.

Craniofacial anomalies often exhibit phenotype variability and non-mendelian inheritance due to their multifactorial origin, involving both genetic and environmental factors. A combination of epidemiologic studies, genome-wide association, and analysis of animal models have provided insight into the effects of gene-environment interactions on craniofacial and brain development and the pathogenesis of congenital disorders. In this chapter, we briefly summarize the etiology and pathogenesis of common craniofacial anomalies, focusing on orofacial clefts, hemifacial microsomia, and microcephaly. We then discuss how environmental risk factors interact with genes to modulate the incidence and phenotype severity of craniofacial anomalies. Identifying environmental risk factors and dissecting their interaction with different genes and modifiers is central to improved strategies for preventing craniofacial anomalies.

The Public Health Importance of Flaviviruses as an Etiological Environmental Factor in Nonsyndromic Cleft Lip and/or Palate: In silico Study.

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.

Vírus e fissuras orofaciais: um histórico isolado e de associação / Viruses and orofacial clefts: an isolated and associational history / Virus y fisuras orofaciales: una historia aislada y asociativa

Os vírus são microrganismos comumente associados as doenças e infectam todos os seres vivos. Atuam de forma direta e indireta levando a pressão seletiva, com papel significativo e ainda em exploração no planeta. As fissuras orofaciais são anomalias congênitas de etiologia complexa e multifatorial, sendo as infecções virais durante a gestação um dos possíveis fatores etiológicos. A história da humanidade frente aos vírus e fissuras orofaciais de forma isolada é vasta, remontando a períodos antes de Cristo, seja por meio de leis para o controle de pragas e/ou por lendas de míticas criaturas deificadas e/ou demonizadas, cuja criação está fundamentada na Teoria Alegórica do surgimento das mitologias, demonstrando assim o interesse do ser humano e sua curiosidade em inovação e explicação destes assuntos. Considerando a relevância histórica, bem como a possível relação etiológica destes dois elementos, uma revisão da literatura foi realizada para apresentar a história mitológica e científica dos vírus e fissuras orofaciais, de forma isolada e associadas para fins de comparação. Para isso, foram utilizadas as bases PubMed/Medline, SciElo, LILACS e Portal Periódicos (CAPES) com os descritores: Virus, Anomalias/Anomalies, Virus and Anomalias/Virus and Anomalies, A History of viruses/História dos vírus, Virus and History/História and Virus, Virus and Myth/Virus and Mito, Anomalias and Mitos/Anomalies and Myths, Vampires and Virus/Vampiros and Virus. Enquanto o histórico mitológico é cheio de teorias contraditórias, o histórico cientifico acadêmico se revela coerente, porém resistente as novas áreas de atuação, não ponderando novas possibilidades e limitando a exploração científica, que só pôde ser alcançada nos séculos atuais. Quanto a associação, a linha de pesquisa relacionando vírus e fissuras orofaciais não possui nem meio século de existência, propiciando um grande campo a ser explorado e na mesma medida limitando os benefícios em prevenção que poderiam ser obtidos através destes estudos.

Viruses are microorganisms commonly associated with diseases that infect all living beings, they act directly and indirectly leading to selective pressure, their role on the planet is significant and still under exploration. Orofacial clefts are congenital anomalies that have a complex multifactorial etiology, with viral infections during pregnancy being one of the possible etiological factors. The history of humanity in the face of viruses and orofacial clefts in isolation is vast, dating back to periods before Christ, whether through laws for pest control and/or legends of mythical deified and/or demonized creatures, whose creation is fundamentalized in the Allegorical Theory of the emergence of mythologies, thus demonstrating the interest of human beings and their curiosity in innovation and explanation of these subjects. Considering the historical relevance, as well as the possible etiology relationship of these two elements, we carried out a literature review to present the mythological and scientific history of viruses and orofacial clefts, isolated and associated for comparison purposes. For this intent, the bases PubMed/Medline, SciElo, LILACS and Portal Periódicos (CAPES) were selected with the descriptors: A History of viruses/História dos vírus, Virus and History/História and Virus, Virus and Myth/Virus and Mito, Anomalias and Mitos/Anomalies and Myths, Vampires and Virus/Vampiros and Virus. While the mythological history is full of contradictory theories, the academic, scientific history proves to be consistent, but resistant to new areas of action, not considering new possibilities and limiting scientific exploration, which can only be achieved in the present centuries. As for the association, the line of research relating viruses and orofacial clefts does not even have half a century of existence, providing a large field to be explored and at the same time limiting the benefits of prevention that could be obtained through these studies.

Los virus son microorganismos comúnmente asociados a enfermedades que infectan a todos los seres vivos, actúan directa e indirectamente provocando presión selectiva, su papel en el planeta es significativo y aún en exploración. Las hendiduras orofaciales son anomalías congénitas que tienen una compleja etiología multifactorial, siendo las infecciones virales durante el embarazo uno de los posibles factores etiológicos. La historia de la humanidad frente a los virus y las hendiduras orofaciales de forma aislada es vasta, remontándose a períodos anteriores a Cristo, ya sea a través de leyes para el control de plagas y/o leyendas de criaturas míticas deificadas y/o demonizadas, cuya creación se fundamentaliza en la Teoría Alegórica del surgimiento de las mitologías, demostrando así el interés del ser humano y su curiosidad en la innovación y explicación de estos temas. Considerando la relevancia histórica, así como la posible relación etiológica de estos dos elementos, realizamos una revisión bibliográfica para presentar la historia mitológica y científica de los virus y las hendiduras orofaciales, aislados y asociados para fines de comparación. Para ello, se seleccionaron las bases PubMed/Medline, SciElo, LILACS y Portal Periódicos (CAPES) con los descriptores: A History of viruses/História dos vírus, Virus and History/História and Virus, Virus and Myth/Virus and Mito, Anomalias and Mitos/Anomalías y Mitos, Vampiros and Virus/Vampiros y Virus. Mientras que la historia mitológica está llena de teorías contradictorias, la historia académica, científica, se muestra coherente, pero resistente a nuevos campos de actuación, no considerando nuevas posibilidades y limitando la exploración científica, que sólo puede alcanzarse en los siglos actuales. En cuanto a la asociación, la línea de investigación que relaciona virus y hendiduras orofaciales no tiene ni medio siglo de existencia, proporcionando un gran campo a ser explorado y al mismo tiempo limitando los beneficios de prevención que podrían ser obtenidos a través de estos estudios.

Higher maternal age is associated with higher occurrence of cleft lip/palate in neonates under intensive care

Aim: To assess the prevalence of cleft lip and/or cleft palate (CL/P) and associated variables in neonates admitted to neonatal intensive care units (ICU). Methods: Medical charts for neonates born and admitted to the ICU between 2012 and 2018 were reviewed. Obstetric and neonatal variables were collected by a trained researcher. In the case group, all neonates with CL/P were included. The control group was formed by matching sex, prematurity and month of birth using random number generation. Neonates with congenital malformations were excluded from the control group. Adjusted logistic regression was used (p<0.05). Results: The prevalence of CL/P was 0.43% (n=15). Five cases were excluded, as pairing was not possible. Twenty neonates were included in the control group. In the final multivariate model, CL/P was only associated with increased maternal age. For each year of increase in maternal age, neonates had a 35.2% higher chance of presenting CL/P (95% confidence interval: 1.021­1.792). Conclusions: Higher maternal age was associated with higher occurrence of CL/P in neonates admitted to the ICU. No other neonatal or maternal independent variables were associated with CL/P. Due to missing data, interpretation of study results must be approached with caution

Environmental Factors at the Periconceptional Period and the Occurrence of Cleft Lip and Palate in a Midwest Brazil Population: A Case-Control Study.

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.

Knowledge of Environmental and Genetic Risk Factors for Cleft Lip and Palate among Dwellers of a Suburban Community in Nigeria.

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.

CONTEXTE: La fente labiale et/ou la fente palatine (CLP) sont répandues condition avec une étiologie multifactorielle. Une compréhension de son les facteurs étiologiques découragent les habitudes néfastes et favorisent la société acceptabilité. OBJECTIFS: Évaluer la connaissance de l'environnement et de la génétique facteurs de risque de CLP et déterminer son effet sur les réseaux sociaux prédisposants habitudes dans une communauté de banlieue au Nigeria. MÉTHODES: Il s'agissait d'une étude transversale descriptive menée à Ifo Local Government Area (LGA), État d'Ogun, Nigéria. Participants étaient des résidents adultes d'Ifo L.G.A. Connaissance du CLP catégorisée dans la description, les facteurs de risque environnement aux et les facteurs génétiques étaient évalué à l'aide d'un intervieweur bien structuré administré questionnaire. RÉSULTATS: Un total de 300 adultes (104 hommes; 196 femmes) âgés de 44,3 ans+ 13,17 ans avec un enseignement principalement secondaire ont participé à l'étude. La majorité des participants (89,7%) avaient un faible taux connaissance globale du CLP, y compris faible connaissance de la description de CLP (81,7%), facteurs environnement aux de CLP (81,3%) et génétique(93,7 %). Le niveau d'éducation élevé était significatif associé à une connaissance accrue de la description du CLP (P <0.05). Aucune autre association significative n'a été notée entre les facteurs sociodémographiques et la connaissance de la CLP. Diminution du tabagisme l'histoire était associée à une grande connaissance de la description du CLP (P = 0,043). CONCLUSION: La majorité de la population avait une faible connaissance du CLP qui a été dans une certaine mesure influencée par leur manque de niveau élevé de éducation. Cette faible connaissance était significativement associée àdes pratiques accrues d'habitudes sociales telles que le tabagisme qui prédisposer les enfants à naître à la CLP. La faible connaissance du CLP montrée dans cette étude souligne la nécessité d'une éducation communautaire accrue et la promotion de la santé pour encourager l'évitement des facteurs de risque qui prédisposer à la condition et promouvoir l'acceptabilité sociétale et quête de traitement de la maladie. Mots-clés: Connaissances, facteurs de risque, fente labiale et palatine, suburbaineNigéria.

Association of maternal heavy metal exposure during pregnancy with isolated cleft lip and palate in offspring: Japan Environment and Children's Study (JECS) cohort study.

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.

Maternal Cigarette Smoking and Cleft Lip and Palate: A Systematic Review and Meta-Analysis.

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.

Double-opposing Z-Plasty Extended with a Pedicled Buccal Fat Pad Flap for Correcting Velopharyngeal Insufficiency after Primary Palatoplasty.

INTRODUCTION: Furlow double-opposing Z-plasty (DOZ) lengthens the soft palate; however, this lengthening is achieved at the expense of increased mucosal flap tension. Thus, its use is limited in patients with severe tension applied on mucosal flap after DOZ. In this study, DOZ was combined with a buccal fat pad (BFP) flap to maximize palatal lengthening and muscle repositioning. METHODS: This study included patients who underwent surgical correction for velopharyngeal insufficiency between December 2016 and February 2019. Patients with more than moderate degree hypernasality following primary palatoplasty were included in the study. Patients younger than 4 years of age, those with a submucous cleft palate, or syndromic patients were excluded. Speech outcomes were investigated for those who underwent DOZ only (DOZ group, n = 17) and those in whom a BFP was used (BFP group, n = 15) pre- and postoperatively. The velopharyngeal gaps between the uvula and pharyngeal wall were measured before and immediately after surgery to estimate the palatal length. RESULTS: Most patients who received a BFP showed improvement in hypernasality. However, the hypernasality of the DOZ group was more severe than that of the BFP group (p = 0.023). The extent of palatal lengthening was 4.4 ± 1.7 mm and 7.5 ± 2.1 mm in the DOZ and BFP groups, respectively (p = 0.001). CONCLUSIONS: BFPs reduced the tension of the DOZ mucosal flap and maximized palatal lengthening and muscle repositioning. They promoted velopharyngeal closure in patients with moderate and moderate-to-severe velopharyngeal insufficiency. Hence, our method improves the surgical outcomes of patients with velopharyngeal insufficiency after primary palatoplasty.

The impact of changing cigarette smoking habits and smoke-free legislation on orofacial cleft incidence in the United Kingdom: Evidence from two time-series studies.

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.

Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.

Tamoxifen is an estrogen receptor (ER) ligand with widespread use in clinical and basic research settings. Beyond its application in treating ER-positive cancer, tamoxifen has been co-opted into a powerful approach for temporal-specific genetic alteration. The use of tamoxifen-inducible Cre-recombinase mouse models to examine genetic, molecular, and cellular mechanisms of development and disease is now prevalent in biomedical research. Understanding off-target effects of tamoxifen will inform its use in both clinical and basic research applications. Here, we show that prenatal tamoxifen exposure can cause structural birth defects in the mouse. Administration of a single 200 mg/kg tamoxifen dose to pregnant wildtype C57BL/6J mice at gestational day 9.75 caused cleft palate and limb malformations in the fetuses, including posterior digit duplication, reduction, or fusion. These malformations were highly penetrant and consistent across independent chemical manufacturers. As opposed to 200 mg/kg, a single dose of 50 mg/kg tamoxifen at the same developmental stage did not result in overt structural malformations. Demonstrating that prenatal tamoxifen exposure at a specific time point causes dose-dependent developmental abnormalities, these findings argue for more considerate application of tamoxifen in Cre-inducible systems and further investigation of tamoxifen's mechanisms of action.

Agenesia e fatores associados em pacientes portadores de fissura labiopalatina: uma revisão de literatura / Agenesis and associated factors in patients with cleft lip and palate: a review of the literature

Objetivo: verificar as principais agenesias dentárias e os fatores associados em portadores de fissura labiopalatina por meio de uma revisão de literatura. Métodos: foi realizada uma revisão de literatura utilizando as bases de dados PubMed, SciELO e Google Acadêmico. Revisão de literatura: foram incluídos 34 artigos, sendo 2 casos clínicos, 15 estudos retrospectivos, 10 revisões de literatura, 4 estudos de caso-controle e 5 estudos transversais; além de 3 referências escolhidas através de outras buscas para complementar a revisão. A partir dos estudos incluídos no trabalho, foi possível verificar que a maior prevalência ocorre no sexo masculino. E a fissura que mais acomete a população é a transforame incisivo. Pôde-se analisar também que não há causa exata, porém, existem fatores predisponentes, como os ambientais e os hereditários. Considerações finais: esta revisão de literatura poderá auxiliar os profissionais de saúde para a realização de diagnóstico e planejamento precoces, a fim de encontrar o melhor e mais eficiente tratamento para cada caso. O tratamento precoce, por uma equipe multidisciplinar, certamente garantirá uma melhor qualidade de vida aos pacientes.(AU)

Objective: to verify the main dental agenesis and associated factors in cleft lip and palate through a literature review. Methods: a literature review was carried out using PubMed, SciELO and Google Scholar databases. Literature review: 34 studies were included, 2 clinical studies, 1 retrospective study, 10 literature reviews, 4 case-control studies and 5 cross-sectional studies. In addition to 3 references chosen through other searches complementary to the review. From the included studies, it was verified a higher frequency of cleft lift and palate for the male sex, and a higher frequency of more severe clefts, such as the incisive transformation, in comparison to the labiopalatine. It can also be analyzed that there is no exact cause; however, there are environmental and hereditary predisposing factors. Final considerations: this literature review may help health professionals to carry out early diagnosis and treatment planning, in order to find the best and most efficient treatment for each case. Early treatment by a multidisciplinary team will certainly guarantee a better quality of life for patients.(AU)

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.