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.

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.

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.

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.

Environmental factors in non-syndromic orofacial clefts: A review based on meta-analyses results.

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.

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.

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.

The effect of maternal smoking and alcohol consumption on lip morphology.

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.

[Multiple Correspondence of Abnormal Birth History with Genetic and Environmental Risk Factors].

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.

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.

Impact of Maternal Smoking on Nonsyndromic Clefts: Sex-Specific Associations With Side and Laterality.

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.

The Role of Environmental Factors in the Etiology of Nonsyndromic Orofacial Clefts.

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.

An overview of cleft lip and palate.

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.

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Current concepts on cleft lip and palate etiology.

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.

[Genetic analysis of a family of Van der Woude syndrome].

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.

Parental age in relation to the severity of cleft lip and/or palate.

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.

Pathogenesis of Cleft Palate in Robin Sequence: Observations From Prenatal Magnetic Resonance Imaging.

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.

Association Between Cleft Lip and/or Cleft Palate and Family History of Cancer: A Case-Control Study.

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.

Association between maternal exposure to tobacco, presence of TGFA gene, and the occurrence of oral clefts. A case control study.

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.