Nonsyndromic Cleft Research Articles

Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes.

Non-syndromic orofacial cleft (NSOC) is one of the most common craniofacial malformations with complex etiology. This study aimed to explore the role of specific SNPs in ZFP36L2 and its functional relevance in zebrafish models. We analyzed genetic data of the Chinese Han population from two previous GWAS, comprising of 2512 cases and 2255 controls. Based on the Hardy-Weinberg Equilibrium (HWE) and minor allele frequency (MAF), SNPs in the ZFP36L2 were selected for association analysis. In addition, zebrafish models were used to clarify the in-situ expression pattern of zfp36l2 and the impact of its Morpholino-induced knockdown. Via association analysis, rs7933 in ZFP36L2 was significantly associated with various non-syndromic cleft lip-only subtypes, potentially conferring a protective effect. Zebrafish embryos showed elevated expression of zfp36l2 in the craniofacial region during critical stages of oral cavity formation. Furthermore, Morpholino-induced knockdown of zfp36l2 led to craniofacial abnormalities, including cleft lip, which was partially rescued by the addition of zfp36l2 mRNA. Our findings highlight the significance of ZFP36L2 in the etiology of NSOC, supported by both human genetic association data and functional studies in zebrafish. These results pave the way for further exploration of targeted interventions for craniofacial malformations.

Detecting Gene-Gene Interaction among DNA Repair Genes in Chinese non-Syndromic Cleft lip with or Without Palate Trios.

The objective of this study is to investigate the gene-gene interactions associated with NSCL/P among DNA repair genes. This study included 806 NSCL/P case-parent trios from China. Quality control process was conducted for genotyped single nucleotide polymorphisms (SNPs) located in six DNA repair genes (ATR, ERCC4, RFC1, TYMS, XRCC1 and XRCC3). We tested gene-gene interactions with Cordell's method using statistical package TRIO in R software. Bonferroni corrected significance level was set as P = 4.24 × 10-4. We also test the robustness of the interactions by permutation tests. Not applicable. A total of 806 NSCL/P case-parent trios (complete trios: 682, incomplete trios: 124) with Chinese ancestry. Not applicable. Not applicable. A total of 118 SNPs were extracted for the interaction tests. Fourteen pairs of significant interactions were identified after Bonferroni correction, which were confirmed in permutation tests. Twelve pairs were between ATR and ERCC4 or XRCC3. The most significant interaction occurred between rs2244500 in TYMS and rs3213403 in XRCC1(P = 8.16 × 10-15). The current study identified gene-gene interactions among DNA repair genes in 806 Chinese NSCL/P trios, providing additional evidence for the complicated genetic structure underlying NSCL/P. ATR, ERCC4, XRCC3, TYMS and RFC1 were suggested to be possible candidate genes for NSCL/P.

Dental Arch Relationships of Saudi Children with Unilateral Cleft Lip and Palate.

To determine dental arch relationships of Saudi children born with nonsyndromic complete unilateral cleft lip and palate (UCLP). This is a retrospective cohort study that comprised dental study models of 74 UCLP Saudi children aged 8-10 years who were recruited from 14 referral cleft centers. All participants had their cleft lip and palate repaired with no history of alveolar bone graft or any orthodontic treatment. Dental arch relationships of UCLP patients were assessed using the Great Ormond Street, London, and Oslo (GOSLON) Yardstick-a clinical tool that categorizes dental relationships of UCLP children into five discrete grades from I to V. The reliability of the rating was assessed with weighted kappa (κ) statistics. Three children (4.1%) had excellent surgical outcomes (grade I), 18 children (24.3%) filled into grade II (good outcome), 22 subjects (29.7%) had grade III (fair outcome), 27 children (36.5%) had grade IV (poor outcome), and 4 subjects (5.4%) were ranked as having very poor outcomes (grade V). The mean GOSLON score was 3.39. Intrarater and interrater agreements were high indicating good reproducibility. Based on the dental arch relationships, the treatment outcome of UCLP Saudi children was unsatisfactory, with a mean GOSLON score of 3.39. Delayed palate repair and the use of presurgical orthopedics may be considered in the future for cleft deformity management. To address the effect of particular cleft surgical protocol on dental arch relationships of UCLP patients. How to cite this article: Alforaidi S, Zreaqat M, Hassan R. Dental Arch Relationships of Saudi Children with Unilateral Cleft Lip and Palate. J Contemp Dent Pract 2023;24(12):987-990.

Effects of nasoalveolar molding on nasolabial aesthetics in patients with cleft lip and palate during pre-adolescence: A systematic review and meta-analysis of retrospective studies.

This study aims to analyze long-term effects of nasoalveolar molding (NAM) as a part of cleft primary management protocols on nasolabial aesthetics for patients with non-syndromic cleft lip and palate by conducting a systematic review and meta-analysis. Six electronic databases and two journals were searched up to July 2023. Studies comparing nasolabial outcomes between NAM and non-NAM protocols were selected for further analysis. Nasolabial aesthetics were the outcome of interest. Data extraction, methodological quality assessment, risk of bias assessment, meta-analysis and subgroup analysis were performed. Seven retrospective cohort studies were selected for a qualitative review and four for a quantitative analysis. The risk of bias assessment was moderate for most studies. Only studies utilizing the Asher-McDade rating (AMR) were included for meta-analyses. The protocols with NAM exhibited a significantly lower AMR score for vermillion border than other protocols. AMR scores for nasal form and nasal symmetry from protocols with NAM were significantly lower than protocols without any pre-surgical infant orthopaedics (PSIO) but not significantly different from protocols with other PSIO techniques. The AMR score for nasolabial profile from protocols with NAM was not significantly different from other protocols. However, subgroup analysis demonstrated that protocol combining NAM and primary rhinoplasty significantly lowered AMR scores for nasal form, nasal symmetry and nasolabial profile. For patients with unilateral cleft lip with or without palate (UCLP), this study found that a protocol combining NAM and primary rhinoplasty improved nasolabial outcomes while a protocol with NAM alone offered only limited benefits. For patients with BCLP, the available evidence remains inconclusive. Performing NAM in combination with primary rhinoplasty improves nasolabial aesthetics in patients with UCLP. PROSPERO (CRD4202128384).

Maternal Exposure to Stress During Covid-19 and Non-Syndromic Orofacial Clefts: A Cohort Retrospective Study.

The coronavirus (COVID-19) pandemic presents an opportunity to study stress's effect on the development of non-syndromic orofacial clefts (NSOFCs). This study was aimed at assessing maternal stress exposure during the pregestational to first trimester pregnancy periods and the development of NSOFCs during a year of the COVID-19 pandemic. Cohort study of infants with NSOFCs and controls matched based on recruitment site and age. Government hospitals in Saudi Arabia between November 2020 and November 2021. Data collection included NSOFC clinical examination and maternal stress exposure assessment using the Modified Life Events Questionnaire, the Fear of COVID-19 Scale, and a focus on the lack of pregnancy planning and a threatened miscarriage. Of the 557 infants recruited, 191 had NSOFCs. Logistic regression analysis with adjusted odds ratios (AORs) that removed the effects of confounders showed that any of the seven stressful life events (AOR:3.78, P < .001) and the family histories of relatives with NSOFCs (AOR:9.73, P < .001) increased the AOR for NSOFC development. In contrast, maternal folic acid (AOR:0.56, P.010), threatened miscarriage (AOR:0.17, P = .001), fear of COVID-19 (AOR:0.83, P = .038), and suspected COVID-19 infection (AOR:0.43, P = .008) decreased the AOR for NSOFC development. Along with an established risk associated with family history of birth defects, stressful life events may be a risk factor for NSOFC development. Beyond folic acid's known benefit, it may be that higher maternal health concerns contribute to increased protective health behaviors during pregnancy. Ongoing research is needed to specify the maternal risk factors for NSOFC.

Unveiling dysregulated lncRNAs and networks in non-syndromic cleft lip with or without cleft palate pathogenesis

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common congenital facial malformation with a complex, incompletely understood origin. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators of gene expression, potentially shedding light on NSCL/P's etiology. This study aimed to identify critical lncRNAs and construct regulatory networks to unveil NSCL/P's underlying molecular mechanisms. Integrating gene expression profiles from the Gene Expression Omnibus (GEO) database, we pinpointed 30 dysregulated NSCL/P-associated lncRNAs. Subsequent analyses enabled the creation of competing endogenous RNA (ceRNA) networks, lncRNA-RNA binding protein (RBP) interaction networks, and lncRNA cis and trans regulation networks. RT-qPCR was used to examine the regulatory networks of lncRNA in vivo and in vitro. Furthermore, protein levels of lncRNA target genes were validated in human NSCL/P tissue samples and murine palatal shelves. Consequently, two lncRNAs and three mRNAs: FENDRR (log2FC = − 0.671, P = 0.040), TPT1-AS1 (log2FC = 0.854, P = 0.003), EIF3H (log2FC = − 1.081, P = 0.041), RBBP6 (log2FC = 0.914, P = 0.037), and SRSF1 (log2FC = 0.763, P = 0.026) emerged as potential contributors to NSCL/P pathogenesis. Functional enrichment analyses illuminated the biological functions and pathways associated with these lncRNA-related networks in NSCL/P. In summary, this study comprehensively delineates the dysregulated transcriptional landscape, identifies associated lncRNAs, and reveals pivotal sub-networks relevant to NSCL/P development, aiding our understanding of its molecular progression and setting the stage for further exploration of lncRNA and mRNA regulation in NSCL/P.

Should left- and right-sided unilateral cleft lip and palate patients be grouped together when reporting the outcomes?

Investigate associations between cleft laterality in patients with non-syndromic unilateral cleft lip and palate (UCLP) and oral-health, dental-arch, speech, audiological, psychological and nasolabial-aesthetic outcomes. Secondary data analysis of the outcomes of 5-year-old children with non-syndromic complete UCLP identified from three studies: Cleft Collective (n = 155), Cleft Care UK (CCUK) (n = 266) and Clinical Standards Advisory Group (CSAG) study (n = 238). Outcome measures included occlusal assessment using the 5-year-old's index score, speech intelligibility rating using the CAPS-A Audit tool, audiological assessment using pure tone audiometry, nasolabial aesthetic assessment using the Asher-McDade tool, oral-health assessment using decayed, missing, filled teeth scores and parent-reported outcomes. Logistic regression with adjustment for age, sex and index-of-multiple-deprivation scores were performed. No differences were found in patient-reported outcomes between the left and right clefts in the Cleft Collective study. From the CCUK study, right clefts had poorer speech (n = 236; 95% CI 1.09, 3.42; and P = .03) and hearing outcomes (n = 211; 95% CI 1.03, 3.43; P = .04). In the CSAG study, patients with left clefts were more likely to be teased (n = 213; 95% CI 0.26, 0.85; and P = .01). Weak associations between cleft laterality, speech, hearing and psychological outcomes were found, however the findings were inconsistent across the studies. This study contributes to evidence of associations between laterality and outcomes in children born with UCLP.

Prevalence, trend, and associated risk factors for cleft lip with/without cleft palate: a national study on live births from 2016 to 2021

BackgroundsCleft lip with or without cleft palate (CL/P) is the most common congenital craniofacial anomaly, including non-syndromic cleft lip with or without cleft palate and cleft palate only. Failure in the fusion of median and lateral nasal processes, the maxillary prominence, and soft tissues around the oral cavity can cause CL/P. Previously, the prevalence has been estimated to be 1 among every 1000 births in 2014 among American neonates and no other reports have been available since. Thus, this study aimed to calculate the prevalence and trend of isolated CL/P among American live births from 2016 to 2021 with its associated risk factors.Methods and materialsIn this cross-sectional population-based retrospective study, we used live birth data provided by the National Center for Health Statistics (NCHS) from the Center for Disease Control and Prevention (CDC). We calculated the prevalence per 10,000 live births of isolated (non-syndromic) CL/P from 2016 to 2021. To examine risk factors for developing isolated CL/P, we used logistic regression modelling.ResultsThe total prevalence per 10,000 births from 2016 to 2021 was 4.88 (4.79–4.97), for both sexes, and 5.96 (5.82–6.10) for males, and 3.75 (3.64–3.87) for females. The prevalence did not show any consistent linear decreasing or increasing pattern. We found significant association between increased odds of developing isolated CL/P among cases with 20 to 24 year-old mothers (OR = 1.07, 1.01–1.13, p = 0.013), mothers who smoked 11 to 20 cigarettes per day (OR = 1.46, 1.33–1.60, p < 0.001), mothers with extreme obesity (OR = 1.32, 1.21–1.43, p < 0.001), mothers with grade II obesity (OR = 1.32, 1.23–1.42, p < 0.001), mothers with pre-pregnancy hypertension (OR = 1.17, 1.04–1.31, p = 0.009), mothers with pre-pregnancy diabetes mellitus (OR = 1.96, 1.71–2.25, p < 0.001), and mothers who used assisted reproductive technology (OR = 1.40, 1.18–1.66, p < 0.001).ConclusionsOur findings suggest a minuscule increase, albeit insignificant, in the trend of CL/P prevalence from 2016 to 2021. Developing CL/P had greater odds among mothers with pre-pregnancy diabetes, smoking, obesity, and pre-pregnancy hypertension mothers along with mothers who used assisted reproductive technology. Isolated CL/P had the highest prevalence in non-Hispanic Whites, American Indian or Alaskan Native and Native Hawaiian and Other Pacific Islanders.

Exploration of the Utility of the Generic ICHOM Standard Set Measures in Evaluating the Speech of Patients with Cleft Lip/Palate.

The International Consortium of Health Outcome Measurements (ICHOM) standard set for cleft care appraisal recommends clinicians assess articulation with percentage consonants correct (PCC) and velopharyngeal function with velopharyngeal competency rating (VPC-R). This study explores the utility and limitations of these generic measures in detecting cleft speech sound disorders by comparing them with two cleft-specific speech-rating systems, cleft audit protocol of speech-augmented Americleft modification (CAPS-A-AM) and Pittsburgh weighted speech scale (PWSS). Consecutive children with repaired, nonsyndromic cleft lip/palate, aged 5 years or older (n = 27) underwent prospective speech evaluations conducted at a single academic institution. These evaluations were conducted, recorded, and evaluated by blinded speech-language pathologists experienced with all tools. When comparing measures of articulation, PCC scores correlated better with scores for relevant subcomponents of CAPS-A-AM than PWSS. When comparing measures of velopharyngeal function, VPC-R scores correlated well with relevant components of both scales. Using a "screening test versus diagnostic test" analogy, VPC-R ratings were 87.5% sensitive and 73.7% specific for detecting velopharyngeal dysfunction according to subcomponents of CAPS-A-AM, and 70.6% sensitive and 100% specific according to subcomponents of PWSS. This exploratory study demonstrates that PCC and VPC-R perform moderately well in detecting articulatory and velopharyngeal dysfunction in patients with cleft lip/palate; however, these tools cannot describe nuances of cleft speech sound disorder. Thus, although PCC and VPC-R adequately track basic minimum outcomes, we encourage teams to consider extending the standard set by adopting a cleft-specific measurement system for further evaluation of the tools.

Relationship between COVID-19 and orofacial clefts.

The work presents the connection between the infection of COVID-19 during pregnancy and non-syndromic orofacial clefts (NSOFC). Aim of the study was to compare the incidence of COVID-19 disease during mother´s pregnancy between a group of the children with NSOFC and a control group of the children without NSOFC. COVID-19 was confirmed by polymerase chain reaction (PCR) test. The study showed significantly higher incidence of COVID-19 disease in the group of mothers who gave birth to a child with NSOFC in comparison to the group of mothers who gave birth to a child without NSOFC. Our results indicate the possible participation of the infection of COVID-19 in the formation of NSOFCs.

Assessment of non-syndromic orofacial cleft severity and associated environmental factors in Saudi Arabia: A cross-sectional study

ObjectiveTo evaluate the relationship between different environmental risk factors and the severity of cleft lip with/without palate (CL ± P) and cleft palate (CP) in Saudi Arabia. MethodsThis was a cross-sectional national study, of government hospitals in 10 cities distributed across major regions of Saudi Arabia, from June 2020 to June 2021. All newborns with CL ± P or CP were clinically examined and evaluated for cleft phenotype severity using the LAHSHAL classification system. Various environmental factors were evaluated by interviewing parents using a validated questionnaire. The severity of CL ± P and CP was evaluated in relation to environmental factors. ResultsWe recruited 174 patients with non-syndromic orofacial cleft (NSOFC); 122 (70.1 %) had CL ± P and 52 (29.9 %) had CP. After adjusting the odds ratios by ordinal regression for CL ± P and logistic regression analysis for CP, environmental factors that significantly increased the severity of CL ± P were family history of NSOFC, maternal illnesses, and maternal medication use (P = 0.02, adjusted odds ratio [AOR]:2.70; P = 0.002, AOR:3.70; and P = 0.03, AOR:2.14, respectively). Folic acid supplementation in the first trimester significantly reduced the severity of CL ± P and CP (P = 0.001, AOR:0.18 and P = 0.001, AOR:0.012, respectively). ConclusionThe severity of CL ± P was affected by some maternal exposures during the 3-month pre-gestation period. Therefore, our results suggest the possibility of controlling the severity of NSOFC.

Association of methylenetetrahydrofolate reductase gene variant C677T and folate levels in non-syndromic cleft lip/palate among Sindhi, Pakistani population.

The object ives of this study were to determine the association of methylenetetrahydrofolate reduc tase (MTHFR) gene variant C67 7 T with non -syndromic cl eft lip/palate (NSCLP) in Pakistani population and compare the m aternal serum foli c acid levels in NSCLP-affected and healthy group. A c om parative cross sec ti onal study was conducted between 2017 and 2019 at Liaquat U niversity of Medi cal and Health Science s, Jamshoro. Sixty motherinfant dy ads were recruited (n=120), inc luding NSCLP-affected and healthy infants alo ng with t heir mother s. The MTHFR C677T vari ant exhibited si gnificant association with NSCLP in dominant and over-domi nant models. No differences in maternal serum folic acid levels were obse rved between both th e groups; however, the folic acid intake during pre-conception period was associated w ith decreased risk for NSC LP. Our stu dy suggested that MTHFR 677 CT genotype was related with decreased risk for NSCLP in Sindhi, Pakistani, population. Pre -conception folic acid may decrease the ri sk for ora l clefts.

Incidence of non-syndromic orofacial cleft during the COVID-19 pandemic in Saudi Arabia

ObjectivesThis is the first national study to investigate the incidence of non-syndromic oro-facial clefts (NSOFC) and Pierre-Robin-Sequence in Saudi Arabia over the Covid-19 pandemic period.MethodsAll maternity hospitals (30-hospitals) in the major regions and cities of Saudi from November 2020-to-2021 were included in the study. Patients were evaluated for cleft phenotype using the LASHAL-classification system. The incidence of NSOFC in Saudi Arabia was calculated by comparing the number of NSOFCs cases born out of all live births during the study period at the included hospitals. Clinical examination was performed and information was gathered using a validated data collection form.ResultsIn one year, 140,380 live-infants were born at the selected hospitals. Of these, 177 were diagnosed with NSOFC giving an incidence of 1.26/1,000 live-births in Saudi Arabia and the highest incidence in Medina city (2.46/1000 live-births). The incidence of cleft lip-and-palate (0.67/1000 live-births) was higher than that of cleft-palate (0.37/1000 live-births) and cleft-lip (0.22/1000 live-births). Pierre-Robin Sequence incidence was (0.04/1000 live-births). There were 21(12.1) or 23(13.2%) of NSOFC’s mothers exposed or vaccinated with Covid-19, respectively.ConclusionThe national incidence of NSOFC in Saudi Arabia was 1.26/1000 live births with variation between phenotypes and regions in the country. In addition, to reporting Covid-19 infection prevalence and vaccine exposure among NSOFC's mothers, this study represents the first of its type to evaluate NSOFC prevalence in Saudi Arabia on a national level.

Effectiveness of pre-alveolar bone graft orthodontics for patients with non-syndromic complete unilateral cleft lip, alveolus and palate: A systematic review and meta-analysis.

Non-syndromic complete unilateral cleft lip, alveolus and palate patients who have had ABG surgery. Orthodontics prior to ABG. Comparison: No orthodontic treatment prior to ABG. Successful eruption of permanent canines. All articles were screened for the title, abstract and full text independently and in duplicate by 2 reviewers. The quality assessment of RCT was performed using Cochrane's risk of bias tool and the CCT was assessed using ROBINS-I tool. Of the 904 studies retrieved in the search, one RCT and one CCT were included. Both studies were judged as high risk of bias. The results from one study showed a statistically significant increase in bone volume and decreased bone defect post-ABG in the orthodontic treatment group. However, there was no difference with respect to other variables. Both included studies were of low quality. There is not enough evidence to recommend orthodontic treatment pre-ABG for patients with complete unilateral cleft lip, alveolus and palate. Future high-quality studies are required to inform patients and clinicians about the effectiveness of pre-graft orthodontic treatment.

Speech in 7- and 10-year-olds born with a unilateral cleft lip and palate: a continued prospective Swedish intercentre study.

The aim of this study was to report longitudinal speech results in consecutively selected children from each of the six cleft centres in Sweden and to compare the results between centres. The children were born with a non-syndromic unilateral cleft lip and palate, and results from the same cohort at 5 years of age have previously been reported. Background data on medical care in terms of surgery, speech therapy, and hearing between 5 and 10 years of age were collected. Speech recordings of 56 children at 7 years and 54 at 10 years of age were blindly and independently assessed by four speech-language pathologists experienced in cleft palate speech. This resulted in measures of percent consonant correct (PCC) and perceived velopharyngeal competence rated on a three-tier scale. No statistically significant differences were found between centres. PCC scores at 7 years of age ranged from 44-100% (median 97.5) and at 10 years of age from 86-100% (median 100). Competent or marginally incompetent velopharyngeal function was found in 95% of the 7-year-olds and 98% of the 10-year-olds. Speech results were slightly better than previous reports of speech in children born with a unilateral cleft lip and palate.

Analysis of Consanguinity as Risk Factor of Nonsyndromic Cleft Lips with or without Palate.

The etiologies of nonsyndromic cleft lips with or without palate (NS CL/P) are multifactorial, which include consanguineous marriages. The incidence of NS CL/P is relatively high in Indonesia notably in one of Indonesia's tribes whose members frequently marry close cousins. Thus, the purpose of this study is to analysis consanguinity as risk factor of NS CL/P in Sasak tribe, East Lombok, Indonesia MATERIALS AND METHODS: An observational analysis was made of a collected database of NS CL/P patients treated in social services in regency hospital of Dr. Soejono Selong, East Lombok, Indonesia. Demographic data such as age, gender, address (urban/rural), parent's education, presence or absence of consanguinity, type of clefts, and a three-generation pedigree were collected by interview and hospital medical record. Before analysis, patient information was anonymized and deidentified. From 2016 to 2018, each of 100 cleft and normal subjects with their Sasak parent were audited. The risk factors were analyzed statistically using odds ratio (OR) and chi-squared test. Consanguineous marriages identified 54 cases (54%), and 10 cases (10%) out of a total each 100 NS CL/P and controls, respectively. The majority of consanguinity (53.7%) was discovered in marriages between first cousins. NS CL/P cases were statistically linked (p = 0.00) with consanguineous marriages (OR: 10; 95% confidence interval: 1.6-3.1); in which the most prevalent case is unilateral cleft lips. Consanguineous marriage increases the risk of NS CL/P in Sasak tribe, East Lombok, Indonesia. The development of strategies to educate communities on the impacts of culture-consanguineous marriage is required. The genetic inheritance from their ancestor may be responsible for the increased incidence of NS CL/P.

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

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. 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. 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.

Oral Cleft and Maternal History of Spontaneous Abortion: A Case-Control Study

To investigate and compare the occurrence of previous spontaneous abortion among mothers of children with nonsyndromic oral clefts (NSOC) and mothers of children without NSOC; to understand if previous spontaneous abortion could be a risk factor for the occurrence of NSOC in subsequent pregnancies. Case-control study. Nonsyndromic oral clefts is an important public health problem. In the context of investigating risk factors for the occurrence of this malformation, previous spontaneous abortion have been considered in the etiology at NSOC. There were 1004 participants. In the case group 502 mothers of children with NSOC, and in the control group 502 mothers of children without NSOC or any other malformation or syndrome. A standardized questionnaire was utilized to interview the maternal history of spontaneous abortion. The data were evaluated using descriptive statistics, and comparisons were performed using the Chi-square test, adopting a significance level of 5%. The prevalence of maternal history of spontaneous abortion was 16.3% in the case group and 15.9% in the control group. Comparing the groups there was no statistical difference (p-value = 0.93). Analyzing the occurrence of previous spontaneous abortion, separating the case group according to the type of cleft in the child, no statistical differences were observed when comparing these groups between them. Maternal history of spontaneous abortion was not associated with NSOC, not representing an independent risk factor for NSOC in the Brazilian population.

MSX1 Gene Polymorphisms in Patients with non-Syndromic Cleft lip and Palate: A Tertiary Care Centre Based Case-Control Study from Central Kerala

Objective The purpose of this study was to investigate the contribution of MSX1 gene polymorphisms to the risk of developing NSCLP. Design Case-Control Study. Setting A tertiary care centre. Patients/Participants The sample consisted of 200 subjects (100 cases and 100 controls). Interventions None. Main Outcome Measure(s) Genotyping was performed by restriction fragment length polymorphism. Allele and genotype frequencies were calculated between patients and controls and analyzed using online Web Tools such as SISA and SNPstats. The MSX1 gene polymorphisms c. 799 GT, c.458 CA can be risk factors in the development of orofacial clefts. Results In the cases, an association was found between NSCLP and c.799 and c.458 of the MSX1 gene when compared with the control. The dominant and overdominant models, c. 799 GT, c.458 CA genotypes and c. 799 T, c.458 A alleles in the population are said to be the main risk factors to develop the NSCLP in our study population. The genotype variation of c 799 G/T and c.458 C/A are revealed to be specifically contributing to an NSCLP-type Cleft lip and Palate. It is worth noting that NSCLP females in the study population showed a stronger association with heterozygous genotypes of c.799 and c.458. However, further investigation with a larger cohort is necessary to confirm these findings. Conclusion Overall the results of the study revealed that MSX1 c 799 G &gt; T and c.458 C &gt; A can be considered as one of the genetic risk factors in the formation of Non-Syndromic Cleft Lip and Palate in the study population.

Epigenetic mechanisms of intrauterine fetal senescence: little-known effects of hyperhomocysteinemia during pregnancy

Today, a whole body of evidence base has been formed showing the negative effect of hyperhomocysteinemia (HHC) during pregnancy on the intrauterine fetal development: risk factors associated with development of congenital neural tube defects, congenital heart defects and non-syndromic oral facial clefts. In addition, numerous studies have shown that HHC is a risk factor for serious pregnancy complications such as repeated pregnancy loss, preterm birth, preeclampsia, placental abruption, intrauterine growth restriction, gestational diabetes mellitus. At the same time, despite multiple clinical and experimental studies, the significance of HHC effects continues to support the interest to this issue. In recent years, new data were revealed about littleknown phenomena pregnancy-associated maternal HHC such as "epigenetic fetal aging" and "fetal atherogenesis". Epigenetic aging is an individual indicator of aging that captures interindividual differences at disease onset throughout life occurring during intrauterine development being reveaked as DNA hypomethylation. Moderate HHC during pregnancy causes fetal DNA hypomethylation, which, according to recent research, may represent the main mechanism underlying health in childhood and adulthood. "Fetal atherogenesis" is another understudied HHC effect emphasizing that the formation of atherosclerotic plaques begins not in adulthood, but in utero. A body of studies has shown that the formation of thickening and fatty streaks in vascular intima involved in the pathogenesis of atherosclerosis begins antenatally. The discovery of new aspects of negative intrauterine HHC impact on fetal development necessitates a detailed study of HHC causes as non-modifiable (genetic defects in enzyme systems), and more importantly, conditionally modifiable causes (lack of cofactors, excessive methionine consumption, medications) for their timely leveling. It is also important to study approaches to HHC correction at the preconception stage of a female reproductive function in order to correctly "program" fetus and newborn development.