Rare craniofacial clefts: Surgical management protocols.

BACKGROUND: Standardization of surgical protocols is an evolving issue owing to the low incidence of rare craniofacial clefts. In this article, we present our surgical management technique for repair of rare craniofacial clefts and evaluate the postoperative results. METHODS: This study was conducted from 2013 to 2022 and included patients who presented with craniofacial clefts. The results were assessed based on parents' satisfaction and objective evaluations by two independent observers. RESULTS: A total of 3679 patients presented with cleft anomalies; of these, 61 patients with 89 rare craniofacial clefts were observed with a prevalence of 2.42/100. The male to female ratio was 1:1.35. Craniofacial cleft "4" and "5" were the most common, with 17 (19.1%) and 16 (17.98%) patients, respectively. Multiple craniofacial clefts were observed in 37.7% of the patients. Associated craniofacial anomalies were found in 39.34% of the patients. The parents of 71.6% of the patients were very satisfied with the results. Based on the scores of two independent observers, 70.27% of the patients showed good results. CONCLUSION: The rare nature of craniofacial clefts and involvement of various structures make the standardization of surgical procedures very challenging. Our experience with these clefts will help new surgeons both in didactics and in technical aspects of patient management. KEY POINTS: 1. We share our experience with rare craniofacial clefts. 2. Each cleft presents with its own unique reconstructive challenges. The literature describes many techniques for each type of cleft, all with multiple permutations. We present a simplified technique that has worked for us over the years for all Tessier clefts.

Case report and functional verification of a novel mutation in the interferon regulatory transcription factor 6 gene in a family with orofacial clefts.

BACKGROUND: This study aimed to identify the causative genetic variant in a Chinese family with orofacial clefts. METHODS: We retrospectively analyzed the clinical information of a family with orofacial clefts. Then, we performed an etiological genetic analysis of the family using whole exome sequencing analysis and Sanger sequencing. We created a hybrid code-shifting mutation cell line (293T-462het) and evaluated its impact on cell proliferation, migration, and apoptosis, as well as E-cadherin and vimentin expression. RESULTS: Whole exome sequencing revealed a novel heterozygous variant c.1386del (p.A462Pfs*28) in the interferon regulatory transcription factor 6 (IRF6) gene in a family with orofacial clefts. Sanger sequencing further confirmed that this heterozygous variant was the genetic cause of orofacial clefts in this family. The c.1386del variant of IRF6 was classified as likely pathogenic. The heterozygous mutation IRF6 (c.1386del) enhanced cell proliferation and migration while inhibiting cell apoptosis and regulating the expression of E-cadherin and vimentin. CONCLUSION: This study identified a novel c.1386del mutation in the IRF6 gene and explored how this mutation leads to lip and palate defects. Our results provide a solid theoretical foundation for future genetic detection of these orofacial defects.

Access to genetic evaluation of 1463 individuals with orofacial cleft in Brazil.

OBJECTIVE: The current study delves into the accessibility of genetic evaluations for individuals with orofacial clefts (OC), comparing data between genetics and treatment centers across Brazil. METHODS: This cross-sectional retrospective study analyzed primary data from 1463 OC individuals registered in the Brazilian Database of Craniofacial Anomalies (BDCA) between 2008 and 2018 without age or sex selection. Diagnostic exam results stemming from research projects until 2023 were considered. RESULTS: Of the 1463 individuals with typical OC, 987 were non-syndromic, 462 were syndromic (SOC), 10 presented atypical forms, and three were not specified OC cases. The average age for accessing laboratory diagnosis was 8.5 years among SOC individuals. Notably, more SOC cases were registered in genetics centers than treatment and rehabilitation centers (37.1 % vs. 29 %, p = 0.0015). Those originating from genetics centers accessed diagnosis at an average age of 7.3 years, while those from treatment and rehabilitation centers experienced delays with an average age of 10.7 years (p = 0.0581). CONCLUSIONS: Irrespective of the center of origin, the data highlight delayed diagnosis and challenges in accessing genetic tests for the syndromic group. Given the widespread reliance on the public health system by most of the Brazilian population, disseminating this data can significantly contribute to shaping an informed perspective on healthcare access. These insights can improve public policies tailored to the unique needs of individuals with OC.

Single-Nucleotide Polymorphisms in WNT Genes in Patients with Non-Syndromic Orofacial Clefts in a Polish Population.

Non-syndromic orofacial cleft (OFC) is the most common facial developmental defect in the global population. The etiology of these birth defects is complex and multifactorial, involving both genetic and environmental factors. This study aimed to determine if SNPs in the WNT gene family (rs1533767, rs708111, rs3809857, rs7207916, rs12452064) are associated with OFCs in a Polish population. The study included 627 individuals: 209 children with OFCs and 418 healthy controls. DNA was extracted from saliva for the study group and from umbilical cord blood for the control group. Polymorphism genotyping was conducted using quantitative PCR. No statistically significant association was found between four variants and clefts, with odds ratios for rs708111 being 1.13 (CC genotype) and 0.99 (CT genotype), for rs3809857 being 1.05 (GT genotype) and 0.95 (TT genotype), for rs7207916 being 0.86 (AA genotype) and 1.29 (AG genotype) and for rs12452064 being 0.97 (AA genotype) and 1.24 (AG genotype). However, the rs1533767 polymorphism in WNT showed a statistically significant increase in OFC risk for the GG genotype (OR = 1.76, p < 0.001). This research shows that the rs1533767 polymorphism in the WNT gene is an important risk marker for OFC in the Polish population.

Pyogenic granuloma of the hard palate leading to alveolar cleft: a case report.

This case report describes a rare occurrence of pyogenic granuloma (PG) in the hard palate deviating from its typical gingival location that led to the formation of an alveolar cleft. The aggressive growth pattern of the lesion, with atypical progression from a pedunculated nodule to an alveolar cleft, raised concern. The diagnosis was based on magnetic resonance imaging and computed tomography findings, which revealed a tadpole-shaped lesion originating from the midline hard palate. The differential diagnosis included a minor salivary gland tumor. Surgical excision was performed under general anesthesia and resulted in a mucosal defect without nasolabial fistula formation or bone exposure. The palatal defect was packed with oxidized regenerated cellulose and closed with Vicryl Rapide sutures, both of which contributed to the patient's successful outcomes. Our comprehensive approach, extending across the stages of surgical planning, execution, and postoperative care, demonstrated the advantages of a multidisciplinary strategy for the accurate diagnosis and effective treatment of palatal PGs. This report makes a meaningful contribution to the existing literature on common oral lesions by emphasizing the importance of a broad differential diagnosis and a systematic approach to oral pathologies. It also raises clinical awareness of PGs with atypical presentations and the diagnostic challenge that they pose.

Growth Patterns Between Ages 0 and 36 Months Among US Children With Orofacial Cleft: A Retrospective Cohort Study.

BACKGROUND: Little is known about how young children with orofacial cleft grow over time. OBJECTIVE: To characterize longitudinal growth patterns from ages 0 to 36 months in US children with an orofacial cleft. DESIGN: A retrospective cohort study. PARTICIPANTS/SETTING: Children with cleft lip, cleft lip and palate, or cleft palate who were younger than age 36 months at a hospital encounter between 2010 and 2019 (N = 1334) were included. The setting was a US tertiary care children's hospital with a cleft center that serves a 5-state region. MAIN OUTCOME MEASURE: Weight-for-age z scores (WAZ) and length-for-age z scores (LAZ). STATISTICAL ANALYSES PERFORMED: Longitudinal growth patterns were characterized using generalized linear mixed models to estimate mean WAZ and LAZ from age 0 to 36 months. RESULTS: Growth in infants with cleft slowed dramatically during the first 3 to 4 months of life, rebounded with catch-up growth until age 12 months for cleft lip and cleft palate and until age 36 months for cleft lip and palate. When comparing populations, children with any type of cleft demonstrated subpar growth compared with World Health Organization standards. Growth deficits were more common in those with cleft lip and palate and cleft palate compared with those with cleft lip. The intraclass coefficient showed that most of the variability in the WAZ (65%) was between individuals, whereas 35% was within an individual. The intraclass coefficient for LAZ showed that most of the variability in the LAZ (74%) was between individuals, whereas 26% was within an individual. The proportion of variance attributable to cleft type and/or comorbidities accounted for <5% of the variance for WAZ and LAZ. WAZ and LAZ were lower in children with comorbidities than those without comorbidities with cleft and World Health Organization standards. CONCLUSIONS: Infants with cleft lip and palate, cleft palate, and a cleft with comorbidities have higher rates of poor growth than peers with cleft lip and a cleft with no comorbidities, respectively.

Orodental malformations associated with human MSX1 sequence variants.

BACKGROUND: MSX1 sequence variants have been known to cause human tooth agenesis (TA) with or without orofacial clefts. However, their roles during the whole processes of tooth development are not fully understood. This study aimed to characterize a 4-membered family with TA carrying a novel MSX1 pathogenic variant and investigate the disease mechanism. METHODS: The authors conducted whole exome analysis to define the disease-causing sequence variant. They performed microcomputed tomography, morphometric analyses, transcriptome profiling, and molecular characterization to study the affected teeth and the gene variant. RESULTS: The authors identified an MSX1 pathogenic variant, p.Glu232∗, in affected family members with TA and concomitant orodental anomalies, namely, prominent maxillary labial frenum, central incisor diastema, median maxillary anterior alveolar cleft, tooth fusion, mandibular molar dysmorphology, thin dentin layer, and slender dental roots. MSX1-defective teeth were not apparently microdontic but had thin dentin layers. The mandibular molars showed a homeotic transformation to maxillary counterparts. Genes involved in extracellular matrix organization and dentinogenesis, such as DMP1 and MMP20, were downregulated in dental pulp tissues of MSX1-defective teeth. The p.Glu232∗-truncated MSX1 properly localized to the nucleus but partially lost its transactivation ability. Analyzing reported cases indicated that truncation sequence variants within the homeobox domain of MSX1 caused a more severe TA phenotype than those outside of the homeobox domain, probably due to dominant negativity compared with haploinsufficiency. CONCLUSIONS: This study provides in vivo evidence that MSX1 contributes to developmental processes of various orodental tissues in humans. PRACTICAL IMPLICATIONS: Clinically, hypertrophic labial frenum, incisor diastema, and median maxillary anterior alveolar cleft might be considered diagnostic for MSX1-associated TA.

Prenatal Ultrasound Imaging of Orofacial Clefts: A Pictorial Essay.

Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and CL with palate (CL/P), are relatively common congenital birth defects occurring in approximately 1 in 500 to 1 in 2500 live births. Detecting OFCs during prenatal ultrasound screening is crucial for informed decision-making and multidisciplinary medical care. This review provides a practical guide for routine and advanced screening for OFCs during mid-pregnancy. The Maarse classification system facilitates effective communication among the multidisciplinary team, categorizing OFCs into five types. Basic ultrasound views encompass coronal, sagittal, and axial imaging of the face and hard palate. Additional visualization techniques are employed in case of suspected anomalies during the initial screening. Advanced ultrasound views provided by the expert in prenatal OFC diagnosis include imaging of the posterior edge of the hard palate and the posterior part of the soft palate. Detected OFCs exhibit a range of severity and affect different structures, underscoring the importance of accurate detection and classification for appropriate treatment planning. Implementing a standardized screening protocol for OFCs is essential. By enhancing detection rates and enabling early diagnosis, prenatal ultrasound screening contributes to improved patient outcomes and facilitates timely intervention by the multidisciplinary team. In conclusion, this review emphasizes the significance of standardized protocols and specialized techniques for prenatal ultrasound screening of OFCs. Early detection and classification of these malformations play a vital role in comprehensive management, ensuring that affected individuals and their families receive the appropriate care and support they need.

Congenital cardiac anomalies in non-syndromic cleft lip and cleft palate patients: A systematic review and meta-analysis.

The aim was to establish a specific and definite connection between non-syndromic orofacial cleft patients and associated congenital heart disease (CHD). Following PRISMA guidelines, selective databases were searched for data collection. Studies showing a definite association of CHD with orofacial cleft were included, and studies non-specific of the association of orofacial cleft with CHD were excluded. Data extraction criteria were study design, frequency of CHD in overall non-syndromic orofacial cleft and in specific cleft type, and most prevalent congenital cardiac anomaly. DerSimonian Laird random effects model was used to estimate the pooled proportion of CHD, along with corresponding 95% confidence intervals (CIs) for each measure. Publication bias was assessed using Fail-Safe N analysis and the Rosenthel approach. Of a total of 182 articles searched, only 30 studies were assessed. The overall pooled estimate of the proportion of CHD in total cleft lips/palates was 16% (95% CI: 13-19). The odds of developing CHD in cleft palates was 4.08 times more as compared to cleft lips with 95% CIs of 3.86-4.33, and 1.65 more as compared to cleft lips and palates both with 95% CI of 1.52-1.68. We affirm the upsurging prevalence of CHD in non-syndromic cleft children and vehemently propose that it is of utmost importance to inculcate it in practice and policy-making to screen all non-syndromic orofacial cleft children for congenital cardiac anomaly. This study was registered on PROSPERO (ID no. CRD42023391597) on February 24, 2023.

Distribution of maternal risk factors for orofacial cleft in infants in Indonesia: a multicenter prospective study.

BACKGROUND: The pathogenesis of orofacial cleft (OFC) is multifactorial, involving both genetic and non-genetic factors, the latter of which play a key role in the development of these anomalies. This paper addresses the incidence of OFC in Indonesia, with a focus on identifying and examining the distribution of contributory factors, including parental medical history, pregnancy history, and environmental influences. METHODS: The study was conducted through the collection of primary data. An interdisciplinary research team from Indonesia administered a standardized questionnaire to parents who had children with OFC and who had provided informed consent. The case group comprised 133 children born with cleft lip and/or palate, and the control was 133 noncleft children born full-term. The risk factors associated with OFC anomalies were analyzed using the chi-square test and logistic regression. All statistical analyses were performed using SPSS version 25. A p-value of 0.05 or less was considered to indicate statistical significance. RESULTS: The study comprised 138 children, of whom 82 were boys (59.4%) and 56 were girls (40.6%). Among them, 45 patients (32.6%) presented with both cleft lip and cleft palate, 25 individuals (18.1%) had a cleft palate only, and 28 patients (20.3%) had a cleft lip only. OFC was found to be significantly associated with a maternal family history of congenital birth defects (p< 0.05), complications during the first trimester (p< 0.05), consumption of local fish (p< 0.05), caffeine intake (p< 0.05), prolonged medication use (p< 0.05), immunization history (p< 0.05), passive smoking (p< 0.05), and X-ray exposure during pregnancy (p< 0.05). CONCLUSION: The findings indicate close relationships between the incidence of OFC and maternal medical history, prenatal factors, and environmental influences.

Review on the Role of IRF6 in the Pathogenesis of Non-syndromic Orofacial Clefts.

Non-syndromic orofacial clefts (NSOCs) are the most common craniofacial malformation. In the complex aetiology and pathogenesis of NSOCs, genetic factors play a crucial role and IRF6, located at chromosome 1q32.2, is the best documented NSOC susceptibility gene. IRF6 is a key factor in oral maxillofacial development and known to contribute the most in NSOCs. It is essential to conduct a complete review of the existing results on IRF6 to further understand its role in the pathogenesis of NSOCs. Thus, the present authors summarised the research progress on the mechanism of IRF6 in NSOCs from both genetic and functional perspectives in this review.

The Global Occurrences of Cleft Lip and Palate in Pediatric Patients and Their Association with Demographic Factors: A Narrative Review.

OBJECTIVE: Orofacial clefts are one of the most common abnormalities that occur in the orofacial area. Due to their high prevalence, special attention provided to risk factors and their possible involvement in the occurrence of orofacial clefts is of importance. The objective of this study was to review the current global occurrence of orofacial clefts and the possible linkage of previously investigated risk factors to the occurrence of orofacial clefts. REVIEW: The risk factors of orofacial clefts can be classified into two groups, modifiable risk factors and non-modifiable risk factors. Due to the extent of elaboration of each risk factor in each group, this current narrative review is limited to several mostly investigated risk factors, which included a review of parental age, sexual disparities, educational attainment, and income. Studies indicate that Asians are more likely than other races to have orofacial clefts, with a higher incidence rate in men than in women. There is evidence that the age of the parents is associated with the chance of the occurrence of orofacial cleft. The prevention of orofacial clefts and the distribution of medical resources depend heavily on a thorough understanding of epidemiology on a global scale. Nevertheless, the earlier studies concentrated on more developed nations or areas, and registry data from low-income nations had significant gaps. The findings of this narrative review can be used as the scientific basis for further research within this area. CONCLUSION: The occurrence rate of orofacial clefts remains high in several regions. Possible associations between parental age, sexual disparities, educational attainment, and family income to the occurrence of orofacial clefts remain contradictory, indicating the importance of further research to obtain more insights.

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

Objective: To 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. Methods: This 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. Results: We 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). Conclusion: The 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.

Utilising massive open online courses to enhance global learning dissemination in cleft lip and palate: a case report of penta helix collaboration.

BACKGROUND: Educating and raising awareness in cleft lip and palate future generations is one vital effort to ensure the improvement of cleft care and research in the future. This study reported the overview in organising and evaluating the Massive Open Online Course (MOOC) in Cleft Lip and Palate as the alternative way for students' capacity building outside their study program whilst also earning credits towards their studies. METHODS: Smile Train cleft charity generously donated recorded lectures from cleft experts around the world in which each of the experts agreed to provide one-hour live discussion sessions. The learning activities ranging from lectures, pre- and post-course evaluation, forum, live discussion sessions, virtual visits to Indonesian Cleft Centre, self-reflection assignments and final project. A survey was released to the participants to collect their feedback. RESULTS: The course mainly attracted dental students, and several allied health professional students. In total, 414 out of 717 participants registered for this MOOC managed to finish the course and received a certificate of completion which was run between August-October 2021. In general, participants positively received the course. CONCLUSIONS: The MOOC model and its objective of disseminating widespread information across geographical boundaries to enhance learning about cleft lip and palate treatment was achieved. This report serves as an example for other educational institutions and stakeholders who plan to use online educational engagement platforms to provide high-quality education and capacity building to participants in lower-middle income countries.

Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts.

Orofacial clefts (OFCs) represent the most prevalent congenital craniofacial anomalies, significantly impacting patients' appearance, oral function, and psychological well-being. Among these, non-syndromic OFCs (NSOFCs) are the most predominant type, with the etiology attributed to a combination of genetic and environmental factors. Rare variants of key genes involved in craniofacial development-related signaling pathway are crucial in the occurrence of NSOFCs, and our recent studies have identified PTCH1, a receptor-coding gene in the Hedgehog signaling pathway, as a causative gene for NSOFCs. However, the role of PTCH2, the paralog of PTCH1, in pathogenesis of NSOFCs remains unclear. Here, we perform whole-exome sequencing to explore the genetic basis of 144 sporadic NSOFC patients. We identify five heterozygous variants of PTCH2 in four patients: p.L104P, p.A131G, p.R557H, p.I927S, and p.V978D, with the latter two co-occurring in a single patient. These variants, all proven to be rare through multiple genomic databases, with p.I927S and p.V978D being novel variants and previously unreported. Sequence alignment suggests that these affected amino acids are evolutionarily conserved across vertebrates. Utilizing predictive structural modeling tools such as AlphaFold and SWISS-MODEL, we propose that these variants may disrupt the protein's structure and function. In summary, our findings suggest that PTCH2 may be a novel candidate gene predicted to be associated with NSOFCs, thereby broadening the spectrum of causative genes implicated in the craniofacial anomalies.

Quantitative assessment of cleft volume and evaluation of cleft's impact on adjacent anatomical structures using CBCT imaging.

OBJECTIVES: To determine pre-operative cleft volume and evaluate cleft´s impact on surrounding anatomical structures in children and adolescents with orofacial clefts using cone bean computed tomography (CBCT) imaging. METHODS: The present retrospective study retrieved CBCT examinations of 68 patients from a previous study. The examinations had been exposed either before (n = 53) or after (n = 15) alveolar bone grafting. Pre-operative volume of cleft was determined, and type and location were evaluated. Morphological changes on the adjacent anatomical structures, including the incisive foramen, the nasal septum and floor, and the inferior turbinate, were assessed. RESULTS: Mean bilateral cleft volume was 0.76 cm3, while mean unilateral cleft volume was 1.08 cm3; the difference was significant (p < 0.001). Variation in cleft volume, however, was large. The incisive foramen was not visible in the majority of cases with bilateral clefts (71%); the difference was significant (p = 0.001). In cases with unilateral clefts, the nasal septum in 87% was curved towards the cleft or graft side. Also, the mean size of the widest part of the inferior turbinate was 8.8 mm on the cleft or graft side and 10.4 mm on the non-cleft side. The difference was significant (p < 0.001). CONCLUSIONS: When required, CBCT is a feasible method for quantitatively illustrating alveolar clefts and their impact on the morphological development of surrounding structures. Variation in cleft volume was large.

Genetic and environmental contributions for the relationship between tooth loss and oral potentially malignant disorders and oral squamous cell carcinoma.

BACKGROUND: To investigate the association between tooth loss and oral potentially malignant disorders and oral squamous cell carcinoma, focusing on epidemiological factors and genetic variants. METHODS: Case-control study, including histologically confirmed oral potentially malignant disorders and oral squamous cell carcinoma cases and healthy controls. Unadjusted and adjusted odds ratios for this association were calculated. Single-nucleotides polymorphisms were tested for individuals with and without missing teeth. RESULTS: Case individuals were more edentulous while controls had fewer missing teeth (p = 0.006). There was an increased risk for the outcomes associated with edentulism (OR = 6.95, p = 0.000), even after adjustments for educational level (OR = 4.7, p = 0.034) and smoking habits (OR = 5.01, p = 0.022). Among individuals with tooth loss, rs1533767 (WNT11), rs3923087, and rs11867417 (AXIN2) were associated with the outcomes (OR = 1.67, p = 0.03, OR = 0.53, p = 0.05, and OR = 0.42, p = 0.00, respectively). CONCLUSIONS: Tooth loss could increase the risk for oral potentially malignant disorders and oral squamous cell carcinoma.

Publicly funded healthcare costs associated with orofacial clefts for children born in Alberta, Canada between 2002 and 2018.

BACKGROUND: Orofacial clefts (OFCs) include cleft palate (CP), cleft lip (CL), and cleft lip with cleft palate (CLP) and require multidisciplinary healthcare services. Alberta, Canada has a publicly funded, universal access healthcare system. This study determined publicly funded healthcare costs for children with an OFC and compared these costs to children without congenital anomalies. METHODS: This retrospective population-based cohort analysis used the Alberta Congenital Anomalies Surveillance System to identify children born between 2002 and 2018 with an isolated OFC. They were matched 1:1 to a reference cohort based on sex and year of birth. The study population included 1614 children, from birth to 17 years of age linked to administrative databases to estimate annual inpatient and outpatient costs. Average annual all-cause costs were compared using two-sample independent t tests. RESULTS: The mean total cleft-related costs per patient were highest for children with CLP ($74,138 CAD, standard deviation (SD) $43,447 CAD), followed by CP ($53,062 CAD, SD $74,366 CAD), and CL ($35,288 CAD, SD $49,720 CAD). The mean total all-cause costs per child were statistically significantly higher (p < .001) in children with an OFC ($56,305 CAD, SD $57,744 CAD) compared to children without a congenital anomaly ($18,600 CAD, SD $61,300 CAD). CONCLUSIONS: Despite public health strategies to mitigate risk factors, the trend for OFCs has remained stable in Alberta, Canada for over 20 years. The costs reported are useful to other jurisdictions for comparison, and to families, healthcare professionals, service planners, and policy makers.

Prenatal detection of orofacial clefts in Denmark from 2009 to 2018.

OBJECTIVE: To investigate the overall and type-specific prenatal detection rates (DRs) of orofacial clefts in a national cohort in Denmark. METHODS: This study was based on data from the Danish Fetal Medicine Database and included all fetuses and children from singleton pregnancies diagnosed with an orofacial cleft prenatally and/or postnatally between 2009 and 2018. The types of cleft included unilateral, bilateral or median cleft lip (CL); unilateral, bilateral or median cleft lip with secondary cleft palate (CLP); and cleft palate (CP). The clefts were grouped as cleft lip with or without cleft palate (CL(P)) or as all clefts (including CP). All cases with discordance between prenatal and postnatal diagnoses were validated in the local patient files (Astraia). Cases without prenatal validation of the postnatal diagnosis were marked as undetected. Postnatally diagnosed cases with a strong prenatal suspicion of a cleft but without an International Classification of Diseases-10 code were registered as prenatally detected. Termination of pregnancy and intrauterine death were registered as true positives even if no autopsy could be performed. Liveborn cases with a prenatal diagnosis but without a postnatal validation were excluded. RESULTS: A total of 994 cases were included in the study, of which 933 were liveborn. The prevalence of orofacial cleft was 1.6 per 1000 live births. There were no differences in the baseline characteristics between detected and undetected cases. The DR for CL(P) was 71.7% (95% CI, 64.8-78.9%), with an increase from 60.0% in 2009 to 73.0% in 2018 (P = 0.018). The type-specific DRs for the entire period were 56.4% (95% CI, 45.0-67.6%) for unilateral CL; 76.6% (95% CI, 71.7-82.9%) for unilateral CLP; 70.5% (95% CI, 52.1-87.6%) for bilateral CL; 82.3% (95% CI, 70.6-93.6%) for bilateral CLP; 0% (0/6) for median CL; 75.0% (3/4) for median CLP; and 3.3% (95% CI, 0.6-5.7%) for CP. A total of 20.9% (208/994) of the cases had associated findings, of which 33.2% (69/208) were genetic aberrations. CONCLUSIONS: The DR for CL(P) has improved in Denmark over the last decade. The DR for CLP is high, with the highest DR for bilateral CLP. However, prenatal detection of CP remains a challenge. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Exposición a ondansetrón en el primer trimestre de gestación y riesgo de malformaciones congénitas: revisión sistemática y metaanálisis / Exposure to ondansetron in the first trimester of pregnancy and risk of congenital malformations: systematic review and meta-analysis

Resumen OBJETIVO: Determinar si la exposición al ondansetrón en el primer trimestre del embarazo se asocia, en general, con mayor riesgo de malformaciones orofaciales, cardiopatías congénitas, defectos del septo interventricular, de labio o paladar hendidos. MÉTODOLOGÍA: Revisión sistemática y metanálisis de estudios aleatorizados, cohortes y casos y controles publicados en las bases de datos de PubMed, EMBASE y LILACS. RESULTADOS: Se incluyeron 15 estudios: 11 de cohorte y 4 de casos y controles, con 245,679 mujeres expuestas al ondansetrón en el primer trimestre del embarazo. No se encontró una asociación estadísticamente significativa con malformaciones congénitas en general (RM 1.1; IC95%: 0.99-1.22; I2: 72%), con cardiopatías congénitas (RM 1.05; IC95%: 0.95-1.19; I2: 78%) y con comunicación interventricular (RM 1.2; IC95%: 0.97-1.45; I2: 85%). Se encontró un pequeño aumento en el riesgo de defectos orofaciales en general (RM 1.17; IC95%: 1.04-1.32; I2:0%), no se encontró un riesgo mayor de defecto de labio (RM 1.01; IC95%: 0.84-1.21; I2%: 0%) ni de paladar hendido (RM 1.16; IC95%: 0.9-1.5; I2: 31%). CONCLUSIÓN: Los resultados muestran que el tratamiento con ondansetrón en el primer trimestre del embarazo no se asocia con un aumento de malformaciones congénitas en general, ni con un incremento de cardiopatías, labio o paladar hendido, pero sí con incremento leve del riesgo de malformaciones orofaciales.

Abstract OBJECTIVE: To determine whether ondansetron exposure in the first trimester is associated with an increased risk of any congenital malformations. As secondary outcomes, determine if it is associated with a higher overall risk of congenital heart disease, interventricular septal defects, orofacial malformations, cleft lip defect (with or without palate) or cleft palate. METHODOLOGY: A systematic review with meta-analysis was carried out. The search was carried out in the following databases: PUBMED, EMBASE and LILACS, randomized studies, cohorts and cases and controls were chosen. RESULTS: 15 studies were included, 11 cohort studies and four case-control studies, with 245,679 women exposed to ondansetron in the first trimester. No statistically significant association was found with overall congenital malformations (OR, 1.1; 95%, CI 0.99-1.22 I2: 72%), nor with congenital heart diseases (OR, 1.05; 95%, CI 0.95-1.19 I2: 78%) not with ventricular septal defects (OR, 1.2 95% CI 0.97 - 1.45 I2: 85%). A small increased risk was found for overall orofacial defects (OR, 1.17 95% CI 1.04 - 1.32 I2:0%), no increased risk was found for lip defect (with or without palate) (OR, 1.01 CI 95% 0.84 -1.21 I2%: 0%) or cleft palate (OR, 1.16 95% CI 0.9 - 1.5 I2: 31%). CONCLUSION: The results show that the use of ondansetron in the first trimester is not associated with an increase in overall congenital malformations, nor with an increase in heart disease, cleft lip and/or palate, but there is a slight increase in the risk of orofacial malformations.