BACKGROUND: An increased prevalence of cleft lip and/or palate (CL/P), a major congenital anomaly, has been observed in the offspring of women with elevated body mass index (BMI) before pregnancy. Likewise, gestational comorbidities, such as hypertension and diabetes mellitus, also increase the risk of CL/P; however, the risk linked to the coexistence of these conditions in women with higher BMI on birth prevalence of CL/P remains unclear. This study focused on the combined effects of a high BMI before pregnancy and gestational comorbidities on the birth prevalence of CL/P. METHODS: Among 98,373 live births from the Japan Environment and Children's Study (JECS), a nationwide birth cohort, 255 mothers of infants with CL/P (74, 112, and 69 infants born with cleft lip, cleft lip and palate, and isolated cleft palate, respectively) were included in the analyses. The association of CL/P birth prevalence with pre-pregnancy BMI and gestational comorbidities (hypertension and diabetes) was examined using multivariate logistic regression analyses after multiple imputations, with adjustments for several maternal (age at delivery, smoking habits, and alcohol intake) and child-related (sex and prevalence of other congenital diseases) variables, obtained through medical record transcriptions and self-reports on JECS transcription forms. RESULTS: Higher prevalence rates of overweight, gestational hypertension, and gestational diabetes mellitus were found in mothers of infants with CL/P (16.1%, 6.3%, and 4.7%, respectively) than in the control group (10.4%, 3.1%, and 3.1%, respectively). The odds ratio [95% confidence interval] for childbirth with CL/P was increased in mothers with high BMI before pregnancy (1.58 [1.11-2.24]). Furthermore, gestational hypertension and diabetes coexisting with high BMI additionally increased the odds ratios for childbirth with CL/P (2.91 [1.28-6.61] and 2.12 [0.87-5.19], respectively). CONCLUSION High maternal BMI, particularly when accompanied by gestational hypertension, was significantly associated with an increased prevalence of childbirth with CL/P.
Humans ; Female ; Cleft Lip/etiology* ; Cleft Palate/etiology* ; Pregnancy ; Japan/epidemiology* ; Prevalence ; Body Mass Index ; Adult ; Male ; Infant, Newborn ; Comorbidity ; Diabetes, Gestational/epidemiology* ; Risk Factors ; Young Adult ; Birth Cohort

Periodontal disease is a risk factor for many systemic diseases such as Alzheimer's disease and adverse pregnancy outcomes. Cleft palate (CP), the most common congenital craniofacial defect, has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection. A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring. However, the precise relationship remains unclear. In this study, the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P. gingivalis injected intravenously and orally into pregnant mice. We investigated an obvious increasing CP (12.5%) in sonicated P. gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium. Then glycolysis and H4K12 lactylation (H4K12la) were detected to elevate in both mouse embryonic palatal mesenchyme (MEPM) cells and macrophages under P. gingivalis exposure which further promoted the transcription of metallopeptidase domain17 (ADAM17), subsequently mediated the shedding of transforming growth factor-beta receptor 1 (TGFBR1) in MEPM cells and mer tyrosine kinase (MerTK) in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate, eventually caused abnormalities in palate fusion and ossification. The abnormal efferocytosis also led to a predominance of M1 macrophages, which indirectly inhibited palatal osteogenesis via extracellular vesicles. Furthermore, pharmacological ADAM17 inhibition could ameliorate the abnormality of P. gingivalis-induced abnormal palate development. Therefore, our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.
Animals ; Female ; Porphyromonas gingivalis ; Pregnancy ; Mice ; Cleft Palate/etiology* ; Glycolysis

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.
Child ; Pregnancy ; Female ; Humans ; Cleft Lip/etiology* ; Cleft Palate/complications* ; Reproductive History ; Abortion, Spontaneous ; Neural Tube Defects/epidemiology* ; Risk Factors

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 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 gene probably underlies the pathogenesis of Van der Woude syndrome in the family and the mutation has been firstly discovered in China.
Abnormalities, Multiple ; genetics ; China ; Cleft Lip ; complications ; diagnostic imaging ; etiology ; genetics ; Cleft Palate ; complications ; diagnostic imaging ; etiology ; genetics ; Cysts ; complications ; genetics ; Female ; Humans ; Interferon Regulatory Factors ; genetics ; Lip ; abnormalities ; Male ; Mutation ; Pedigree ; Ultrasonography

OBJECTIVE: This study aims to investigate whether dexamethasone (DEX) can down-regulate the PAR complex and disrupt the cell polarity in the palatal epithelium during palatal fusion. METHODS: Pregnant rats were randomly divided into control and DEX groups, which were injected intraperitoneally with 0.9% sodium chloride (0.1 mL) and DEX (6 mg·kg ⁻¹), respectively, every day from E10 to E12. The palatal epithelial morphology was observed using hematoxylin and eosin staining and scanning electron microscopy. Immunofluorescence staining, Western Blot analysis, and real-time polymerase chain reaction were performed to detect the expression of PAR3, PAR6, and aPKC. RESULTS: The incidence of cleft palate in DEX group (46.15%) was significantly higher than that in control group (3.92%), and the difference was statistically significant (χ2=24.335, P=0.00). DEX can also retard the growth of the palatal shelves and the short palatal shelves. The morphology and arrangement of MEE cells changed from polarized bilayer cells to nonpolarized monolayer ones. Additionally, the spherical structure decreased, which caused the cleft palate. PAR3 and PAR6 were only detected in the palatal epithelium, and aPKC was expressed in the palatal epithelium and mesenchyme. DEX can reduce the expression levels of PAR3, PAR6, and aPKC in the protein and gene levels. CONCLUSIONS DEX can down-regulate the complex gene expression in the MEE cells, thereby destroying the cell polarity and causing cleft palate.
Animals ; Carrier Proteins ; physiology ; Cell Polarity ; drug effects ; Cleft Palate ; etiology ; Dexamethasone ; pharmacology ; Epithelial Cells ; drug effects ; Female ; Glucocorticoids ; pharmacology ; Palate ; Pregnancy ; Rats

In this study, we sought to determine the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) to understand the etiology of the disease. A total of 200 NSCLP cases and 327 controls were recruited at the Maternal and Child Health Hospital of Xuzhou City. We conducted face-to-face interviews with the mothers of both cases and controls. The factors increasing the risk of NSCLP were a positive family history [odds ratio (OR)=56.74], pesticide exposure (OR=8.90), and indoor decoration pollution (OR=4.32). On the other hand, the factors decreasing the risk of NSCLP were a high education level (OR=0.22) and supplementation of folic acid (OR=0.23) and multivitamins (OR=0.16). Positive family history, pesticide exposure, and indoor decoration pollution are associated with the risk of NSCLP. In contrast, high education level and folic acid and multivitamin supplementation are protective factors against NSCLP.
Case-Control Studies ; China ; epidemiology ; Cleft Lip ; epidemiology ; etiology ; prevention & control ; Cleft Palate ; epidemiology ; etiology ; prevention & control ; Environmental Pollutants ; toxicity ; Female ; Folic Acid ; administration & dosage ; therapeutic use ; Humans ; Infant, Newborn ; Logistic Models ; Maternal Exposure ; adverse effects ; Pregnancy ; Risk Factors ; Socioeconomic Factors ; Surveys and Questionnaires

Cleft Palate ; surgery ; Humans ; Incidence ; Oral Fistula ; epidemiology ; etiology ; Palate ; surgery ; Postoperative Complications ; epidemiology ; Reconstructive Surgical Procedures ; adverse effects ; Statistics as Topic

OBJECTIVETo evaluate the velopharyngeal status of cleft palate patients after operation in silent mode by visual analog scale.

METHODSA total of 82 patients with cleft lip and palate after operation were examined by nasopharyngeal fiber endoscopy with 11 voice samples. The velopharyngeal status was evaluated by three experienced experts using qualitative method and visual analog scale (VAS) method in silent mode. The Spearman correlation relationship was analyzed between VAS value and qualitative grade. The VAS value range of 10 non-nasal consonant voice samples was divided according to qualitative classification.

RESULTSVAS values could accurately reflect the outcome of the qualitative classification. The poorer the velopharyngeal status was, the lower the VAS value, and vice versa. The whole effectiveness of value range was greater than 70%.

CONCLUSIONSVAS values can accurately reflect the outcome of the qualitative classification about velopharyngeal function, and VAS value grading velopharyngeal status is reliable. This study proposed VAS values range standards for different velopharyngeal qualitative classification.

Adolescent ; Adult ; Child ; Child, Preschool ; Cleft Palate ; complications ; physiopathology ; surgery ; Female ; Humans ; Male ; Postoperative Period ; Velopharyngeal Insufficiency ; etiology ; physiopathology ; Visual Analog Scale ; Young Adult

OBJECTIVETo investigate the biomechanical changes of internal midface distraction after different types of maxillary osteotomy in patients with cleft lip and palate (CLP).

METHODS3-D finite element (FEM) analysis was used. 3-D models of Le Fort I, II, III osteotomy and soft tissue were established. Based on the new pattern of internal midface distractor, the distraction of maxillary complex was simulated to advance 10 mm anteriorly. The mechanical change was studied.

RESULTSThe maxillary complex in CLP were advanced after distraction. Constriction of alveolar crest and palate occurred in Le Fort I osteotomy, but not in Le Fort II and III osteotomy. The maxillary complex was moved anteriorly en bloc after Le Fort III osteotomy, but some degree of rotation of maxillary complex was observed during the distraction after Le Fort I and II osteotomy. In vertical direction, the maxillary complex had more counterclockwise rotation after Le Fort II osteotomy.

CONCLUSION3-D FEM analysis can be used for the study of internal distraction. It can reflect the maxillary movement and provide the theory basis for preoperative design.

Biomechanical Phenomena ; Cleft Lip ; complications ; physiopathology ; surgery ; Cleft Palate ; complications ; physiopathology ; surgery ; Craniofacial Dysostosis ; etiology ; physiopathology ; surgery ; Female ; Finite Element Analysis ; Humans ; Maxilla ; surgery ; Osteogenesis, Distraction ; Osteotomy ; Young Adult

Metabonomics approach is a science that systematically studies the regularity of changes of metabolites and reveals the nature of metabolic activities of the lives in the dynamic process of metabolism. In this study, pregnant C57BL/6J mice were randomly divided into two groups with 15 mice in each. The ones in the experimental group were intraperitoneally injected with Dexamethasone and the others in the control group with isotonic Na chloride from 10th to 12th day of gestational period. On 17.5th day, all the mice were executed. The livers were extracted and prepared into aqueous soluble liver tissue extracts. The technology of nuclear magnetic resonance (NMR) was used to detect the endogenous small molecule metabolites. Finally, through the method of principal component analysis (PCA), changes of metabolites ingredients could be determined. The experimental results showed that there was significant difference in PCA scores plot between the two groups. Furthermore, the difference was in line with that of incidence of cleft palate in the embryos between the two groups. Therefore, metabonomics results can be used to reflect the changes of metabolites group interfered by Dexamethasone in the course of pregnancy of C57BL/6J mice and this method opens up a new way for further study of pathogenic mechanism of cleft lip with or without palate.
Abnormalities, Drug-Induced ; etiology ; metabolism ; Animals ; Cleft Palate ; chemically induced ; Dexamethasone ; toxicity ; Embryo, Mammalian ; Female ; Magnetic Resonance Spectroscopy ; methods ; Metabolomics ; Mice ; Mice, Inbred C57BL ; Pregnancy