Risk Of Orofacial Clefts Research Articles

Time series analysis on association between ambient air pollutants and orofacial clefts during pregnancy in Lanzhou, China.

Current studies on air pollutant exposure during pregnancy and orofacial clefts (OFCs) have inconsistent results, and few studies have investigated refined susceptible windows for OFCs. We aim to estimate association between air pollution and OFCs during the first trimester of pregnancy and identify specific susceptible windows. Birth data was obtained from Birth Defects Surveillance Network in Lanzhou from 2014 to 2019. Air pollution data and temperature data were obtained from ambient air monitoring stations and China Meteorological Data Network, respectively. A distribution lag nonlinear model (DLNM) was applied to estimate weekly-exposure-lag-response association between air pollutant levels and OFCs. The study included 320,787 perinatal infants from 2014 to 2019, of which 685 (2.14‰) were OFCs. The results demonstrated that exposure of pregnant women to aerodynamic diameter ≤ 10μm (PM10) at lag 4-5weeks was significantly associated with the risk of OFCs, with the greatest impact at the lag 4week (RR = 1.029, 95% CI = 1.001-1.057). Exposure to sulfur dioxide (SO2) at lag 2-4weeks was significantly associated with the risk of OFCs, with the greatest impact at the lag 3week (RR = 1.096, 95% CI = 1.041-1.177). This study provides further evidence that exposure to air pollution increases the risk of OFCs in the first trimester of pregnancy.

Alkali and alkaline earth elements in maternal serum and occurrence of orofacial clefts in offspring

Alkali elements (AEs) and alkaline earth elements (AEEs) play critical roles in numerous physiological and pathological processes. However, the effects of maternal exposure to AEs and AEEs on the risk for fetal orofacial clefts (OFCs) remain unclear. We explored the associations between levels of eight AEs and AEEs in maternal serum during pregnancy and occurrence of fetal OFCs. Concentrations of four AEs and four AEEs in maternal serum of 130 OFC cases and 260 non-malformed controls were assessed. Multilevel mixed-effects logistic regression and bayesian kernel machine regression (BKMR) were performed to evaluate the single and combined effects, respectively, of exposure to AEs and AEEs on OFC risk. When individual elements were analyzed separately as categorical variables, the odds of OFCs increased by 2.08-fold (1.10–3.93) and 2.35-fold (1.24–4.45) for sodium and by 1.98-fold (1.04–3.77) and 1.92-fold (1.21–3.61) for strontium but decreased by 0.54-fold (0.29–0.98) and 0.42-fold (0.22–0.78) for potassium in the second and third tertiles, respectively, with the lowest tertile concentration being used as the referent. When all eight elements were considered as a mixture, potassium and calcium showed protective effects, whereas sodium and strontium increased odds of OFCs in the BKMR model. No joint effect on OFC risk was observed when the eight elements were considered as a mixture. Taken together, higher levels of sodium and strontium in maternal serum were associated with an increased odds of fetal OFCs, whereas higher levels of potassium in maternal serum were associated with a decreased odds of OFCs.

Genome-wide Interaction Study Implicates VGLL2 and Alcohol Exposure and PRL and Smoking in Orofacial Cleft Risk.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting approximately 1 in 700 births. NSCL/P has complex etiology including several known genes and environmental factors; however, known genetic risk variants only account for a small fraction of the heritability of NSCL/P. It is commonly suggested that gene-by-environment (G×E) interactions may help explain some of the “missing” heritability of NSCL/P. We conducted a genome-wide G×E interaction study in cases and controls of European ancestry with three common maternal exposures during pregnancy: alcohol, smoking, and vitamin use using a two-stage design. After selecting 127 loci with suggestive 2df tests for gene and G x E effects, 40 loci showed significant G x E effects after correcting for multiple tests. Notable interactions included SNPs of 6q22 near VGLL2 with alcohol and 6p22.3 near PRL with smoking. These interactions could provide new insights into the etiology of CL/P and new opportunities to modify risk through behavioral changes.

Maternal Stressful Life Events During the Periconceptional Period and Orofacial Clefts: A Systematic Review and Meta-Analysis.

To assess whether women who experience stressful life events during the periconceptional period are at higher risk of giving birth to a baby with an orofacial cleft (OFC). Systematic review and meta-analysis of studies reporting the proportion of babies born with OFC to mothers exposed and unexposed to population-level or personal-level stressful life events during the periconceptional period. Six electronic databases were searched from inception to August 2020. Risk of bias was assessed using the Newcastle-Ottawa scale. Odds ratios (ORs) for the odds of OFC in babies of exposed mothers relative to unexposed controls were extracted and/or calculated. Random effects meta-analysis was undertaken, stratified by cleft subtype. Of 12 eligible studies, 8 examined experience of personal events and 4 examined population-level events. Studies demonstrated low-moderate risk of bias and there was indication of publication bias. There was some evidence that personal stressful life events were associated with greater odds of cleft lip and/or palate (six studies, OR 1.63, 95% confidence interval (CI) 1.16, 2.30, P = 0.001) and cleft palate only (six studies, OR 1.45, 95% CI 1.02, 2.06, P = 0.04). Population-level events were associated with higher odds of OFC in studies that did not specify subtype (three studies, OR 1.64, 95% CI 1.19, 2.25, P = 0.002), but subtype stratified analyses were underpowered. Heterogeneity was high. Limited evidence indicated a weak positive association between maternal stressful life events during the periconceptional period and risk of OFC in the offspring, but further studies with greater consistency in research design are needed.

Genetic models and approaches to study orofacial clefts.

Orofacial clefts (OFCs) are common craniofacial birth defects with heterogeneous phenotype and etiology. Geneticists have applied nearly every available method and technology for further understanding of the genetic architectures of OFCs. This review describes the evidence for a genetic etiology in OFCs, statistical genetic approaches employed to identify genetic causes, and how the results have shaped our current understanding of the genetic architectures of syndromic and nonsyndromic OFCs. There has been rapid progress toward elucidating the genetic architectures of OFCs due to the availability of large collections of DNA samples from cases, controls, and families with OFCs and the consistent adoption of new methodologies and novel statistical approaches as they are developed. Genetic studies have identified rare and common variants influencing risk of OFCs in both Mendelian and complex forms of OFCs, blurring the distinction traditional categories used in genetic studies and clinical medicine.

Maternal Common Cold or Fever During Pregnancy and the Risk of Orofacial Clefts in the Offspring: A Systematic Review and Meta-analysis.

The common cold and/or an associated fever during pregnancy have/has been suspected to harm the developing fetus. We sought possible correlations between a maternal common cold or fever during pregnancy and the risk of orofacial clefts in the offspring. We systematically searched PubMed and Embase using appropriate keywords, and we checked the reference lists of retrieved articles. We used random-effects models to estimate overall relative risks. Incidence of orofacial clefts. We included 13 case-control studies. Modest but statistically significant associations were found between a maternal common cold and cleft lip with or without a cleft palate (CL/CP) (odds ratio [OR] 2.17; 95% confidence interval [CI] 1.66–2.83) and a cleft palate only (CPO) (OR 3.08; 95% CI 1.5–6.34). Furthermore, maternal fever was also associated with an increased risk of CL/CP (OR 1.91, 95% CI 1.3–2.8) and CPO (OR 1.48, 95% CI 0.83–2.63) in the offspring. Further analyses of maternal influenza (alone) yielded similar results. Although evidence of heterogeneity should be carefully evaluated, our findings suggest that maternal common cold or fever during pregnancy may be associated with a greater risk of CL/CP or CPO in the offspring. Future cohort studies using valid assessments of maternal common cold exposure during pregnancy that consider the severity of fever are needed to clarify the contribution of maternal common cold or fever status to the risk of orofacial clefts in children.

Nausées et vomissements gravidiques : quelle place pour l’ondansétron ?

Although there is no recommendation in France relating to the treatment of nausea and vomiting of pregnancy, there are some in other countries, where ondansetron, widely used, appears to be an effective second-line treatment option behind doxylamine/vitamin B6 association and metoclopramide. However, based on some recent publication suggesting an increased risk of orofacial clefts and congenital heart defects in fetuses exposed in utero to ondansetron in the 1st trimester of pregnancy, the European Medicines Agency now states that this drug should not longer be used during this period. This 2019 decision is controversial and whether ondansetron can be used in pregnant women with severe vomiting during pregnancy is still in question.

First trimester exposure to ambient gaseous air pollutants and risk of orofacial clefts: a case\u2013control study in Changsha, China

BackgroundA growing body of studies have investigated the association between air pollution exposure during early pregnancy and the risk of orofacial clefts, but these studies put more emphasis on particulate matter and reported inconsistent results, while research on the independent effects of gaseous air pollutants on orofacial clefts has been quite inadequate, especially in China.MethodsA case–control study was conducted in Changsha, China from 2015 to 2018. A total of 446 cases and 4460 controls were included in the study. Daily concentrations of CO, NO2, SO2, O3, PM2.5 and PM10 during the first trimester of pregnancy were assigned to each subject using the nearest monitoring station method. Multivariate logistic regression models were applied to evaluate the associations of monthly average exposure to gaseous air pollutants with orofacial clefts and its subtypes before and after adjusting for particulate matter. Variance inflation factors (VIFs) were used to determine if the effects of gaseous air pollutants could be independent of particulate matter.ResultsIncrease in CO, NO2 and SO2 significantly increased the risk of cleft lip with or without cleft palate (CL/P) in all months during the first trimester of pregnancy, with aORs ranging from 1.39 to 1.48, from 1.35 to 1.61 and from 1.22 to 1.35, respectively. The risk of cleft palate only (CPO) increased with increasing NO2 exposure levels in the first trimester of pregnancy, with aORs ranging from 1.60 to 1.66. These effects sustained and even exacerbated after adjusting for particulate matter. No significant effect of O3 was observed.ConclusionsOur study suggested that maternal exposure to CO, NO2, and SO2 during the first trimester of pregnancy might contribute to the development of orofacial clefts, and the associations were potentially independent of particulate matter.

Variant analyses of candidate genes in orofacial clefts in multi-ethnic populations.

Cleft lip with/without cleft palate and cleft palate only is congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000live births worldwide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome-wide association studies and whole-exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11. We sequenced these five genes in 1255 multi-ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in silico predictive tools. Ninteen total variants of interest were found, with variant types including stop-gain, missense, synonymous, intronic, and splice-site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11. This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.

A case control study on the risk factors of non-syndromic orofacial clefts

Background: Orofacial clefts (OFCs) are the most common craniofacial malformation of the new born in the world. In India OFCs are the 3rd most common congenital anomaly following anencephaly and club foot. Objectives were to study the association of family history, medications during pregnancy, passive smoking with non-syndromic OFC, and to determine the pattern of OFCs in the study population.Methods: This is a hospital-based, matched case-control study conducted in a tertiary care centre, Thrissur, Kerala. We interviewed 30 mothers of children affected by non-syndromic OFCs. Mothers were asked about their sociodemographic details and other suspected risk factors using a semi structured questionnaire.Results: In our study unilateral left sided cleft lip was found to be more prevalent 62%. Those who had a family history of OFCs was found to have a significantly higher risk of OFC (OR 26.333). Medications for diabetes mellitus, hypertension, thyroid dysfunction, bronchial asthma, analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) during first trimester of pregnancy posed a higher risk for OFCs (OR 7.222). Maternal age at pregnancy greater than or equal to 30 was also found to be a significant risk factor.Conclusions: In our study we found out that family history is a risk factor for OFCs. We conclude that exposure of the mother to passive smoking should be avoided during pregnancy and family members should be made aware of the health hazards of passive smoking. Medications should only be taken after consulting a doctor preferably an obstetrician. Self-medication during pregnancy should be strictly avoided.

Variant Analyses of Candidate Genes in Orofacial Clefts in Multi‐Ethnic Populations

Cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. CL/P and CPO fall under the larger category of orofacial clefts (OFCs), which affect ~1.2/1000 live births world-wide and imposes significant social and financial burdens on affected individuals and their families. The etiology of orofacial clefts is complex and likely results from a combination of genetic mutations with environmental covariates. Recent genome wide association studies (GWAS) and whole exome sequencing (WES) for orofacial clefting identified significant genetic associations and variants in several genes. Of these genes, we investigated the role of common and rare variants in the SHH, RORA, MRPL53, ACVR1, and GDF11 genes. We sequenced these five genes in multi-ethnic CL/P and CPO samples in order to find mutations that may provide potential explanations for OFCs missing heritability. In total, 19 variants of interest were found, seven of which were in SHH, one in RORA, three in MRPL53, six in ACVR1, and two in GDF11. Types of mutations found included stop-gained, missense, synonymous, intronic, and splice site variants. Of these 19 variants, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11. Rare and novel variants were further analyzed using in-silico predictive tools such as SIFT, Polyphen-2, Provean score, CADD, and HOPE. This study provides evidence that mutations in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of OFCs in various populations.

Diagnostic Accuracy of Prenatal Fetal Ultrasound to Detect Cleft Palate in High-Risk Fetuses: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis investigated the accuracy of prenatal fetal ultrasound (US) to detect cleft palate during the second and third trimester (12-36 weeks) of pregnancy in high-risk fetuses. Pubmed and Embase databases were searched for studies that performed prenatal fetal US (comparator) and postnatal examination (reference standard) in fetuses at high risk for orofacial clefts. Risk of bias among included studies was assessed using the QUADAS-2. Area under the summary receiver operating characteristic (SROC) curve and pooled sensitivity and specificity were calculated. This meta-analysis included 7 studies involving 663 high-risk fetuses. The individual studies showed that prenatal fetal US accurately predicted the possibility of cleft palate in these fetuses. Pooled sensitivity was 87% (95% CI 71%-95%), pooled specificity was 98% (95%CI 90%-100%), and the area under the SROC curve was 0.98 (95% CI 0.97-0.99). Second and third trimester fetal US has excellent sensitivity and specificity for the detection of cleft palate in high-risk pregnancies.

The Mafb cleft-associated variant H131Q is not required for palatogenesis in the mouse.

Orofacial clefts (OFCs) are common birth defects with complex etiology. Genome wide association studies for OFC have identified SNPs in and near MAFB. MAFB is a transcription factor critical for structural development of digits, kidneys, skin, and brain. MAFB is also expressed in the craniofacial region. Previous sequencing of MAFB in a Filipino population revealed a novel missense variant significantly associated with an increased risk for OFC. This MAFB variant, leading to the amino acid change H131Q, was knocked into the mouse Mafb, resulting in the MafbH131Q allele. The MafbH131Q construct was engineered to allow for deletion of Mafb ("Mafbdel "). Mafbdel/del animals died shortly after birth. Conversely, MafbH131Q/H131Q mice survived into adulthood at Mendelian ratios. Mafbdel/del and MafbH131Q/H131Q heads exhibited normal macroscopic and histological appearance at all embryonic time points evaluated. The periderm was intact based on expression of keratin 6, p63, and E-cadherin. Despite no effect on craniofacial morphogenesis, H131Q inhibited the Mafb-dependent promoter activation of Arhgap29 in palatal mesenchymal, but not ectodermal-derived epithelial cells in a luciferase assay. Mafb is dispensable for murine palatogenesis in vivo, and the cleft-associated variant H131Q, despite its lack of morphogenic effect, altered the expression of Arhgap29 in a cell-dependent context.

RERE deficiency contributes to the development of orofacial clefts in humans and mice.

Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7 and GRHL3. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH). Cleft lip has previously been described in one individual with NEDBEH. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest (CNC) cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox; Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of orofacial clefts in individuals with proximal 1p36 deletions and NEDBEH and that RERE expression in CNC cells and their derivatives is required for normal palatal development.

Determination of organochlorine pesticides in human umbilical cord and association with orofacial clefts in offspring

Studies based on questionnaires suggested that maternal exposure to pesticides increases the risk for orofacial clefts (OFCs). However, whether organochlorine pesticides (OCPs) exposure in vivo affects the occurrence of OFCs remains unclear. The aims of this study are to investigate the association of OCP exposure with the risk of OFCs by examining the concentrations of OCPs in human umbilical cords, and investigate the potential dietary sources of OCPs in umbilical cord tissues. A case-control study consisting of 89 OFC cases and 129 nonmalformed controls with available tissues of umbilical cord was conducted. Concentrations of twenty specific OCPs were determined in the umbilical cord by gas chromatograph-mass spectrometry, and seven OCPs with detection rate larger than 50% were included in analyses. The individual effect and joint effect of multiple OCPs in umbilical cords on the risk for OFCs were investigated using multivariate logistic models and Bayesian Kernel Machine Regression (BKMR). No difference was found in the median levels of ΣOCPs between cases (1.04 ng/g) and controls (1.03 ng/g). No significant associations were observed between levels of OCPs in umbilical cords and risk for OFCs in either multivariate logistic models or BKMR models. Maternal consumptions of beans or bean products were positively correlated with levels of β-hexachlorocyclohexane, heptachlor epoxide, p,p′-DDE, and ∑OCPs in umbilical cord, respectively. In conclusion, we didn’t find the association between in utero exposure to OCPs and the risk for OFCs. Maternal consumptions of beans or bean products may be a source of OCPs exposure.

Risk of non-syndromic orofacial clefts by maternal rural-urban residence and race/ethnicity: A population-based case-control study in Washington State 1989-2014.

Orofacial clefts (OFC) have multifactorial aetiology. Established risk factors explain a small proportion of cases. To evaluate OFC risk by maternal rural residence and race/ethnicity, and test whether these associations changed after US-mandated folic acid fortification. This population-based case-control study included all non-syndromic OFC cases among Washington State singleton livebirths between 1989-2014 and birth year-matched controls. Data sources included birth certificates and hospital records. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for OFC by maternal rural-urban residence (adjusted for maternal race/ethnicity) and by maternal race/ethnicity. We evaluated additive and multiplicative effect measure modification by time of folic acid fortification (before vs. after). Probabilistic quantitative bias analysis accounted for potential differential case ascertainment for infants born to Black mothers. The overall non-syndromic OFC birth prevalence was 1.0 per 1000 livebirths (n=2136 cases). Among controls (n=25826), 76% of mothers were urban residents and 72% were of White race/ethnicity. OFC risk was slightly higher for infants born to rural than to urban mothers, adjusting for race/ethnicity (OR 1.12, 95% CI 1.01, 1.25). The association was similar before and after US-mandated folic acid fortification. Compared with infants born to White mothers, OFC risk was higher for American Indian mothers (OR 1.73, 95% CI 1.35, 2.23) and lower for Black (OR 0.62, 95% CI 0.48, 0.81), Hispanic (OR 0.75, 95% CI 0.64, 0.87), and Asian/Pacific Islander (API) mothers (OR 0.87, 95% CI 0.74, 1.02). Bias analysis suggests the observed difference for Black mothers may be explained by selection bias. Post-fortification, the association of OFC with maternal API race/ethnicity decreased and with maternal Black race/ethnicity increased relative to maternal White race/ethnicity. Infants born to rural mothers and to American Indian mothers in Washington State during 1989-2014 were at higher OFC risk before and after US-mandated folic acid fortification.

The Association Between Influenza Infection Rates and the Incidence of Orofacial Clefts in the United States

Objective: To investigate seasonal variation of orofacial clefts (OC) and measure association between United States (U.S.) influenza incidences and OC development for the purpose of identifying a potential modifiable risk factor for pregnant women. Design: Retrospective population-based observational study from 2004 to 2013. Setting: National Inpatient Sample Database (NIS), Wide-ranging Online Data for Epidemiologic Research (WONDER) Database, and National Respiratory and Enteric Virus Surveillance System’s (NRVESS) FluView database. Patients: U.S.-born infants with OC from 2004 to 2013 and monthly influenza incidence from 2003 to 2013. Main outcome measures: Using logistic regression, monthly odds ratios (OR) of OC were derived using January as baseline. Mixed-effects logistic regression was utilized to test association between national influenza and OC incidences. Results: There were 58 270 U.S. babies born with OC from 2004 to 2013. September births had the highest OC association (OR = 1.094, 95% CI = 1.051-1.138, E-value = 1.41), followed by June. For each additional influenza case per 1000 people, odds of OC event occurring during the 2nd month of pregnancy, or 7 months before delivery, was increased by 2.7 (OR = 2.659, CI = 1.456-4.856, E-value = 4.76). Odds of OC event occurring was decreased at the 3rd month of pregnancy, or 6 months before delivery by 7.8 (OR = 0.129, 95% CI = 0.068-0.246, E-value = 14.99). Conclusion: September and June births have the highest OC association. There is increased risk for OC with influenza occurring at the 2nd pregnancy month. Conversely, there are protective effects against OC with influenza occurring at the 3rd pregnancy month. These findings demonstrate an association between influenza rate and OC, suggesting a connection between maternal immune activation (mIA) and OC. Although further research is needed to determine the definitive link between the use of flu vaccines and OC occurrence, as well as the mechanism behind mIA secondary to influenza infection impacting OC incidence, this study presents a modifiable risk factor that could decrease the potential for mIA causing OC.

Environmental mechanisms of orofacial clefts.

Orofacial clefts (OFCs) are among the most common birth defects and impart a significant burden on afflicted individuals and their families. It is increasingly understood that many nonsyndromic OFCs are a consequence of extrinsic factors, genetic susceptibilities, and interactions of the two. Therefore, understanding the environmental mechanisms of OFCs is important in the prevention of future cases. This review examines the molecular mechanisms associated with environmental factors that either protect against or increase the risk of OFCs. We focus on essential metabolic pathways, environmental signaling mechanisms, detoxification pathways, behavioral risk factors, and biological hazards that may disrupt orofacial development.

Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta-analyses.

There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). Studies of different measures of nutritional intake or folate status have been done to investigate the possible role of folate in the prevention of OFC. Only one knowledge synthesis has attempted to bring together different types of evidence. The aim of the present work was to update it. Evidence for associations between OFC and dietary folate, supplement use, folic acid fortification, biomarkers of folate status, and variants of MTHFR (C677T and A1298C) were included. Potentially eligible articles were systematically identified from PubMed, Medline, Embase, and Web of Science (2007-2020) and combined using random-effects meta-analysis when appropriate. Quality assessments were conducted using the Newcastle-Ottawa scale and Cochrane's risk of bias tool. Sixty-four studies published since the previous knowledge synthesis were identified, with eight of these identified through a supplementary search from October, 2018 to August, 2020. There was an inverse association between folic acid-containing supplement use before or during pregnancy and cleft lip with or without cleft palate (CL/P) (OR 0.60, 95% CI 0.51-0.69), with considerable between-study heterogeneity. The prevalence of CL/P showed a small decline post-folic acid fortification in seven studies (OR 0.94, 95% CI 0.86-1.02). No association was found between OFC and genetic markers of folate status. The coronavirus-19 pandemic has threatened food availability globally and therefore there is a need to maintain and even enhance surveillance concerning maternal intake of folate and related vitamins. The risk of non-syndromic OFC was reduced among pregnant women with folic acid-containing supplements during the etiologically relevant period. However, high heterogeneity between included studies, incomplete reporting of population characteristics and variation in timing of exposure and supplement types mean that conclusions should be drawn with caution.

Parents of Children With Nonsyndromic Orofacial Clefting Show Altered Palate Shape.

The unaffected relatives of individuals with nonsyndromic orofacial clefts have been shown to exhibit subtle craniofacial differences compared with the general population. Here, we investigate whether these morphological differences extend to the shape of the palate. We conducted a geometric morphometric analysis to compare palate shape in the clinically unaffected parents of children with nonsyndromic cleft lip with or without cleft palate and adult controls of European, Asian, and African ancestry. We conducted pairwise group comparisons using canonical variates analysis, and then confirmed and characterized findings of shape differences using Euclidean distance matrix analysis. Significant differences in palate shape were detected in unaffected mothers (but not fathers) compared to demographically matched controls. The differences in shape were ancestry-specific; mothers of Asian-derived and African-derived ancestry showed wider and shorter palates with higher posterior palatal vaults, while mothers of European-derived ancestry showed narrower palates with higher anterior palatal vaults. Our findings suggest that altered palate shape is a subclinical phenotypic feature, which may be indicative of elevated orofacial cleft risk. The risk phenotype varied by sex and ancestry, suggesting possible etiologic heterogeneity among demographic groups. Understanding the genetic basis of these informative palate shape traits may reveal new genes and pathways relevant to nonsyndromic orofacial clefting.