Risk Of Clefts Research Articles

Maternal Folic Acid Intake and Risk of Nonsyndromic Orofacial Clefts: A Hospital-Based Case-Control Study in Bangalore, India.

Orofacial clefts are the most common congenital anomaly worldwide. Cleft etiology appears to be multifactorial, with genetic and environmental components. Although periconceptional folic acid supplementation has been shown to be protective for neural tube defects, current evidence for its role in cleft prevention is mixed with few studies from low- and middle-income countries. To investigate the association between periconceptional folic acid intake and incidence of nonsyndromic orofacial clefts among infants in Bangalore, India. A hospital-based case-control study (106 cases, 212 controls) utilizing a questionnaire to collect data on prenatal supplements, dietary folate, and potentially confounding factors. Multivariate logistic regression analysis was used to assess relationships between folic acid supplementation and all nonsyndromic clefts, and in separate analyses for cleft lip and/or palate (CL/P) and cleft palate (CP), adjusting for statistically significant variables. A statistically significant protective association was found for separate folic acid supplements (not combined with iron or multivitamins) taken in the periconceptional period and all clefts combined (adjusted odds ratio [OR]: 0.62, 95% confidence interval [CI], 0.45-0.86) and CL/P (adjusted OR: 0.57; 95% CI, 0.38-0.86). Higher levels of dietary folate were found to be associated with a reduced risk for all clefts (adjusted OR: 0.98, 95% CI, 0.96-0.99), CL/P (adjusted OR: 0.98, 95% CI, 0.96-0.99), and CP (adjusted OR: 0.96, 95% CI, 0.93-0.99). This study provides limited evidence for a protective association of periconceptional folic acid supplementation with nonsyndromic orofacial clefts. The low proportion of mothers taking folic acid supplements in the periconceptional period highlights the need for increased education and awareness regarding prenatal nutrition.

The functional variant of NTN1 contributes to the risk of nonsyndromic cleft lip with or without cleft palate

Previous genome-wide association study of nonsyndromic cleft lip with or without cleft palate (NSCL/P) identified a susceptible variant (rs4791774). We hypothesized that the functional single nucleotide polymorphism (SNP) may be in linkage disequilibrium with this lead SNP. The potential functional SNP (rs4791331) was identified by bioinformatic analysis. A case–control study with 891 orofacial cleft cases and 830 controls was designed to investigate its association with orofacial cleft. The allele-specific DNA-protein binding preference was predicted by JASPAR database. Cell proliferation, cycle and apoptosis, luciferase activity and netrin-1 (NTN1) expression were examined after transfection with the rs4791331 C/T vector in HEK-293 and HEPM cell lines. Forty-six lip tissues of NSCL/P patients were collected to detect NTN1 expression. ntn1a knockout zebrafish models were generated by CRISPR/Cas9 and observed with micro-CT. In the case–control study, the rs4791331-T allele was associated with an increased risk of nonsyndromic orofacial cleft (OR = 1.41, 95% CI = 1.19–1.68), as well as the subgroups cleft lip only (OR = 1.46, 95% CI = 1.14–1.87) and cleft lip and palate (OR = 1.58, 95% CI = 1.27–1.96). The T allele of rs4791331 exhibited anti-apoptotic effects and promoted cell cycle progression at the G1/S transition. Decreased enhancer activity and reduced NTN1 expression following transfection of the T allele were observed. Carriers of the CT/TT genotypes showed significantly lower expression of NTN1 than CC carriers. The ntn1a−/− zebrafish showed relatively wider intermaxillary fissures. These results indicate that rs4791331 (C > T) disrupted motif binding and led to abnormal expression of NTN1, which may be involved in the development of NSCL/P.

Intravenous Ondansetron in Pregnancy and Risk of Congenital Malformations

This pharmacoepidemiology study uses Medicaid data to estimate associations between first-trimester use of intravenous ondansetron and risk of cardiac malformations and oral cleft in children of exposed mothers.

Exploring GRHL3 polymorphisms and SNP-SNP interactions in the risk of non-syndromic oral clefts in the Brazilian population.

To investigate the association of single-nucleotide polymorphisms (SNP) in grainyhead-like 3 (GRHL3) and to verify its possible interactions with others genes responsible for craniofacial development in the risk of non-syndromic oral cleft (NSOC). Applying TaqMan allelic discrimination assays, we evaluated GRHL3 SNPs (rs10903078, rs41268753, and rs4648975) in an ancestry-structured case-control sample composed of 1,127 Brazilian participants [272 non-syndromic cleft palate only (NSCPO), 242 non-syndromic cleft lip only (NSCLO), 319 non-syndromic cleft lip and palate (NSCLP), and 294 healthy controls]. Additionally, SNP-SNP interactions of GRHL3 and previously reported variants in FAM49A, FOXE1, NTN1, and VAX1 were verified in non-syndromic cleft lip with or without cleft palate (NSCL±P). To eliminate false-positive associations, Bonferroni correction or 1,000 permutation method was applied. The multiple logistic regression analysis showed that the CC genotype of rs10903078 (p=.03) and the haplotype C-C formed by the SNPs rs10903078 and rs41268753 (p=.04) were associated with NSCLO, but the p-values did not withstand Bonferroni correction. However, SNP-SNP test revealed significant interactions between GRHL3 SNPs and FAM49A (rs7552), FOXE1 (rs3758249), VAX1 (rs7078160 and rs751231), and NTN1 (rs9891446). Our results confirm the importance of GRHL3 and its interactions with previously NSOC-associated genes, including FAM49A, FOXE1, NTN1, and VAX1, in the pathogenesis of NSOC in the Brazilian population.

Association between cystathionine beta-synthase c.844ins68 polymorphism and risk of non-syndromic cleft lip/palate: A meta-analysis of family-based and case-control studies

Both genetics and environmental factors play a role in the occurrence of non-syndromic cleft lip/palate (NSCL/P). This meta-analysis evaluated the association between cystathionine beta-synthase (CBS) c.844ins68 polymorphism and risk of NSCL/P in family-based and case-control studies. The PubMed, Web of Science, Scopus, and Cochrane Library databases were searched for articles published until September 2018. RevMan 5.3 software was used to calculate the odds ratio (OR) for the association between CBS c.844ins68 polymorphism and risk of NSCL/P by using five genetic models in the studies. The transmission disequilibrium test (TDT) was conducted for family-based studies. Three case-control and three family-based studies were evaluated. Based on the analysis of five genetic models, risk of NSCL/P was not related to CBS c.844ins68 polymorphism in case-control studies. The results of family-based studies did not show any association between the CBS c.844ins68 allele and NSCL/P either. The results of this meta-analysis showed that there was no association between CBS c.844ins68 polymorphism and risk of NSCL/P; therefore, this polymorphism does not play a role in susceptibility to NSCL/P.

Association of Maternal First-trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring

(JAMA. 2018;320(23):2429–2437) Ondansetron, a 5-HT3 receptor antagonist, has become the most frequently prescribed drug for nausea and vomiting during pregnancy. However, this medication is not formally approved for this use, and available evidence regarding ondansetron and fetal safety is limited or conflicting. The American College of Obstetricians and Gynecologists has concluded that further studies are warranted. Therefore, the authors of the present study investigated potential associations between ondansetron exposure during the first trimester of pregnancy and the risk of cardiac malformations and/or oral clefts in neonates.

Helping Pregnant Women and Clinicians Understand the Risk of Ondansetron for Nausea and Vomiting During Pregnancy

(JAMA. 2018;320 (23):2425–2426) Nausea and vomiting during the first trimester of pregnancy is often unresponsive to conservative treatment and commonly requires antiemetic pharmacotherapy. First line agents, as per the American College of Obstetricians and Gynecologists’ treatment algorithm, are pyridoxine, alone or in combination with doxylamine. However, while the safety of pyridoxine has been well established, there remain concerns regarding potential effects of other antiemetic drugs on fetal development. In particular, the study by Huybrechts et al addressed concerns about potential associations between ondansetron, a serotonin receptor agonist and third-line agent, and fetal congenital malformations. The study found no significant associations between ondansetron and cardiac abnormalities [adjusted risk difference (aRR), −0.8; 95% confidence interval (CI), 0.92-1.06] and overall congenital anomalies. A small but significantly increased risk of oral clefts with first-trimester exposure to ondansetron was found (aRR, 1.24; 95% CI, 1.03-4.08).

Polymorphic Variants of V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (rs13041247 and rs11696257) and Risk of Non-Syndromic Cleft Lip/Palate: Systematic Review and Meta-Analysis

Background: Non-syndromic cleft lip/palate (NSCL/P) has an etiology, including both genetic and environmental factors. Herein, we evaluated the association of rs13041247 and rs11696257 v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) polymorphisms with the risk of NSCL/P in a meta-analysis. Methods: The PubMed/Medline, Scopus, Cochrane Library, Web of Science, and HuGE Navigator databases were systematically searched to retrieve relevant articles published up to January 2019. The Newcastle–Ottawa scale was applied for quality evaluation of retrieved articles. The 95% confidence interval (CI) and crude odds ratio (OR) were calculated for each study using the Review Manager 5.3 software to show the association between MAFB polymorphisms and risk of NSCL/P. The comprehensive meta-analysis 2.0 software was used to calculate the publication bias. In addition, sensitivity analysis was carried out to show the stability of results. Results: Of 102 articles retrieved from the databases, 10 articles were analyzed in this meta-analysis. Ten articles, including eleven studies reporting rs13041247 MAFB polymorphism, included 3082 NSCL/P patients and 4104 controls. Three studies that reported rs11696257 MAFB polymorphism involved 845 NSCL/P patients and 927 controls. The rs11696257 MAFB polymorphism was not associated with the risk of NSCL/P, but the CC and TC genotypes of rs13041247 polymorphism were associated with the risk of NSCL/P. Nevertheless, the C allele and CC and TC genotypes were associated with a significant decline in the risk of NSCL/P in population-based studies. Conclusions: The results of this meta-analysis demonstrated that the risk of NSCL/P was related to rs13041247 polymorphism, not rs11696257 MAFB polymorphism. Well-designed studies are required to assess the interaction of MAFB and other genes with environmental factors in different ethnic groups.

Exploring the association between SPRY gene family and non-syndromic oral clefts among Chinese populations using data of a next-generation sequencing study

To explore the association between SPRY gene family and the risk of non-syndromic oral clefts among Chinese populations, in respect of single nucleotide polymorphisms (SNPs) association and parent-of-origin effects. Based on case-parent design, this study used the data of SPRY gene family in a next generation sequencing study of 183 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios (549 participants) recruited from 2016 to 2018, to analyze the effects of SNP association and parent-of-origin. The sequencing study adopted a two-stage design. In the first stage, whole exome sequencing was conducted among 24 NSCL/P trios with family history to explore potential signals. Then in the second stage, another 159 NSCL/P trios were used as validation samples to verify the signals found in the first stage. The data of general information, disease features and parental environmental exposures for participants were collected through questionnaires. Blood samples were collected from each participant for DNA extraction and sequencing. Transmission disequilibrium tests (TDT) were conducted to test for the association between SNPs and NSCL/P, while Z score tests were applied to analyze parent-of-origin effects. The analyses were performed using Plink (v1.07). TRIO package in R (v3.5.1). Besides, famSKAT analyses were conducted in the first stage to combine the effect of SNPs located on the same gene, using famSKAT package in R(V3.5.1). Bonferroni method was adopted to correct multiple tests in the second stage. Twenty-two SNPs in SPRY gene family were included for analyses after the quality control process in the first stage. Based on the variants annotation, functional prediction and statistical analysis, rs1298215244 (SPRY1) and rs504122 (SPRY2) were included in the second verification stage. TDTs in the verification stage revealed that rs1298215244: T>C, rs504122: G>C and rs504122: G>T were associated with the risk of NSCL/P after Bonferroni corrections, where rs504122: G>T was a rare variation. Although the test for parent-of-origin effect of rs1298215244: T>C reached nominal significance level, no SNP showed significant association with NSCL/P through parent-of-origin effect after Bonferroni corrections. This study found that SNPs (including both common and rare variants) among the SPRY gene family were associated with the risk of NSCL/P among Chinese populations. This study failed to detect parent-of-origin effects among the SPRY gene family.

WNT10A rs147680216 G>A mutation indicates a higher risk for non-syndromic oral cleft in a northeastern Chinese population

Non-syndromic oral cleft lip and palate is a heterogeneous group of congenital malformations that consist of cleft palate, and cleft lip with or without cleft palate. The members of the wingless type mouse mammary tumour virus (MMTV) integration site family (Wnts) regulate various developmental processes including craniofacial development, and have a role in that of cleft lip and palate. We aimed to identify the potential polymorphisms in the Wnt10a gene, and to explore the association between the variations in the gene and the risk of development of cleft palate. A total of 198 affected patients (cleft lip, n=67; cleft palate, n=48; and both, n=83) together with 187 healthy controls were enrolled (all from the Chinese Han population in NE China). A fragment of 316 bp was amplified from the blood genome of each participant by polymerase chain reaction (PCR) using specific primers that targeted the Homo sapiens Wnt10a gene. By using the restriction enzyme AluI, the population analysed were classified into three genotypes, GG (316 bp), GA (316 bp, 117bp, 199bp) and AA (117bp, 199bp) based on the rs147680216 G/A polymorphism (Gly>Ser mutation at position 213 of Wnt10a protein) of theWnt10a gene. The frequency of allele A in the affected group was significantly higher (14.1% compared with 3.2% in the control group). The allele G with an odds ratio (OR) of 0.201 and 95% CI of 0.445 to 0.091 was not a risk factor for the condition in the affected group. However, the distribution of the genotype did affect its occurrence in the affected group (p<0.001), but not the classification of types (p=0.901). In conclusion we found an rs147680216 G>A mutation that was associated with non-syndromic cleft lip and palate in the Wnt10a gene.

Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate.

Cleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 nonmalformed controls. Our findings indicated that rare, protein‐altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss‐of‐function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene‐level analyses, the burden of rare alleles showed greater case‐association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10‐fold increase in protein‐altering variants in CLP cases (p = .03), including multiple case occurrences of a rare frameshift mutation (K400 fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.

Levels of polycyclic aromatic hydrocarbons in umbilical cord and risk of orofacial clefts

Polycyclic aromatic hydrocarbons (PAHs), which are ubiquitous in the environment, have been found to cause orofacial clefts (OFCs) in mouse model. However, evidence from the human study with markers of intrauterine exposure is absent. We explored the associations between the levels of sixteen PAHs in umbilical cord tissue and risk for OFCs using multivariable logistic models and Bayesian Kernel Machine Regression (BKMR). This case-control study included 89 OFC cases and 129 controls without congenital malformations. Concentrations of PAHs in umbilical cord tissue were detected using gas chromatography coupled to triple quadrupole tandem mass spectrometry. The median levels of ΣPAHs, Σlow molecular weight polycyclic aromatic hydrocarbons, and Σhigh molecular weight polycyclic aromatic hydrocarbons were all higher in cases of total OFCs and its subtypes than in controls, although the differences were not statistically significant. No statistical associations between levels of PAHs in umbilical cord tissue and risk for OFCs were observed in either multivariable logistic models or BKMR models. Maternal using a stove for heating and lower frequency of ventilation in the bedroom/living room, and consumptions of fresh green vegetables were positively correlated with levels of PAHs in umbilical cord. In conclusion, our results did not suggest that in utero exposure to PAHs were associated with the risk for OFCs, in estimating whether single effect of PAHs or joint effects of multiple PAHs.

Levels of uranium and thorium in maternal scalp hair and risk of orofacial clefts in offspring

Uranium and thorium are common radioactive elements that exist in the environment. However, few environmental epidemiological studies have focused on their possible effects on congenital malformations. Here, we explored the association between uranium and thorium concentrations in maternal scalp hair grown from 3 months before to 3 months after conception, namely during the periconceptional period and the risk of orofacial clefts (OFCs) in offspring. Our study included 153 women whose pregnancies were affected by OFCs (cases) and 601 women who delivered infants without birth defects (controls) from four provinces in China. Face-to-face interviews were used to collect sociodemographic characteristics with a structured questionnaire. Concentrations of uranium and thorium in maternal scalp hair grown during the periconceptional period were detected using inductively coupled plasma-mass spectrometry. The risk of OFCs in association with higher concentrations of the two radioactive elements was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for potential confounding factors. The levels of uranium and thorium in maternal hair were in agreement with the published literature. After adjusting for several confounders, the ORs of thorium in the highest, upper, and lower quartile versus the lowest quartile were 2.63 (95% CI, 1.41–4.92), 1.98 (95% CI, 1.03–3.79), and 2.73 (95% CI, 1.46–5.12), respectively. No association was found between levels of uranium and the risk of OFCs. Maternal periconceptional exposure to thorium may be a risk factor for OFCs in offspring.

Do Unaffected Parents of Children with Orofacial Clefts have Decreased Facial Integration Compared to Controls?

Orofacial clefts are the most common congenital craniofacial anomaly affecting humans. Non‐syndromic clefts may result from decreased integration of the palate during fetal facial growth. This study will investigate whether this pattern is detectable in individuals who do not have a cleft, but do have a child with an orofacial cleft (and therefore carry genetic risk factors for clefting). In order to examine this, we hypothesize that 1) facial shape differences exist between unaffected parents of children with clefts (cases) compared to adults with no history of clefting (controls), and 2) cases will have lower facial integration values compared to controls.For this study, 3D facial scans were obtained from the University of Pittsburgh Center for Craniofacial and Dental Genetics (CCDG). 34 landmarks were placed on n=230 case faces of unaffected parents from the Pitt Orofacial Cleft Study and n=490 control faces from the Pitt 3D Facial Norms Study. Landmarks were aligned using Generalized Procrustes Analysis (GPA) and geometric morphometrics were used for quantifying facial phenotypes. Facial shape differences as a function of age were removed prior to all analyses using linear regression. Canonical Variate Analysis (CVA) was employed to examine shape differences in three different subsets of facial landmarks: a midfacial nose and mouth dataset, a lower facial mouth and jaw dataset and a third dataset consisting of the nose and jaw. Two Block Partial Least Squares analysis (2B PLS) was used to measure the strength of integration by comparing RV coefficients between the case and control populations.Results from the CVA identify significant differences in facial morphology, including jaw width, chin projection, nasal height and mouth width, between cases and controls across all datasets (nose/mouth midfacial set p&lt;0.001, mouth/jaw lower facial set p&lt;0.001, and nose/jaw dataset p=0.028). 2B PLS results, however, showed overall equivalent or higher integration levels in case faces compared to the controls. When comparing levels of integration within the midface (nose and mouth dataset), case samples demonstrate significant (p&lt;0.001) overall higher integration levels (RV=0.352) compared to control samples (RV=0.301). This pattern is also seen within the nose and jaw dataset, with cases (RV=0.614) showing increased integration compared to controls (RV=0.554). Interestingly, integration levels within the lower facial mouth and jaw dataset were nearly identical in both case samples (RV=0.444) and controls (RV=0.447).While facial shape differences exist between unaffected cleft relatives and controls with no family history of clefting, integration values were actually higher in case samples compared to control samples. This indicates that integration in facial soft tissue structures may not serve as a good indicator of cleft risk. Future studies will examine skeletal structures (such as the maxilla and mandible) to test if differences in integration are quantifiable in the facial skeleton only.Support or Funding InformationNIDCR: R01‐DE016148, U01‐DE020078This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Use of ondansetron during pregnancy and the risk of major congenital malformations: A systematic review and meta-analysis

AimsTo investigate whether ondansetron use during pregnancy is associated with increased rates of major or subgroups of malformations. MethodsPubMed/MEDLINE, Cochrane and Reprotox® databases were searched. Observational studies comprising an exposed and control group (healthy and/or disease-matched) were included. ResultsNo significant increased risk for major malformations, heart defects, orofacial clefts, genitourinary malformations or hypospadias were identified in our primary analysis. A significant heterogeneity existed for isolated cleft palate. Elevated point estimates and altered statistical significances were present for some of the outcomes among secondary analyses. ConclusionsOndansetron use during pregnancy was not associated with a significant increase in rate of major or selected subgroups of malformations in our primary analysis. However, results of the secondary analyses warrant the need for continued surveillance. These results may be reassuring for pregnant women in whom ondansetron use is clinically indicated since the absolute risks of possible concerns appear to be low.

Association between oral cleft and transcobalamin 2 polymorphism in a sample study from Nassiriya, Iraq.

Orofacial clefts are common congenital defects whose prevalence differs between geographical regions and ethnic groups. The inheritance is complex, involving the contribution of both genetic and environmental factors. The involvement of genes belonging to the folate pathway is still matter of debate, with strong evidences of association and conflicting results. After demonstrating the contribution, for a sample from the Italian population, of common mutations mapping on three genes of the folate pathway, our group tried to unravel their contribution in independent sample studies with different ethnicity. In the present investigation a set of 34 triads with oral cleft from Nassiriya, Iraq, has been genotyped for rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS polymorphisms. Association analysis evidenced a decreased risk of cleft for children carrying the 667G allele at TCN2 gene (P = 0.02). This evidence further supported the relationship between polymorphisms of folate related genes and oral clefts, and outlined the relevance of studying populations having different ethnicity.

Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring

Evidence for the fetal safety of ondansetron, a 5-HT3 receptor antagonist that is commonly prescribed for nausea and vomiting during pregnancy, is limited and conflicting. To evaluate the association between ondansetron exposure during pregnancy and risk of congenital malformations. A retrospective cohort study nested in the 2000-2013 nationwide Medicaid Analytic eXtract. The cohort consisted of 1 816 414 pregnancies contributed by 1 502 895 women enrolled in Medicaid from 3 months before the last menstrual period through 1 month or longer after delivery; infants were enrolled in Medicaid for at least 3 months after birth. The final date of follow-up was December 31, 2013. Analyses were conducted between November 1, 2017, and June 30, 2018. Propensity score stratification was used to control for treatment indication and other confounders. Ondansetron dispensing during the first trimester, the period of organogenesis. Primary outcomes were cardiac malformations and oral clefts diagnosed during the first 90 days after delivery. Secondary outcomes included congenital malformations overall and subgroups of cardiac malformations and oral clefts. Among 1 816 414 pregnancies (mean age of mothers, 24.3 [5.8] years), 88 467 (4.9%) were exposed to ondansetron during the first trimester. Overall, 14 577 of 1 727 947 unexposed and 835 of 88 467 exposed infants were diagnosed with a cardiac malformation, for an absolute risk of 84.4 (95% CI, 83.0 to 85.7) and 94.4 (95% CI, 88.0 to 100.8) per 10 000 births respectively. The absolute risk of oral clefts was 11.1 per 10 000 births (95% CI, 10.6 to 11.6; 1921 unexposed infants) and was 14.0 per 10 000 births (95% CI, 11.6 to 16.5; 124 exposed infants). The risk of any congenital malformation was 313.5 per 10 000 births (95% CI, 310.9 to 316.1; 54 174 unexposed infants) and was 370.4 (95% CI, 358.0 to 382.9; 3277 exposed infants). The adjusted relative risk (RR) for cardiac malformations was 0.99 (95% CI, 0.93 to 1.06) and the adjusted risk difference (RD) was -0.8 (95% CI, -7.3 to 5.7 per 10 000 births). For oral clefts, the adjusted RR was 1.24 (95% CI, 1.03 to 1.48) and the RD was 2.7 (95% CI, 0.2 to 5.2 per 10 000 births). The adjusted estimate for congenital malformations overall was an RR of 1.01 (95% CI, 0.98 to 1.05) and an RD of 5.4 (95% CI, -7.3 to 18.2 per 10 000 births). Among offspring of mothers enrolled in Medicaid, first-trimester exposure to ondansetron was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders but was associated with a small increased risk of oral clefts.

Maternal periconceptional consumption of sprouted potato and risks of neural tube defects and orofacial clefts

BackgroundThe association between maternal consumption of sprouted potato during periconceptional period on the development of neural tube defects (NTDs) or orofacial clefts (OFCs) remains unclear. We aimed to examine the association between maternal consumption of sprouted potatoes during periconceptional period and risks of NTDs or OFCs.MethodsSubjects included 622 NTD cases, 135 OFC cases and 858 nonmalformed controls, were recruited from a case-control study in Shanxi Province of northern China between 2002 and 2007. Information on demographics, maternal sprouted potato consumption, lifestyle behaviors and folic acid supplementation was collected.ResultsConsumption of sprouted potatoes was associated with elevated odds of total NTDs (OR = 2.20; 95% CI, 1.12–4.32) and anencephaly (OR = 2.48; 95% CI, 1.10–5.58); no association for spina bifida or encephalocele. Sprouted potato consumption increased the risk of total OFCs (OR = 3.49; 95% CI, 1.29–9.49) and cleft lip with or without cleft palate (CL ± P) (OR = 4.03; 95% CI, 1.44–11.28).ConclusionMaternal consumption of sprouted potatoes during periconceptional period may increase the risks of NTDs and OFCs. Given that potato is commonly consumed around the world, improper preservation and use should be a matter of concern in respect of the potential teratogenicity.

Higher concentration of selenium in placental tissues is associated with reduced risk for orofacial clefts

Growing evidence suggests that essential trace element imbalance during pregnancy may contribute to fetal malformations, but the role of essential trace elements in the occurrence of orofacial clefts (OFCs) is unknown. We aimed to examine the association between concentrations of zinc (Zn), manganese (Mn), selenium (Se), cobalt (Co), molybdenum (Mo), and nickel (Ni) in placental tissues and the risk for OFCs in offspring in a rural population in northern China with a high prevalence of OFCs. The case-control study subjects were 103 OFC infants and 206 non-malformed infants. The concentrations of selected trace elements in placental tissues were determined using inductively coupled plasma-mass spectrometry. Sociodemographic information was collected from the mothers through face-to-face interviews using a structured questionnaire. The risk for OFCs in association with higher concentrations of the trace elements was estimated using the odds ratio (OR) with its 95% confidence interval (95% CI). The placental median concentrations of Se and Ni were significantly lower, but those of Mo were significantly higher in OFC cases than in controls (all P<0.05). A Se concentration above the median of all subjects was associated with a 58% reduced risk for OFCs (adjusted OR 0.42, 95% CI 0.23, 0.77) after adjusting for potential confounding factors. The risk for OFCs decreased with increases in placental Se concentrations, with adjusted ORs of 0.45 (95% CI 0.22, 0.92) for the second tertile and 0.22 (95% CI 0.10, 0.49) for the top tertile of Se concentration, with the lowest tertile concentration as the referent (Ptrend<0.001). No association was observed between placental Zn, Mn, Co, Mo, or Ni concentration and risk for OFC. The concentration of Se in placental tissues was dose-dependently associated with decreased risk for OFCs in offspring. This finding suggests that maternal Se intake during pregnancy may protect against OFCs in offspring.

Association Studies Between Regulatory Regions of IRF6/TP63 Genes and Nonsyndromic Oral Clefts.

To evaluate genetic variants within the regulatory regions of interferon regulatory factor 6 (IRF6) and TP63 for the etiology of nonsyndromic oral clefts risk factors. We performed allelic transmission disequilibrium test analysis on 5 eligible single-nucleotide polymorphisms (SNPs) and SNP haplotypes using the Family-Based Association Test. The study sample consisted of 334 case-parent trios of nonsyndromic oral clefts from Taiwanese population, separated into nonsyndromic cleft lip/palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) groups. We found all 3 selected SNPs of the IRF6 gene show significant association with nonsyndromic oral clefts (rs2235371, P = 5.10E-07; rs642961, P = .00194; and rs77542756, P = 9.08E-07). Haplotype analyses identified 3 possible SNP combination haplotypes in the IRF6 gene and found that C-G-G showed significant undertransmission (P = .058), whereas 2 other haplotypes, T-G-A and C-A-G (P = 2.71E-06 and P = 5.00E-04, respectively), were significantly overtransmitted to the NSCL/P children but not to the NSCPO children. For the TP63 gene, we failed to detect evidence of nonsyndromic oral cleft association in the 2 SNPs within the TP63 large intron 1 region. We used a family-based analysis in 334 Taiwanese case-parent trios to evaluate selected SNPs of IRF6 genes and TP63 genes for a risk of orofacial clefting. This study provides additional evidence for an association between IRF6 and NSCL/P, including the genetic variants within the 5'-noncoding region of the gene. We also confirmed that NSCL/P and NSCPO individuals belong to different groups. For the TP63, our data did not favor the direct involvement of TAp63 isoforms during orofacial development.