OVERVIEW OF DRUG-INDUCED OROFACIAL CLEFT.

An embryopathy with the disappointment of the nasal cycles as well as a combination of the palatal racks causes orofacial cleft (OFC). Perhaps the most pervasive distortion among live births is this extreme birth condition. The two kinds of human clefts are cleft of the lip with or without a palate (CL±P) and cleft palate only (CPO). They are both hereditary in origin, although ecological impacts play a part in the advancement of these innate irregularities. The capacity of prescriptions at the beginning of cleft lip is analyzed in this overview. The data came from epidemiological investigation, (ii) laboratory animal trials, and (iii) genetic investigation in humans. These investigations have tracked down a connection between prescriptions of corticosteroids and antiepileptics taken during gestation and an improved probability of having OFC-positive children, however, no connection between anti-inflammatory medicine and OFC has been found.

Investigation of exposure to heavy metals (Hg, Pb, Cd, Co, and Cr) as the cause of congenital anomaly cases (orofacial cleft) in infants.

Orofacial cleft (OFC) is one of the most common congenital defects, with worldwide cases occurring in approximately 1:700 to 1:1000 births. This incidence is among the highest birth defects in Indonesia, and the incidence rate in Bandung Regency (14.69%) is the second-highest in West Java province. The purpose of this study was to analyze the association of heavy metal factors that accumulate in infants to the risk of OFC in Bandung Regency. The method was used by testing heavy metals Hg, Pb, Cd, Co, and Cr in infant blood. The total sample were 54 samples, where the case respondent of 32 and 22 respondents as the control group. Blood samples were analyzed using ICP-MS Agilent 7900. The correlation using statistic analyze namely chi-square analysis (bivariate) and multiple logistic regression (multivariate). The results showed that there was a significant difference in the concentration of heavy metals Hg, Pb, and Cd as well as an increase in Pb and Cd in the infant's blood which was thought to be significantly associated with the risk of OFC.

Suppression of microRNA 124-3p and microRNA 340-5p ameliorates retinoic acid-induced cleft palate in mice.

The etiology of cleft lip with or without cleft palate (CL/P), a common congenital birth defect, is complex, with genetic and epigenetic, as well as environmental, contributing factors. Recent studies suggest that fetal development is affected by maternal conditions through microRNAs (miRNAs), a group of short noncoding RNAs. Here, we show that miR-129-5p and miR-340-5p suppress cell proliferation in both primary mouse embryonic palatal mesenchymal cells and O9-1 cells, a neural crest cell line, through the regulation of Sox5 and Trp53 by miR-129-5p, and the regulation of Chd7, Fign and Tgfbr1 by miR-340-5p. Notably, miR-340-5p, but not miR-129-5p, was upregulated following all-trans retinoic acid (atRA; tretinoin) administration, and a miR-340-5p inhibitor rescued the cleft palate (CP) phenotype in 47% of atRA-induced CP mice. We have previously reported that a miR-124-3p inhibitor can also partially rescue the CP phenotype in atRA-induced CP mouse model. In this study, we found that a cocktail of miR-124-3p and miR-340-5p inhibitors rescued atRA-induced CP with almost complete penetrance. Taken together, our results suggest that normalization of pathological miRNA expression can be a preventive intervention for CP.

Transgenerational adverse effects of valproate? A patient report from 90 affected families.

BACKGROUND: Valproate use during pregnancy increases risk in malformations and neurodevelopmental disorders. Data from the experimental setting in mice showed valproate is a direct inhibitor of histone deacetylase, inducing histone hyperacetylation, histone methylation, and DNA demethylation causing congenital malformations with an epigenetic inheritance. We investigated potential transgenerational adverse effects of valproate. METHODS: We questioned 108 individuals (from 90 families) suffering complications due to valproate exposure in utero who were parents themselves (85 women and 23 men) about the occurrence of malformations and neurodevelopmental disorders in their children. All were member of Aide aux Parents d'Enfants souffrants du Syndrome de l'AntiConvulsivant (APESAC), a charity created in 2011 to provide personal assistance and support to families suffering complications due to valproate exposure during pregnancy. RESULTS: Among their 187 children they reported 43 (23%) children with malformation(s) (26 hand or foot malformations; 15 dysmorphic facial features; 10 renal/urologic malformations; 6 spina bifida; 4 cardiac malformation; 2 craniosynostosis; 2 cleft lip and palate) and 82 (44%) children with neurodevelopmental disorders (63 problematic behaviors and autism; 41 psychomotor disorders; 16 language problems; 16 attention deficit; 5 mental retardation). Only 88 (47%) children had neither malformation nor developmental disorders. CONCLUSION: These data add to the need for funding pharmacoepidemiological investigations of epigenetic inheritance caused by drugs causing malformations or neurodevelopmental disorders. Individuals exposed in utero to valproate must be informed about the risk, so they can consider fertility options, antenatal diagnosis, and adequate early surveillance.

Exposure to corticosteroids in pregnancy is associated with adverse perinatal outcomes among infants of mothers with inflammatory bowel disease: results from the PIANO registry.

OBJECTIVE: Active inflammatory bowel disease (IBD) during pregnancy may require the use of corticosteroids. The aim of this study was to investigate the impact of in utero corticosteroid exposure on adverse pregnancy outcomes, congenital malformations, infections and neurocognitive development among offspring of mothers with IBD. DESIGN: Using the prospective Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes registry, data were collected at each trimester, delivery; and in the 12 months post partum. Bivariate statistics and multivariate logistic regression models compared pregnancy outcomes by corticosteroid exposure. RESULTS: A total of 1490 mothers with IBD were enrolled, with 1431 live births recorded. Corticosteroid use was associated with increased risk of preterm birth, small for gestational age, low birth weight (LBW), intrauterine growth restriction and neonatal intensive care unit (NICU) admission. On adjusted multivariate models, corticosteroid use was associated with preterm birth (OR 1.79, 95% CI 1.18 to 2.73), LBW (OR 1.76, 95% CI 1.07 to 2.88) and NICU admission (OR 1.54, 95% CI 1.03 to 2.30). Late corticosteroid use (second and/or third trimester) was associated with serious infections at 9 and 12 months (4% vs 2% and 5% vs 2%, respectively, p=0.03 and p=0.001). There were five newborns with in utero corticosteroid exposure born with orofacial clefts versus one without corticosteroid exposure. Developmental milestones were similar across corticosteroid exposure groups. CONCLUSION: In this prospective pregnancy registry, offspring of women exposed to corticosteroids during pregnancy were more likely to have adverse pregnancy outcomes. This emphasises the importance of controlling disease activity before and during pregnancy with steroid-sparing therapy.

Tenofovir Alafenamide for Pregnant Chinese Women With Active Chronic Hepatitis B: A Multicenter Prospective Study.

BACKGROUND & AIMS: Data on long-term tenofovir alafenamide (TAF) therapy for pregnant women with active chronic hepatitis B (CHB) (immune clearance and reactivation phases, currently and previously diagnosed) and their infants are lacking. METHODS: Pregnant women with active CHB treated with TAF and tenofovir disoproxil fumarate (TDF) were enrolled in this multicenter prospective study, and infants received immunoprophylaxis. The primary outcomes were rates of adverse (safety) events in pregnant women and defects in infants and fetuses. The secondary outcomes were virologic responses in pregnant women, infants' safety, hepatitis B surface antigen (HBsAg) status, and growth conditions. RESULTS: One hundred three and 104 pregnant women were enrolled and 102 and 104 infants were born in the TAF and TDF groups, respectively. In the TAF group, the mean age, gestational age, alanine aminotransferase level, and viral loads at treatment initiation were 29.3 years, 1.3 weeks, 122.2 U/L, and 5.1 log10 IU/mL, respectively. TAF was well-tolerated, and the most common adverse event was nausea (29.1%) during a mean of 2 years of treatment. Notably, 1 (1.0%) TAF-treated pregnant woman underwent induced abortion due to noncausal fetal cleft lip and palate. No infants in either group had birth defects. In the TAF group, the hepatitis B e antigen seroconversion rate was 20.7% at postpartum month 6, infants had normal growth parameters, and no infants were positive for HBsAg at 7 months. The TDF group had comparable safety and effectiveness profiles. CONCLUSIONS: TAF administered throughout or beginning in early pregnancy is generally safe and effective for pregnant women with active CHB and their infants.

Maternal exposure to ambient air pollution and risk of congenital heart defects in Suzhou, China.

Background: More and more studies have investigated the association between maternal exposure to ambient air pollution during pregnancy and incidence of congenital heart defects (CHDs), but results are controversial. The aim of this study was to investigate whether maternal exposure to air pollutants (PM10, PM2.5, NO2, CO, SO2) are associated with an increased risk of congenital heart defects in Suzhou city, China. Methods: Based on the birth defect monitoring system of Suzhou city and the Environmental Health Department of Suzhou CDC, the birth defect monitoring data and concentrations of five air pollutants (PM10, PM2.5, NO2, CO, SO2) in Suzhou city from 2015 to 2019 were obtained. The distribution of demographic characteristics of children with birth defects and exposure to air pollutant concentrations during different pregnancy periods were analyzed, Chi-square test was used to analyze whether there were statistical differences in the distribution of parturient woman age, pregnant weeks, times of pregnancy, as well as fetal sex and birth weight among children with congenital heart defects and other defects. Logistic regression model was further established to calculate the adjusted odds ratios (aORs) and 95% confidence intervals (CI) for the association between exposure to these ambient air pollutants during pregnancy and CHDs. Results: A total of 5,213 infants with birth defects were recruited in this study from 2015 to 2019, the top five birth defects in Suzhou were syndactyly, congenital heart disease, ear malformation, cleft lip and palate, and hypospadias, and the proportion of congenital heart disease increased. The level of maternal exposures (mean ± sd) was highest in first trimester amongst pregnant women in Suzhou city. Compared to other birth defects, we observed significant increasing associations between PM2.5 exposure during second and third trimester with risk of CHDs, aORs were 1.228 and 1.236 (95% CI: 1.141-1.322, 1.154-1.324 separately) per a 10 µg/m3 change in PM2.5 concentration. Maternal NO2 exposure was significantly associated with CHDs in first trimester (aOR = 1.318; 95% CI: 1.210-1.435). Conclusions: Our study contributes to explore the current state of Suzhou air quality and the association between maternal air pollution exposure and congenital heart defects. Exposure to PM2.5 and NO2 is thought to increase the risk of CHDs, but comprehensive description of these associations will be needed in future studies.

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

BACKGROUND: A 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. METHODS: A 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. RESULTS: Increase 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. CONCLUSIONS: Our 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.

[Nausea and vomiting in pregnancy: A place for ondansetron?] / 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.

The important role of MDM2, RPL5, and TP53 in mycophenolic acid-induced cleft lip and palate.

ABSTRACT: Mycophenolate embryopathy (MPE) is a mycophenolic acid (MPA)-induced congenital malformation with distinctive symptoms. Cleft lip/palate (CLP) is one of the most common symptoms of MPE. The aim of this study was to screen and verify hub genes involved in MPA-induced CLP and to explore the potential molecular mechanisms underlying MPE.Overlapping genes related to MPA and CLP were obtained from the GeneCards database. These genes were further analyzed via bioinformatics. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results were visualized with the Cytoscape ClueGO plug-in. Gene protein-protein interaction (PPI) networks were constructed based on data obtained from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database.Overall, 58 genes related to MPA and CLP were identified. The genes most relevant to MPA-induced CLP included ABCB1, COL1A1, Rac1, TGFß1, EDN1, and TP53, as well as the TP53-associated genes MDM2 and RPL5. GO analysis demonstrated gene enrichment regarding such terms as ear, mesenchymal, striated muscle, and ureteric development. KEGG analysis demonstrated gene enrichment in such pathways as the HIF-1 signaling pathway, glycosylphosphatidylinositol-anchor biosynthesis, the TNF signaling pathway, and hematopoietic stem cell development.Bioinformatic analysis was performed on the genes currently known to be associated with MPA-induced CLP pathogenesis. MPA-induced CLP is mediated by multiple ribosome stress related genes and pathways. MDM2, RPL5 and TP53 could be the main contributor in this pathogenesis, along with several other genes. ABCB1 polymorphism could be related to the probability of MPA-induced CLP.

Anti-asthma Drugs Formoterol and Budesonide (Symbicort) Induce Orofacial Clefts, Gastroschisis and Heart Septum Defects in an In Vivo Model.

BACKGROUND: We had a case in which three consecutive pregnancies resulted in birth of three children with an orofacial cleft. Their mother suffered from bronchial asthma and was treated using symbicort (corticosteroid budesonide plus bronchodilator formoterol) during her pregnancies. A hypothesis was assessed: these anti-asthmatics can induce an orofacial cleft in experimental model. MATERIALS AND METHODS: A single administration of one of five increasing doses (including therapeutically used ones) of Symbicort, budesonide or formoterol was injected into the amnion of a chick embryo on day 4 or 5 of incubation. The teratogenic/lethal effects of the anti-asthmatics were assessed on a total of 600 embryos. RESULTS: For budesonide, the teratogenic/lethal effect started at a dose 0.003 µg per embryo, for formoterol at 0.3 µg and for Symbicort 0.03 µg. Orofacial clefts and gastroschisis after exposure were found for all three anti-asthmatics. Heart septum defects occurred after exposure to formoterol. CONCLUSION: The present results support those clinical/epidemiological studies pointing out that anti-asthmatics have the potential to induce orofacial clefts, gastroschisis and heart malformations during prenatal development in human.

Grupo de Estudio de Cefaleas de la Sociedad Española de Neurología (GECSEN)» / Comments on «Headache: Pregnancy and breastfeeding. Recommendations of the Spanish Society of Neurology's Headache Study Group»

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Phenytoin Inhibits Cell Proliferation through microRNA-196a-5p in Mouse Lip Mesenchymal Cells.

Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes crucial for cellular functions. In this study, we examined which miRNAs are associated with CL. Among 10 candidate miRNAs (miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR-144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, and miR-710) identified through our bioinformatic analysis of CL-associated genes, overexpression of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 inhibited cell proliferation through suppression of genes associated with CL in cultured mouse embryonic lip mesenchymal cells (MELM cells) and O9-1 cells, a mouse cranial neural crest cell line. In addition, we found that phenytoin, an inducer of CL, decreased cell proliferation through miR-196a-5p induction. Notably, treatment with a specific inhibitor for miR-196a-5p restored cell proliferation through normalization of expression of CL-associated genes in the cells treated with phenytoin. Taken together, our results suggest that phenytoin induces CL through miR-196a-5p induction, which suppresses the expression of CL-associated genes.

Anti-epileptic drug topiramate upregulates TGFß1 and SOX9 expression in primary embryonic palatal mesenchyme cells: Implications for teratogenicity.

Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFß1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFß1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFß1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFß1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate.

Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

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 ß-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.

Surgical Reconstruction of Cocaine-Induced Cleft Lip: A Case Report.

INTRODUCTION: Cocaine is known to cause necrosis of the soft tissues secondary to its vasoconstrictive effects, which has negative functional and cosmetic outcomes of the midface and adjacent structures. To our knowledge, cleft lip caused by cocaine use has not been described in the literature. CASE PRESENTATION: A 52-year-old man presented with a deformity of the lip and nasal sill, septal perforation, and hard palate fistula secondary to long-term cocaine use. The patient underwent lip reconstruction using a modified Millard technique and had a lasting favorable cosmetic outcome more than 5 years after surgery. DISCUSSION: We report a case of cocaine abuse causing cleft lip, and successful reconstruction with a modified Millard technique.

The anti-epileptic drug valproic acid causes malformations in the developing craniofacial skeleton of zebrafish larvae.

Valproic acid (VPA) is an anti-epileptic drug known to cause congenital craniofacial abnormalities, including orofacial clefts (OFC). The exact mechanisms by which VPA leads to craniofacial skeletal malformations are poorly understood. In this study, we investigated the effects of VPA on cartilage and bone formation in the zebrafish larval head during 1-13 hpf (early) and 25-37 hpf (late) development in which cranial neural crest cells (CNCCs) arise and then proliferate and differentiate, respectively. Double-staining for cartilage and bone at 5 dpf revealed that VPA reduced cartilage and bone formation in a dose-dependent manner after both early or late exposure. Several different CNCC-derived cartilage and bone elements were affected in both groups. In the early group (100 µM VPA), the posterior head length and the ethmoid plate were reduced in length (both p < 0.01), while mineralization of 4 out of 9 bone elements was often lacking (all p < 0.01). In the late group (100 µM VPA), also the posterior head length was reduced as well as the length of the ceratohyals (both p < 0.01). Similar to early exposure, mineralization of 3 out of 9 bone elements was often lacking (all p < 0.01). These results indicate that both CNCC formation (early) and differentiation (late) are hampered by VPA treatment, of which the consequences for bone and cartilage formation are persistent at 5 dpf. Indeed, we also found that the expression of several genes related to cartilage and bone was upregulated at 5 dpf. These data indicate a compensatory reaction to the lack of cartilage and bone. Altogether, VPA seems to induce craniofacial malformations via disturbed CNCC function leading to defects in cartilage and bone formation.

Risk of malformation after ondansetron in pregnancy: An updated systematic review and meta-analysis.

Ondansetron is increasingly used off label to treat nausea and vomiting during pregnancy. The main objective of this study was to evaluate the risk of major congenital malformations (MCM), cardiac defects and orofacial clefts associated with first trimester exposure to ondansetron using a meta-analytic approach. MEDLINE, ClinicalTrials.gov and Scopus were searched until November 2019. All comparative cohort and case-control studies on MCM, cardiac or orofacial defects and use of ondansetron during pregnancy were included. A team of paired reviewers independently extracted data using a proprietary collaborative WEB-based meta-analysis platform (metaPreg.org). Pooled odd ratios with corresponding 95% CIs were calculated using random effects models. From 214 records initially retrieved, 12 studies were included. Using all available information to date, first trimester exposure to ondansetron was found to be associated with an increased risk of (a) ventricular septal defects (VSD) (OR 1.11, 95% CI 1.00-1.23; p < .05; n = 6 studies; I2 = 0%) and (b) oral clefts (OR 1.22, 95% CI 1.00-1.49; p < .05; n = 4 studies; I2 = 0%). No significant association was observed for the risk of cleft palate but, when excluding the study that contributed to the study heterogeneity, we found an OR of 1.48 (95% CI 1.19-1.84; p < .01; n = 5 studies; I2 = 0%). No statistically significant association was found for MCM, overall cardiac malformations, atrial septal defects and cleft lip with or without cleft palate. Exploratory investigations of other malformations showed an increased risk of diaphragmatic hernia, hypoplastic left heart and "respiratory system anomalies."

Uranium concentration in umbilical cord may increase the risk for orofacial clefts.

BACKGROUND: Orofacial clefts (OFCs) are common kind of congenital malformations. The teratogenicity of uranium (U) has been documented in animal study that maternal exposure to U can increase incidence of external malformations including cleft palate. However, there is limited evidence of the association of in utero exposure to U with OFCs risk in humans. OBJECTIVE: This study aimed to investigate the association between in utero exposure to U and the risk of OFCs and its subtypes. METHOD: All subjects were from a case-control study in Shanxi Province, northern China. Eighty-four OFCs cases and 142 healthy controls were included in this study. We used U concentration in umbilical cord as biomarkers to represent intrauterine exposure, which was detected by inductively coupled plasma mass spectrometry. Unconditional logistic regression was used to investigated the association between U level and the risk of OFCs and its subtypes. RESULTS: The median of U concentration in umbilical cord is 0.745 ng/g in case group and 0.455 ng/g in control group. When the U concentration was divided into two categories, high level of U exposure increased the risk of OFCs (OR: 2.08, 95% CI: 1.13-3.86) and its subtype cleft lip with cleft palate (CLP) (OR: 2.72, 95% CI: 1.21-6.14). When divided into three categories, high level of U elevated the risk for OFCs (OR: 2.40, 95% CI: 1.14-5.06) and CLP (OR: 3.04, 95% CI: 1.20-7.74). Meanwhile, a dose-response relationship between the U concentration and the risk of total OFCs (P for trend = 0.009) and CLP (P for trend = 0.007) was found. CONCLUSION: Our study found that in utero exposure to high level of U was associated with increased risk of OFCs and its subtype CLP.