Orofacial Clefts In Offspring Research Articles

Epigenetic implications in maternal diabetes and metabolic syndrome-associated risk of orofacial clefts.

Orofacial clefts (OFCs) are one of the most common types of structural birth defects. The etiologies are complicated, involving with genetic, epigenetic, and environmental factors. Studies have found that maternal diabetes and metabolic syndrome are associated with a higher risk of OFCs in offspring. Metabolic syndrome is a clustering of several disease risk factors, including hyperglycemia, dyslipidemia, obesity, and hypertension. Metabolic disease during pregnancy can increase risk of adverse outcomes and significantly influence fetal development, including orofacial formation and fusion. An altered metabolic state may contribute to developmental disorders or congenital defects including OFCs, potentially through epigenetic modulations, such as histone modification, DNA methylation, and noncoding RNA expression to alter activities of critical morphogenetic signaling or related developmental genes. This review summarizes the currently available evidence and underlying mechanisms of how the maternal metabolic syndrome is associated with OFCs in mostly human and some animal studies. It may provide a better understanding of the interactions between intrauterine metabolic status and fetal orofacial development which might be applied toward prevention and treatments of OFCs.

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.

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.

Maternal multivitamin intake and orofacial clefts in offspring: Japan Environment and Children's Study (JECS) cohort study

ObjectivesOrofacial clefts are common birth defects with a lack of strong evidence regarding their association with maternal nutrition. We aimed to determine whether a relationship exists between maternal nutrient or...

Selected essential trace elements in maternal serum and risk for fetal orofacial clefts

BackgroundDisturbances in the homeostasis of essential trace elements (ETEs) may interfere with embryonic organogenesis. However, the effect of ETEs on the development of orofacial clefts (OFCs) remains unclear. ObjectivesThis study examined associations between concentrations of iron (Fe), zinc (Zn), selenium (Se), cuprum (Cu), cobalt (Co), and molybdenum (Mo) in maternal serum and risk for OFCs in offspring. MethodsA total of 130 cases of OFCs and 260 nonmalformed controls were included in this study. Concentrations of Fe, Zn, Se, Cu, Co, and Mo in maternal serum were detected by inductively coupled plasma mass spectrometry. We examined associations between levels of the six ETEs in maternal serum and risk for OFCs for each element separately using multilevel mixed-effects logistic regression and for all elements collectively using Bayesian kernel machine regression (BKMR). ResultsHigher concentrations of Mo and Co in maternal serum were associated with a decreased risk for OFCs in a dose-dependent manner, with odds ratios and 95% confidence intervals of 0.37 (0.20–0.66) for the second tertile of Mo, 0.28 (0.15–0.54) for the third tertile of Mo, 0.54 (0.29–1.00) for the second tertile of Co, and 0.47 (0.25–0.87) for the third tertile of Co, with the lowest tertile as the referent. When all six ETEs were considered together, increased levels of ETEs were associated with a decreased risk for OFCs. In addition, Mo showed a protective effect against risk for OFCs when the other ETEs were fixed at their 25th, 50th, or 75th percentile, whereas the protective effect of Co turned to a null effect in the BKMR model. No association was observed between levels of Fe, Zn, Se, or Cu and risk for OFCs in either statistical model. ConclusionElevated concentrations of Mo in maternal serum were associated with a reduced risk for OFCs.

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.

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 between concentrations of barium and aluminum in placental tissues and risk for orofacial clefts

Natural exposure to and increasing use of barium and aluminum in various products, such as plastics, rubber, and food additives, raise concerns for their potential health impacts on pregnant women and vulnerable fetuses. We investigated whether there are associations between barium and aluminum concentrations in placental tissues and the risk for orofacial clefts (OFCs) in offspring. In this case-control study, we recruited 103 women with OFC-affected pregnancies and 206 women who delivered healthy newborns. Concentrations of barium and aluminum in placental tissues were measured using inductively coupled plasma-mass spectrometry. Information on maternal sociodemographic characteristics and diet was collected via face-to-face interviews using a structured questionnaire. Aluminum concentrations in placental tissues were not associated with OFC risk. However, a higher concentration of barium in placental tissues was associated with an increased risk for OFCs, with an adjusted odds ratio (OR) of 2.42 (95% confidence interval [95% CI] 1.34–4.40) for total cleft lip with or without cleft palate (CL ± P), and 1.90 (95% CI 1.03–3.50) for isolated CL ± P. There was a positive dose–response relationship between placental barium concentrations and OFC risk. Maternal exposure to barium may increase the risk for OFCs in offspring.

A population-based case-control study of the association between weather-related extreme heat events and orofacial clefts.

Limited epidemiologic research exists on the association between weather-related extreme heat events (EHEs) and orofacial clefts (OFCs). We estimated the associations between maternal exposure to EHEs in the summer season and OFCs in offspring and investigated the potential modifying effect of body mass index on these associations. We conducted a population-based case-control study among mothers who participated in the National Birth Defects Prevention Study for whom at least 1 day of their first two post-conception months occurred during summer. Cases were live-born infants, stillbirths, and induced terminations with OFCs; controls were live-born infants without major birth defects. We defined EHEs using the 95th and the 90th percentiles of the daily maximum universal apparent temperature distribution. We used unconditional logistic regression with Firth's penalized likelihood method to estimate adjusted odds ratios and 95% confidence intervals, controlling for maternal sociodemographic and anthropometric variables. We observed no association between maternal exposure to EHEs and OFCs overall, although prolonged duration of EHEs may increase the risk of OFCs in some study sites located in the Southeast climate region. Analyses by subtypes of OFCs revealed no associations with EHEs. Modifying effect by BMI was not observed. We did not find a significantly increased risk of OFCs associated with maternal exposure to EHEs during the relevant window of embryogenesis. Future studies should account for maternal indoor and outdoor activities and for characteristics such as hydration and use of air conditioning that could modify the effect of EHEs on pregnant women.

Secondhand smoke during the periconceptional period increases the risk for orofacial clefts in offspring.

To examine whether exposure to secondhand smoke (SHS) during the periconceptional period among nonsmoking women is associated with an increased risk for orofacial clefts (OFCs) in offspring in a population with low rates of maternal active smoking but high rates of SHS exposure. We recruited 240 women with OFC-affected pregnancies and 1420 women who delivered healthy infants from a population-based case-control study in northern China during 2002 and 2016. Data including self-reported SHS exposure were collected by trained health care workers through face-to-face interviews. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to estimate the association between SHS exposure and OFC risk. The unadjusted ORs for OFCs and cleft lip with or without cleft palate (CL±P) in association with SHS exposure were both 1.6 (95% CI 1.2, 2.1). After adjusting for maternal fever or flu, farming occupation, infant sex, and history of pregnancy affected by birth defects, the adjusted ORs were both 1.6 (95% CI 1.2, 2.2). Frequent SHS exposure (>6times/week) was associated with an even higher risk for OFCs (adjusted OR 2.6, 95% CI 1.8, 3.8) and for CL±P (adjusted OR 2.5, 95% CI 1.7, 3.7). Maternal SHS exposure during the periconceptional period increases the risk for OFCs in offspring among nonsmoking mothers.

Concentrations of selected heavy metals in placental tissues and risk for neonatal orofacial clefts

Orofacial clefts (OFCs) have multifactorial etiologies. Prenatal exposure to heavy metals can induce OFCs in animal models, but evidence from studies of human subjects is scarce. We examined whether concentrations of mercury (Hg), cadmium (Cd), lead (Pb), and arsenic (As) in placental tissues are associated with risk for OFCs in offspring. This population-based case-control study included 103 newborns affected by OFCs with available placental tissues and 206 controls randomly selected from 509 non-malformed newborns with available placenta samples, recruited in five rural counties in northern China. Sociodemographic information was collected using a structured questionnaire in face-to-face interviews. The concentrations of Hg, Cd, Pb, and As in placental tissues were analyzed using an inductively coupled plasma-mass spectrometry in helium mode. The median concentrations of Hg (7.4 ng/g), Cd (57.1 ng/g), and Pb (96.1 ng/g) were all statistically significantly higher in OFC cases than in controls (Hg 5.5 ng/g, Cd 38.6 ng/g, and Pb 67.9 ng/g, respectively); no differences were observed between the two groups in median concentrations of As. Concentrations above the median for all subjects were associated with a 2.33-fold (95% confidence interval [CI] 1.33–2.09) increased OFC risk for Cd and a 3.08-fold (95% CI 1.74–5.47) increased risk for Pb. The risk for OFCs increased with concentration tertiles, with an adjusted odds ratio of 3.06 (95% CI 1.36–6.88) for the second tertile and 8.18 (95% CI 6.64–18.37) for the highest tertile of Cd, and 3.88 (95% CI 1.78–8.42) for the second tertile and 5.17 (95% CI 2.37–11.29) for the highest tertile of Pb. The association between Hg concentration and OFC risk was borderline nonsignificant after adjusting for confounding factors. Prenatal exposure to Cd and Pb, as reflected by their concentrations in placental tissues, is associated with an increased risk for neonatal OFCs.

Maternal Multivitamin Intake and Orofacial Clefts in Offspring: Japan Environment and Children's Study (JECS)

Maternal Multivitamin Intake and Orofacial Clefts in Offspring: Japan Environment and Children's Study (JECS)

Maternal exposure to ozone and PM2.5 and the prevalence of orofacial clefts in four U.S. states

BackgroundWhile there is some evidence that maternal exposure to ambient air pollution is associated with orofacial clefts in offspring, the epidemiologic studies have been largely equivocal. We evaluated whether maternal exposure to elevated county-level ambient fine particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) and ozone during early gestation was associated with a higher prevalence of orofacial clefts. MethodsBirth data consisting of 4.7 million births from 2001 to 2007 were obtained from National Birth Defects Prevention Network for four states — Arizona, Florida, New York (excluding New York City), and Texas. The air pollution exposure assessment for gestational weeks 5–10 was based on county-level average concentrations of PM2.5 and ozone data generated using a Bayesian fusion model available through CDC's Environmental Public Health Tracking Network. Two outcomes were analyzed separately: cleft lip with or without cleft palate, cleft palate alone. In logistic regression analyses, we adjusted for factors that were suspected confounders or modifiers of the association between the prevalence of orofacial clefts and air pollution, i.e., infant sex, race-ethnicity, maternal education, smoking status during pregnancy, whether this was mother's first baby, maternal age. ResultsEach 10µg/m3 increase in PM2.5 concentration was significantly associated with cleft palate alone (OR =1.43, 95% CI: 1.11–1.86). There was no significant association between PM2.5 concentration and cleft lip with or without cleft palate. No associations were observed between ozone exposure and the two outcomes of orofacial clefts. ConclusionsOur study suggests that PM2.5 significantly increased the risk of cleft palate alone, but did not change the incidence of cleft lip with or without palate. Ozone levels did not correlate with incidence of orofacial clefts.

A Case-Control Study of Maternal Occupation and the Risk of Orofacial Clefts.

The aim of this study was to examine the association between maternal occupation and risk of orofacial clefts in offspring. Data were obtained from the Texas Birth Defects Registry and vital records for 1999 to 2009 deliveries. We used automated software to assist in classifying occupations into standard codes. Using multivariable logistic regression, the risk for cleft lip with or without cleft palate (CLP) or cleft palate only (CP) in offspring was compared between women in each of 20 major occupation groups to women in every other occupation group. Significant positive associations were observed between business/finance and architecture/engineering occupations and CP and between cleaning-related occupations and CLP. A significant negative association was observed between office and administrative support occupations and CLP. This study supports previous reports of increased risk of orofacial clefts in offspring among women in certain occupations.

Maternal alcohol binge-drinking in the first trimester and the risk of orofacial clefts in offspring: a large population-based pooling study.

Using individual participant data from six population-based case–control studies, we conducted pooled analyses to examine maternal alcohol consumption and the risk of clefts among >4600 infants with cleft lip only, cleft lip with cleft palate, or cleft palate only and >10,000 unaffected controls. We examined two first-trimester alcohol measures: average number of drinks/sitting and maximum number of drinks/sitting, with five studies contributing to each analysis. Study-specific odds ratios (ORs) were estimated using logistic regression and pooled to generate adjusted summary ORs. Across studies, 0.9–3.2 % of control mothers reported drinking an average of 5+ drinks/sitting, while 1.4–23.5 % reported drinking a maximum of 5+ drinks/sitting. Compared with non-drinkers, mothers who drank an average of 5+ drinks/sitting were more likely to deliver an infant with cleft lip only (pooled OR 1.48; 95 % confidence intervals 1.01, 2.18). The estimate was higher among women who drank at this level 3+ times (pooled OR 1.95; 1.23, 3.11). Ever drinking a maximum of 5+ drinks/sitting and non-binge drinking were not associated with cleft risk. Repeated heavy maternal alcohol consumption was associated with an increased risk of cleft lip only in offspring. There was little evidence of increased risk for other cleft types or alcohol measures.

Lack of association of polymorphic variants of genes encoding zinc transporters with the risk of orofacial cleft-affected pregnancies.

Maternal zinc deficiency seems to be a risk factor for orofacial clefts in offspring. This study was undertaken to investigate the involvement of polymorphic variants of genes for zinc transporters in the susceptibility of clefting. PCRRFLP analysis was used to analyze single nucleotide polymorphisms of SLC30A1 (rs7526700, rs2278651, rs611386), SLC30A4 (rs2453531, rs8029246), SLC30A5 (rs351444, rs164393, rs6886492), SLC39A1 (rs10127484, rs11264736), and SLC39A3 (rs759071, rs4806874, rs10415622) in mothers of children with non-syndromic cleft lip with or without cleft palate (CL/P) and control mothers. The allele, genotype, and haplotype distribution was found to be similar among case and control mothers. Also, the gene-by-gene interaction analysis conducted using the Multifactor Dimensionality Reduction approach revealed no significant interactive genetic effect on having a child with a cleft. In conclusion, our results demonstrated that the analyzed polymorphic variants of genes for zinc transporters are not implicated in abnormal palatogenesis in the investigated group of women from the Polish population.

Parental exposures and risk of nonsyndromic orofacial clefts in offspring: A case-control study in Greece

Objective To investigate the association between cleft lip and/or palate and nongenetic factors in Greece. Methods We designed a case-control study including 35 patients with nonsyndromic cleft lip and/or palate, retrospectively selected, and 35 control patients matched for prefecture of residence, prospectively selected from pediatric population hospitalized for abdominal pain or injury. Parents were interviewed about drug uptake, diseases, habits, non-occupational exposure to pollutants, and occupation. Questions covered the period from one year before until three months after conception. Results High-risk paternal occupations (mostly farmers) were significantly more frequent in cleft lip and/or palate than in controls ( p = 0.039) and increased significantly the cleft lip and/or palate risk in offspring (OR: 3.00; 95% CI: 1.03–8.70). Maternal occupation did not correlate with cleft lip and/or palate. Parental disease, drugs uptake, hazardous habits, maternal folate supplementation and non-occupational exposure to pollutants did not correlate with cleft lip and/or palate. There was a suggestion of increased risk with maternal passive exposure to tobacco (OR: 1.81; 95% CI: 0.69–4.74) and with residential proximity to industries (OR: 1.70; 95% CI: 0.61–4.74). Conclusions Paternal high-risk occupations probably exert a teratogenic effect on spermatogenesis or result in maternal contamination, and deserve specific preventive policies. The relation of smoking and residential proximity to industries with occurrence of cleft lip and/or palate deserves further study.

Relation between the concentration of zinc in maternal whole blood and the risk of an infant being born with an orofacial cleft

We investigated the relation between concentrations of maternal zinc and copper and the risk of an infant being born with an orofacial cleft. We did a case–control study using 116 mothers of children with isolated cleft lip with or without cleft palate (cleft group), and 64 mothers of unaffected children (control group). Mothers with a whole blood zinc concentration of 47.1 μmol/L or less had a risk 2.5 times higher of having a child with an orofacial cleft than those with a higher concentration (or level) (95% CI 1.03–6.23; p < 0.05). A low zinc concentration combined with a high copper concentration was seen only in the cleft group. This evidence suggests an association between concentrations of maternal zinc and the risk of orofacial clefts in offspring.

Parent's Occupation and Isolated Orofacial Clefts in Norway: A Population-based Case-control Study

Occupational factors have been associated with risk of orofacial clefts in offspring, although data are limited. We explored associations between parent's occupation and isolated orofacial clefts using a population-based case-control study. Cases were restricted to infants born with an isolated orofacial cleft in Norway during the period 1996 to 2001 (314 with cleft lip with or without palate [CLP] and 118 with cleft palate only [CPO]). Controls (n = 763) were chosen randomly from all Norwegian live births. We considered full-time employment during the first 3 months of pregnancy. Several maternal occupations previously associated with clefts showed some evidence of association, including hairdressers (CLP; adjusted odds ratio = 4.8; 95% confidence interval [CI]: 0.99-23). Mothers working in manufacturing and in food production had increased odds for babies with CPO (3.8; 1.3-11, and 7.1; 1.5-33, respectively). Among fathers' occupations previously associated with clefts, an association was suggested for woodworking both for CLP (1.7; 0.85-3.2) and for CPO (2.0; 0.82-4.7). Fathers working as professional housekeepers showed substantial increased odds of CPO (12; 3.3-46). Taken together with previous studies, these results suggest that exposures in certain occupations may influence the risk of orofacial clefting in offspring. Specific exposures accompanying these occupations warrant exploration.

Congenital malformations and maternal occupation: a registry based case-control study.

OBJECTIVES: To investigate the relations between congenital malformations and maternal occupation during pregnancy with a registry based case-control study. METHODS: Analysis was performed on data derived from the Florence Eurocat...