George L. Wehby

The impact of orofacial clefts on quality of life and healthcare use and costs

Orofacial clefts are common birth defects that may impose a large burden on the health, quality of life, and socioeconomic well-being of affected individuals and families. They also result in significant healthcare use and costs. Understanding the impact of orofacial clefts on these outcomes is important for identifying unmet needs and developing public policies to reduce the burden of orofacial clefts at the individual, family and societal levels. This paper reviews and summarizes the main findings of recent studies that have evaluated the impact of orofacial clefts on these outcomes, with a focus on quality of life, socioeconomic outcomes, long-term health, and healthcare use and costs. Several studies identify an increased burden of orofacial clefts on these outcomes, but some of the findings are inconsistent. A summary of the primary limitations of the studies in this area is presented, along with recommendations and directions for future research.

Folic acid and orofacial clefts: a review of the evidence

Orofacial clefts are common and burdensome birth defects with a complex genetic and environmental etiology. The contribution of nutritional factors and supplements to the etiology of orofacial clefts has long been theorized and studied. Multiple studies have evaluated the role of folic acid in the occurrence and recurrence of orofacial clefts, using observational and non-randomized interventional designs. While preventive effects of folic acid on orofacial clefts are commonly reported, the evidence remains generally inconsistent. This paper reviews the findings of the main studies of the effects of folic acid on orofacial clefts, summarizes study limitations, and discusses research needs with a focus on studying the effects of high dosage folic acid on the recurrence of oral clefts using a randomized clinical trial design. The role of folic acid in the prevention of neural tube defects is also briefly summarized and discussed as a reference model for orofacial clefts.

Review on Genetic Variants and Maternal Smoking in the Etiology of Oral Clefts and Other Birth Defects

A spectrum of adverse pregnancy outcomes, including preterm birth, low birth weight, and birth defects has been linked with maternal smoking during pregnancy. This article includes a review of studies investigating interactions between genetic variants and maternal smoking in contributing to birth defects using oral clefting as a model birth defect. The primary gene-smoking studies for other major birth defects are also summarized. Gene-environment interaction studies for birth defects are still at an early stage with several mixed results, but evolving research findings have begun to document clinically and developmentally important interactions. As samples and data become increasingly available, more effort is needed in designing innovative analytical methods to study gene-environment interactions.

Prenatal care effectiveness and utilization in Brazil

The impact of prenatal care use on birth outcomes has been understudied in South American countries. This study assessed the effects of various measures of prenatal care use on birth weight (BW) and gestational age outcomes using samples of infants born without and with common birth defects from Brazil, and evaluated the demand for prenatal care. Prenatal visits improved BW in the group without birth defects through increasing both fetal growth rate and gestational age, but prenatal care visits had an insignificant effect on BW in the group with birth defects when adjusting for gestational age. Prenatal care delay had no effects on BW in both infant groups but increased preterm birth risk in the group without birth defects. Inadequate care versus intermediate care also increased LBW risk in the group without birth effects. Quantile regression analyses revealed that prenatal care visits had larger effects at low compared with high BW quantiles. Several other prenatal factors and covariates such as multivitamin use and number of previous live births had significant effects on the studied outcomes. The number of prenatal care visits was significantly affected by several maternal health and fertility indicators. Significant geographic differences in utilization were observed as well. The study suggests that more frequent use of prenatal care can increase BW significantly in Brazil, especially among pregnancies that are uncomplicated with birth defects but that are at high risk for low birth weight. Further research is needed to understand the effects of prenatal care use for pregnancies that are complicated with birth defects.

Identification of Functional Variants for Cleft Lip with or without Cleft Palate in or near PAX7, FGFR2, and NOG by Targeted Sequencing of GWAS Loci

Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans.

Academic Achievement of Children and Adolescents With Oral Clefts

BACKGROUND AND OBJECTIVE: Previous studies of academic achievement of children with oral clefts have mostly relied on small, clinic-based samples prone to ascertainment bias. In the first study in the United States to use a population-based sample with direct assessment, we evaluated the academic achievement of children with oral clefts relative to their classmates. METHODS: Children born with isolated oral clefts in Iowa from 1983 to 2003 were identified from the Iowa Registry for Congenital and Inherited Disorders and matched to unaffected classmates by gender, school/school district, and month and year of birth. Academic achievement was assessed by using standardized tests of academic progress developed by the Iowa Testing Programs. Iowa Testing Programs data were linked to birth certificates for all children. Regression models controlled for household demographic and socioeconomic factors. The analytical sample included 588 children with clefts contributing 3735 child-grade observations and 1874 classmates contributing 13 159 child-grade observations. RESULTS: Children with oral clefts had lower scores than their classmates across all domains and school levels, with a 5-percentile difference in the overall composite score. Children with clefts were approximately one-half grade level behind their classmates and had higher rates of academic underachievement and use of special education services by 8 percentage points. Group differences were slightly lower but remained large and significant after adjusting for many background characteristics. CONCLUSIONS: Children with oral clefts underperformed across all academic areas and grade levels compared with their classmates. The results support a model of early testing and intervention among affected children to identify and reduce academic deficits.

Explaining Racial/Ethnic Disparities in Children’s Dental Health: A Decomposition Analysis

OBJECTIVES We measured racial/ethnic inequalities in US childrens dental health and quantified the contribution of conceptually relevant factors. METHODS Using data from the 2007 National Survey of Childrens Health, we investigated racial/ethnic disparities in selected child dental health and preventive care outcomes. We employed a decomposition model to quantify demographic, socioeconomic, maternal health, health insurance, neighborhood, and geographic effects. RESULTS Hispanic children had the poorest dental health and lowest preventive dental care utilization, followed by Black then White children. The model explanatory variables accounted for 58% to 77% of the disparities in dental health and 89% to 100% of the disparities in preventive dental care. Socioeconomic status accounted for 71% of the gap in preventive dental care between Black children and White children and 55% of that between Hispanic children and White children. Maternal health, age, and marital status; neighborhood safety and social capital; and state of residence were relevant factors. CONCLUSIONS Reducing US childrens racial/ethnic dental health disparities-which are mostly socioeconomically driven-requires policies that recognize the multilevel pathways underlying them and the need for household- and neighborhood-level interventions.

Associated Anomalies Among Infants With Oral Clefts at Birth and During a 1-year Follow-Up

Reports of birth defects rates may focus on defects observed in the newborn period or include defects diagnosed at older ages. However, little information is available on the rates of additional anomalies detected after birth or on the ages at which such anomalies are diagnosed. The aims of this work were to describe the initial diagnoses of oral clefts, isolated or associated with other defects, in newborn infants ascertained in hospitals of the ECLAMC network, and diagnostic changes that occurred due to detection of additional defects during a 1‐year follow‐up period. Seven hundred ten liveborn infants with cleft lip only (CLO), cleft lip with cleft palate (CLP), or cleft palate (CP) were ascertained between 2003 and 2005. Prevalence estimates of isolated and associated (ASO) clefts, diagnoses in infants with associated clefts, and the percentage of isolated clefts that were reclassified as associated were established. Birth prevalence estimates (per 1,000) were as follows: Total: 1.7; CLP: 0.94 (ASO = 23.5%); CP: 0.46 (ASO = 42.3%); CLO: 0.28 (ASO = 7.6%). Initial diagnoses in infants with associated clefts included 38 infants with chromosomal abnormalities, 33 with non‐chromosomal syndromes, 16 with malformation sequences, and 98 with multiple anomalies of unknown etiology. Seven percent of newborns initially classified as isolated were later reclassified as associated. Ten infants without associated defects or clinically suspected syndromes were diagnosed as syndromic only through laboratory findings or family history, illustrating the difference between the terms associated versus isolated, which refers to presence or absence of associated anomalies, and syndromic versus non‐syndromic, which refers to etiology.

The impact of altitude on infant health in South America.

Several studies report that altitude reduces birth weight. However, much remains unknown about effects in various altitude ranges and about the heterogeneity in altitude effects by fetal health endowments. This study estimates the effects of altitude in South America on the means and quantiles of birth weight and gestational age separately for two large samples born at altitude ranges of 5 to 1,280 m and 1,854 to 3,600 m. The study finds significant negative altitude effects on birth weight and gestational age in the low-altitude sample and on birth weight in the high-altitude sample. Altitude effects are larger for infants with very low fetal health endowments. The study finds differences in the effects of several inputs such as socioeconomic status and maternal fertility history and health between the two altitude samples. The study highlights the importance of adverse altitude effects on infant health when evaluating the costs and returns of policies that change the number of individuals who reside at higher altitude in both low and high altitude ranges.

Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.