Prenatal exposure to polycyclic aromatic hydrocarbons and cognition in early childhood.

BACKGROUND: Epidemiological evidence for gestational polycyclic aromatic hydrocarbon (PAH) exposure and adverse child cognitive outcomes is mixed; little is known about critical windows of exposure. OBJECTIVE: We investigated associations between prenatal PAH exposure and child cognition in a large, multi-site study. METHODS: We included mother-child dyads from two pooled prospective pregnancy cohorts (CANDLE and TIDES, N = 1,223) in the ECHO-PATHWAYS Consortium. Seven urinary mono-hydroxylated PAH metabolites were measured in mid-pregnancy in both cohorts as well as early and late pregnancy in TIDES. Child intelligence quotient (IQ) was assessed between ages 4-6. Associations between individual PAH metabolites and IQ were estimated with multivariable linear regression. Interaction terms were used to examine effect modification by child sex and maternal obesity. We explored associations of PAH metabolite mixtures with IQ using weighted quantile sum regression. In TIDES, we averaged PAH metabolites over three periods of pregnancy and by pregnancy period to investigate associations between PAH metabolites and IQ. RESULTS: In the combined sample, PAH metabolites were not associated with IQ after full adjustment, nor did we observe associations with PAH mixtures. Tests of effect modification were null except for the association between 2-hydroxynaphthalene and IQ, which was negative in males (ßmales = -0.67 [95%CI:-1.47,0.13]) and positive in females (ßfemales = 0.31 [95%CI:-0.52,1.13])(pinteraction = 0.04). In analyses across pregnancy (TIDES-only), inverse associations with IQ were observed for 2-hydroxyphenanthrene averaged across pregnancy (ß = -1.28 [95%CI:-2.53,-0.03]) and in early pregnancy (ß = -1.14 [95%CI:-2.00,-0.28]). SIGNIFICANCE: In this multi-cohort analysis, we observed limited evidence of adverse associations of early pregnancy PAHs with child IQ. Analyses in the pooled cohorts were null. However, results also indicated that utilizing more than one exposure measures across pregnancy could improve the ability to detect associations by identifying sensitive windows and improving the reliability of exposure measurement. More research with multiple timepoints of PAH assessment is warranted.

Prenatal exposure to polycyclic aromatic hydrocarbons is not associated with behavior problems in preschool and early school-aged children: A prospective multi-cohort study.

BACKGROUND: Epidemiological study findings are inconsistent regarding associations between prenatal polycyclic aromatic hydrocarbon (PAH) exposures and childhood behavior. This study examined associations of prenatal PAH exposure with behavior at age 4-6 years in a large, diverse, multi-region prospective cohort. Secondary aims included examination of PAH mixtures and effect modification by child sex, breastfeeding, and child neighborhood opportunity. METHODS: The ECHO PATHWAYS Consortium pooled 1118 mother-child dyads from three prospective pregnancy cohorts in six U.S. cities. Seven PAH metabolites were measured in prenatal urine. Child behavior was assessed at age 4-6 using the Total Problems score from the Child Behavior Checklist (CBCL). Neighborhood opportunity was assessed using the socioeconomic and educational scales of the Child Opportunity Index. Multivariable linear regression was used to estimate associations per 2-fold increase in each PAH metabolite, adjusted for demographic, prenatal, and maternal factors and using interaction terms for effect modifiers. Associations with PAH mixtures were estimated using Weighted Quantile Sum Regression (WQSR). RESULTS: The sample was racially and sociodemographically diverse (38% Black, 49% White, 7% Other; household-adjusted income range $2651-$221,102). In fully adjusted models, each 2-fold increase in 2-hydroxynaphthalene was associated with a lower Total Problems score, contrary to hypotheses (b = -0.80, 95% CI = -1.51, -0.08). Associations were notable in boys (b = -1.10, 95% CI = -2.11, -0.08) and among children breastfed 6+ months (b = -1.31, 95% CI = -2.25, -0.37), although there was no statistically significant evidence for interaction by child sex, breastfeeding, or neighborhood child opportunity. Associations were null for other PAH metabolites; there was no evidence of associations with PAH mixtures from WQSR. CONCLUSION: In this large, well-characterized, prospective study of mother-child pairs, prenatal PAH exposure was not associated with child behavior problems. Future studies characterizing the magnitude of prenatal PAH exposure and studies in older childhood are needed.

Maternal exposure to urinary polycyclic aromatic hydrocarbons (PAH) in pregnancy and childhood asthma in a pooled multi-cohort study.

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbons (PAH) may increase risk of pediatric asthma, but existing human studies are limited. OBJECTIVES: We estimated associations between gestational PAHs and pediatric asthma in a diverse US sample and evaluated effect modification by child sex, maternal asthma, and prenatal vitamin D status. METHODS: We pooled two prospective pregnancy cohorts in the ECHO PATHWAYS Consortium, CANDLE and TIDES, for an analytic sample of N = 1296 mother-child dyads. Mono-hydroxylated PAH metabolites (OH-PAHs) were measured in mid-pregnancy urine. Mothers completed the International Study on Allergies and Asthma in Childhood survey at child age 4-6 years. Poisson regression with robust standard errors was used to estimate relative risk of current wheeze, current asthma, ever asthma, and strict asthma associated with each metabolite, adjusted for potential confounders. We used interaction models to assess effect modification. We explored associations between OH-PAH mixtures and outcomes using logistic weighted quantile sum regression augmented by a permutation test to control Type 1 errors. RESULTS: The sociodemographically diverse sample spanned five cities. Mean (SD) child age at assessment was 4.4 (0.4) years. While there was little evidence that either individual OH-PAHs or mixtures were associated with outcomes, we observed effect modification by child sex for most pairs of OH-PAHs and outcomes, with adverse associations specific to females. For example, a 2-fold increase in 2-hydroxy-phenanthrene was associated with current asthma in females but not males (RRfemale = 1.29 [95 % CI: 1.09, 1.52], RRmale = 0.95 [95 % CI: 0.79, 1.13]; pinteraction = 0.004). There was no consistent evidence of modification by vitamin D status or maternal asthma. DISCUSSION: This analysis, the largest cohort study of gestational PAH exposure and childhood asthma to date, suggests adverse associations for females only. These preliminary findings are consistent with hypothesized endocrine disruption properties of PAHs, which may lead to sexually dimorphic effects.

Community participation in youth with craniofacial microsomia.

PURPOSE: To examine differences in community participation and environmental support for youth with and without craniofacial microsomia. METHODS: This study involved secondary analyses of a subset of data (n = 396) from a longitudinal cohort study. Multiple linear and Poisson regression analyses and Wilcoxon Mann-Whitney tests were used to estimate differences in community participation and environmental support between youth with craniofacial microsomia and youth without craniofacial microsomia, stratified based on their history of education and health-related service use. Chi-square analyses were used to explore item-level group differences in change desired across community activities. RESULTS: Statistically significant differences were found in community participation frequency (ES = -0.52; p < 0.001), level of involvement (r = -0.16; p = 0.010), and desire for change in participation when comparing youth with craniofacial microsomia and non-affected peers not receiving services (p < 0.001). There were no statistically significant differences between youth with craniofacial microsomia and non-affected peers receiving services. CONCLUSIONS: Results suggest lower community participation in youth with craniofacial microsomia as compared to non-affected peers not receiving services. This may suggest opportunities for designing and testing interventions to promote community participation among youth with craniofacial microsomia, so as to support their transition to adulthood.Implications for rehabilitationYouth with craniofacial microsomia may have unmet rehabilitation needs related to their community participation.Rehabilitation professionals should pay attention to participation of youth with craniofacial microsomia in activities that place a higher demand on involvement with others.Rehabilitation professionals should appraise participation frequency and involvement of youths with craniofacial microsomia to gain accurate insight into their current community participation.

Prenatal urinary metabolites of polycyclic aromatic hydrocarbons and toddler cognition, language, and behavior.

BACKGROUND: Animal and epidemiological studies suggest that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may negatively impact toddler neurodevelopment. METHODS: We investigated this association in 835 mother-child pairs from CANDLE, a diverse pregnancy cohort in the mid-South region of the U.S. PAH metabolite concentrations were measured in mid-pregnancy maternal urine. Cognitive and Language composite scores at ages 2 and 3 years were derived from the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-3). Behavior Problem and Competence scores at age 2 were derived from the Brief Infant and Toddler Social Emotional Assessment (BITSEA). We used multivariate linear or Poisson regression to estimate associations with continuous scores and relative risks (RR) of neurodevelopment delay or behavior problems per 2-fold increase in PAH, adjusted for maternal health, nutrition, and socioeconomic status. Secondary analyses investigated associations with PAH mixture using Weighted Quantile Sum Regression (WQS) with a permutation test extension. RESULTS: 1- hydroxypyrene was associated with elevated relative risk for Neurodevelopmental Delay at age 2 (RR = 1.20, 95% CI: 1.03,1.39). Contrary to hypotheses, 1-hydroxynaphthalene was associated with lower risk for Behavior Problems at age 2 (RR = 0.90, 95% CI: 0.83,0.98), and combined 1- and 9-hydroxyphenanthrene was associated with 0.52-point higher (95% CI: 0.11,0.93) Cognitive score at age 3. For PAH mixtures, a quintile increase in hydroxy-PAH mixture was associated with lower Language score at age 2 (ßwqs = -1.59; 95% CI: -2.84, -0.34; ppermutation = 0.07) and higher Cognitive score at age 3 (ßwqs = 0.96; 95% CI: 0.11, 1.82; ppermutation = 0.05). All other estimates were consistent with null associations. CONCLUSION: In this large southern U.S. population we observed some support for adverse associations between PAHs and neurodevelopment.

Prediction of school-age IQ, academic achievement, and motor skills in children with positional plagiocephaly.

INTRODUCTION: Children with positional plagiocephaly and/or brachycephaly (PPB) are at risk of early developmental delay, but little is known about early life factors associated with school-age neurodevelopment. This study examined associations of demographic characteristics, prenatal risk factors and early neurodevelopment assessment with school-age IQ, academic performance, and motor development in children with PPB. METHODS: The study sample consisted of 235 school-age children with PPB followed since infancy. Outcome measures included IQ using the Differential Ability Scales-Second Edition, academic achievement as measured by the Wechsler Individualized Achievement Tests-Third Edition), and motor function using the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition. Linear regression was used to examine the incremental improvement of model fit of demographics, prenatal and early life characteristics, severity of PPB, and neurodevelopment at ages 7, 18, and 36 months as measured by the Bayley-3 on school-age scores. RESULTS: Mean age at school-age assessment was 9.0 years. Adjusted r2 for demographic, prenatal, and early life risk factors ranged from 0.10 to 0.22. Addition of PPB severity and Bayley-3 measures at ages 7 and 18 months did not meaningfully change model fit. Adjusted r2 after inclusion of Bayley-3 at 36 months ranged from 0.35 to 0.41. CONCLUSION: This study suggests that PPB severity and very early life neurodevelopment have little association with school-age neurodevelopment above and beyond demographic and early life risk factors. However, preschool-age neurodevelopmental assessment may still be useful in identifying children with PPB at risk for delay and who may benefit from early intervention.

Caregiver Perspectives on School Participation Among Students With Craniofacial Microsomia.

IMPORTANCE: Knowledge of unmet school participation needs for students with craniofacial microsomia (CFM) can inform decisions regarding intervention support. OBJECTIVE: To compare students with and without CFM on school participation (i.e., frequency, involvement, desire for participation to change) and caregivers' perceptions of environmental support for participation in occupations. DESIGN: Cross-sectional design using secondary analyses of a subset of data. SETTING: Multisite cohort study. PARTICIPANTS: Caregivers of students with CFM (n = 120) and of students without CFM (n = 315), stratified by history of education- and health-related service use. OUTCOMES AND MEASURES: School participation and environmental support, obtained with the Participation and Environment Measure-Children and Youth. RESULTS: Significant group differences were found in frequency of school participation (effect size [ES] = -0.38, 95% confidence interval [-0.64, -0.12], p = .005), level of involvement (ES = -0.14, p = .029), and desired change (p = .001), with students with CFM exhibiting greater participation restriction than students without CFM and no history of service use. No statistically significant group differences were found in environmental support for participation in the school setting. Item-level findings showed statistically significant higher desire for participation to change in three of five school occupations (odds ratio = 1.77-2.39, p = .003-.045) for students with CFM compared with students without CFM and no history of service use. CONCLUSIONS AND RELEVANCE: The results suggest that students with CFM experience restriction in participation at school. WHAT THIS ARTICLE ADDS: Students with CFM may benefit from targeted school-based interventions to optimize their inclusion.

Behavioral Adjustment of Preschool Children With and Without Craniofacial Microsomia.

OBJECTIVE: The study aim was to assess behavioral adjustment in preschool children with and without craniofacial microsomia (CFM). DESIGN: Multisite cohort study of preschoolers with CFM ("cases") or without CFM ("controls"). PARTICIPANTS: Mothers (89%), fathers (9%), and other caregivers (2%) of 161 preschoolers. OUTCOME MEASURE: Child Behavior Check List (CBCL 1.5-5); linear regressions with standardized effect sizes (ES) adjusted for sociodemographic confounds. RESULTS: Child Behavior Check Lists for 89 cases and 72 controls (average age 38.3 ± 1.9 months). Children were male (54%), white (69%), and of Latino ethnicity (47%). Cases had microtia with mandibular hypoplasia (52%), microtia only (30%), or other CFM-associated features (18%). Nearly 20% of cases had extracranial anomalies. Composite CBCL scores were in the average range compared to test norms and similar for cases and controls. On the subscales, cases' parents reported higher Anxious/Depressed scores (ES = 0.35, P = .04), Stress Problems (ES = 0.40, P = .04), Anxiety Problems (ES = 0.34, P = .04), and Autism Spectrum Problems (ES = 0.41, P = .02); however, the autism subscale primarily reflected speech concerns. Among cases, more problems were reported for children with extracranial anomalies and certain phenotypic categories with small ES. CONCLUSIONS: Behavioral adjustment of preschoolers with CFM was comparable to peers. However, parental reports reflected greater concern for internalizing behaviors; thus, anxiety screening and interventions may benefit children with CFM. Among cases, more problems were reported for those with more complex presentations of CFM. Craniofacial microsomia-related speech problems should be distinguished from associated psychosocial symptoms during developmental evaluations.

Cognitive, Motor, and Language Development of Preschool Children With Craniofacial Microsomia.

OBJECTIVE: To examine neurodevelopment in preschool-aged children with craniofacial microsomia (CFM) relative to unaffected peers. DESIGN: Multisite, longitudinal cohort study. SETTING: Tertiary care centers in the United States. PARTICIPANTS: We included 92 children with CFM ("cases") through craniofacial centers and clinics. Seventy-six children without CFM (controls) were included from pediatric practices and community advertisements. This study reports on outcomes assessed when participants were an average age of 38.4 months (SD = 1.9). MAIN OUTCOME MEASURES: We assessed cognitive and motor skills using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), and language function using subtests from the Clinical Evaluation of Language Fundamentals-Preschool, second edition (CELF-P2). RESULTS: Case-control differences were negligible for Bayley-III cognitive (effect sizes [ES] = -0.06, P = .72) and motor outcomes (ES = -0.19, P = .25). Cases scored lower than controls on most scales of the CELF-P2 (ES = -0.58 to -0.20, P = .01 to .26). Frequency counts for "developmental delay" (ie, one or more scores > 1 SD below the normative mean) were higher for cases (39%) than controls (15%); however, the adjusted odds ratio = 1.73 (P = 0.21) was not significant. Case-control differences were most evident in children with microtia or other combinations of CFM-related facial features. CONCLUSIONS: Cognitive and motor scores were similar for preschool-aged children with and without CFM. However, children with CFM scored lower than controls on language measures. We recommend early monitoring of language to identify preschoolers with CFM who could benefit from intervention.

Do Infant Motor Skills Mediate the Association Between Positional Plagiocephaly/Brachycephaly and Cognition in School-Aged Children?

OBJECTIVE: Positional plagiocephaly/brachycephaly (PPB) is associated with lower cognitive scores in school-aged children. This study tested the hypothesis that infant motor skills mediate this association. METHODS: Children with a history of PPB (cases, n = 187) and without PPB (controls, n = 149) were followed from infancy through approximately 9 years of age. Infant motor skills were assessed using the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-3), and cognition was assessed using the Differential Ability Scales, 2nd edition (DAS-2). The Bayley-3 motor composite was examined as a mediator of the association between PPB and DAS-2 general cognitive ability (GCA) scores. In secondary analyses, mediation models were examined for the DAS-2 verbal ability, nonverbal ability, and working memory scores; models using the Bayley-3 fine versus gross motor scores also were examined. RESULTS: Cases scored lower than controls on the DAS-GCA (ß = -4.6; 95% CI = -7.2 to -2.0), with an indirect (mediated) effect of ß = -1.5 (95% CI = -2.6 to -0.4) and direct effect of ß = -3.1 (95% CI = -5.7 to -0.5). Infant motor skills accounted for approximately 33% of the case-control difference in DAS-2 GCA scores. Results were similar for other DAS-2 outcomes. Evidence of mediation was greater for Bayley-3 gross motor versus fine motor scores. CONCLUSION: Infant motor skills partially mediate the association between PPB and cognition in school-aged children. Monitoring motor development and providing intervention as needed may help offset associated developmental concerns for children with PPB. IMPACT: To our knowledge, this study is the first longitudinal investigation of the development of children with and without PPB from infancy through the early school years and the first to examine motor skills as a mediator of cognitive outcomes in this population. The findings highlight the importance of early motor skills for other developmental outcomes. LAY SUMMARY: Infants' motor skills are related to the development of PPB and its association with later cognition. If your child has PPB, physical therapists may have an important role in assessing and providing treatment to promote motor development.

Motor Function in School-Aged Children With Positional Plagiocephaly or Brachycephaly.

OBJECTIVE: To determine whether children with a history of positional plagiocephaly/brachycephaly (PPB) show persistent deficits in motor development. METHODS: In a longitudinal cohort study, we completed follow-up assessments with 187 school-aged children with PPB and 149 participants without PPB who were originally enrolled in infancy. Primary outcomes were the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition (BOT-2) composite scores. RESULTS: Children with PPB scored lower than controls on the BOT-2. Stratified analyses indicated that differences were restricted to children who had moderate-severe PPB. No consistent differences were observed in children who had mild PPB. CONCLUSION: Children who had moderate-severe PPB in infancy show persistent differences in motor function. We suggest close developmental monitoring and early intervention to address motor deficits.

Surgical Approach and Periprocedural Outcomes by Race and Ethnicity of Children Undergoing Craniosynostosis Surgery.

BACKGROUND: Surgical repair for craniosynostosis varies depending on the infant's age, location of suture fusion, and approach (e.g., open versus endoscopic). Existing data suggest possible racial and ethnic disparities in timely access to surgical care for craniosynostosis that may, in turn, be associated with surgical approach and perioperative outcomes. This study examined racial and ethnic variation in craniosynostosis operations by surgical approach and perioperative outcomes. METHODS: Data were collected by the 2013 to 2015 Pediatric National Surgical Quality Improvement Program. Patients aged younger than 24 months with diagnoses and procedure codes consistent with surgery for craniosynostosis were identified. Periprocedural characteristics and surgical approach (open, endoscopic/minimally invasive, or both) were examined descriptively, overall, and separately by race and ethnicity. RESULTS: The authors identified 1982 admissions. Mean age at surgery was 7.8 ± 4.7 months. Ninety-one percent of procedures were classified as open operations, 5.8 percent were endoscopic, and 3.4 percent were both open and endoscopic. Relative to white/non-Hispanic patients, Hispanic and nonwhite patients underwent surgery at older ages, experienced longer operative and anesthesia times, and were hospitalized longer. Hispanic patients had the highest rates of open operations. CONCLUSIONS: These data suggest that Hispanic and nonwhite patients tend to undergo craniosynostosis repair at older ages and to have lengthier operations than white/non-Hispanic patients. Although we were unable to examine the root cause(s) of these differences, delayed diagnosis is one factor that might result in surgery at an older age and more complex operations requiring open surgery. Prospective studies examining racial/ethnic disparities are needed to inform a comparison of outcomes associated with surgical approach.

Speech, Language, and Communication Skills of Adolescents With Craniofacial Microsomia.

Purpose Youth with craniofacial microsomia (CFM) have anomalies and comorbidities that increase their risk for speech, language, and communication deficits. We examined these outcomes in youth with and without CFM and explored differences as a function of CFM phenotype and hearing status. Method Participants included youth ages 11-17 years with CFM (n = 107) and demographically similar controls (n = 306). We assessed speech intelligibility, articulation, receptive and expressive language, and parent and teacher report measures of communication. Hearing status was also screened at the study visit. Group differences were estimated using linear regression analyses with standardized effect sizes (ES) adjusted for demographic characteristics (adjusted ES) or negative binomial regression. Results Youth with CFM scored lower than unaffected peers on most measures of intelligibility, articulation, expressive language, and parent- and-teacher-rated communication. Differences were most pronounced among participants with CFM who had mandibular hypoplasia plus microtia (adjusted ES = -1.15 to -0.18). Group differences were larger in youth with CFM who failed the hearing screen (adjusted ES = -0.73 to 0.07) than in those who passed the hearing screen (adjusted ES = -0.34 to 0.27). Conclusions Youth with CFM, particularly those with mandibular hypoplasia plus microtia and/or hearing loss, should be closely monitored for speech and language concerns. Further research is needed to identify the specific needs of youth with CFM as well as to document the course of speech and language development in children with CFM.

Dynamics of Face and Head Movement in Infants with and without Craniofacial Microsomia: An Automatic Approach.

BACKGROUND: Craniofacial microsomia (CFM) is a congenital condition associated with malformations of the bone and soft tissue of the face and the facial nerves, all of which have the potential to impair facial expressiveness. We investigated whether CFM-related variation in expressiveness is evident as early as infancy. METHODS: Participants were 113 ethnically diverse 13-month-old infants (n = 63 cases with CFM and n = 50 unaffected matched controls). They were observed in 2 emotion induction tasks designed to elicit positive and negative effects. Facial and head movement was automatically measured using a computer vision-based approach. Expressiveness was quantified as the displacement, velocity, and acceleration of 49 facial landmarks (eg, lip corners) and head pitch and yaw. RESULTS: For both cases and controls, all measures of expressiveness strongly differed between tasks. Case-control differences were limited to infants with microtia plus mandibular hypoplasia and other associated CFM features, which were the most common phenotypes and were characterized by decreased expressiveness relative to control infants. CONCLUSIONS: Infants with microtia plus mandibular hypoplasia and those with other associated CFM phenotypes were less facially expressive than same-aged peers. Both phenotypes were associated with more severe involvement than microtia alone, suggesting that infants with more severe CFM begin to diverge in expressiveness from controls by age 13 months. Further research is needed to both replicate the current findings and elucidate their developmental implications.

Cognitive Outcomes and Positional Plagiocephaly.

: media-1vid110.1542/5972296741001PEDS-VA_2018-2373Video Abstract BACKGROUND: Studies have revealed an association between positional plagiocephaly and/or brachycephaly (PPB) and development, although little is known about long-term outcomes. We examined cognition and academic achievement in children with and without PPB, testing the hypothesis that children who had PPB as infants would score lower than controls. METHODS: We enrolled 187 school-aged children with a history of PPB and 149 controls. Exposures were the presence or absence and severity of infancy PPB (mild, moderate to severe). Cognitive and academic outcomes were assessed by using the Differential Ability Scales, Second Edition and Wechsler Individual Achievement Test, Third Edition, respectively. RESULTS: Children with PPB scored lower than controls on most scales of the Differential Ability Scales, Second Edition (standardized effect sizes [ESs] = -0.38 to -0.20) and the Wechsler Individual Achievement Test, Third Edition (ESs = -0.22 to -0.17). Analyses by PPB severity revealed meaningful differences among children with moderate to severe PPB (ESs = -0.47 to -0.23 for 8 of 9 outcomes), but few differences in children with mild PPB (ESs = -0.28 to 0.14). CONCLUSIONS: School-aged children with moderate to severe PPB scored lower than controls on cognitive and academic measures; associations were negligible among children with mild PPB. The findings do not necessarily imply that these associations are causal; rather, PPB may serve as a marker of developmental risk. Our findings suggest a role for assessing PPB severity in clinical practice: providing developmental assessment and intervention for infants with more severe deformation and reassurance and anticipatory guidance for patients with mild deformation.

Methods and Challenges in a Cohort Study of Infants and Toddlers With Craniofacial Microsomia: The Clock Study.

OBJECTIVE: The Craniofacial microsomia: Longitudinal Outcomes in Children pre-Kindergarten (CLOCK) study is a longitudinal cohort study of neurobehavioral outcomes in infants and toddlers with craniofacial microsomia (CFM). In this article, we review the data collection and methods used to characterize this complex condition and describe the demographic and clinical characteristics of the cohort. SETTING: Craniofacial and otolaryngology clinics at 5 study sites. PARTICIPANTS: Infants with CFM and unaffected infants (controls) ages 12 to 24 months were recruited from the same geographical regions and followed to age 36 to 48 months. METHODS: Phenotypic, neurodevelopmental, and facial expression assessments were completed during the first and third waves of data collection (time 1 and time 3, respectively). Medical history data were taken at both of these time points and during an intermediate parent phone interview (time 2). RESULTS: Our cohort includes 108 cases and 84 controls. Most cases and controls identified as white and 55% of cases and 37% of controls identified as Hispanic. Nearly all cases had microtia (95%) and 59% had mandibular hypoplasia. Cases received extensive clinical care in infancy, with 59% receiving care in a craniofacial clinic and 28% experiencing at least one surgery. Study visits were completed at a study site (92%) or at the participant's home (8%). CONCLUSIONS: The CLOCK study represents an effort to overcome the challenges of characterizing the phenotypic and neurodevelopmental outcomes of CFM in a large, demographically and geographically diverse cohort.

Infant/toddler motor skills as predictors of cognition and language in children with and without positional skull deformation.

PURPOSE: To estimate associations between early motor abilities (at two age points, 7 and 18 months on average) and cognitive/language outcomes at age 3. To determine whether these associations are similar for children with and without positional plagiocephaly and/or brachycephaly (PPB). METHODS: The Bayley Scales of Infant/Toddler Development 3 were given at all age points to 235 children with PPB and 167 without PPB. Linear regressions assessed longitudinal associations between fine and gross motor scales and cognition/language. Item analyses examined the contributions of specific motor skills. RESULTS: Associations between 7-month motor skills and cognition/language were modest overall (effect sizes [ES] = - 0.08 to 0.10, p = .13 to .95). At 18 months, both fine and gross motor skills were associated with outcomes for children with PPB (ES = 0.21 to 0.41, p < .001 to .01), but among those without PPB, only fine motor skills were associated with outcomes (ES = 0.21 to 0.27, p < .001 to .001). CONCLUSIONS: Toddlers' motor skills were associated with cognition and language at 3 years, particularly among children with PPB. Interventions targeting early motor development in infants and toddlers with PPB may have downstream benefits for other outcomes.

Neurodevelopment of Infants with and without Craniofacial Microsomia.

OBJECTIVES: To determine whether infant cases with craniofacial microsomia (CFM) evidence poorer neurodevelopmental status than demographically similar infants without craniofacial diagnoses ("controls"), and to examine cases' neurodevelopmental outcomes by facial phenotype and hearing status. STUDY DESIGN: Multicenter, observational study of 108 cases and 84 controls aged 12-24 months. Participants were assessed by the Bayley Scales of Infant and Toddler Development-Third Edition and the Preschool Language Scales-Fifth Edition (PLS-5). Facial features were classified with the Phenotypic Assessment Tool for Craniofacial Microsomia. RESULTS: After adjustment for demographic variables, there was little difference in Bayley Scales of Infant and Toddler Development-Third Edition or Preschool Language Scales-Fifth Edition outcomes between cases and controls. Estimates of mean differences ranged from -0.23 to 1.79 corresponding to standardized effect sizes of -.02 to 0.12 (P values from .30 to .88). Outcomes were better among females and those with higher socioeconomic status. Among cases, facial phenotype and hearing status showed little to no association with outcomes. Analysis of individual test scores indicated that 21% of cases and 16% of controls were developmentally delayed (OR 0.68, 95% CI 0.29-1.61). CONCLUSIONS: Although learning problems have been observed in older children with CFM, we found no evidence of developmental or language delay among infants. Variation in outcomes across prior studies may reflect differences in ascertainment methods and CFM diagnostic criteria.

Hospital and clinical care costs associated with atrial fibrillation for Medicare beneficiaries in the Cardiovascular Health Study and the Framingham Heart Study.

BACKGROUND: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs. METHODS AND RESULTS: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation. The total clinical and hospital medical costs paid by Medicare Parts A and B (drug costs from Medicare Part D costs were not included) in the year prior to diagnosis (or matching) were compared with costs in the following year. Estimates were adjusted for other medical conditions and adjusted to 2009 dollars. In the Cardiovascular Health Study, 513 participants were diagnosed with new-onset atrial fibrillation and survived 30 days post-atrial fibrillation diagnosis, and 513 referents (as a control cohort) were identified, with a mean age of 77 years. In the Framingham Heart Study, we identified 336 participants diagnosed with atrial fibrillation, who survived 30 days post-atrial fibrillation diagnosis and matched these participants to 336 referents. We compared these new-onset atrial fibrillation participants with referents, using a difference in difference design to account for both time trends and differences between the two groups. The adjusted incremental cost for participants with atrial fibrillation, compared with referents, was US$18,060 (95% confidence interval: US$14,965-US$21,155) in the Cardiovascular Health Study and US$20,012 (95% confidence interval: US$15,057-US$24,966) in the Framingham Heart Study. The pooled estimate was US$18,601 (95% confidence interval: US$15,981-US$21,234). CONCLUSION: Atrial fibrillation was associated with increased costs in the year after diagnosis in two community-based cohorts, even after careful accounting for age, time period, and systematically measured comorbidities.

Head shape at age 36 months among children with and without a history of positional skull deformation.

OBJECTIVE In this study, the authors examined head shape through age 36 months for children with and without a history of positional plagiocephaly and/or brachycephaly (PPB). METHODS Infants with PPB (cases) were identified through a craniofacial clinic at the time of diagnosis. Infants without diagnosed PPB were identified through a participant registry. Clinician ratings of 3D cranial images were used to confirm the presence or absence of PPB. The cohort included 235 case infants (diagnosed PPB, confirmed with 3D imaging), 167 unaffected controls (no diagnosed PPB, no deformation detected), and 70 affected controls (no diagnosed PPB, discernible skull deformation). Participants were seen in infancy (age 7 months, on average) and again at ages 18 and 36 months. At each visit, automated 3D measures of skull deformation quantified posterior flattening and generated an absolute asymmetry score. The authors also used automated 2D measures to approximate overall asymmetry (approximate oblique cranial length ratio) and calculate the cephalic index. They used linear regression to compare cases to unaffected controls and to compare affected versus unaffected controls on all measures. They also calculated the proportion of children in each group with "persistent PPB," defined as one or more head shape measures above the 95th percentile relative to unaffected controls at 36 months. RESULTS Head shape became more rounded and symmetric for children with and without PPB, particularly between infancy and age 18 months. However, children with PPB continued to show greater skull deformation and asymmetry than unaffected controls at age 36 months. These differences were large in magnitude, ranging from 1 to 2 standard deviations (SDs), and in most (85.6%) of the cases, there was evidence of persistent PPB at 36 months. Similarly, although differences were more modest (i.e., 0.26-0.94 SD), affected controls continued to exhibit skull deformation on most measures relative to unaffected controls and approximately 30% had persistent PPB. Within the case group, head shape at 36 months was similar for untreated patients with PPB and for those who received helmet treatment and for patients with and without a history of torticollis. CONCLUSIONS Although head shape continues to improve, children with a history of skull deformation in infancy continue to exhibit measureable cranial flattening and asymmetry through age 36 months.