Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, d,l-leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD. Folate is a water-soluble B vitamin that is essential for normal neurodevelopment and abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid. Most significantly, case-series, open-label, and single and double-blind placebo-controlled studies suggest that d,l-leucovorin, a reduced folate that can bypass the blockage at the folate receptor alpha by using the reduced folate carrier, an alternate pathway, can substantially improve particular symptoms in children with ASD, especially those positive for folate receptor alpha autoantibodies. This article reviews the current evidence for treating core and associated symptoms and underlying pathophysiological mechanisms in children with ASD with d,l-leucovorin.

Reading Aloud, Play, and Social-Emotional Development.

OBJECTIVES: To determine impacts on social-emotional development at school entry of a pediatric primary care intervention (Video Interaction Project [VIP]) promoting positive parenting through reading aloud and play, delivered in 2 phases: infant through toddler (VIP birth to 3 years [VIP 0-3]) and preschool-age (VIP 3 to 5 years [VIP 3-5]). METHODS: Factorial randomized controlled trial with postpartum enrollment and random assignment to VIP 0-3, control 0 to 3 years, and a third group without school entry follow-up (Building Blocks) and 3-year second random assignment of VIP 0-3 and control 0 to 3 years to VIP 3-5 or control 3 to 5 years. In the VIP, a bilingual facilitator video recorded the parent and child reading and/or playing using provided learning materials and reviewed videos to reinforce positive interactions. Social-emotional development at 4.5 years was assessed by parent-report Behavior Assessment System for Children, Second Edition (Social Skills, Attention Problems, Hyperactivity, Aggression, Externalizing Problems). RESULTS: VIP 0-3 and VIP 3-5 were independently associated with improved 4.5-year Behavior Assessment System for Children, Second Edition T-scores, with effect sizes (Cohen's d) ∼-0.25 to -0.30. Receipt of combined VIP 0-3 and VIP 3-5 was associated with d = -0.63 reduction in Hyperactivity (P = .001). VIP 0-3 resulted in reduced "Clinically Significant" Hyperactivity (relative risk reduction for overall sample: 69.2%; P = .03; relative risk reduction for increased psychosocial risk: 100%; P = .006). Multilevel models revealed significant VIP 0-3 linear effects and age × VIP 3-5 interactions. CONCLUSIONS: Phase VIP 0-3 resulted in sustained impacts on behavior problems 1.5 years after program completion. VIP 3-5 had additional, independent impacts. With our findings, we support the use of pediatric primary care to promote reading aloud and play from birth to 5 years, and the potential for such programs to enhance social-emotional development.

Enhancing Parent Talk, Reading, and Play in Primary Care: Sustained Impacts of the Video Interaction Project.

OBJECTIVE: To determine the early impacts of pediatric primary care parenting interventions on parent cognitive stimulation in low socioeconomic status families and whether these impacts are sustained up to 1.5 years after program completion. STUDY DESIGN: This randomized controlled trial included assignment to 1 of 2 interventions (Video Interaction Project [VIP] or Building Blocks) or to a control group. Mother-newborn dyads were enrolled postpartum in an urban public hospital. In VIP, dyads met with an interventionist on days of well-child visits; the interventionist facilitated interactions in play and shared reading through provision of learning materials and review of videotaped parent-child interactions. In Building Blocks, parents were mailed parenting pamphlets and learning materials. We compare the trajectories of cognitive stimulation for parents in VIP and control from 6 to 54 months. RESULTS: There were 546 families that contributed data. VIP was associated with enhanced reading, parent verbal responsivity, and overall stimulation at all assessment points, with analyses demonstrating a 0.38 standard deviation increase in cognitive stimulation overall. Trajectory models indicated long-term persistence of VIP impacts on reading, teaching, and verbal responsivity. CONCLUSIONS: VIP is associated with sustained enhancements in cognitive stimulation in the home 1.5 years after completion of the program and support expansion of pediatric interventions to enhance developmental trajectories of children of low socioeconomic status. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00212576.

Developmental delay in young children with sleep-disordered breathing before and after tonsil and adenoid surgery.

OBJECTIVE: Our objective was to determine the developmental status of young children with sleep-disordered breathing (SDB) as measured by the Ages and Stages Questionnaire (ASQ-3) and to evaluate improvement after treatment. METHODS: The ASQ-3 was completed at entry, 3 months and 6 months after adenotonsillectomy or adenoidectomy. The questionnaire consists of 30 items that assess five domains: communication, gross motor, fine motor, problem solving and personal-social. Domain scores were compared with normative values: abnormal ≥2 SDs and borderline ≥1 but <2 SDs below the mean. RESULTS: 80 children, mean (SD) age 3.0 (0.94) years, 62.5% male, 77.5% African American, were enrolled. Median (range) apnea-hypopnea index (AHI) was 12.6 (1.4-178.5). At entry, 22 (27.5%) children scored in the abnormal range in at least one developmental area and an additional 23 (28.8%) had at least one borderline score. A generalized linear model including gender, AHI, maternal education and prematurity showed that only prematurity was an independent predictor of at least one abnormal or borderline entry score (likelihood ratio test p < 0.001). Adjusting for covariates and excluding children with a history of prematurity, the prevalence of at least one abnormal or borderline score (based on 112 observations of 70 children) was estimated at 49% (95% CI [37, 62]) at baseline; 34% (95% CI [17, 56]) at 3 months; and 22% (95% CI [10, 41]) at 6 months. Post-hoc pairwise comparison of time points showed the baseline versus 6-month difference to be statistically significant (p = 0.015). CONCLUSIONS: The 27.5% baseline prevalence of abnormal ASQ scores in children with SDB indicates it is a risk factor for developmental delay. Significant improvements in score classifications were found 6 months after surgery.

Promotion of Positive Parenting and Prevention of Socioemotional Disparities.

OBJECTIVE: The goal of this study was to determine what effects pediatric primary care interventions, focused on promotion of positive parenting through reading aloud and play, have on the socioemotional development of toddlers from low-income, primarily immigrant households. METHODS: This randomized controlled trial included random assignment to 1 of 2 interventions (Video Interaction Project [VIP] or Building Blocks [BB]) or to a control group. Mother-newborn dyads were enrolled postpartum in an urban public hospital. In VIP, dyads met with an interventionist on days of well-child visits; the interventionist facilitated interactions in play and shared reading through provision of learning materials and review of videotaped parent-child interactions. In BB, parents were mailed parenting pamphlets and learning materials. This article analyzes socioemotional outcomes from 14 to 36 months for children in VIP and BB versus control. RESULTS: A total of 463 dyads (69%) contributed data. Children in VIP scored higher than control on imitation/play and attention, and lower on separation distress, hyperactivity, and externalizing problems, with effect sizes ∼0.25 SD for the sample as a whole and ∼0.50 SD for families with additional psychosocial risks . Children in BB made greater gains in imitation/play compared with control. CONCLUSIONS: These findings support the efficacy of VIP, a preventive intervention targeting parent-child interactions, for enhancing socioemotional outcomes in low-income toddlers. Given the low cost and potential for scalability of primary care interventions, findings support expansion of pediatric-based parenting programs such as VIP for the primary prevention of socioemotional problems before school entry.

Mothers' feeding behaviors in infancy: Do they predict child weight trajectories?

OBJECTIVE: To determine associations between mothers' feeding behaviors in infancy and children's weight from infancy through to toddlerhood in urban, low-income, minority families and to explore the contribution of concerns about infant eating/weight. METHODS: One hundred sixty-nine mother-infant dyads (88% African-American) were recruited from an inner city pediatric practice. Questionnaires measuring restrictive feeding, pressuring to eat, and concerns about infant overeating/weight and undereating/weight were administered, and infants weighed and measured, at 6-12 months. Anthropometric data up to 30 months were obtained from multiple (8.9 ± 2.6) well-child visits, with 84% completing 11 visits. RESULTS: Higher pressuring was associated with lower weight-for-length z-scores (WLZ) over the period from baseline out to 30 months and higher restriction with higher child WLZ over the same period. Pressuring and concern about infant undereating/weight were independently associated with WLZ, but the relationship between restrictive feeding and WLZ was reduced by accounting for concern about infant overeating/weight. Child weight trajectories were not influenced by feeding behavior. CONCLUSIONS: Mothers restricted heavier infants and pressured leaner infants to eat, and the relationship between restriction and higher infant weight was mediated by concern about infant overeating/weight. Correcting misperceptions and discussing feeding with mothers reporting concern may help prevent excessive early weight gain.

Primary Care Parenting Intervention and Its Effects on the Use of Physical Punishment Among Low-Income Parents of Toddlers.

OBJECTIVES: As part of a large randomized controlled trial, the authors assessed the impact of 2 early primary care parenting interventions-the Video Interaction Project (VIP) and Building Blocks (BB)-on the use of physical punishment among low-income parents of toddlers. They also determined whether the impact was mediated through increases in responsive parenting and decreases in maternal psychosocial risk. METHODS: Four hundred thirty-eight mother-child dyads (161 VIP, 113 BB, 164 Control) were assessed when the children were 14 and/or 24 months old. Mothers were asked about their use of physical punishment and their responsive parenting behaviors, depressive symptoms, and parenting stress. RESULTS: The VIP was associated with lower physical punishment scores at 24 months, as compared to BB and controls. In addition, fewer VIP parents reported ever using physical punishment as a disciplinary strategy. Significant indirect effects were found for both responsive parenting and maternal psychosocial risk, indicating that the VIP affects these behaviors and risk factors, and that this is an important pathway through which the VIP affects the parents' use of physical punishment. CONCLUSION: The results support the efficacy of the VIP and the role of pediatric primary care, in reducing the use of physical punishment among low-income families by enhancing parent-child relationships. In this way, the findings support the potential of the VIP to improve developmental outcomes for at-risk children.

Reducing maternal depressive symptoms through promotion of parenting in pediatric primary care.

We studied associations between 2 pediatric primary care interventions promoting parental responsiveness and maternal depressive symptoms among low-income mothers. This randomized controlled trial included 2 interventions (Video Interaction Project [VIP], Building Blocks [BB]) and a control group. VIP is a relationship-based intervention, using video-recordings of mother-child dyads to reinforce interactional strengths. BB communicates with parents via parenting newsletters, learning materials, and questionnaires. At mean (SD) child age 6.9 (1.2) months, depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9), parental responsiveness was assessed with StimQ-I. A total of 407 dyads were assessed. Rates of mild depressive symptoms were lower for VIP (20.6%) and BB (21.1%) than Controls (32.1%, P = .04). Moderate depressive symptoms were lower for VIP (4.0%) compared to Controls (9.7%, P = .031). Mean PHQ-9 scores differed across 3 groups (F = 3.8, P = .02): VIP mothers scored lower than controls (P = .02 by Tukey HSD). Parent-child interactions partially mediated VIP-associated reductions in depressive symptoms (indirect effect -.17, 95% confidence interval -.36, -.03).

Primary care strategies for promoting parent-child interactions and school readiness in at-risk families: the Bellevue Project for Early Language, Literacy, and Education Success.

OBJECTIVE: To determine the effects of pediatric primary care interventions on parent-child interactions in families with low socioeconomic status. DESIGN: In this randomized controlled trial, participants were randomized to 1 of 2 interventions (Video Interaction Project [VIP] or Building Blocks [BB]) or the control group. SETTING: Urban public hospital pediatric primary care clinic. PARTICIPANTS: Mother-newborn dyads enrolled post partum from November 1, 2005, through October 31, 2008. INTERVENTIONS: In the VIP group, mothers and newborns participated in 1-on-1 sessions with a child development specialist who facilitated interactions in play and shared reading by reviewing videos made of the parent and child on primary care visit days; learning materials and parenting pamphlets were also provided. In the BB group, parenting materials, including age-specific newsletters suggesting interactive activities, learning materials, and parent-completed developmental questionnaires, were mailed to the mothers. MAIN OUTCOME MEASURES: Parent-child interactions were assessed at 6 months with the StimQ-Infant and a 24-hour shared reading recall diary. RESULTS: A total of 410 families were assessed. The VIP group had a higher increased StimQ score (mean difference, 3.6 points; 95% confidence interval, 1.5 to 5.6 points; Cohen d, 0.51; 0.22 to 0.81) and more reading activities compared to the control group. The BB group also had an increased overall StimQ score compared with the control group (Cohen d, 0.31; 95% confidence interval, 0.03 to 0.60). The greatest effects for the VIP group were found for mothers with a ninth-grade or higher reading level (Cohen d, 0.68; 95% confidence interval, 0.33 to 1.03). CONCLUSIONS: The VIP and BB groups each led to increased parent-child interactions. Pediatric primary care represents a significant opportunity for enhancing developmental trajectories in at-risk children. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00212576.

Randomized controlled trial of primary care pediatric parenting programs: effect on reduced media exposure in infants, mediated through enhanced parent-child interaction.

OBJECTIVES: To determine whether pediatric primary care-based programs to enhance parenting and early child development reduce media exposure and whether enhanced parenting mediates the effects. DESIGN: Randomized controlled trial. SETTING: Urban public hospital pediatric primary care clinic. PARTICIPANTS: A total of 410 mother-newborn dyads enrolled after childbirth. INTERVENTIONS: Patients were randomly assigned to 1 of 2 interventions, the Video Interaction Project (VIP) and Building Blocks (BB) interventions, or to a control group. The VIP intervention comprised 1-on-1 sessions with a child development specialist who facilitated interactions in play and shared reading through review of videotapes made of the parent and child on primary care visit days; learning materials and parenting pamphlets were also provided. The BB intervention mailed parenting materials, including age-specific newsletters suggesting activities to facilitate interactions, learning materials, and parent-completed developmental questionnaires (Ages and Stages questionnaires). OUTCOME MEASURES: Electronic media exposure in the home using a 24-hour recall diary. RESULTS: The mean (SD) exposure at 6 months was 146.5 (125.0) min/d. Exposure to VIP was associated with reduced total duration of media exposure compared with the BB and control groups (mean [SD] min/d for VIP, 131.6 [118.7]; BB, 151.2 [116.7]; control, 155.4 [138.7]; P = .009). Enhanced parent-child interactions were found to partially mediate relations between VIP and media exposure for families with a ninth grade or higher literacy level (Sobel statistic = 2.49; P = .01). CONCLUSION: Pediatric primary care may represent an important venue for addressing the public health problem of media exposure in young children at a population level. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00212576.

Sources of parenting information in low SES mothers.

This study examined 3 questions: (1) What are sources from which low socioeconomic status (SES) mothers of newborns receive parenting information? (2) To what extent are sociodemographic characteristics associated with sources? (3) To what extent are sources associated with intentions regarding activities with infants? In this cross-sectional analysis, mothers were interviewed during the postpartum period about potential sources of information about parenting and asked if and when they planned to initiate shared reading and television exposure during infancy. Maternal high school graduation, US birth, non-Latina ethnicity, language English, higher SES, and firstborn child were each associated with one or more categories representing important sources of parenting information. In adjusted analyses, print, physicians and other health care professionals, and family/friends as important sources of information were each significantly associated with increased frequency of intention to begin shared reading in infancy; television as an important source was associated with intention to begin television in infancy.

Maternal literacy and associations between education and the cognitive home environment in low-income families.

OBJECTIVE: To determine whether maternal literacy level accounts for associations between educational level and the cognitive home environment in low-income families. DESIGN: Analysis of 369 mother-infant dyads participating in a long-term study related to early child development. SETTING: Urban public hospital. PARTICIPANTS: Low-income mothers of 6-month-old infants. MAIN EXPOSURE: Maternal literacy level was assessed using the Woodcock-Johnson III/Bateria III Woodcock-Munoz Tests of Achievement, Letter-Word Identification Test. Maternal educational level was assessed by determining the last grade that had been completed by the mother. MAIN OUTCOME MEASURE: The cognitive home environment (provision of learning materials, verbal responsivity, teaching, and shared reading) was assessed using StimQ, an office-based interview measure. RESULTS: In unadjusted analyses, a maternal literacy level of ninth grade or higher was associated with increases in scores for the overall StimQ and each of 4 subscales, whereas a maternal educational level of ninth grade or higher was associated with increases in scores for the overall StimQ and 3 of 4 subscales. In simultaneous multiple linear regression models including both literacy and educational levels, literacy continued to be associated with scores for the overall StimQ (adjusted mean difference, 3.7; 95% confidence interval, 1.7-5.7) and all subscales except teaching, whereas maternal educational level was no longer significantly associated with scores for the StimQ (1.8; 0.5-4.0) or any of its subscales. CONCLUSIONS: Literacy level may be a more specific indicator of risk than educational level in low-income families. Studies of low-income families should include direct measures of literacy. Pediatricians should develop strategies to identify mothers with low literacy levels and promote parenting behaviors to foster cognitive development in these at-risk families.

Infant television and video exposure associated with limited parent-child verbal interactions in low socioeconomic status households.

OBJECTIVE: To assess verbal interactions related to television and other electronic media exposure among mothers and 6 month-old-infants. DESIGN: Cross-sectional analysis of 154 mother-infant dyads participating in a long-term study related to early child development. SETTING: Urban public hospital. PARTICIPANTS: Low socioeconomic status mothers of 6-month-old infants. Main Exposure Media exposure and content. MAIN OUTCOME MEASURES: Mother-infant verbal interaction associated with media exposure and maternal coviewing. RESULTS: Of 154 low socioeconomic status mothers, 149 (96.8%) reported daily media exposure in their infants, with median exposure of 120 (interquartile range, 60-210) minutes in a 24-hour period. Among 426 program exposures, mother-infant interactions were reported during 101 (23.7%). Interactions were reported most frequently with educational young child-oriented media (42.8% of programs), compared with 21.3% of noneducational young child-oriented programs (adjusted odds ratio, 0.4; 95% confidence interval, 0.1-0.98) and 14.7% of school-age/teenage/adult-oriented programs (adjusted odds ratio, 0.2; 95% confidence interval, 0.1-0.3). Among coviewed programs with educational content, mothers reported interactions during 62.7% of exposures. Coviewing was not reported more frequently for educational young child-oriented programs. CONCLUSIONS: We found limited verbal interactions during television exposure in infancy, with interactions reported for less than one-quarter of exposures. Although interactions were most commonly reported among programs with educational content that had been coviewed, programs with educational content were not more likely to be coviewed than were other programs. Our findings do not support development of infant-directed educational programming in the absence of strategies to increase coviewing and interactions.

Mothers' expectations for shared reading after delivery: implications for reading activities at 6 months.

OBJECTIVE: To determine whether mothers with plans related to shared reading and baby books in the home at the time of delivery of their newborns would be more likely to engage in shared reading behaviors at age 6 months. METHODS: This was a cohort study with enrollment after birth and follow-up at 6 months in an urban public hospital. Predictors included mothers' attitudes and resources related to shared reading during the postpartum period. Outcomes included mothers' shared reading activities and resources at 6 months, as assessed by the StimQ-READ measure. RESULTS: A total of 173 mother-infant dyads were assessed. In multiple regression analyses adjusting for sociodemographics and maternal depression and literacy, StimQ-READ score at 6 months was increased in association with all 3 postpartum predictors: plans for reading as a strategy for school success (adjusted mean 1.7-point increase in 6-month score; 95% confidence interval [95% CI], 0.3-3.0), plans to read in infancy (3.1-point increase; 95% CI, 1.6-4.6), and having baby books in the home (2.3-point increase; 95% CI, 0.9-3.6). In multiple logistic regression analysis, mothers with 2 or more attitudes and resources had an adjusted odds ratio of 6.2 (95% CI, 2.0-18.9) for having initiated reading at 6 months. CONCLUSIONS: Maternal attitudes and resources in early infancy related to shared reading are important predictors of reading behaviors by 6 months. Cumulative postnatal attitudes and resources are the strongest predictors of later behaviors. Additional research is needed regarding whether guidance about shared reading in early infancy or pregnancy would enhance programs such as Reach Out and Read.

Attitudes about shared reading among at-risk mothers of newborn babies.

OBJECTIVE: Attitudes about shared reading among at-risk mothers of newborn babies have not been the focus of previous study. Better understanding of factors associated with these attitudes would facilitate pediatricians' provision of anticipatory guidance. We sought to assess sociodemographic correlates of attitudes regarding and resources available for shared reading among multiethnic, low socioeconomic status (SES) mothers of newborns. METHODS: This was a cross-sectional analysis of consecutive mother-infant dyads enrolled during the postpartum period onto an urban public hospital. Dependent variables were attitudes and resources related to shared reading with infants. Independent variables were family sociodemographics, reading difficulties, and social risks. RESULTS: A total of 211 mother-newborn dyads were assessed; 23.7% reported not planning to look at books together until 12 months or later, 42.2% reported no baby books in the home, and 19.9% reported concerns about shared reading. In multiple logistic regression analyses, independent significant associations with not planning to share books together in infancy were lower maternal education, not speaking English, and firstborn. Independent significant associations of not having baby books were not speaking English, firstborn, and perceived difficulty reading in their native language. CONCLUSIONS: Many at-risk mothers of newborn babies do not report plans to read in infancy and do not have appropriate books in the home. Consideration should be given to universal provision of early anticipatory guidance addressing shared reading, either during the postpartum period or during initial well-child care visits.