Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring.

BACKGROUND: To examine the prospective association between multivitamin supplementation during pregnancy and biomarker measures of maternal plasma folate and vitamin B12 levels at birth and child's Autism Spectrum Disorder (ASD) risk. METHODS: This report included 1257 mother-child pairs, who were recruited at birth and prospectively followed through childhood at the Boston Medical Center. ASD was defined from diagnostic codes in electronic medical records. Maternal multivitamin supplementation was assessed via questionnaire interview; maternal plasma folate and B12 were measured from samples taken 2-3 days after birth. RESULTS: Moderate (3-5 times/week) self-reported supplementation during pregnancy was associated with decreased risk of ASD, consistent with previous findings. Using this as the reference group, low (≤2 times/week) and high (>5 times/week) supplementation was associated with increased risk of ASD. Very high levels of maternal plasma folate at birth (≥60.3 nmol/L) had 2.5 times increased risk of ASD [95% confidence interval (CI) 1.3, 4.6] compared to folate levels in the middle 80th percentile, after adjusting for covariates including MTHFR genotype. Similarly, very high B12 (≥536.8 pmol/L) showed 2.5 times increased risk (95% CI 1.4, 4.5). CONCLUSION: There was a 'U shaped' relationship between maternal multivitamin supplementation frequency and ASD risk. Extremely high maternal plasma folate and B12 levels at birth were associated with ASD risk. This hypothesis-generating study does not question the importance of consuming adequate folic acid and vitamin B12 during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B12 exposure in-utero on early brain development.

Investigating Potential Biomarkers in Autism Spectrum Disorder.

BACKGROUND: Early identification and treatment of individuals with autism spectrum disorder (ASD) improves outcomes, but specific evidence needed to individualize treatment recommendations is lacking. Biomarkers that could be routinely measured within the clinical setting could potentially transform clinical care for patients with ASD. This demonstration project employed collection of biomarker data during regular autism specialty clinical visits and explored the relationship of biomarkers with clinical ASD symptoms. METHODS: Eighty-three children with ASD, aged 5-10 years, completed a multi-site feasibility study integrating the collection of biochemical (blood serotonin, urine melatonin sulfate excretion) and clinical (head circumference, dysmorphology exam, digit ratio, cognitive and behavioral function) biomarkers during routine ASD clinic visits. Parents completed a demographic survey and the Aberrant Behavior Checklist-Community. Cognitive function was determined by record review. Data analysis utilized Wilcoxon two-sample tests and Spearman correlations. RESULTS: Participants were 82% male, 63% White, 19% Hispanic, with a broad range of functioning. Group means indicated hyperserotonemia. In a single regression analysis adjusting for race and median household income, higher income was associated with higher levels of blood serotonin and urine melatonin sulfate excretion levels (p = 0.004 and p = 0.04, respectively). Melatonin correlated negatively with age (p = 0.048) and reported neurologic problems (p = 0.02). Dysmorphic status correlated with higher reported stereotyped behavior (p = 0.02) and inappropriate speech (p = 0.04). CONCLUSION: This demonstration project employed collection of multiple biomarkers, allowed for examination of associations between biochemical and clinical measures, and identified several findings that suggest direction for future studies. This clinical research model has promise for integrative biomarker research in individuals with complex, heterogeneous neurodevelopmental disorders such as ASD.

Health-care use and expenditures for children in special education with special health-care needs: is dual classification a marker for high use?

OBJECTIVES: Children with special health-care needs are an important group for policy and research planning. Special education engages a group of children with increased utilization of services related to education. While increased service utilization in education or health-care settings is often used to classify children as having special needs, considerable heterogeneity exists within each group. The extent to which being identified in two functionally defined systems--special education and health care--relates to health-care utilization is unknown. We sought to determine health-care and mental health utilization and expenditures for children dually classified as receiving special education and having special health-care needs (SHCN) compared with those who only have SHCN, only are in special education, or don't fall into either category. METHODS: A nationally representative sample of children aged 5-17 years from the Medical Expenditure Panel Survey was used to compare mean health-care and mental health utilization and expenditures for the four groups. RESULTS: Dually classified children had significantly higher mean utilization of health-care services than the other three groups (p < 0.05). Mean 12-month total health-care expenditures were highest for dually classified children ($3,891/year) (p < 0.05) and higher for children classified only as having SHCN ($1,426/year) than for children with neither classification ($644/year, p < 0.05). CONCLUSIONS: Children dually classified as receiving special education and having SHCN represent a subgroup of children with SHCN with high levels of health-care utilization and expenditures. This information can assist policy makers in identifying characteristics that place children at risk for very high expenditures, and in allocating health-care resources.

Use of developmental milestones in pediatric residency training and practice: time to rethink the meaning of the mean.

OBJECTIVE: Pediatricians frequently report the use of developmental milestones in monitoring young children's development, despite evidence that use of screening tools improves detection of developmental delays. METHODS: Core texts in the field of pediatrics and developmental-behavioral pediatrics were reviewed for content and presentation on child development. Most texts included and many focused on developmental milestones, many with an emphasis on 50th percentile milestone data. Problems and limitations in the use of 50th percentile milestones to monitor young children's development and to identify children whose development is suspicious for delay, include questionable utility in clinical decision making and the potential to increase parental anxiety. RESULTS: The recommendation is made to reconsider a focus on 50th percentile milestone data in pediatric training and practice, in favor of measures that have better clinical utility and are more psychometrically sound. CONCLUSION: A conceptual approach to the presentation of developmental milestones differentiates the use of the 10th, 50th, and 90th percentiles of age of achievement of skills, based on the clinical purpose of surveillance.

Relationship between speech-sound disorders and early literacy skills in preschool-age children: impact of comorbid language impairment.

OBJECTIVE: Disorders of articulation or speech-sound disorders (SSD) are common in early childhood. Children with these disorders may be at risk for reading difficulties because they may have poor auditory, phonologic, and verbal memory skills. METHODS: We sought to characterize the reading and writing readiness of preschool children with SSD and identify factors associated with preliteracy skills. Subjects were 125 children aged 3 to 6 years with moderate to severe SSD; 53% had comorbid language impairment (LI). Reading readiness was measured with the Test of Early Reading Ability-2 (TERA) and writing skills with the Test of Early Written Language-2 (TEWL), which assessed print concept knowledge. Linear regression was used to examine the association between SSD severity and TERA and TEWL scores and analysis of variance to examine the effect of comorbid LI. Performance on a battery of speech and language tests was reduced by way of factor analysis to composites for articulation, narrative, grammar, and word knowledge skills. RESULTS: Early reading and writing scores were significantly lower for children with comorbid LI but were not related to SSD severity once language status was taken into account. Composites for grammar and word knowledge were related to performance on the TERA and TEWL, even after adjusting for Performance IQ. Below average language skills in preschool place a child at risk for deficits in preliteracy skills, which may have implications for the later development of reading disability. CONCLUSION: Preschool children with SSD and LI may benefit from instruction in preliteracy skills in addition to language therapy.

Postdischarge growth failure among extremely low birth weight infants: Correlates and consequences.

OBJECTIVE: To describe the prevalence and correlates of postdis-charge growth failure among extremely low birth weight (ELBW) infants (weighing less than 1 kg) and its impact on growth and development. METHODS: One hundred fifty-four ELBW infants were followed to 20 months corrected age. Growth failure was defined as a decrease in weight z score (standard deviation score) of over 0.67 during one of three periods: between 40 weeks and four months (period I), between four and eight months (period II), and between eight and 20 months corrected age (period III). A decrease in weight z score of this magnitude is comparable to crossing major growth percentiles (eg, from 25th to 10th percentile). Developmental outcomes were assessed at 20 months. RESULTS: Growth failure occurred in 8% of infants during period I, 28% during period II and 12% during period III. This resulted in poorer growth attainment and motor function at 20 months. Significant predictors of growth failure included chronic lung disease during periods I and III, and cerebral palsy during period III. Growth failure during period II, while more common, was not associated with specific sequelae of prematurity. It may represent a physiological process comparable to shifts in weight percentiles in term-born infants. CONCLUSIONS: Postdischarge growth failure is common among ELBW infants and contributes to poorer growth outcomes. It is associated with poorer motor outcomes when it occurs early after discharge or later in infancy. A decrease in weight z score of over 0.67 can serve as a useful indicator of growth failure in ELBW infants.

Feasibility of Conducting Autism Biomarker Research in the Clinical Setting.

OBJECTIVE: Recruitment and completion of research activities during regular clinical care has the potential to increase research participation in complex neurodevelopmental disorders. We evaluated the feasibility, and effect on clinical care, of conducting biomarker research within a subspecialty clinical visit for autism spectrum disorder (ASD). METHODS: Children, aged 5 to 10 years, were recruited by providers in ASD clinics at 5 institutions. Biomarkers collected were growth measurements, head circumference, neurologic and dysmorphology examinations, digit ratio (2D:4D) measurement, and platelet serotonin and urinary melatonin sulfate excretion levels. Parents completed the Aberrant Behavior Checklist-Community and a medical/demographic questionnaire. Cognitive level was abstracted from the medical record. Parents and clinicians completed surveys on the effect of the study on the clinical visit. RESULTS: Eighty-three children and their caregivers participated. Factors limiting participation included difficulty reaching families by phone and parent concern about the study blood draw requirement. All children completed at least 4 of 7 planned research activities. Demographic factors, educational placement, and child behavior were not associated with completion of study activities. Lower nonverbal cognitive function was weakly associated with fewer activities completed. Forty-four percent of clinicians reported an effect of the research study on the clinical visit. However, neither parent-reported nor clinician-reported effect was associated with the degree of study activity completion. CONCLUSION: Recruiting study participants in the context of scheduled ASD clinical visits required significant effort. However, once recruited, participants completed most study activities, regardless of behavioral symptom severity. Research activities did not adversely affect the clinical visit.

How do primary care physicians identify young children with developmental delays? A national survey.

Little is known about the current practices of primary care physicians regarding developmental surveillance and screening during pediatric preventive care visits. We conducted a mailed survey of a random national sample of pediatricians and family physicians to describe their practices and identify factors that predict use of developmental screening tools, an efficacious way of identifying children with developmental delays. Most physicians reviewed developmental milestones and prompted parents for developmental concerns at preventive care visits. Approximately half of the physicians used a formal developmental screening instrument. Female physician gender predicted higher rates of use of screening tools for family physicians, but not for pediatricians. Most physicians seemed committed to the early diagnosis of developmental delays. Substantial variability in surveillance and screening practices, barriers of time and reimbursement, and under-reliance on parent-completed questionnaires underscore areas for improvement.

"He is just a little shy like me": screening for autism in a young child.

CASE: Jacob is a 22-month-old wonderful boy, who is being seen a few months late for his 18-month-old visit because of scheduling snafus, as both parents work outside the home. At this visit, it is routine in our practice to administer the Modified Checklist for Autism in Toddlers (MCHAT) and the Parents' Evaluation of Developmental Status (PEDS). On the PEDS, in response to the question, "Do you have any concerns about how your child talks or makes speech sounds?" the parents respond "He only says 2 words in Hebrew and none in English." On the MCHAT, they reply "no" to 3 items: (1) "Does your child ever pretend, for example, to talk on the phone or take care of a doll or pretend other things?" (2) "Does your child respond to his/her name when you call?" and (3) "Does your child sometimes stare at nothing or wander with no purpose?" This results in failing 1 critical and 3 total items. Our practice protocol recommends a referral for a diagnostic evaluation. Jacob has been a healthy child, and this is the first time that his parents have fallen behind in routine health care maintenance visits. His medical history is unremarkable. He was born at term, weighing 3.2 kg, without any perinatal complications. His parents had emigrated from the Poland in their teenage years and have been married for 8 years. They also have a 5-year-old daughter. They both report that, in Poland, there are some relatives who were "very late talkers," but they do not know about any definitive family history of autism. At the 15-month visit, the parents reported that Jacob had expressive jargoning but no recognizable words. They stated then that he was not interested in toys but liked to play with the television remote control. He is in full-time child care--initially with a nanny in their home, but at 15 months started 3 days a week in a center-based childcare with many families from their community, where children speak Polish, English, and Hebrew at home. His mother works full time as an accountant and father as a physicist in a commercial laboratory. Both have graduate degrees and are trilingual. The parents are conflicted in their interpretation of Jacob's behavior. His father is concerned that he is autistic and his mother feels that "he is just a little shy like me." His physical examination is normal. He is somewhat inhibited and anxious but will sit still on the examination table and alone during the examination. You update his immunizations and then struggle with where to head next.

PEDS and ASQ developmental screening tests may not identify the same children.

OBJECTIVE: In analyzing data from a larger study, we noticed significant disagreement between results of 2 commonly used developmental screening tools (Parents' Evaluation of Developmental Status [PEDS; parent concern questionnaire] and Ages & Stages Questionnaires [ASQ; parent report of developmental skills]) delivered to children at the same visit in primary care. The screens have favorable reported psychometric properties and can be efficient to use in practice; however, there is little comparative information about the relative performance of these tools in primary care. We sought to describe the agreement between the 2 screens in this setting. METHODS: Parents of 60 children aged 9 to 31 months completed PEDS and ASQ screens at the same visit. Concordance (PEDS and ASQ results agree) and discordance (results differ) for the 2 screens were determined. RESULTS: The mean age of children was 17.6 months, 77% received Medicaid, and 50% of parents had a high school education or less. Overall, 37% failed the PEDS and 27% failed the ASQ. Thirty-one children passed (52%) both screens; 9 (15%) failed both; and 20 (33%) failed 1 but not the other (13 PEDS and 7 ASQ). Agreement between the 2 screening tests was only fair, statistically no different from agreement by chance. CONCLUSIONS: There was substantial discordance between PEDS and ASQ developmental screens. Although these are preliminary data, clinicians need to be aware that in implementing revised American Academy of Pediatrics screening guidelines, the choice of screening instrument may affect which children are likely to be identified for additional evaluation.

Sugar-coaters and straight talkers: communicating about developmental delays in primary care.

OBJECTIVES: The goals were to investigate parents' and early intervention (EI) specialists' beliefs and experiences regarding discussing child development in primary care and to identify communication barriers and opportunities. METHODS: Focus groups were held with (1) mothers of young children with typical development, (2) mothers of young children who received EI services, and (3) EI specialists. Seven groups (N = 46 participants) were conducted in the greater Cleveland, Ohio, area. Meetings were audio-recorded, transcribed, coded, and analyzed, to identify themes. RESULTS: Most mothers reported a preference for a nonalarmist style of communication when developmental delays are suspected. In contrast, some mothers preferred a more direct style, including the use of labels to help them understand their child's development. The importance of preparation to accept information about developmental delays emerged as a theme in all groups. Elements contributing to preparedness included information about expected developmental skills, suggestions for promoting skills, and a specific time frame for follow-up evaluation. Mothers of children with disabilities perceived that early reassurance of normalcy by providers in response to their concerns led to self-doubt and increased difficulty accepting the diagnosis. CONCLUSIONS: Mothers and EI specialists have clear ideas about factors that promote or impede communication regarding child development. This information can inform primary care providers' approaches to monitoring and screening the development of young children and to communicating with parents regarding suspected developmental delays.

Communication about child development during well-child visits: impact of parents' evaluation of developmental status screener with or without an informational video.

BACKGROUND: The American Academy of Pediatrics recommends periodic administration of standardized developmental screening instruments during well-child visits to facilitate timely identification of developmental delay. However, little is known about how parents and physicians communicate about child development or how screening impacts communication. OBJECTIVE: Our goal was to examine whether parent-physician communication about child development is affected by (1) administration of a developmental screen or (2) video presentation on child development before well-child visits. METHODS: Six primary care pediatricians in a practice serving predominantly Medicaid-insured children participated. Fifteen parents of children 9 to 31 months of age per pediatrician were assigned to 1 of 3 previsit conditions (n = 89): (1) usual care; (2) parent completed the Parents' Evaluation of Developmental Status screen; or (3) parent viewed 5-minute "activation" video before completing the Parents' Evaluation of Developmental Status. Visits were audiorecorded and coded by blinded raters using a classification system that assesses communication content. Outcomes included visit length, physicians' questions, information giving, reassurance or counseling about development, and parents' concerns and requests for developmentally related services. RESULTS: Mean visit duration was similar for the 3 groups (22.5 minutes). Physicians made more information-giving and counseling statements about development and raised more developmental concerns in group 3 (video plus the Parents' Evaluation of Developmental Status) than in group 1 (usual care) visits. A trend toward increased use of such communication was also seen in group 2 (Parents' Evaluation of Developmental Status only). Parents were more likely to raise a developmental concern in group 3 than in group 1. No parent requested early intervention, therapy, or other related services. CONCLUSIONS: Use of a validated screening test did not increase average visit duration, an important consideration in primary care. Although use of the Parents' Evaluation of Developmental Status alone led to some increase in parent-physician communication about development and developmental concerns, additional increase in communication was seen with the addition of a brief parent activation video shown before the Parents' Evaluation of Developmental Status was completed.

How do primary care physicians manage children with possible developmental delays? A national survey with an experimental design.

OBJECTIVE: Although early detection and treatment of developmental delays can improve outcome, little is known about factors that influence how primary care physicians manage young children with probable developmental delays. The objective of this study was to describe physician referral practices for children with developmental delays and to test whether the probability of referral is increased by 1) the expression of parental concern; 2) female gender in a child with language delay; 3) disruptive, as opposed to avoidant behaviors; and 4) physician characteristics, including female gender or being a pediatrician. METHODS: A cross-sectional survey was mailed to a national random sample of 800 pediatricians and 800 family practice physicians in primary care practice, using an experimental randomized block design. Recipients randomly received alternative variants of clinical vignettes, which differed only in regard to the variable specific to each of the first 3 hypotheses. Physicians answered questions about the likelihood of referral on a 5-point scale for listed referral options. Hypotheses were tested using multivariable logistic regression modeling. A total of 55% of pediatricians and 43% of family practice physicians returned the survey, for an overall response rate of 49%. RESULTS: A girl with language delay was 60% more likely to be referred to audiology than a boy (odds ratio: 1.6; 95% confidence interval: 1.1-2.3), and respondents who were female or pediatricians were more likely to refer patients. The expression of parental concern did not increase the probability of referral to diagnostic and treatment services, and avoidant rather than disruptive patient behaviors were associated with an increased probability of referral. CONCLUSIONS: Patient gender and type of behavioral presentation seem to influence referrals to diagnostic and treatment services for young children with probable developmental delays described in clinical vignettes. These findings can guide targeted educational interventions to increase rates of detection and referral for young children with developmental delays.