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1.  Reliability and Applicability of the Bayley Scale of Infant Development-II for Children With Cerebral Palsy 
Annals of Rehabilitation Medicine  2013;37(2):167-174.
To obtain reliability and applicability of the Korean version Bayley Scale of Infant Development-II (BSID-II) in evaluating the developmental status of children with cerebral palsy (CP).
The inter-rater reliability of BSID-II scores from 68 children with CP (46 boys and 22 girls; mean age, 32.54±16.76 months; age range, 4 to 78 months) was evaluated by 10 pediatric occupational therapists. Patients were classified in several ways according to age group, typology, and the severity of motor impairment by the level of the Gross Motor Function Classification System (GMFCS). The measures were performed by video analysis, and the results of intraclass correlation (ICC) were obtained for each of the above classifications. To evaluate the clinical applicability of BSID-II for CP, its correlation with the Gross Motor Function Measure (GMFM), which has been known as the standard motor assessment for CP, was investigated.
ICC was 0.99 for the Mental scale and 0.98 for the Motor scale in all subjects. The values of ICC ranged from 0.92 to 0.99 for each age group, 0.93 to 0.99 for each typology, and 0.99 to 1.00 for each GMFCS level. A strong positive correlation was found between the BSID-II Motor raw score and the GMFM total score (r=0.84, p<0.001), and a moderate correlation was observed between the BSID-II Mental raw score and the GMFM total score (r=0.65, p<0.001).
The Korean version of BSID-II is a reliable tool to measure the functional status of children with CP. The raw scores of BSID-II showed a great correlation with GMFM, indicating validity of this measure for children with CP on clinical basis.
PMCID: PMC3660476  PMID: 23705110
Cerebral palsy; Child development; Reliability; Gross motor function
2.  Relationships between Physical and Cognitive Functioning and Activities of Daily Living in Children with Cerebral Palsy 
[Purpose] The purpose of the present study was to evaluate the relationship between physical function, cognitive function, and activities of daily living in children with cerebral palsy. [Subjects] Sixty-eight children who had been diagnosed with cerebral palsy and have participated in inpatient or outpatient rehabilitation programs were enrolled in the present study. We used 3 clinical assessments: the Gross Motor Function Measure (GMFM), the Bayley Infant Development Screening Test-II (BSID-II), and the Wee Functional Independence Measure (WeeFIM). [Results] The GMFM was positively correlated with the BSID-II motor scale and the BSID-II cognitive scale, but not with the WeeFIM scores. The BSID-II motor scale was significantly correlated with the GMFM and BSID-II cognitive scale, but not with the WeeFIM. [Conclusion] The results of this study provide evidence of the necessity of including cognitive and physical impairments in the examination and evaluation of children with cerebral palsy in research and clinical settings.
PMCID: PMC3804975  PMID: 24259815
Activities of daily living; Cerebral palsy; Cognition
3.  Predictive Value of Test of Infant Motor Performance for Infants based on Correlation between TIMP and Bayley Scales of Infant Development 
Annals of Rehabilitation Medicine  2011;35(6):860-866.
To assess the relationship of scores on the test of infant motor performance (TIMP), with those on the Bayley scales of infant development (BSID), and to investigate the sensitivity and specificity of TIMP and the optimal cut-off value of TIMP scores using ROC analysis.
Seventy-six preterm and term infants were recruited from neonatal intensive care units. Subjects were tested with the TIMP at their initial visit and after 6 months, they were tested by using BSID.
In the reliability study, TIMP scores showed highly significant correlation with the Bayley physical developmental index (BPDI) (p=0.001) and Bayley mental developmental index (BMDI) (p=0.017). Receiver operator characteristics (ROC) curve analysis was performed to evaluate the TIMP test for screening infant motor development. ROC analysis showed an area under the curve (AUC) of 0.825 (p=0.005) in BPDI and 0.992 (p=0.014) in BMDI, indicating an excellent classification performance of the model. The optimal cut-off value where a sensitivity of 86%, and specificity of 68% were achieved with the TIMP was 1.50 (between average and below average) in BPDI and where a sensitivity of 100%, and specificity of 66% were achieved with the TIMP was 1.50 in BMDI.
Our results indicate that the TIMP provides a reliable and valid measurement that can be used for the evaluation of motor function in preterm and term infants. TIMP was highly sensitive and specific with the follow-up examination of BSID. Therefore it can be used as a reliable screening tool for neonates and infants aged <4 months.
PMCID: PMC3309382  PMID: 22506215
Test of infant motor performance; Bayley scales of infant development
4.  Presurgical and postsurgical assessment of the neurodevelopment of infants with single-suture craniosynostosis: comparison with controls 
Journal of neurosurgery  2007;107(2 Suppl):103-110.
Although most infants with single-suture craniosynostosis (SSC) appear to have neurodevelopmental test scores in the average range, SSC has been associated with cognitive and motor delays during infancy. Whether and when surgery improves such deficits are not yet known. The authors aimed to compare the pre- and postsurgical neurodevelopmental status of patients with SSC with those of control infants without craniosynostosis.
The authors conducted a large, multicenter, longitudinal study of 168 infants with craniosynostosis and 115 controls without synostosis who were of similar age, race, sex, and socioeconomic status. The authors assessed participants by using the Bayley Scales of Infant Development, Second Edition (BSID-II) and the Preschool Language Scale, Third Edition (PLS-3) at enrollment, before patients’ intracranial surgery, and when participants were 18 months of age (after surgery for patients).
After adjusting for potential confounding factors in linear regression analyses, the authors found a tendency for patients to perform similarly to or slightly worse than controls on neurodevelopmental examinations at both visits. After surgery, the patients’ mean scores were 0.6 to three points lower than those of controls on the five BSID-II and PLS-3 scales (p = 0.02–0.07). Compared with controls, patients had 2.3 and 1.9 times the adjusted odds of scoring in the delayed range on either BSID-II scale (Mental Development Index and Psychomotor Development Index) for the first and second visits, respectively (p = 0.001 and p = 0.015, respectively). The patients’ mean adjusted test scores were nearly unrelated to the timing of their surgery.
These findings support recommendations for neurodevelopmental screening in infants with SSC. Longer follow-up, as is being conducted with the patients in the present study, will be critical for identifying the potential longer-term correlates of SSC and its surgical correction.
PMCID: PMC3417768  PMID: 18459881
cranioplasty; neurodevelopment; pediatric neurosurgery; single-suture craniosynostosis
5.  Motor and Cognitive Outcomes Through Three Years Of Age In Children Exposed To Prenatal Methamphetamine 
Neurotoxicology and teratology  2011;33(1):176-184.
Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown.
To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age.
IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n=204) were identified by self-report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n=208) were matched (race, birth weight, maternal education, type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n=350) of the IDEAL study with completed 1 and/or 3 year visits (n= 330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n=356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n= 331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (≥3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time.
Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P = 0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age.
There were no differences in cognition as assessed by the BSID-II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years.
PMCID: PMC3033584  PMID: 21256431
prenatal exposure; neurodevelopment; Bayley; Peabody
6.  An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome 
BMC Neurology  2014;14(1):232.
Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug’s effect on the cognitive and behavioral manifestations of the disorder.
Participants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η2) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett’s post hoc testing.
Significant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period.
The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.
Trial registration
NCT01531582 –
PMCID: PMC4276108  PMID: 25491305
Angelman syndrome; Cognitive impairment; Ataxia; Epilepsy; Seizure; Autism
7.  UP-BEAT (Upper Limb Baby Early Action–observation Training): protocol of two parallel randomised controlled trials of action–observation training for typically developing infants and infants with asymmetric brain lesions 
BMJ Open  2013;3(2):e002512.
Infants with asymmetric brain lesions are at high risk of developing congenital hemiplegia. Action–observation training (AOT) has been shown to effectively improve upper limb motor function in adults with chronic stroke. AOT is based on action observation, whereby new motor skills can be learnt by observing motor actions. This process is facilitated by the Mirror Neuron System, which matches observed and performed motor actions. This study aims to determine the efficacy of AOT in: (1) influencing the early development of reaching and grasping of typically developing infants and (2) improving the upper limb activity of infants with asymmetric brain lesions.
Methods and analysis
This study design comprises two parallel randomised sham-controlled trials (RCTs) in: (1) typically developing infants (cohort I) and (2) infants with asymmetric brain lesions (eg, arterial stroke, venous infarction, intraventricular haemorrhage or periventricular leukomalacia; cohort II). Cohort II will be identified through a neonatal ultrasound or neonatal MRI. A sham control will be used for both RCTs, taking into consideration that it would be unethical to give no intervention to an at-risk population. Based on a two-tailed t test of two independent means, with a significance (α) level of 0.05, 80% power, predicted effect size of 0.8 and a 90% retention rate, we require 20 participants in each group (total sample of 40) for cohort I. The sample size for cohort II was based on the assumption that the effect size of the proposed training would be similar to that found by Heathcock et al in preterm born infants (n=26) with a mean effect size of 2.4. Given the high effect size, the calculation returned a sample of only four participants per group, on a two-tailed t test, with a significance (α) level of 0.05 and 80% power. As cohort II will consist of two subgroups of lesion type (ie, arterial stroke and venous infarction), we have quadrupled the sample to include 16 participants in each group (total sample of 32). Infants will be randomised to receive either AOT or standard Toy Observation Training (TOT). Both interventions will be of 4 weeks’ duration, from the infant's 9th–13th post-term week of age. Three sessions of 5 min each will be performed each day for 6 days/week (total of 6 h over 28 days). Parents of the AOT group will repeatedly show the infant a grasping action on a set of three toys, presented in random order. Parents of the TOT group will show the infant the same set of three toys, in random order, without demonstrating the grasping action. At 14, 16 and 18 weeks, the quantity and quality of reaching and grasping will be measured using the Grasping and Reaching Assessment of Brisbane; symmetry of reaching and grasping will be measured using the Hand Assessment of Infants (HAI) and pressure of grasping for each hand with a customised pressure sensor. At 6 months’ corrected age, the primary outcome measures will be the HAI and Bayley Scales of Infant and Toddler Development (third edition; BSID III), to measure cognitive and motor development. At 8 months, HAI and EEG will be used to measure brain activity and cortical coherence. At 12 months, the primary outcome measures will again be HAI and BSID III.
This paper outlines the theoretical basis, study hypotheses and outcome measures for two parallel RCTs comparing the novel intervention Action–observation training with standard TOT in: (1) influencing the early development of reaching and grasping of typically developing infants and (2) improving the upper limb motor activity of infants with asymmetric brain lesions.
Trial Registration
ACTRN1261100991910. Web address of trial
PMCID: PMC3586152  PMID: 23418301
Rehabilitation Medicine
8.  Use of the Ages and Stages Questionnaire and Bayley Scales of Infant Development-II in Neurodevelopmental Follow-up of Extremely Low Birth Weight Infants 
For infants born extremely low birth weight (ELBW), we examined the 1) correlation between results on the Ages and Stages Questionnaire (ASQ), and the Bayley Scales of Infant Development II (BSID-II) at 18-22 months corrected age; 2) degree to which earlier ASQ assessments predict later BSID-II results; 3) impact of ASQ use on follow-up study return rates.
Study Design
ASQ data were collected at 4, 8, 12, and 18-22 months corrected age. The BSID-II was completed at 18-22 months corrected age. ASQ and BSID-II 18 – 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses.
ASQ sensitivity and specificity at 18-22 months were 73% and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results.
For ELBW infant assessment, the ASQ cannot substitute for the BSID-II, but appears to improve tracking success.
PMCID: PMC3139816  PMID: 21311498
Bayley Scales of Infant Development; Ages and Stages Questionnaire; neurodevelopment; developmental assessment; developmental screening; NICU
9.  Association Between Feeding Difficulties and Language Delay in Preterm Infants Using Bayley III 
The Journal of pediatrics  2013;163(3):680-685.e3.
To evaluate the relationship between abnormal feeding patterns and language performance on the Bayley Scales of Infant Development-III (BSID-III) at 18–22 months adjusted age among a cohort of extremely premature infants.
Study design
This is a descriptive analysis of 1477 preterm infants born ≤ 26 weeks gestation or enrolled in a clinical trial between January 1, 2006 and March 18, 2008 at a NICHD Neonatal Research Network center who completed the 18 month Neurodevelopmental Follow-Up assessment. At 18–22 months adjusted age, a comprehensive neurodevelopmental evaluation was performed by certified examiners including the Receptive and Expressive Language Subscales of the BSID-III and a standardized adjusted age feeding behaviors and nutritional intake. Data were analyzed using bivariate and multilevel linear and logistic regression modeling.
Abnormal feeding behaviors were reported in 193 (13%) of these infants at 18–22 months adjusted age. Abnormal feeding patterns, days of mechanical ventilation, hearing impairment and Gross Motor Functional Classification Score ≥ 2 each independently predicted lower composite language scores.
At 18 months adjusted age, premature infants with a history of feeding difficulties are more likely to have language delay. Neuromotor impairment and days of mechanical ventilation are both important risk factors associated with these outcomes.
PMCID: PMC3755022  PMID: 23582139
10.  Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deficiency and common mental disorders: a prospective community-based study 
Antenatal anaemia, iron deficiency and common mental disorders (CMD) are prevalent in low- and middle-income countries. The aim of this study was to examine the direct and indirect effects of antenatal exposures to these risks and infant motor development.
A cohort of women who were pregnant with a single foetus and between 12 and 20 weeks pregnant in 50 randomly-selected rural communes in Ha Nam province was recruited. Participants provided data twice during pregnancy (early and late gestation) and twice after giving birth (8 weeks and 6 months postpartum). The Edinburgh Postnatal Depression Scale was used at all four data collection waves to detect CMD (score ≥ 4). Maternal anaemia (Hb < 11 g/dL) and iron deficiency (ferritin < 15 ng/mL) were evaluated at early and late gestation. Infants’ motor development was assessed by the Bayley of Infant and Toddler Development Motor Scales (BSID-M) at the age of six months. Direct and indirect effects of the exposures on the outcome were examined with Path analysis.
In total, 497 of 523 (97%) eligible pregnant women were recruited and 418 mother-infant pairs provided complete data and were included in the analyses. The prevalence of anaemia was 21.5% in early pregnancy and 24.4% in late pregnancy. There was 4.1% iron deficiency at early pregnancy and 48.2% at late pregnancy. Clinically significant symptoms of CMD were apparent among 40% women in early pregnancy and 28% in late pregnancy. There were direct adverse effects on infant BSID-M scores at 6 months of age due to antenatal anaemia in late pregnancy (an estimated mean reduction of 2.61 points, 95% Confidence Interval, CI, 0.57 to 4.65) and CMD in early pregnancy (7.13 points, 95% CI 3.13 to 11.13). Iron deficiency and anaemia in early pregnancy were indirectly related to the outcome via anaemia during late pregnancy.
Antenatal anaemia, iron deficiency, and CMD have a negative impact on subsequent infant motor development. These findings highlight the need to improve the quality of antenatal care when developing interventions for pregnant women that aim to optimise early childhood development in low- and middle-income countries.
PMCID: PMC3890590  PMID: 24401012
Infant development; Pregnancy; Common mental disorders; Micronutrient deficiencies; Vietnam
11.  Case-Control Study of Neurodevelopment in Deformational Plagiocephaly 
Pediatrics  2010;125(3):e537-e542.
We assessed the neurodevelopment of infants with and without deformational plagiocephaly (DP), at an average age of 6 months.
The Bayley Scales of Infant Development III (BSID-III) were administered to 235 case subjects and 237 demographically similar, control participants. Three-dimensional head photographs were randomized and rated for severity of deformation by 2 craniofacial dysmorphologists who were blinded to case status.
We excluded 2 case subjects with no photographic evidence of DP and 70 control subjects who were judged to have some degree of DP. With control for age, gender, and socioeconomic status, case subjects performed worse than control subjects on all BSID-III scales and subscales. Case subjects’ average scores on the motor composite scale were ~10 points lower than control subjects’ average scores (P < .001). Differences for the cognitive and language composite scales were ~5 points, on average (P < .001 for both scales). In subscale analyses, case subjects’ gross-motor deficits were greater than their fine-motor deficits. Among case subjects, there was no association between BSID-III performance and the presence of torticollis or infant age at diagnosis.
DP seems to be associated with early neurodevelopmental disadvantage, which is most evident in motor functions. After follow-up evaluations of this cohort at 18 and 36 months, we will assess the stability of this finding. These data do not necessarily imply that DP causes neurodevelopmental delay; they indicate only that DP is a marker of elevated risk for delays. Pediatricians should monitor closely the development of infants with this condition.
PMCID: PMC3392083  PMID: 20156894
plagiocephaly; neurodevelopmental; Back to Sleep campaign
12.  Developmental outcome of very low birth weight infants in a developing country 
BMC Pediatrics  2012;12:11.
Advances in neonatal care allow survival of extremely premature infants, who are at risk of handicap. Neurodevelopmental follow up of these infants is an essential part of ongoing evaluation of neonatal care. The neonatal care in resource limited developing countries is very different to that in first world settings. Follow up data from developing countries is essential; it is not appropriate to extrapolate data from units in developed countries. This study provides follow up data on a population of very low birth weight (VLBW) infants in Johannesburg, South Africa.
The study sample included all VLBW infants born between 01/06/2006 and 28/02/2007 and discharged from the neonatal unit at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Bayley Scales of Infant and Toddler Development Version 111 (BSID) 111 were done to assess development. Regression analysis was done to determine factors associated with poor outcome.
178 infants were discharged, 26 were not available for follow up, 9 of the remaining 152 (5.9%) died before an assessment was done; 106 of the remaining 143 (74.1%) had a BSID 111 assessment. These 106 patients form the study sample; mean birth weight and mean gestational age was 1182 grams (SD: 197.78) and 30.81 weeks (SD: 2.67) respectively. The BSID (111) was done at a median age of 16.48 months. The mean cognitive subscale was 88.6 (95% CI: 85.69 - 91.59), 9 (8.5%) were < 70, mean language subscale was 87.71 (95% CI: 84.85 - 90.56), 10 (9.4%) < 70, and mean motor subscale was 90.05 (95% CI: 87.0 - 93.11), 8 (7.6%) < 70. Approximately one third of infants were identified as being at risk (score between 70 and 85) on each subscale. Cerebral palsy was diagnosed in 4 (3.7%) of babies. Factors associated with poor outcome included cystic periventricular leukomalacia (PVL), resuscitation at birth, maternal parity, prolonged hospitalisation and duration of supplemental oxygen. PVL was associated with poor outcome on all three subscales. Birth weight and gestational age were not predictive of neurodevelopmental outcome.
Although the neurodevelopmental outcome of this group of VLBW infants was within the normal range, with a low incidence of cerebral palsy, these results may reflect the low survival of babies with a birth weight below 900 grams. In addition, mean subscale scores were low and one third of the babies were identified as "at risk", indicating that this group of babies warrants long-term follow up into school going age.
PMCID: PMC3293066  PMID: 22296705
13.  Early prediction of cerebral palsy after neonatal intensive care using motor development trajectories in infancy 
Early human development  2013;89(10):781-786.
Neonatal intensive care unit (NICU) patients are at high-risk for developmental disabilities such as cerebral palsy (CP). Early identification of CP is essential to effective rehabilitation, but diagnosis is often delayed, especially in preterm infants. We hypothesized longitudinal evaluation of motor trajectories in the NICU Follow-up clinic could distinguish in infancy who developed CP by 3 years of age.
Study Design and subjects
Retrospective study of 606 patients in the NICU Follow-up clinic at Vanderbilt University with birthweight <1500 g or a diagnosis of hypoxic ischemic encephalopathy.
Outcomes measures
Assessments included neurologic exams, the Developmental Assessment of Young Children (DAYC), the Bayley Scales of Infant Development (BSID) and the Gross Motor Function Classification Scale.
A decrease in DAYC scores between 6 and 12 months was present in preterm and term infants later diagnosed with CP, but not in children without CP (−23 vs. +1.5, p <0.001). DAYC score decreases in infancy were highly predictive of later CP (p <0.001). BSID scores quantified severe motor delays but did not add to prediction of CP diagnosis.
Standardized assessments of motor milestones quantitatively predict the risk of CP in former NICU patients by 12 months, allowing for timely diagnosis, counseling and therapy in high-risk infants.
PMCID: PMC3759619  PMID: 23856349
Neurodevelopment; NICU; Predictive testing; Motor development; Cerebral palsy
14.  Neurodevelopment and In Utero Antiretroviral Exposure of HIV-Exposed Uninfected Infants 
Pediatrics  2010;125(2):e250-e260.
Antiretroviral (ARV) drugs are routinely provided to HIV-infected pregnant women to prevent HIV mother-to-child transmission. Although ARV use has significantly reduced mother-to-child transmission to <2% in the United States, it remains crucial to monitor uninfected infants and children for adverse consequences of in utero ARV exposure.
We studied neurodevelopmental function in HIV-exposed uninfected children who were enrolled in Pediatric AIDS Clinical Trials Group 219/219C, a multisite, prospective, cohort study. Mental and motor functioning were assessed with the Bayley Scales of Infant Development (BSID), first and second editions. ARV exposure information was collected during pregnancy or within the first years of life. Linear regression methods were used to evaluate the association of in utero ARV exposure on Mental Developmental Index and Psychomotor Developmental Index at 2 years of age, controlling for demographic factors (age, gender, and race/ethnicity) and potential confounders: test version, primary language, primary caregiver, caregiver education level, low birth weight, geographic and urban/rural location, birth year, and maternal illicit drug use.
Among 1840 infants who were born between 1993 and 2006, 1694 (92%) were exposed to ARV in utero and 146 (8%) were not exposed. After controlling for confounders, children who were exposed in utero to any ARV did not have lower Mental Developmental Index and Psychomotor Developmental Index scores than unexposed children. Among low birth weight infants, significantly higher BSID scores were observed for prenatally ARV-exposed than unexposed children. Maternal illicit drug use was reported for 17% of mothers but was not associated with BSID scores.
Mental and motor functioning scores were not lower for infants with in utero ARV exposure compared with no exposure. Although these results are reassuring, continued evaluation of uninfected children with in utero ARV exposure for long-term adverse outcomes is important.
PMCID: PMC2951128  PMID: 20083530
Bayley scales; mental development; motor development; maternal health; antiretroviral treatment; low birth weight
15.  Developmental outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study 
Journal of pediatric surgery  2013;48(10):10.1016/j.jpedsurg.2013.02.041.
To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at two years of age.
This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at two years of age.
BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 +/− 15, 95 +/−16, and 95 +/− 11. Ten percent (5/47) scored more than two standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 +/−14, 94+/−16, 93 +/− 13, 97+/− 10, and 94 +/− 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At two years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors.
CDH patients on average have lower developmental scores at two years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.
PMCID: PMC3884579  PMID: 24094947
congenital diaphragmatic hernia; neurodevelopment; Hollingshead; socioeconomic status
16.  Motor performance and functional ability in preschool- and early school-aged children with Juvenile Idiopathic Arthritis: a cross-sectional study 
To describe the level of motor performance and functional skills in young children with JIA.
In a cross-sectional study in 56 preschool-aged (PSA) and early school- aged children (ESA) with JIA according to ILAR classification, motor performance was measured with the Bayley Scales of Infant Development II (BSID2) and the Movement Assessment Battery for Children (M-ABC). Functional skills were measured with the Pediatric Evaluation of Disability Inventory (PEDI). Disease outcome was measured with a joint count on swelling/range of joint motion, functional ability and joint pain.
Twenty two PSA children (mean age 2.1 years) with a mean Developmental Index of the BSID2 of 77.9 indicating a delayed motor performance; 45% of PSA children showed a severe delayed motor performance. Mean PEDI scores were normal, 38% of PSA scored below -2 SD in one or more domains of the PEDI. Thirty four ESA children (mean age 5.2 years) with a mean M-ABC 42.7, indicating a normal motor performance, 12% of ESA children had an abnormal score. Mean PEDI scores showed impaired mobility skills, 70% of ESA children scored below -2 SD in one or more domains of the PEDI. Disease outcome in both age groups demonstrated low to moderate scores. Significant correlations were found between age at disease onset, disease duration and BSID2 or M-ABC and between disease outcome and PEDI in both age cohorts.
More PSA children have more impaired motor performance than impaired functional skills, while ESA children have more impairment in functional skills. Disease onset and disease duration are correlated with motor performance in both groups. Impaired motor performance and delayed functional skills is primarily found in children with a polyarticular disease course. Clinical follow up and rehabilitation programs should also focus on motor performance and functional skills development in young children with JIA.
PMCID: PMC2246124  PMID: 18199326
17.  Fetal Cerebrovascular Resistance and Neonatal EEG Predict 18-month Neurodevelopmental Outcome in Infants with Congenital Heart Disease 
The purpose of this study was to investigate early markers of risk for neurobehavioral compromise in congenital heart disease (CHD) survivors.
Fetuses < 24 wks gestational age (GA) were enrolled in this prospective pilot study for serial Doppler assessment of the middle cerebral and umbilical artery. The cerebral-to-placental resistance ratio (CPR) and MCA pulsatility index (PI) z-scores for GA were calculated. After birth, subjects underwent high-density (128-lead) electroencephalogram (EEG) and beta frequency (12–24Hz) band EEG power, a measure of local neural synchrony, was analyzed. Neurodevelopment was assessed at 18-months with the Bayley Scales of Infant Development III (BSID).
13 subjects were enrolled: 4 with hypoplastic left heart syndrome (HLHS), 4 with transposition of the great arteries (TGA), and 5 with tetralogy of Fallot (TOF). Compared with subjects with normal CPR, those with CPR<1(N=7) had lower mean BSID cognitive scores (91.4±4.8 vs. 99.2±3.8, p=.008). Fetal MCA PI z-score also correlated with BSID cognitive score (r=.589, p=0.044) as did neonatal EEG left frontal polar (r=.58, p=.037) and left frontal (r=.77,p=.002) beta power. Furthermore, fetal Doppler measures were associated with EEG power: fetuses with CPR<1 had lower left frontal polar (t=2.36, p=.038) and left frontal (t=2.85, p=.016) beta power as newborns compared with fetuses with normal CPR, and fetal MCA PI z-score correlated with neonatal EEG left frontal polar (r=.596, p=.04) and left frontal (r=.598, p=.04) beta power.
In CHD fetuses with HLHS, TGA, and TOF, abnormal cerebrovascular resistance predicted decreased neonatal EEG left frontal beta power and lower 18-mo cognitive development scores.
PMCID: PMC3612978  PMID: 22351034
congenital heart disease; neurodevelopment; fetal cerebral Doppler; fetal cerebrovascular resistance; hypoplastic left heart syndrome; tetralogy of Fallot; transposition of the great arteries; neonatal high-density electroencephalogram
18.  Association between maternal antenatal depression and infant development: a hospital-based prospective cohort study 
To examine the association between antenatal depression and infant development after controlling for confounding factors.
A hospital-based prospective cohort study (Hokkaido Study on Environment and Children’s Health) was conducted between July 2002 and October 2005 in Sapporo, Japan. Of 309 mothers who delivered at Sapporo Toho Hospital during the study period and who agreed with the clinical assessment of depression, 154 mother–infant pairs were eligible for analysis. Antenatal depression was assessed between the second and third trimesters using the Edinburgh Postnatal Depression Scale (EPDS), and infant development was assessed at 6 months by the Bayley Scales of Infant Development II (BSID-II). Data on potential confounders, including socioeconomic status, birth complications, postnatal depression and child care environment, were obtained from medical records and self-administered questionnaires. Univariable and multivariable analyses were conducted in which the EPDS score was entered as an independent variable and the BSID-II scores as a dependent variable, adjusting for confounders.
Although the antenatal EPDS score tended to be related to the BSID-II score in the univariable analysis, this correlation was lost in the multivariable analysis. However, based on a series of linear regression analyses, antenatal depression was found to be significantly related to shorter gestational age (β = −0.25, 95 % confidence interval (CI) [−1.20, −0.17]), and shorter gestational age was significantly related to a lower BSID-II (mental development) score (β = 0.23, 95 % CI [0.00, 0.00]).
Gestational age is an important confounder in the association between maternal antenatal depression and infant development. A delay in infant development may be related to a shorter gestational period caused by maternal depression during pregnancy.
PMCID: PMC3890074  PMID: 23913005
Maternal depression; Pregnancy; Infant development; Gestational age; Cohort study
19.  Development at Age 36 Months in Children With Deformational Plagiocephaly 
Pediatrics  2013;131(1):e109-e115.
Infants and toddlers with deformational plagiocephaly (DP) have been shown to score lower on developmental measures than unaffected children. To determine whether these differences persist, we examined development in 36-month-old children with and without a history of DP.
Participants included 224 children with DP and 231 children without diagnosed DP, all of who had been followed in a longitudinal study since infancy. To confirm the presence or absence of DP, pediatricians blinded to children’s case status rated 3-dimensional cranial images taken when children were 7 months old on average. The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was administered as a measure of child development.
Children with DP scored lower on all scales of the BSID-III than children without DP. Differences were largest in cognition, language, and parent-reported adaptive behavior (adjusted differences = –2.9 to –4.4 standard score points) and smallest in motor development (adjusted difference = –2.7). Children in the control group who did not have previously diagnosed DP but who were later rated by pediatricians to have at least mild cranial deformation also scored lower on the BSID-III than unaffected controls.
Preschool-aged children with a history of DP continue to receive lower developmental scores than unaffected controls. These findings do not imply that DP causes developmental problems, but DP may nonetheless serve as a marker of developmental risk. We encourage clinicians to screen children with DP for developmental concerns to facilitate early identification and intervention.
PMCID: PMC3529956  PMID: 23266929
plagiocephaly; developmental assessment; preschool age; Back to Sleep
20.  Impact of caste on the neurodevelopment of young children from birth to 36 months of age: a birth cohort study in Chitwan Valley, Nepal 
BMC Pediatrics  2014;14:56.
Caste, a proxy of socioeconomic position, can influence the neurodevelopment of children through several pathways, including exposure to toxic elements. Studies from developing countries where caste is represented by prevailing caste groups and people are highly exposed to toxic elements can provide useful insights into the mechanisms of neurodevelopmental inequities among children. This study aims to investigate the impact of caste on the neurodevelopment of children from birth to 36 months of age in Chitwan Valley, Nepal, where people are exposed to high levels of arsenic (As) and lead (Pb).
Participants (N = 94) were mother-infant pairs from the Chitwan district in Nepal. The neurodevelopment of the infants was assessed using the Brazelton Neonatal Behavioral Assessment Scale, Third Edition, (NBAS III) at birth and the Bayley Scales of Infant Development, Second Edition, (BSID II) at ages 6, 24, and 36 months. Caste was categorized based on surname, which, in Nepal generally refers to one of four caste groups. We also measured the concentrations of As and Pb in cord blood.
Caste was positively associated with the state regulation cluster score of the NBAS III at birth after adjustment for covariates (p for trend < 0.01). Adding cord blood As levels attenuated the association (p for trend = 0.12). With regard to neurodevelopment at six months of age, the third-ranked caste group scored higher than the first-ranked caste group on the Mental Development Index (MDI) of the BSID II (coefficient = 3.7; 95% confidence interval (CI) = 1.3 to 6.0). This difference remained significant after adjustment for cord blood As levels and other covariates was made (coefficient = 3.9; 95% CI = 1.2 to 6.7). The remaining clusters of the NBAS III and BSID II at 6, 24, and 36 months were not significantly associated with caste group.
Caste was positively associated with the state regulation cluster score of NBAS III at birth. This association was partially mediated by cord blood As levels. However, the negative impact of caste on neurodevelopment disappeared as the children grew. Furthermore, an inverse association between caste and MDI at six months of age was observed. Additional studies are needed to elucidate the mechanism of how caste affects neurodevelopment.
PMCID: PMC3941607  PMID: 24571600
Nepal; Caste system; Socioeconomic position; Child development; Toxic elements; Essential elements
21.  Validation of the Functional Status II questionnaire in the assessment of extremely-low-birthweight infants 
The increased survival of infants born at extremely low birthweight (ELBW) has been associated with significant morbidity, including higher rates of neurodevelopmental disability. However, formalized testing to evaluate these problems is both time-consuming and costly. The revised Functional Status questionnaire (FS-II) was designed to assess caregivers’ perceptions of the functional status of children with chronic diseases.
We evaluated the reliability and validity of the FS-II for ELBW infants at 18 to 22 months corrected age using data from the US Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN). Exploratory factor analyses were conducted using data from the network’s first follow-up study of 1080 children born in 1993 to 1994 (508 males, 572 females [53%]), and results were confirmed using data from the next network follow-up of 4022 children born in 1995 to 2000 (1864 males, 2158 females [54%]).
Results suggest that a two-factor solution comprising measures of general health and independence is most appropriate for ELBW infants. These factors differed from those found among chronically ill children, and new, more appropriate scales are presented for screening ELBW survivors. Both scales demonstrated good internal consistency: Cronbach’s α=0.87 for general health and α=0.75 for independence. Construct validity of the scales was assessed by comparing mean scores on the scales according to scores on the Bayley Scales of Infant Development, second edition (BSID-II), and medical conditions.
As hypothesized, infants with greater functional impairments according to their BSID-II scores or medical conditions had lower scores on the general health and independence scales, supporting the validity of the scales.
PMCID: PMC3031102  PMID: 19459909
22.  Developmental Status of Children of Teen Mothers: Contrasting Objective Assessments with Maternal Reports 
Descriptive study compared adolescent mothers’ subjective perceptions of their children’s development with objective developmental assessments.
Volunteer sample of mother/child pairs was recruited from urban high school. Thirty-three mothers completed Ages and Stages Questionnaire (A&SQ). Children were administered Bayley Scales of Infant Development (BSID).
On the BSID, group mean scores all fell within the normal range. However, almost 20% of individual children had one or more delays. Almost 73% of mothers accurately assessed their children’s development on the (A&SQ) when compared to BSID results. Eighteen percent of mothers suspected delays when there were none objectively identified. A single mother identified delay in a different domain than that identified on the BSID.
Findings that almost 20% of these children had developmental delays support other research that children of adolescent mothers are at risk for delays. Findings that teen mothers varied in their abilities to assess their children’s development reinforce the need for education of teen mothers about child development. Further study needed to determine the best models of this education in school and community settings.
PMCID: PMC3561665  PMID: 19720265
23.  Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double-blind, Randomized, Placebo-Controlled Trial 
Stem Cells (Dayton, Ohio)  2012;31(3):581-591.
Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children with CP were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy. The main outcomes were changes in scores on the following measures during the 6 months treatment period: the gross motor performance measure (GMPM), gross motor function measure, and Bayley scales of infant development-II (BSID-II) Mental and Motor scales (18). F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. The incidence of serious adverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain. Stem Cells2013;31:581–591
PMCID: PMC3744768  PMID: 23281216
Umbilical cord blood; Erythropoietin; Cerebral palsy; Clinical trial; Function
24.  A study of the correlation between BSID-III and KICDT for children with developmental delay 
[Purpose] The aim of the present study was to evaluate the usefulness of the BSID-III through the comparison of results from the BSID-III and KICDT and analyzing the correlation for each item. [Subjects] The subjects of the study were 27 children diagnosed with delayed development who had visited a pediatric rehabilitation care facility between January 2012 and October 2013. They are younger than 42 months of age. Other children with a congenital lesion or other conditions revealed by brain CT or MRI were excluded. [Results] The cognitive and fine motor categories among the lower categories of the BSID-III demonstrated strong correlations with the lower categories of the KICDT; however, the social-emotional category did not show any correlation. As a result, the BSID-III may be a useful testing tool for screening or for identification of developmental stages in children with delayed development. [Conclusion] Studies with various groups and ages should be done in the future, and there should be the Korean standards for the BSID-III.
PMCID: PMC4305579  PMID: 25642089
Bayley scale of infant development-III; Korean infant and child development test; Developmental delay
25.  A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations 
Angelman syndrome (AS) is a neurodevelopmental disorder caused by a deletion on chromosome 15, uniparental disomy (UPD), imprinting defect, or UBE3A mutation. It is characterized by intellectual disability with minimal speech and certain behavioral characteristics. We used standardized measures to characterize the developmental profile and to analyze genotype-phenotype correlations in AS.
The study population consisted of 92 children, between 5 months and 5 years of age, enrolled in a Natural History Study. Each participant was evaluated using the Bayley Scales of Infant and Toddler Development (Third Edition) (BSID-III), the Vineland Adaptive Behavior Scales (Second Edition) (VABS-II), and the Aberrant Behavior Checklist.
74% had a deletion and 26% had UPD, an imprinting defect or a UBE3A mutation (“non-deletion”). The mean±standard deviation (SD) BSID-III cognitive scale developmental quotient (DQ) was 40.5±15.5. Participants with deletions were more developmentally delayed than the non-deletion participants in all BSID-III domains except in expressive language skills. The cognitive DQ was higher than the DQ in each of the other domains, and the receptive language DQ was higher than the expressive language DQ. In the VABS-II, deletion participants had weaker motor and language skills than the non-deletion participants.
Children with AS have a distinct developmental and behavioral profile; their cognitive skills are stronger than their language and motor skills, and their receptive language skills are stronger than expressive language skills. Developmental outcomes are associated with genotype, with deletion patients having worse outcomes than non-deletion patients.
PMCID: PMC2997715  PMID: 20729760
Angelman syndrome; Development; Behavior; Phenotype

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