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1.  NICU Network Neurobehavioral Profiles Predict Developmental Outcomes in a Low Risk Sample 
Latent profile analysis (LPA) has been used previously to classify neurobehavioral responses of infants prenatally exposed to cocaine and other drugs of abuse. The objective of this study was to define NICU Network Neurobehavioral Scale (NNNS) profile response patterns in a cohort of infants with no known cocaine exposure or other risks for neurobehavior deficits, and determine whether these profiles predict neurobehavioral outcomes in these low-risk infants. NNNS exams were performed on 355 low-risk infants at approximately 5 weeks after birth. LPA was used to define discrete profiles based on the standard NNNS summary scales. Associations between the infant profiles and neurobehavioral outcomes at one to three years of age were examined.
Twelve of the 13 summary scales were used and three discrete NNNS profiles identified: social/easy going infants (44%), hypotonic infants (24%), and high arousal/difficult infants (32%). Statistically significant associations between NNNS profiles and later neurobehavioral outcomes were found for psychomotor development and externalizing behaviors. Hypotonic infants had both lower psychomotor development and lower externalizing scores compared to the other two profiles.
In conclusion, three distinct profiles of the NNNS summary scores were identifiable using LPA among infants with no known cocaine exposure. These profile patterns were associated with early childhood neurobehavioral outcome, similar to findings reported in a study of infants with substantial cocaine exposure, demonstrating the utility of this profiling technique in both exposed and unexposed populations.
PMCID: PMC3376022  PMID: 22686386
2.  Neonatal Neurobehavior Predicts Medical and Behavioral Outcome 
Pediatrics  2009;125(1):e90-e98.
This study examined the NICU Network Neurobehavioral Scale (NNNS) as a predictor of negative medical and behavioral findings one month to 4½ years of age.
. The sample included 1248 mother-infant dyads (42% born <37 weeks’ gestational age) participating in a longitudinal study of the effects of prenatal substance exposure on child development. Mothers were recruited at 4 urban university-based centers and were mostly African-American and on public assistance. At 1 month of age, infants were tested with the NICU Network Neurobehavioral Scale (NNNS). Latent Profile Analysis (LPA) was carried out on NNNS summary scales to identify discrete behavioral profiles. The validity of the NNNS was examined using logistic regression to predict prenatal drug exposure, medical and developmental outcomes through 4½ years of age including adjustment for gestational age and socioeconomic status (SES).
. Five discrete behavioral profiles were reliably identified with the most extreme negative profile found in 5.8% of the infants. The profiles showed statistically significant associations with prenatal drug exposure, gestational age and birthweight, head ultrasound, neurological and brain disease findings and abnormal scores on measures of behavior problems, school readiness and IQ through 4½ years of age.
The NNNS may be useful to identify infant behavioral needs to be targeted in well-baby pediatric care, as well as for referrals to community based early intervention services.
PMCID: PMC2873896  PMID: 19969621
NNNS; neonatal assessment; neurobehavioral; developmental outcomes; in utero drug exposure; latent profile analysis
3.  Patterns of Altered Neurobehavior in Preterm Infants within the NICU 
The Journal of pediatrics  2012;162(3):470-476.e1.
To investigate differences in neurobehavior between preterm infants at term and full term infants, changes in neurobehavior between 34 weeks postmenstrual age (PMA) and term equivalent in the preterm infant, and relationships of neurobehavior to perinatal exposures.
Study design
In this prospective cohort study, 75 infants were tested at 34 weeks PMA and again at term using the NICU Network Neurobehavioral Scale (NNNS). Infants had an MRI at term equivalent. Regression was used to investigate differences in NNNS domains of function across time and in relation to perinatal exposures.
At term equivalent, premature infants demonstrated altered behavior compared with full term infants with poorer orientation (p<.001), lower tolerance of handling (p<.001), lower self regulation (p<.001), poorer reflexes (p<.001), more stress (p<.001), hypertonicity (p<.001), hypotonia (p<.001), and more excitability (p=.007). Preterm infants, from 34 weeks PMA to term equivalent, demonstrated changes in motor functions with declining quality of movement (p=.006), increasing hypertonia (p<.001), decreasing hypotonia (p=.001) and changes in behavior with increasing arousal (p<.001), increasing excitability (p<.001), and decreasing lethargy (p<.001). Cerebral injury was associated with more excitability (p=.002). However, no associations between any of the perinatal exposures and developmental change from 34 weeks PMA to term equivalent were detected.
Preterm infants have altered neurobehavior in a broad number of domains at term equivalent. Cerebral injury alters neurobehavior but does not appear to impair early neurobehavioral change. Important neurobehavioral changes occur prior to term, and this provides an opportunity for interventions within the NICU.
PMCID: PMC3582758  PMID: 23036482
NNNS; Premature Infant Development; Cerebral Injury; Trajectory; Developmental Differences in Early Premature Infants; Abnormality; Behavior; Function; Neurobehavior
4.  Infant Growth Before and After Term: Effects on Neurodevelopment in Preterm Infants 
Pediatrics  2011;128(4):e899-e906.
To identify sensitive periods of postnatal growth for preterm infants relative to neurodevelopment at 18 months' corrected age.
We studied 613 infants born at <33 weeks' gestation who participated in the DHA for Improvement of Neurodevelopmental Outcome trial. We calculated linear slopes of growth in weight, length, BMI, and head circumference from 1 week of age to term (40 weeks' postmenstrual age), term to 4 months, and 4 to 12 months, and we estimated their associations with Bayley Scales of Infant Development, 2nd Edition, Mental (MDI) and Psychomotor (PDI) Development Indexes in linear regression.
The median gestational age was 30 (range: 2–33) weeks. Mean ± SD MDI was 94 ± 16, and PDI was 93 ± 16. From 1 week to term, greater weight gain (2.4 MDI points per z score [95% confidence interval (CI): 0.8–3.9]; 2.7 PDI points [95% CI: 1.2–.2]), BMI gain (1.7 MDI points [95% CI: 0.4–3.1]; 2.5 PDI points [95% CI: 1.2–3.9]), and head growth (1.4 MDI points [95% CI: −0.0–2.8]; 2.5 PDI points [95% CI: 1.2–3.9]) were associated with higher scores. From term to 4 months, greater weight gain (1.7 points [95% CI: 0.2–3.1]) and linear growth (2.0 points [95% CI: 0.7–3.2]), but not BMI gain, were associated with higher PDI. From 4 to 12 months, none of the growth measures was associated with MDI or PDI score.
In preterm infants, greater weight and BMI gain to term were associated with better neurodevelopmental outcomes. After term, greater weight gain was also associated with better outcomes, but increasing weight out of proportion to length did not confer additional benefit.
PMCID: PMC3182845  PMID: 21949135
growth; motor development; cognitive development; preterm infants
Depression and anxiety  2012;29(6):515-522.
Maternal depression is associated with a higher incidence of behavioral problems in infants, but the effects of maternal depression as early as 1 month are not well characterized. The objective of this study is to determine the neurobehavioral effects of maternal depression on infants exposed and not exposed to methamphetamine (MA) using the NICU Network Neurobehavioral Scale (NNNS).
Four hundred twelve mother–infant pairs were enrolled (MA = 204) and only biological mothers with custody of their child were included in the current analysis. At the 1-month visit (n = 126 MA-exposed; n = 193 MA-unexposed), the Beck Depression Inventory-II (BDI-II) was administered, and the NNNS was administered to the infant. Exposure was identified by self-report and/or gas chromatography/mass spectroscopy confirmation of amphetamine and metabolites in newborn meconium. Unexposed subjects were matched, denied amphetamine use, and had negative meconium screens. General Linear Models tested the effects of maternal depression and prenatal MA exposure on NNNS, with significance accepted at P < .05.
The MA group had an increased incidence of depression-positive diagnosis and increased depression scores on the BDI-II. After adjusting for covariates, MA exposure was associated with increased arousal and handling scores, and a decreased ability to self-regulate. Maternal depression was associated with higher autonomic stress and poorer quality of movement. No additional differences were observed in infants whose mothers were both depressed and used MA during pregnancy.
Maternal depression is associated with neurodevelopmental patterns of increased stress and decreased quality of movement, suggesting maternal depression influences neurodevelopment in infants as young as 1 month.
PMCID: PMC3717341  PMID: 22555777
amphetamine; drug; antenatal
6.  Maternal depression and neurobehavior in newborns prenatally exposed to methamphetamine 
Neurotoxicology and teratology  2008;31(3):177-182.
The effects of maternal depression on neonatal neurodevelopment in MA exposed neonates have not been well characterized.
To determine the neurobehavioral effects of maternal depressive symptoms on neonates exposed and not exposed to methamphetamine (MA) using the NICU Network Neurobehavioral Scale (NNNS).
The purpose of the IDEAL study is to determine the effects of prenatal MA exposure on child outcome. IDEAL screened 13,808 subjects, 1632 were eligible and consented and 176 mothers were enrolled. Only biological mothers with custody of their child at the one-month visit (n=50 MA; n=86 comparison) had the Addiction Severity Index (ASI) administered. The NNNS was administered to the neonate by an examiner blinded to MA exposure within the first five days of life. General Linear Models tested the effects of maternal depression and prenatal MA exposure on NNNS outcomes, with and without covariates. Significance was accepted at p<.05.
After adjusting for covariates, regardless of exposure status, maternal depressive symptoms were associated with lower handling and arousal scores, elevated physiological stress scores and an increased incidence of hypotonicity. When adjusting for covariates, MA exposure was associated with lower arousal and higher lethargy scores.
Maternal depressive symptoms are associated with neurodevelopmental patterns of decreased arousal and increased stress. Prenatal MA exposure combined with maternal depression was not associated with any additional neonatal neurodevelopmental differences.
PMCID: PMC2684459  PMID: 19059478
Prenatal exposure; Neurodevelopment; Drugs; Depression
7.  Prenatal methadone exposure and neonatal neurobehavioral functioning 
Pediatric research  2009;66(6):704-709.
Opioid-exposed infants display a wide and variable range of dysregulated neurobehavioral functioning, but the regulatory difficulties experienced by these infants outside the defined clusters of neonatal abstinence syndrome (NAS) have not been well described, and may have implications for the infant’s developmental course. This study describes the neurobehavioral functioning of neonates prenatally exposed to methadone using the NICU Network Neurobehavioral Scale (NNNS) and explores the relationships between maternal factors and infant functioning. The relationship between NNNS measures, NAS severity and need for pharmacotherapy for NAS were also evaluated. Infants who required pharmacological treatment for NAS showed more dysregulated behavior and signs of stress/abstinence as indicated by NNNS scores, but NNNS scores were not significantly correlated with maternal methadone dose. The determination of the range of the methadone exposed infant’s neurobehavioral repertoire could guide the optimal treatment of all such infants, particularly those requiring only non-pharmacological care.
PMCID: PMC2796281  PMID: 19690513
8.  Mother-infant consultation during drug treatment: Research and innovative clinical practice 
This paper details a model for consulting with mothers and infants, and drug treatment staff used in a residential drug treatment program and relevant to other treatment settings. The role of parent-infant consultation based on the Neonatal Network Neurobehavioral Scale (NNNS) was evaluated.
A sequential cohort model was used to assign participants to 1. NNNS consultation versus 2. standard care. The effects of NNNS consultation were evaluated using the Parenting Stress Index and NNNS summary scores.
Participants in the NNNS consultation condition had significantly less stress overall, and less stress related to infant behavior than participants in standard care. There were no differences in infant behavior on the NNNS Summary scores.
The implications for NNNS consultation in drug treatment programs is outlined. The importance of prevention/intervention to establish satisfactory mother-infant interaction in recovery programs which include a central parenting component is indicated.
PMCID: PMC2275235  PMID: 18254953
9.  Prenatal Exposure to Bisphenol A and Phthalates and Infant Neurobehavior 
Neurotoxicology and teratology  2011;33(5):558-566.
To examine the association of prenatal exposure to bisphenol A and select common phthalates with infant neurobehavior measured at 5 weeks.
We compared the concentration of maternal urinary metabolites of bisphenol A and phthalates at two distinct time points in pregnancy (16w, 26w) with scores on the NICU Network Neurobehavioral Scale (NNNS) at 5 weeks of age in a cohort of 350 mother/infant pairs.
Prenatal exposure to BPA was not significantly associated with neurobehavioral outcomes at 5 weeks. Significant associations between prenatal exposure to measured phthalates and infant neurobehavioral outcomes differed by type of phthalate and were only seen with exposure measured at 26 weeks. Higher total di-butyl phthalate (DBP) metabolites at 26w was associated with improved behavioral organization evidenced by decreased arousal (p=.04), increased self-regulation (p=.052), and decreased handling (p=.02). In males, higher total di-2-ethylhexyl phthalate (DEHP) metabolites at 26w was associated with more nonoptimal reflexes (p=.02).
The association between prenatal phthalate exposure and infant neurobehavior differed by type of phthalate and was evident only with exposure measured at 26w. Prenatal exposure to DBP was associated with improved behavioral organization in 5-week-old infants. Prenatal exposure to DEHP was associated with nonoptimal reflexes in male infants. There was no evidence of an association between prenatal BPA exposure and infant neurobehavior.
PMCID: PMC3183357  PMID: 21854843
Bisphenol A; Infant neurobehavior; Phthalates; Prenatal exposure
10.  Depressive Symptoms During Pregnancy: Impact on Neuroendocrine and Neonatal Outcomes 
Infant behavior & development  2010;34(1):26-34.
To explore the interplay of maternal depressive symptoms on the infant limbic-hypothalamic-pituitary-axis (LHPA) and neurological development.
Pregnant women were monitored for depressive symptoms using the Beck Depression Inventory (BDI) at 28, 32, and 37 weeks of gestation and at delivery. A mixture growth curve analysis divided the women into three risk groups: low/stable, intermediate, and high/increasing depression based on BDI scores. The infant neuroendocrine system was examined using cord blood for adrenocorticotrophic hormone (ACTH) and cortisol measurements. Two week old infants were examined using Neonatal Intensive Care Unit Neurobehavioral Scale (NNNS).
Infants born to women of the high/increasing depression group had significant ACTH elevation at birth. On NNNS examination, these infants were more hypotonic and habituated to auditory and visual stimuli.
When compared to non-depressed women, maternal depressive symptoms, even in the absence of major depressive disorder, appeared to facilitate a different developmental pathway for the infant LHPA and early neurological development.
PMCID: PMC3053131  PMID: 21035873
Depression; Pregnancy; Infant Outcomes; Neuroendocrine System
11.  A randomised multicentre study of human milk versus formula and later development in preterm infants. 
Whether breast milk influences later neurodevelopment has been explored in non-randomised studies, potentially confounded by social and demographic differences between feed groups. Here in a strictly randomised prospective multicentre trial, Bayley psychomotor and mental development indices (PDI and MDI) were assessed at 18 months postterm in survivors of 502 preterm infants assigned to receive, during their early weeks, mature donor breast milk or a preterm formula. These diets were compared as sole enteral feeds or as supplements to the mother's expressed breast milk. No differences in outcome at 18 months were seen between the two diet groups despite the low nutrient content of donor milk in relation to the preterm formula and to the estimated needs of preterm infants. These results contrast with those reported from our parallel two centre study that compared infants randomly assigned a standard term formula or the preterm formula during their early weeks; those fed standard formula, now regarded as nutritionally insufficient for preterm infants, were substantially disadvantaged in PDI and MDI at 18 months post-term. It is shown here that infants from that study fed solely on standard formula had significantly lower developmental scores at 18 months than those fed on donor breast milk in the present study; yet the standard formula had a higher nutrient content than the donor milk. Thus, donor milk feeding was associated with advantages for later development that may have offset any potentially deleterious effects of its low nutrient content for preterm infants. As these outcome advantages were not confounded by the social and educational biases usually associated with mothers' choice to breast feed, our data add significant support to the view that breast milk promotes neurodevelopment.
PMCID: PMC1061016  PMID: 8154907
12.  Prenatal Methamphetamine Use and Neonatal Neurobehavioral Outcome 
Neurotoxicology and teratology  2007;30(1):20-28.
Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How prenatal MA exposure affects neonatal neurobehavior is unknown.
To examine the neurobehavioral effects of prenatal MA exposure.
The Infant Development, Environment and Lifestyle (IDEAL) study screened 13,808 subjects and 1632 were eligible and consented. 166 (n=74 exposed) were enrolled in a longitudinal follow up. Exposure was determined by meconium assay and self-report with alcohol, marijuana, and tobacco present in both groups. The NICU Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life. Analyses conducted on NNNS summary scores included exposure group effects, heavy MA use effects, association with frequency of use by trimester, and dose-response relationships with amphetamine metabolites.
After adjusting for covariates, exposure to MA was associated with increased physiological stress. Heavy MA use was related to lower arousal, more lethargy, and increased physiological stress. First trimester MA use was related to elevated physiological stress. Third trimester use was related to poorer quality of movement. Higher level of amphetamine metabolites in meconium was associated with increased CNS stress.
Prenatal MA exposure was associated with neurobehavioral patterns of decreased arousal, increased stress, and poor quality of movement. The dose response relationships may represent neurotoxic effects from MA.
PMCID: PMC2358984  PMID: 18031987
prenatal exposure; neurodevelopment; drug; meconium
13.  Prenatal methamphetamine exposure and neonatal neurobehavioral outcome in the USA and New Zealand 
Neurotoxicology and teratology  2010;33(1):166-175.
Methamphetamine (MA) use among pregnant women is a world-wide problem, but little is known of its impact on exposed infants.
The prospective, controlled longitudinal Infant Development, Environment and Lifestyle (IDEAL) study of prenatal MA exposure from birth to 36 months was conducted in the US and NZ. The US cohort has 183 exposed and 196 comparison infants; the NZ cohort has 85 exposed and 95 comparison infants. Exposure was determined by self-report and meconium assay with alcohol, marijuana, and tobacco exposures present in both groups. The NICU Neurobehavior Scale (NNNS) was administered within 5 days of life. NNNS summary scores were analyzed for exposure including heavy exposure and frequency of use by trimester and dose-response relationship with the amphetamine analyte.
MA Exposure was associated with poorer quality of movement, more total stress/abstinence, physiological stress, and CNS stress with more nonoptimal reflexes in NZ but not in the USA. Heavy MA exposure was associated with lower arousal and excitability. First trimester MA use predicted more stress and third trimester use more lethargy and hypotonicity. Dose-response effects were observed between amphetamine concentration in meconium and CNS stress.
Across cultures, prenatal MA exposure was associated with a similar neurobehavioral pattern of under arousal, low tone, poorer quality of movement and increased stress.
PMCID: PMC2974956  PMID: 20615464
Prenatal exposure; Methamphetamine; Neurodevelopment; Meconium
14.  Prenatal Dichlorodiphenyldichloroethylene (DDE) exposure and neurodevelopment: A follow-up from 12 to 30 months of age 
Neurotoxicology  2009;30(6):1162-1165.
In order to evaluate the persistency of the association between DDE and infant neurodevelopment we assessed mental and psychomotor development between 12 and 30 months of age in an ongoing cohort in Mexico.
A total of 270 singleton children without perinatal asphyxia diagnosis, with a birth weight ≥ 2 kg, mothers > 15 years of age with organochlorine maternal serum levels measured at least in one trimester of pregnancy, and who were evaluated at least in two of the four visits at 12, 18, 24 and 30 months of age, were included in this report. The Spanish version of Bayley Scales of Infant Development II (BSID-II) was administered to the children and Psychomotor Development Index (PDI) and Mental Development Index (MDI) were calculated. Information about stimulation at home was measured using the Home Observation of Measurement of the Environment (HOME) at six months, and breastfeeding history was obtained through direct interviews with the mothers.
Maternal serum DDE levels were determined during pregnancy by means of electron capture gas-liquid chromatography. The association between DDE prenatal exposure and neurodevelopment was estimated using separate generalized mixed effects models.
Our results suggest that the association between prenatal DDE and infant neurodevelopment does not persist beyond 12 months of age even after adjusting for known risk factors for neurodevelopment. In addition, we observed an interaction between early home stimulation and mental improvement at 24 and 30 months of age(p<0.001).
The association of DDE with infant neurodevelopment seems to be reversible. However, we cannot rule out that other DDT metabolites may play a role in neurodevelopment.
PMCID: PMC2789862  PMID: 19733589
15.  Grade and Laterality of Intraventricular Hemorrhage to Predict 18–22 Month Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
To determine whether extremely low birth weight (ELBW) infants with bilateral compared to unilateral intraventricular hemorrhage (IVH) have worse neurodevelopmental outcomes at 18–22 months.
166 ELBW infants (<1000 g) admitted to a Cincinnati NICU from 1998–2005 with a head ultrasound showing Grade I–IV IVH and neurodevelopmental assessment at 18–22 months corrected age were included. Multivariable linear and logistic regression models were developed to determine the impact of laterality and grade of IVH and other clinical variables to predict scores on the Bayley Scales of Infant Development, Second Edition, Mental Development Index (MDI) and Psychomotor Development Index (PDI) and the combined outcome of neurodevelopmental impairment (NDI).
Infants with bilateral grade IV IVH had lower adjusted mean Bayley scores compared with infants with unilateral grade IV IVH. For grades I, II, and III IVH, bilaterality of IVH was not associated with lower mean Bayley scores. Infants with grade IV IVH had the highest odds of NDI. The probability of NDI increased with sepsis and postnatal steroid use.
ELBW infants with bilateral compared to those with unilateral grade IV IVH had worse neurodevelopmental outcomes. Infants with grades I–III IVH had similar outcomes whether they had unilateral or bilateral IVH.
PMCID: PMC3475499  PMID: 22220735
premature; sepsis; steroids; Bayley; cognitive; motor
Infant behavior & development  2011;34(2):280-292.
Traditionally, developmental psychology, occupational/physical therapy, and behavioral pediatrics view similar infant behaviors from temperament, sensory processing, or neurobehavioral theoretical perspectives. This study examined the relations between similar and unique summary scores of three infant assessments (Early Infancy Temperament Questionnaire - EITQ, the Infant Sensory Profile - ISP, and the NICU Network Neurobehavioral Scale – NNNS) in a healthy sample of 100, one-month-old infants. A Principal Components Analysis of selected subscale scores derived from the three assessments suggested a three-factor model. Temperament and sensory summary scores had the strongest relations on two factors: Sensory-Affective Reactivity and Engagement. A third factor had strong relations between state regulation and motor competence. This new integrative model also validates an existing model and expands explanation of infant behavior across disciplines and methods which have significant implications for assessment, intervention, and management practices.
PMCID: PMC3109213  PMID: 21397952
Infancy; measurement; temperament; neonatal exam; sensory processing; multidisciplinary
17.  Fatty acid ethyl esters in meconium are associated with poorer neurodevelopmental outcomes to two years of age 
The Journal of pediatrics  2008;152(6):788-792.
To determine the relationship between fatty acid ethyl esters (FAEE) in meconium and neurodevelopment in infants exposed to alcohol in utero at 6.5 months, 1 year, and 2 years of age.
Study design
A secondary analysis of a prospective cohort of high risk mothers and their infants recruited after admission to a labor and delivery unit. Mothers were screened for drug and alcohol use during pregnancy using clinical interview and urine screening. Meconium was analyzed for FAEE in 216 newborn infants. Outcome measures included the Bayley Scales of Infant Development Mental (MDI) and Psychomotor (PDI) Developmental Index scores in infants at 6.5 months, 1 year, and 2 years of age.
After controlling for prenatal visits and maternal factors, increasing concentrations of FAEE were significantly associated with poorer mental and psychomotor development (β±standard error) at all follow-up visits: ethyl myristate (MDI −2.46±1.24, P=0.05; PDI −3.88±1.67, P=0.02), ethyl oleate (MDI −1.94± 0.65, P<0.01; PDI −2.60±0.93, P<0.01), ethyl linoleate (MDI −1.92±0.60, P<0.01; PDI −2.28±0.84, P<0.01), ethyl linolenate (MDI −1.99±0.74, P<0.01; PDI −2.98±1.04, P<0.01), and ethyl arachidonate (MDI −2.40±1.11, P=0.03; PDI −3.32±1.51, P=0.03).
FAEE in meconium may be a marker for identifying newborns at risk for neurodevelopmental delay from alcohol exposure in utero.
PMCID: PMC2452987  PMID: 18492517
ethanol; pregnancy; prenatal alcohol exposure; fetal alcohol syndrome; fetal alcohol spectrum disorder; neurodevelopment
18.  A Predictive Model for Neurodevelopmental Outcome Following the Norwood Procedure 
Pediatric cardiology  2012;34(2):327-333.
Neurodevelopmental outcomes following the Norwood procedure for single right ventricular lesions are worse than those in the normal population. It would be valuable to identify which patients at the time of Norwood discharge are at greatest risk of neurodevelopmental impairment later in childhood. As such, we sought to construct and validate a model to predict poor neurodevelopmental outcome using variables readily available to the clinician. Using data from 14-month neurodevelopmental outcome of the Single Ventricle Reconstruction (SVR) trial, a Classification and Regression Tree (CART) analysis model was developed to predict severe neurodevelopmental impairment, defined as a Psychomotor Development Index (PDI) of <70 on the Bayley Scales of Infant Development®-II. The model was then validated using data from subjects enrolled in the Infant Single Ventricle (ISV) trial.
PDI scores were <70 in 138 of 313 subjects (44%). Predictors of PDI<70 were: post-Norwood length of ICU stay >46 days, genetic syndrome or other anomalies, birth weight <2.7 kg, additional cardiac surgical procedures, and use of ≥5 medications at hospital discharge. Using these risk factors, the CART model correctly identified 75% of SVR subjects with PDI<70. When the CART model was applied to 70 subjects from the ISV trial, the correct classification rate was 67%.
This model of variables from the Norwood hospitalization can help identify infants at risk for neurodevelopmental impairment. However, given the overall high prevalence of neurodevelopmental impairment and the fact that nearly one-third of severely affected children would not have been identified by these risk factors, close surveillance and assessment for early intervention services is warranted for all infants following the Norwood procedure.
PMCID: PMC3505274  PMID: 22864647
Neurodevelopment; congenital heart; outcomes
19.  Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage 
To determine whether death and/or neurodevelopmental impairment (NDI) after severe intracranial hemorrhage (ICH; grade 3 or 4) differs by gestational age (GA) at birth in extremely low birth weight (ELBW) infants.
Study Design
Demographic, perinatal and neonatal factors potentially contributing to NDI for ELBW infants (23 to 28 weeks gestation) were obtained retrospectively; outcome data came from the ELBW Follow-up Study. NDI was defined at 18 to 22 months corrected age as moderate/severe cerebral palsy, Bayley Scales of Infant Development II cognitive or motor score <70, and/or blindness or deafness. Characteristics of younger versus older infants with no versus severe ICH associated with death or NDI were compared. Generalized linear mixed models predicted death or NDI in each GA cohort.
Of the 6638 infants, 61.8% had no ICH and 13.6% had severe ICH; 39% of survivors had NDI. Risk-adjusted odds of death or NDI and death were higher in the lower GA group. Lower GA increased the odds of death before 30 days for infants with severe ICH. Necrotizing enterocolitis (particularly surgical NEC), late onset infection, cystic periventricular leukomalacia and post-natal steroids contributed to mortality risk. NDI differed by GA in infants without ICH and grade 3, but not grade 4 ICH. Contributors to NDI in infants with severe ICH included male gender, surgical NEC and post-hemorrhagic hydrocephalus requiring a shunt.
GA contributes to the risk of death in ELBW infants, but not NDI among survivors with severe ICH. Male gender, surgical NEC and need for a shunt add additional risk for NDI.
PMCID: PMC3777699  PMID: 22814942
infant; premature; extremely low birth weight; death; neurodevelopmental impairment
20.  Organophosphate Pesticide Exposure and Neurodevelopment in Young Mexican-American Children 
Environmental Health Perspectives  2007;115(5):792-798.
Organophosphate (OP) pesticides are widely used in agriculture and homes. Animal studies suggest that even moderate doses are neurodevelopmental toxicants, but there are few studies in humans.
We investigated the relationship of prenatal and child OP urinary metabolite levels with children’s neurodevelopment.
Participating children were from a longitudinal birth cohort of primarily Latino farm-worker families in California. We measured six nonspecific dialkylphosphate (DAP) metabolites in maternal and child urine as well as metabolites specific to malathion (MDA) and chlorpyrifos (TCPy) in maternal urine. We examined their association with children’s performance at 6 (n = 396), 12 (n = 395), and 24 (n = 372) months of age on the Bayley Scales of Infant Development [Mental Development (MDI) and Psychomotor Development (PDI) Indices] and mother’s report on the Child Behavior Checklist (CBCL) (n = 356).
Generally, pregnancy DAP levels were negatively associated with MDI, but child measures were positively associated. At 24 months of age, these associations reached statistical significance [per 10-fold increase in prenatal DAPs: β = −3.5 points; 95% confidence interval (CI), −6.6 to −0.5; child DAPs: β = 2.4 points; 95% CI, 0.5 to 4.2]. Neither prenatal nor child DAPs were associated with PDI or CBCL attention problems, but both prenatal and postnatal DAPs were associated with risk of pervasive developmental disorder [per 10-fold increase in prenatal DAPs: odds ratio (OR) = 2.3, p = 0.05; child DAPs OR = 1.7, p = 0.04]. MDA and TCPy were not associated with any outcome.
We report adverse associations of prenatal DAPs with mental development and pervasive developmental problems at 24 months of age. Results should be interpreted with caution given the observed positive relationship with postnatal DAPs.
PMCID: PMC1867968  PMID: 17520070
Bayley Scales of Infant Development; Child Behavior Checklist; DAPs; farmworker; Mexican Americans; neurodevelopment; organophosphates; pervasive developmental disorder; pesticides
21.  The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth 
Aims: To describe perinatal factors associated with later morbidity among extremely preterm children at 30 months of age corrected for prematurity.
Population: Of 308 surviving children born at ⩽25 weeks gestation in the United Kingdom and Ireland from March to December 1995, 283 (92%) were evaluated at 30 months of age corrected for prematurity.
Methods: Cerebral palsy, severe motor disability, and Bayley scores were used as dependent variables in sequential multiple regression analyses to identify factors associated with adverse outcomes.
Results: Adverse outcomes were consistently more common in boys. Factors related to perinatal illness, ultrasound evidence of brain injury, and treatment (particularly postnatal steroids) were associated with adverse motor outcomes (cerebral palsy, disability or Bayley psychomotor development index). Increasing duration of postnatal steroid treatment was associated with poor motor outcomes. A score was developed for severe motor disability with good negative predictive value. In contrast, mental development was associated with a broader range of factors: ethnic group, maternal educational level, the use of antenatal steroids, and prolonged rupture of membranes in addition to chronic lung disease.
Conclusion: Male sex is a pervasive risk factor for poor outcome at extremely low gestations. Avoidable or effective treatment factors are identified, which may indicate the potential for improving outcome.
PMCID: PMC1721849  PMID: 15724037
22.  Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008 
BMC Pediatrics  2012;12:198.
While survival rates of extremely preterm infants have improved over the last decades, the incidence of neurodevelopmental disability (ND) in survivors remains high. Representative current data on the severity of disability and of risk factors associated with poor outcome in this growing population are necessary for clinical guidance and parent counselling.
Prospective longitudinal multicentre cohort study of preterm infants born in Switzerland between 240/7 and 276/7 weeks gestational age during 2000–2008. Mortality, adverse outcome (death or severe ND) at two years, and predictors for poor outcome were analysed using multilevel multivariate logistic regression. Neurodevelopment was assessed using Bayley Scales of Infant Development II. Cerebral palsy was graded after the Gross Motor Function Classification System.
Of 1266 live born infants, 422 (33%) died. Follow-up information was available for 684 (81%) survivors: 440 (64%) showed favourable outcome, 166 (24%) moderate ND, and 78 (11%) severe ND. At birth, lower gestational age, intrauterine growth restriction and absence of antenatal corticosteroids were associated with mortality and adverse outcome (p < 0.001). At 360/7 weeks postmenstrual age, bronchopulmonary dysplasia, major brain injury and retinopathy of prematurity were the main predictors for adverse outcome (p < 0.05). Survival without moderate or severe ND increased from 27% to 39% during the observation period (p = 0.02).
In this recent Swiss national cohort study of extremely preterm infants, neonatal mortality was determined by gestational age, birth weight, and antenatal corticosteroids while neurodevelopmental outcome was determined by the major neonatal morbidities. We observed an increase of survival without moderate or severe disability.
PMCID: PMC3546845  PMID: 23272671
Development; Disability; Mortality; Outcome; Preterm
23.  Outcome of Extremely Low Birth Weight Infants with Congenital Heart Defects in the Eunice Kennedy Shriver NICHD Neonatal Research Network 
Pediatric cardiology  2012;33(8):1415-1426.
Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401–1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998 and December 31, 2005. Neonatal morbidities and 18–22 months’ corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index < 70, bilateral blindness, or hearing impairment requiring aids. Poisson regression models were used to estimate relative risks for outcomes while adjusting for gestational age, small for gestational-age status, and other variables. Of 14,457 ELBW infants, 110 (0.8 %) had isolated CHD, and 13,887 (96 %) had no major birth defect. The most common CHD were septal defects, tetralogy of Fallot, pulmonary valve stenosis, and coarctation of the aorta. Infants with CHD experienced increased mortality (48 % compared with 35 % for infants with no birth defect) and poorer growth. Surprisingly, the adjusted risks of other short-term neonatal morbidities associated with prematurity were not significantly different. Fifty-seven (52 %) infants with CHD survived to 18–22 months’ corrected age, and 49 (86 %) infants completed follow-up. A higher proportion of surviving infants with CHD were impaired compared with those without birth defects (57 vs. 38 %, p = 0.004). Risk of death or NDI was greater for ELBW infants with CHD, although 20% of infants survived without NDI.
PMCID: PMC3687358  PMID: 22644414
heart defects; congenital; follow-up studies
24.  Association of Neuroprotection and Oxidative Stress Gene Polymorphism With Neurodevelopmental Outcomes After Preterm Birth 
Obstetrics and gynecology  2012;120(3):542-550.
To estimate the associations between neuronal homeostasis, neuroprotection, and oxidative stress candidate gene polymorphisms and neurodevelopmental disability.
This was a nested case-control analysis of a randomized trial of magnesium sulfate administered to women at imminent risk for early (prior to 32 weeks) preterm birth for the prevention of death or cerebral palsy in their offspring. We evaluated 21 single nucleotide polymorphisms (SNPs) in 17 genes associated with neuronal homeostasis, neuroprotection or oxidative stress in umbilical cord blood. Cases were infant deaths (n=43) and children diagnosed with cerebral palsy (n=24), mental delay (Bayley Mental Developmental Index <70; n=109) and/or psychomotor delay (Bayley Psychomotor Developmental Index <70; n=91). Controls were race- and gender-matched children with normal neurodevelopment. Associations between each SNP and each outcome were assessed in logistic regression models assuming an additive genetic pattern, conditional on maternal race and infant gender, and adjusting for study drug assignment, gestational age at birth, and maternal education.
The odds of cerebral palsy were increased more than 2.5 times for each copy of the minor allele (A) of Vasoactive intestinal polypeptide (VIP) (rs17083008) (aOR 2.67 95% CI 1.09–6.55; p=0.03), and 4.5 times for each copy of the minor allele (T) of N-methyl-D-aspartate receptor subunit 3A (GRIN3A, rs3739722) (aOR 4.67 95% CI 1.36–16.01; p=0.01).The association between the receptor for advanced glycation endproducts (AGER, rs3134945) SNP and mental delay was modulated by study drug allocation (p=0.02).
VIP and NMDA receptor subunit 3A (GRIN3A) SNPs may be associated with cerebral palsy at age 2 in infants after preterm birth.
PMCID: PMC3904537  PMID: 22914463
25.  Association of Impaired Linear Growth and Worse Neurodevelopmental Outcome in Infants with Single Ventricle Physiology: A Report from the Pediatric Heart Network Infant Single Ventricle Trial 
The Journal of pediatrics  2012;162(2):250-256.e2.
To describe neurodevelopmental outcomes in infants with single ventricle (SV) physiology and determine factors associated with worse outcomes.
Study design
Neurodevelopmental outcomes for infants with SV enrolled in a multicenter drug trial were assessed at 14 months of age using the Bayley Scales of Infant Development-II. Multivariable regression analysis was used to identify factors associated with worse outcomes.
Neurodevelopmental testing was performed at 14±1 months in 170/185 subjects in the trial. Hypoplastic left heart syndrome was present in 59% and 75% had undergone the Norwood operation. Mean psychomotor (PDI) and mental developmental indices (MDI) were 80±18 and 96±14 respectively (normal 100±15, P<0.001 for each). Group-based trajectory analysis provided a two-group model (high” and “low”) for height z-score trajectory and brain type natriuretic peptide (BNP) trajectory. The predicted PDI scores were 15 points higher in the “high” height z-score trajectory compared with the “low” cluster (P<.001). A higher number of serious adverse events during the trial was associated with lower PDI scores (P=.02). The predicted MDI scores were 13–17 points lower in “low height trajectory- high BNP trajectory” group compared with the other three groups (P<.001). MDI scores were also lower in subjects who required extracorporeal membrane oxygenation during the neonatal hospitalization (P=.01) or supplemental oxygen at discharge (P=.01).
Neurodevelopmental outcome at 14 months of age is impaired in infants with SV physiology. Low height trajectory and high BNP trajectory were associated with worse neurodevelopmental outcomes. Efforts to improve nutritional status alone may not improve neurodevelopmental outcomes.
PMCID: PMC3547153  PMID: 22939929

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