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1.  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
2.  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
3.  Level of NICU Quality of Developmental Care and Neurobehavioral Performance in Very Preterm Infants 
Pediatrics  2012;129(5):e1129-e1137.
To examine the relation between the neurobehavior of very preterm infants and the level of NICU quality of developmental care.
The neurobehavior of 178 very preterm infants (gestational age ≤29 weeks and/or birth weight ≤1500 g) from 25 NICUs participating in a large multicenter, longitudinal study (Neonatal Adequate Care for Quality of Life, NEO-ACQUA) was examined with a standardized neurobehavioral assessment, the NICU Network Neurobehavioral Scale (NNNS). A questionnaire, the NEO-ACQUA Quality of Care Checklist was used to evaluate the level of developmental care in each of the NICUs. A factor analyses applied to NEO-ACQUA Quality of Care Checklist produced 2 main factors: (1) the infant-centered care (ICC) index, which measures parents’ involvement in the care of their infant and other developmentally oriented care interventions, and (2) the infant pain management (IPM) index, which measures the NICU approach to and the procedures used for reducing infant pain. The relations between NNNS neurobehavioral scores and the 2 indexes were evaluated.
Infants from NICUs with high scores on the ICC evidenced higher attention and regulation, less excitability and hypotonicity, and lower stress/abstinence NNNS scores than infants from low-care units. Infants from NICUs with high scores on the IPM evidenced higher attention and arousal, lower lethargy and nonoptimal reflexes NNNS scores than preterm infants from low-scoring NICUs.
Very preterm infant neurobehavior was associated with higher levels of developmental care both in ICC and in IPM, suggesting that these practices support better neurobehavioral stability.
PMCID: PMC4074610  PMID: 22492762
preterm infant; very low birth weight; developmental care; pain management; neurobehavioral examination; NNNS
4.  Neurobehavioral Outcomes of Infants Exposed to MDMA (Ecstasy) and Other Recreational Drugs During Pregnancy 
Neurotoxicology and Teratology  2012;34(3):303-310.
3,4-methylenedioxymethamphetamine (MDMA) or “Ecstasy” is one of the most widely used illicit recreational drugs among young adults. MDMA is an indirect monoaminergic agonist and reuptake inhibitor that primarily affects the serotonin system. Preclinical studies in animals have found prenatal exposure related to neonatal tremors and long-term learning and memory impairments. To date, there are no prospective studies of the sequelae of prenatal exposure to MDMA in humans, despite concerns about its potential for harmful effects to the fetus. The present study is the first to prospectively identify MDMA-using women during pregnancy and to document patterns and correlates of use with neonatal and early infancy outcomes of offspring.
All mothers and infants were prospectively recruited through the Case Western Reserve University (CWRU) and University of East London (UEL) Drugs and Infancy Study (DAISY) that focused on recreational drug use in pregnant women. Women were interviewed about substance use prior to and during pregnancy and infants were seen at 1 and 4 months using standardized, normative assessments of neonatal behavior, and cognitive and motor development, including the NICU Network Neurobehavioral Scale (NNNS), the Bayley Mental and Motor Development Scales (MDI, PDI), and the Alberta Infant Motor Scales (AIMS). The sample was primarily middle class with some university education and in stable partner relationships. The majority of women recruited had taken a number of illicit drugs prior to or during pregnancy. Group differences between those polydrug using women who had specifically used MDMA during pregnancy (n = 28) and those who had not (n = 68) were assessed using chi-square and t-tests. MDMA and other drug effects were assessed through multiple regression analyses controlling for confounding variables.
Women who used MDMA during pregnancy had fewer prior births and more negative sequelae associated with their drug use, including more health, work, and social problems. MDMA exposed infants differed in sex ratio (more male births) and had poorer motor quality and lower milestone attainment at 4 months, with a dose-response relationship to amount of MDMA exposure. These findings suggest risk to the developing infant related to MDMA exposure and warrant continued follow-up to determine whether early motor delays persist or resolve.
PMCID: PMC3367027  PMID: 22387807
Methylenedioxymethamphetamine “MDMA”; “Ecstasy”; infant development; drugs; sex ratio; motor skills; Townes-Brocks
5.  Chronic Lung Disease and Developmental Delay at 2 Years of Age in Children Born Before 28 Weeks' Gestation 
Pediatrics  2009;124(2):637-648.
Extremely low gestational age newborns (ELGANs) are at increased risk of chronic lung disease (CLD) and of developmental delay. Some studies have suggested that CLD contributes to developmental delay.
Patients and Methods
We examined data collected prospectively on 915 infants born before the 28th week of gestation in 2002–2004 who were assessed at 24 months of age with the Bayley Scales of Infant Development-2nd Edition or the Vineland Adaptive Behavior Scales. We excluded infants who were not able to walk independently (Gross Motor Function Classification System score < 1) and, therefore, more likely to have functionally important fine motor impairments. We defined CLD as receipt of oxygen at 36 weeks' postmenstrual age and classified infants as either not receiving mechanical ventilation (MV) (CLD without MV) or receiving MV (CLD with MV).
Forty-nine percent of ELGANs had CLD; of these, 14% were receiving MV at 36 weeks' postmenstrual age. ELGANs without CLD had the lowest risk of a Mental Developmental Index (MDI) or a Psychomotor Developmental Index (PDI) of <55, followed by ELGANs with CLD not receiving MV, and ELGANs with CLD receiving MV (9%, 12%, and 18% for the MDI and 7%, 10%, and 20% for the PDI, respectively). In time-oriented multivariate models, the risk of an MDI of <55 was associated with the following variables: gestational age of <25 weeks; single mother; late bacteremia; pneumothorax; and necrotizing enterocolitis. The risk of a PDI of <55 was associated with variables such as single mother, a complete course of antenatal corticosteroids, early and persistent pulmonary dysfunction, pulmonary deterioration during the second postnatal week, pneumothorax, and pulmonary interstitial emphysema. CLD, without or with MV, was not associated with the risk of either a low MDI or a low PDI. However, CLD with MV approached, but did not achieve, nominal statistical significance (odds ratio: 1.9 [95% confidence interval: 0.97–3.9]) for the association with a PDI of <55.
Among children without severe gross motor delays, risk factors for CLD account for the association between CLD and developmental delay. Once those factors are considered in time-oriented risk models, CLD does not seem to increase the risk of either a low MDI or a low PDI. However, severe CLD might increase the risk of a low PDI.
PMCID: PMC2799188  PMID: 19620203
lung disease; prematurity; preterm infant; neurodevelopmental outcome
6.  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
7.  Post-neonatal Mortality, Morbidity, and Developmental Outcome after Ultrasound-Dated Preterm Birth in Rural Malawi: A Community-Based Cohort Study 
PLoS Medicine  2011;8(11):e1001121.
Using data collected as a follow-up to a randomized trial, Melissa Gladstone and colleagues show that during the first two years of life, infants born preterm in southern Malawi are disadvantaged in terms of mortality, growth, and development.
Preterm birth is considered to be associated with an estimated 27% of neonatal deaths, the majority in resource-poor countries where rates of prematurity are high. There is no information on medium term outcomes after accurately determined preterm birth in such settings.
Methods and Findings
This community-based stratified cohort study conducted between May–December 2006 in Southern Malawi followed up 840 post-neonatal infants born to mothers who had received antenatal antibiotic prophylaxis/placebo in an attempt to reduce rates of preterm birth (APPLe trial ISRCTN84023116). Gestational age at delivery was based on ultrasound measurement of fetal bi-parietal diameter in early-mid pregnancy. 247 infants born before 37 wk gestation and 593 term infants were assessed at 12, 18, or 24 months. We assessed survival (death), morbidity (reported by carer, admissions, out-patient attendance), growth (weight and height), and development (Ten Question Questionnaire [TQQ] and Malawi Developmental Assessment Tool [MDAT]). Preterm infants were at significantly greater risk of death (hazard ratio 1.79, 95% CI 1.09–2.95). Surviving preterm infants were more likely to be underweight (weight-for-age z score; p<0.001) or wasted (weight-for-length z score; p<0.01) with no effect of gestational age at delivery. Preterm infants more often screened positively for disability on the Ten Question Questionnaire (p = 0.002). They also had higher rates of developmental delay on the MDAT at 18 months (p = 0.009), with gestational age at delivery (p = 0.01) increasing this likelihood. Morbidity—visits to a health centre (93%) and admissions to hospital (22%)—was similar for both groups.
During the first 2 years of life, infants who are born preterm in resource poor countries, continue to be at a disadvantage in terms of mortality, growth, and development. In addition to interventions in the immediate neonatal period, a refocus on early childhood is needed to improve outcomes for infants born preterm in low-income settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Being born at term in Africa is not necessarily straightforward. In Malawi, 33 of every 1,000 infants born die in the first 28 days after birth; the lifetime risk for a mother dying during or shortly after pregnancy is one in 36. The comparable figures for the United Kingdom are three infants dying per 1,000 births and a lifetime risk of maternal death of one in 4,700. But for a baby, being born preterm is even more risky and the gap between low- and high-income countries widens still further. According to a World Health Organization report in 2010, a baby born at 32 weeks of gestation (weighing around 2,000 g) in Africa has little chance of survival, while the chances of survival for a baby born at 32 weeks in North America or Europe are similar to one born at term. There are very few data on the longer term outcomes of babies born preterm in Africa and there are multiple challenges involved in gathering such information. As prenatal ultrasound is not routinely available, gestational age is often uncertain. There may be little routine follow-up of preterm babies as is commonplace in high-income countries. Data are needed from recent years that take into account both improvements in perinatal care and adverse factors such as a rising number of infants becoming HIV positive around the time of birth.
Why Was This Study Done?
We could improve outcomes for babies born preterm in sub-Saharan Africa if we understood more about what happens to them after birth. We cannot assume that the progress of these babies will be the same as those born preterm in a high-income country, as the latter group will have received different care, both before and after birth. If we can document the problems that these preterm babies face in a low-income setting, we can consider why they happen and what treatments can be realistically tested in this setting. It is also helpful to establish baseline data so that changes over time can be recorded.
The aim of this study was to document four specific outcomes up to the age of two years, on which there were few data previously from rural sub-Saharan Africa: how many babies survived, visits to a health center and admissions to the hospital, growth, and developmental delay.
What Did the Researchers Do and Find?
The researchers examined a group of babies that had been born to mothers who had taken part in a randomized controlled trial of an antibiotic to prevent preterm birth. The trial had previously shown that the antibiotic (azithromycin) had no effect on how many babies were born preterm or on other measures of the infants' wellbeing, and so the researchers followed up babies from both arms of the trial to look at longer term outcomes. From the original group of 2,297 women who took part in the trial, they compared 247 infants born preterm against 593 term infants randomly chosen as controls, assessed at 12, 18, or 24 months. The majority of the preterm babies who survived past a month of age (all but ten) were born after 32 weeks of gestation. Compared to the babies born at term, the infants born preterm were nearly twice as likely to die subsequently in the next two years, were more likely to be underweight (a third were moderately underweight), and to have higher rates of developmental delay. The commonest causes of death were gastroenteritis, respiratory problems, and malaria. Visits to a health center and admissions to hospital were similar in both groups.
What Do these Findings Mean?
This study documents longer term outcomes of babies born preterm in sub-Saharan Africa in detail for the first time. The strengths of the study include prenatal ultrasound dating and correct adjustment of follow-up age (which takes into account being born before term). Because the researchers defined morbidity using routine health center attendances and self-report of illnesses by parents, this outcome does not seem to have been as useful as the others in differentiating between the preterm and term babies. Better means of measuring morbidity are needed in this setting.
In the developed world, there is considerable investment being made to improve care during pregnancy and in the neonatal period. This investment in care may help by predicting which mothers are more likely to give birth early and preventing preterm birth through drug or other treatments. It is to be hoped that some of the benefit will be transferable to low-income countries. A baby born at 26 weeks' gestation and admitted to a neonatal unit in the United Kingdom has a 67% chance of survival; preterm babies born in sub-Saharan Africa face a starkly contrasting future.
Additional Information
Please access these Web sites via the online version of this summary at
UNICEF presents useful statistics on mother and child outcomes
The World Health Organization has attempted to analyse preterm birth rates worldwide, including mapping the regional distribution and has also produced practical guides on strategies such as Kangaroo Mother Care, which can be used for the care of preterm infants in low resource settings
Healthy Newborn Network has good information on initiatives taking place to improve neonatal outcomes in low income settings
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on research being conducted into preterm birth
Tommy's is a nonprofit organization that funds research and provides information on the risks and causes of premature birth
PMCID: PMC3210771  PMID: 22087079
8.  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
9.  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
10.  Prenatal Methamphetamine Exposure and Neonatal and Infant Neurobehavioral Outcome: Results from the IDEAL Study 
Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How MA use during pregnancy affects neonatal and infant neurobehavior is unknown.
The Infant Development, Environment, and Lifestyle (IDEAL) study screened 34,833 subjects at 4 clinical centers. 17,961 were eligible and 3,705 were consented, among which 412 were enrolled for longitudinal follow-up. Exposed subjects were identified by self-report and/or GC/MS confirmation of amphetamine and metabolites in meconium. Comparison subjects were matched (race, birth weight, maternal education, 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, or phencyclidine. The NICU Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life and again at one month to 380 enrollees (185 exposed, 195 comparison). ANOVA tested exposure effects on NNNS summary scores at birth and one month. GLM repeated measures analysis assessed the effect of MA exposure over time on the NNNS scores with and without covariates.
By one month of age, both groups demonstrated higher quality of movement (P=.029), less lethargy (P=.001), and fewer asymmetric reflexes (P=.012), with no significant differences in NNNS scores between the exposed and comparison groups. Over the first month of life, arousal increased in exposed infants but decreased in comparison infants (p=.031) and total stress was decreased in exposed infants with no change in comparison infants (p=.026).
Improvement in total stress and arousal were observed in MA-exposed newborns by one month of age relative to the newborn period.
PMCID: PMC3942806  PMID: 24588296
11.  Impact of low-level gestational exposure to organophosphate pesticides on neurobehavior in early infancy: a prospective study 
Environmental Health  2013;12:79.
National data suggest widespread gestational exposure to organophosphate pesticides (OPs) based on the detection of OP metabolites in the urine of pregnant women. Associations with early infant neurobehavior are largely understudied, with only two studies reporting abnormal reflexes in newborns in association with gestational exposure to OPs. Our objective was to utilize biological markers of OP metabolites in pregnant women and a comprehensive assessment of infant neurobehavior to determine the association of gestational exposure to OPs with neurobehavioral outcomes during early infancy.
Among a cohort of 350 mother/infant pairs, we measured six common dialkylphosphate metabolites of OP pesticides in maternal urine, at two times during pregnancy (16 w & 26 w gestation), then calculated aggregate concentrations of diethylphosphate, dimethylphosphate, and total dialkyphosphate metabolites. We measured infant neurobehavior at about five weeks of age using the NICU Network Neurobehavioral Scale (NNNS), a comprehensive assessment of neurobehavior in young infants. Analyses of associations between gestational exposure to OPs and neurobehavior at five weeks included multiple linear and logistic regression.
After adjustment for covariates, higher creatinine-corrected urinary concentrations of diethylphosphate metabolites were associated with improved attention and reduced lethargy and hypotonia in young infants. Higher creatinine-corrected urinary concentrations of total dialkylphosphate metabolites were associated with fewer signs of autonomic stress. Women who were white, married, had advanced education, and reported more frequent consumption of fresh fruits and vegetables had higher concentrations of OP metabolites during pregnancy.
In this sample of pregnant women whose urinary concentrations of dialkylphosphate metabolites are representative of national exposure levels, we found no detrimental effects of gestational exposure to OPs on neurobehavioral outcomes among young infants. These results are important as they suggest there may be minimal to no detectable adverse impact of low level prenatal OP exposure on the neurobehavior of young infants.
PMCID: PMC3848803  PMID: 24034442
NNNS; Organophosphates; Pesticides; Neurobehavior; Infancy; Prenatal exposure
12.  Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants 
Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association.
The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores.
Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058).
These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD. (J Thorac Cardiovasc Surg 2014;148:2560-8)
PMCID: PMC4376113  PMID: 25282659
13.  Comparison of Bayley-2 and Bayley-3 scores at 18 months in term infants following neonatal encephalopathy and therapeutic hypothermia 
Neuroprotection trials for neonatal encephalopathy use moderate or severe disability as an outcome, with the Bayley Scales of Infant Development, Second Edition (Bayley-2) Index scores of <70 as part of the criteria. The Bayley Scales of Infant and Toddler, 3rd Development, Third Edition (Bayley-3) have superseded Bayley-2 and yield higher than expected scores in typically developing and high-risk infants. The aim of this study, therefore, was to compare Bayley-2 scores and Bayley-3 scores in term-born infants surviving neonatal encephalopathy treated with hypothermia.
Sixty-one term-born infants (37 males, 24 females; median gestational age at birth 40wks, range 36–42wks; median birthweight 3280g, range 2295–5050) following neonatal encephalopathy and hypothermia had contemporaneous assessment at 18 months using the Bayley-2 and Bayley-3.
The median Bayley-3 Cognitive Composite score was 7 points higher than the median Bayley-2 Mental Developmental Index (MDI) score and the median Bayley-3 Motor Composite score was 18 points higher than the median Bayley-2 Psychomotor Developmental Index (PDI) score. Ten children had a Bayley-2 MDI of <70; only three children had Bayley-3 combined Cognitive/Language scores of <70. Eleven children had Bayley-2 PDI scores of <70 and four had modified Bayley-3 Motor Composite scores of <70. Applying regression equations to Bayley-3 scores adjusted rates of severe delay to similar proportions found using Bayley-2 scores.
Fewer children were classified with severe delay using the Bayley-3 than the Bayley-2, which prohibits direct comparison of scores. Increased Bayley-3 cut-off thresholds for classifying severe disability are recommended when comparing studies in this clinical group using Bayley-2 scores.
PMCID: PMC4287199  PMID: 23927586
14.  Birth weight- and fetal weight-growth restriction: impact on neurodevelopment 
Early human development  2012;88(9):765-771.
The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA).
To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found.
Study design
Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II.
B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70.
Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.
PMCID: PMC3694609  PMID: 22732241
15.  Neonatal Neurobehavior Effects following Buprenorphine versus Methadone Exposure 
Addiction (Abingdon, England)  2012;107(0 1):63-73.
To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior.
Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this sub-study.
Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI, and Vienna, Austria.
39 full-term infants.
The NICU Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30.
While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer Stress-Abstinence signs (P<0.001), were less Excitable (P<0.001) and less Over-Aroused (P<0.01), exhibited less Hypertonia (P<0.007), and had better Self-Regulation (P<0.04) and required less Handling (P<0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher Self-Regulation scores (P<0.01), and demonstrated the least amount of Excitability (P<0.02) and Hypertonia (P<0.02) on average. Quality of Movement was negatively correlated with peak NAS score (P<0.01), number of days treated with morphine for NAS (P<0.01) and total amount of morphine received (P<0.03). Excitability scores were positively related to total morphine dose (P<0.03).
While neurobehavior improves during the first month of postnatal life for in utero agonist-medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure.
PMCID: PMC4337995  PMID: 23106928
neonatal abstinence syndrome; NICU Network Neurobehavioral Scale (NNNS); neurobehavior
16.  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
17.  Maternal Blood Manganese and Early Neurodevelopment: The Mothers and Children’s Environmental Health (MOCEH) Study 
Environmental Health Perspectives  2015;123(7):717-722.
Manganese is an essential trace element and common component of water, soil, and air. Prenatal manganese exposure may affect fetal and infantile neurodevelopment, but reports on in utero manganese exposure and infant neurodevelopment are rare.
This study was conducted to investigate a relationship between maternal blood manganese level and neurodevelopment of infants at 6 months of age.
Data were obtained from the Mothers and Children’s Environmental Health (MOCEH) birth cohort study. The study population included 232 pairs of pregnant women and their infants at 6 months of age. Maternal blood manganese was measured at term, just before delivery. Mental and psychomotor development in infancy was assessed at 6 months of age using the Bayley Scales of Infant Development. The relationship between maternal blood manganese level and the mental and psychomotor development indexes (MDI and PDI) was estimated for manganese modeled as a linear and as a categorical variable and using penalized splines for nonlinear modeling.
Mean ± SD maternal blood manganese concentration was 22.5 ± 6.5 μg/L. After adjustment for potential confounders, blood manganese was used as a continuous variable in a linear and nonlinear model. Associations between maternal blood manganese and MDI and PDI scores followed an inverted U-shape dose–response curve after adjustment for potential confounders, with lower scores associated with both low and high blood concentrations [MDI: likelihood-ratio test (LRT) p = 0.075, PDI: LRT p = 0.038]. Associations of both outcomes with increasing blood manganese shifted from positive to negative at concentrations of 24–28 μg/L in this cohort of term, normal birth weight children.
Although no cut-off point has been established to define manganese toxicity, both high and low blood manganese levels may be associated with neurobehavioral function in infants.
Chung SE, Cheong HK, Ha EH, Kim BN, Ha M, Kim Y, Hong YC, Park H, Oh SY. 2015. Maternal blood manganese and early neurodevelopment: the Mothers and Children’s Environmental Health (MOCEH) study. Environ Health Perspect 123:717–722;
PMCID: PMC4492260  PMID: 25734517
18.  Effect of maternal job strain during pregnancy on infant neurodevelopment by gender at 6 and 12 months: Mothers and Children’s Environmental Health (MOCEH) study 
Limited evidence is available regarding the association between prenatal job strain and infant neurodevelopment. Most studies used stress indicators other than job strain to explain the relationship between prenatal maternal stress and child development. The objective of this study was to investigate the association between maternal job strain during pregnancy and neurodevelopment in infancy.
Mothers and Children’s Environmental Health (MOCEH) study, an on-going prospective birth cohort study, has been conducted in South Korea since 2006. Job strain during pregnancy was measured using Korean version of Job Content Questionnaire (JCQ). Infant neurodevelopment was assessed using Korean Bayley Scale of Infant Development II (K-BSID-II) at 6 and 12 months of age. A total of 343 mother-child pairs that completed JCQ and K-BSID-II more than once were included. Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) defined in the K-BSID-II were used as outcome variables.
Compared to infants from mothers with low job strain, significant (p < 0.05) decreases in PDI were found in infants from mothers with active and passive job at 6 months of age. After stratification by infant sex, boys in the high strain group had a lower MDI score than boys in the low job strain group at 12 months. On the other hand, girls in the high strain and active groups had higher MDI scores than girls in the low job strain group at 12 months. PDI at 12 months also showed different results by sex. Boys in the high strain and passive job groups had lower PDI scores than boys in the low job strain group. However, such difference was not observed in girls.
The findings of this study suggest that prenatal job strain affects infant neurodevelopment in a gender-dependent manner.
PMCID: PMC4392800  PMID: 25866667
Cognition; Job strain; Infant neurodevelopment; Prenatal psychosocial stress
19.  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
20.  Patterned feeding experience for preterm infants: study protocol for a randomized controlled trial 
Trials  2015;16:255.
Neurobehavioral disabilities occur in 5–15 % of preterm infants with an estimated 50–70 % of very low birth weight preterm infants experiencing later dysfunction, including cognitive, behavioral, and social delays that often persist into adulthood. Factors implicated in poor neurobehavioral and developmental outcomes are hospitalization in the neonatal intensive care unit (NICU) and inconsistent caregiving patterns. Although much underlying brain damage occurs in utero or shortly after birth, neuroprotective strategies can stop lesions from progressing, particularly when these strategies are used during the most sensitive periods of neural plasticity occurring months before term age. The purpose of this randomized trial is to test the effect of a patterned feeding experience on preterm infants’ neurobehavioral organization and development, cognitive function, and clinical outcomes.
This trial uses an experimental, longitudinal, 2-group design with 120 preterm infants. Infants are enrolled within the first week of life and randomized to an experimental group receiving a patterned feeding experience from the first gavage feeding through discharge or to a control group receiving usual feeding care experience. The intervention involves a continuity of tactile experiences associated with feeding to train and build neuronal networks supportive of normal infant feeding experience. Primary outcomes are neurobehavioral organization as measured by Neurobehavioral Assessment of the Preterm Infant at 3 time points: the transition to oral feedings, NICU discharge, and 2 months corrected age. Secondary aims are cognitive function measured using the Bayley Scales of Infant and Toddler Development, Third Edition at 6 months corrected age, neurobehavioral development (sucking organization, feeding performance, and heart rate variability), and clinical outcomes (length of NICU stay and time to full oral feeding). The potential effects of demographic and biobehavioral factors (perinatal events and conditions of maternal or fetal/newborn origin and immunologic and genetic biomarkers) on the outcome variables will also be considered.
Theoretically, the intervention provided at a critical time in neurologic system development and associated with a recurring event (feeding) should enhance neural connections that may be important for later development, particularly language and other cognitive and neurobehavioral organization skills.
Trial registration
NCT01577615 11 April 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0781-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4460964  PMID: 26041365
Preterm infant; Infant feeding; Neonatal care; Nursing care; Neurodevelopment; Cognitive development; Clinical outcomes; Length of stay; Feeding experience
21.  Newborn neurobehavioral patterns are differentially related to prenatal maternal Major Depressive Disorder and Serotonin Reuptake Inhibitor treatment 
Depression and Anxiety  2011;28(11):1008-1019.
Prenatal serotonin reuptake inhibitor (SRI) exposure has been related to adverse newborn neurobehavioral outcomes; however these effects have not been compared to those that may arise from prenatal exposure to maternal major depressive disorder (MDD) without SRI treatment. This study examined potential effects of MDD with and without SRI treatment on newborn neurobehavior.
This was a prospective, naturalistic study. Women were seen at an outpatient research center twice during pregnancy (26–28 and 36–38 weeks gestational age (GA)). Psychiatric diagnoses were assessed using the Structured Clinical Interview for the DSM-IV; medication use was measured with the Timeline Follow-Back instrument. Three groups were established based upon MDD diagnosis and SRI use: Control (N=56), MDD (N=20) or MDD+SRI (N=36). Infants were assessed on a single occasion within 3 weeks of birth with the NICU Network Neurobehavioral Assessment Scale (NNNS). Generalized Linear Modeling was used to examine neurobehavioral outcomes by exposure group and infant age at assessment.
Full-term infants exposed to MDD+SRIs had a lower GA than CON or MDD-exposed infants and, controlling for GA, had lower quality of movement and more central nervous system stress signs. In contrast, MDD-exposed infants had the highest quality of movement scores, while having lower attention scores than CON and MDD+SRI-exposed infants.
MDD+SRI-exposed infants appear to have a different neurobehavioral profile than MDD-exposed infants in the first three weeks after delivery; both groups may have different neurobehavioral profiles with increasing age from birth.
PMCID: PMC3215845  PMID: 21898709
infant; motor quality; central nervous system; depression; pregnancy; treatment
22.  Hyperglycaemia after Stage I palliation does not adversely affect neurodevelopmental outcome at 1 year of age in patients with single-ventricle physiology☆,☆☆ 
Hyperglycaemia has been associated with worse outcome following traumatic brain injury and cardiac surgery in adults. We have previously reported no relationship between early postoperative hyperglycaemia and worse neurodevelopmental outcome at 1 year following biventricular repair of congenital heart disease. It is not known if postoperative hyperglycaemia results in worse neurodevelopmental outcome after infant cardiac surgery for single-ventricle lesions.
Secondary analysis of postoperative glucose levels in infants <6 months of age undergoing Stage I palliation for various forms of single ventricle with arch obstruction. The patients were enrolled in a prospective study of genetic polymorphisms and neurodevelopmental outcomes assessed at 1 year of age with the Bayley Scales of Infant Development-II yielding two indices: mental developmental index (MDI) and psychomotor developmental index (PDI).
Stage I palliation was performed on 162 infants with 13 hospital and 15 late deaths (17.3% 1-year mortality). Neurodevelopmental evaluation was performed in 89 of 134 (66.4%) survivors. Glucose levels at admission to the cardiac intensive care unit and during the first 48 postoperative hours were available for 85 of 89 (96%) patients. Mean admission glucose value was 274 ± 91 mg dl−1; the maximum was 291 ± 90 mg dl−1, with 69 of 85 (81%) patients having at least one glucose value >200 mg dl−1. Only two patients had a value <50 mg dl−1. Mean MDI and PDI scores were 88 ± 16 and 71 ± 18, respectively. There were no statistically significant correlations between initial, mean, minimum or maximum glucose measurements and MDI or PDI scores. Only delayed sternal closure resulted in a statistically significant relationship between initial, minimum and maximum glucose values within the context of a multivariate analysis of variance model.
Hyperglycaemia following Stage I palliation in the neonatal period was not associated with lower MDI or PDI scores at 1 year of age.
PMCID: PMC2840384  PMID: 19699107
Congenital heart disease; Hyperglycaemia; Patient outcomes; Postoperative care
23.  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
24.  Neonatal Neurobehavioral Abnormalities and MRI Brain Injury in Encephalopathic Newborns Treated With Hypothermia 
Early human development  2013;89(9):733-737.
Neonatal Encephalopathy (NE) is a prominent cause of infant mortality and neurodevelopmental disability. Hypothermia is an effective neuroprotective therapy for newborns with encephalopathy. Post-hypothermia functional-anatomical correlation between neonatal neurobehavioral abnormalities and brain injury findings on MRI in encephalopathic newborns has not been previously described.
To evaluate the relationship between neonatal neurobehavioral abnormalities and brain injury on magnetic resonance imaging (MRI) in encephalopathic newborns treated with therapeutic hypothermia.
Study Design
Neonates with hypoxic ischemic encephalopathy (HIE) referred for therapeutic hypothermia were prospectively enrolled in this observational study. Neurobehavioral functioning was assessed with the NICU Network Neurobehavioral Scale (NNNS) performed at target age 14 days. Brain injury was assessed by MRI at target age 7–10 days. NNNS scores were compared between infants with and without severe MRI injury.
Subjects & Outcome Measures
Sixty-eight term newborns (62% males) with moderate to severe encephalopathy underwent MRI at median 8 days (range 5–16) and NNNS at median 12 days of life (range 5–20). Fifteen (22%) had severe injury on MRI.
Overall Total Motor Abnormality Score and individual summary scores for Nonoptimal Reflexes and Asymmetry were higher, while Total NNNS Z-score across cognitive/behavioral domains was lower (reflecting poorer performance) in infants with compared to those without severe MRI injury (p<0.05).
Neonatal neurobehavioral abnormalities identified by the NNNS are associated with MRI brain injury in encephalopathic newborns post-hypothermia. The NNNS can provide an early functional assessment of structural brain injury in newborns, which may guide rehabilitative therapies in infants after perinatal brain injury.
PMCID: PMC3780358  PMID: 23787090
25.  Parental Presence and Holding in the Neonatal Intensive Care Unit and Associations with Early Neurobehavior 
To investigate the effects of parental presence and infant holding in the NICU on neurobehavior at term equivalent.
Study Design
Prospective cohort enrolled 81 infants born <30 weeks gestation. Nurses tracked parent visitation, holding, and skin-to-skin care throughout the NICU hospitalization. At term, the NICU Network Neurobehavioral Scale was administered. Associations between visitation, holding, and early neurobehavior were determined using linear and logistic regression.
The mean hours/week of parent visitation was 21.33±20.88 (median= 13.90; interquartile range 10.10–23.60). Infants were held an average of 2.29±1.47 days/week (median= 2.00; interquartile range 1.20–3.10). Over the admission, visitation hours decreased (p=0.01), while holding frequencies increased (p<0.001). More visitation was associated with better quality of movement (p=0.02), less arousal (p=0.01), less excitability (p=0.03), more lethargy (p=0.01) and more hypotonia (p<0.01). More holding was associated with improved quality of movement (p<0.01), less stress (p<0.01), less arousal (p=0.04) and less excitability (p<0.01).
Infants of caregivers who were visited and held more often in the NICU had differences in early neurobehavior by term equivalent, which supports increased early parenting in the NICU.
PMCID: PMC3700586  PMID: 23412640
Parenting; holding; visitation; premature infant; NICU Network Neurobehavioral Scale (NNNS); development; caregiver; skin-to-skin; interaction; attachment

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