Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6-7 years of age following hypothermia for neonatal encephalopathy. STUDY DESIGN: Out of 208 participants, 124 had MRI and primary outcome (death or IQ <70) data. The relationship between injury pattern and outcome was assessed. RESULTS: Death or IQ <70 occurred in 4 of 50 (8%) of children with pattern 0 (normal MRI), 1 of 6 (17%) with 1A (minimal cerebral lesions), 1 of 4 (25%) with 1B (extensive cerebral lesions), 3 of 8 (38%) with 2A (basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction), 32 of 49 (65%) with 2B (2A with cerebral lesions), and 7 of 7 (100%) with pattern 3 (hemispheric devastation), P < .001; this association was also seen within hypothermia and control subgroups. IQ was 90 ± 13 among the 46 children with a normal MRI and 69 ± 25 among the 50 children with an abnormal MRI. In childhood, for a normal outcome, a normal neonatal MRI had a sensitivity of 61%, specificity of 92%, a positive predictive value of 92%, and a negative predictive value of 59%; for death or IQ <70, the 2B and 3 pattern combined had a sensitivity of 81%, specificity of 78%, positive predictive value of 70%, and a negative predictive value of 87%. CONCLUSIONS: The Neonatal Research Network MRI pattern of neonatal brain injury is a biomarker of neurodevelopmental outcome at 6-7 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00005772.

Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants.

Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age. Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin. Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = -.322, p = .009; r= -.381, p= .002), lower mean albumin (r = -.276, p= .029; r= -.385, p= .002), and lower mean bilirubin (r = -.293, p= .020; r= -.337 p= .007). Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.

Conservatively managed fetal goiter: an alternative to in utero therapy.

Fetal goiter may arise from a variety of etiologies including iodine deficiency, overtreatment of maternal Graves' disease, inappropriate maternal thyroid replacement and, rarely, congenital hypothyroidism. Fetal goiter is often associated with a retroflexed neck and polyhydramnios, raising concerns regarding airway obstruction in such cases. Prior reports have advocated for cordocentesis and intra-amniotic thyroid hormone therapy in order to confirm the diagnosis of fetal thyroid dysfunction, reduce the size of the fetal goiter, reduce polyhydramnios, aid with the assistance of maternal thyroid hormone therapy and reduce fetal malpresentation. We report two cases of conservatively managed fetal goiter, one resulting in a vaginal delivery, and no evidence of postnatal respiratory distress despite the presence of polyhydramnios and a retroflexed neck on prenatal ultrasound.

Is phototherapy exposure associated with better or worse outcomes in 501- to 1000-g-birth-weight infants?

AIM: To compare risk-adjusted outcomes at 18- to 22-month-corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy. METHODS: Outcomes at 18 to 22-month-corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables. RESULTS: Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501- to 1000-g-BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60-1.20), death or adverse neurodevelopmental endpoints. However, among infants 501-750 g BW, the rate of significant developmental impairment with MDI < 50 was significantly higher for NoPTx (29%) than PTx (12%) (p = 0.004). CONCLUSIONS: Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI < 50 in the 501- to 750-g-BW NoPTx group is concerning and consistent with NRN Trial results.

Aluminum content of parenteral nutrition in neonates: measured versus calculated levels.

BACKGROUND AND OBJECTIVE: Aluminum (Al) is associated with significant central nervous system toxicity and bone and liver damage. Because Al is a contaminant of parenteral nutrition (PN) components including calcium and phosphate additives, premature infants are at potentially high risk for toxicity. The US Food and Drug Administration (FDA) has mandated PN component product labeling and recommended maximum Al daily exposure limits. The objective of this article is to determine the actual Al content of neonatal PN solutions, compare these values to the calculated amounts from manufacturers' PN product labels, and ascertain whether the actual Al exposure exceeds the FDA recommended maximum of 5 microg . kg(-1) . day(-1). MATERIALS AND METHODS: Samples from 40 neonatal patient PN solutions were selected for sampling and Al content determination. Samples were also taken from 16 manufacturer's component products used in PN formulation. All of the samples were sent to Mayo Laboratories for Al content measurement. The calculated Al concentrations in PN samples were determined from the manufacturer's labeled content. RESULTS: Both measured and calculated Al concentrations exceeded the FDA recommended safe limit of <5 microg . kg(-1) . day(-1). The actual measured Al content was significantly lower than the calculated Al content in both the patient PN solutions and the component product samples. CONCLUSIONS: Al exposure exceeded the FDA recommended maximum limit for all patient samples; however, the actual measured Al content of all the samples was significantly less than the calculated Al content based on manufacturer's labels. These findings suggest that manufacturers label their products with actual Al content at the time of product release rather than at time of expiration. Periodic monitoring of Al levels should be considered with prolonged PN therapy. Changes in manufacturing processes, including the use of better raw materials, are essential to reduce Al contamination to meet FDA mandates.

Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation.

BACKGROUND: Aluminum toxicity can cause serious central nervous system and bone toxicities. Aluminum is a contaminant of parenteral nutrition (PN) solution components. Premature neonates requiring high doses of calcium and phosphate to mineralize their bones, children with impaired renal function, and children on PN therapy for prolonged duration are at the highest risk. Effective in July 2004, the U.S. Food and Drug Administration (FDA) mandated labeling requirements for aluminum content in all PN solution components. To assess the aluminum exposure in neonatal and pediatric populations, this study aims to determine patients' daily aluminum load (mug/kg/d) delivered from PN solutions. METHODS: The study included all inpatients who received PN during calendar year 2006 (13,384 PN patient days). The calculated parameters of mug/kg/d and mug/L of parentally administered aluminum were stratified according to patient age and weight. Aluminum content by product and manufacturer were tabulated. RESULTS: Forty-nine percent of the PN patient days were in patients weighing < 3 kg. These patients also received the largest amounts of aluminum (range, 30-60 mug/kg/d). Meeting the FDA regulation was possible only in patients weighing > 50 kg. CONCLUSIONS: Currently available parenteral products used to make PN solutions contain amounts of aluminum that make it impossible to meet the new FDA rule of <5 mug/kg/d of aluminum exposure. Manufacturers must identify, develop, and adopt new methods to reduce the aluminum contamination in their products. Health care professionals should calculate aluminum loads in patients and make informed decisions when choosing PN products.