Trends in Preterm Body Composition and Neurodevelopmental Outcomes after Discharge.

INTRODUCTION: Body composition, specifically fat-free mass (FFM), of preterm infants is associated with improved neurodevelopmental outcomes. Little is known about body composition of preterm infants after discharge. Preterm body composition was measured by air displacement plethysmography (ADP) at two time points, inpatient (35-40 weeks postmenstrual age [PMA]) and outpatient (48-58 weeks PMA), with neonatal factors and neurodevelopmental testing at 4-6 months corrected age. We hypothesized increased FFM is positively associated with neurodevelopment. METHODS: From 2007 to 2011, 510 infants admitted to the Medical University of South Carolina's neonatal intensive care unit underwent ADP. A total of 379 of 510 (74%) had anthropometrics at birth, an ADP scan with FFM, fat mass, fat percent z-scores, and an outpatient neurodevelopmental evaluation (CAT/CLAMS, Peabody Gross Motor). Variables were compared using multivariate analyses for body composition measurements. RESULTS: The infants were 32 ± 4.8 weeks gestational age at birth with an average birth weight of 1,697 ± 932 g. Most (56%) infants received maternal milk at discharge. CAT, CLAMS, and gross motor scores had positive correlations with FFM z-scores at inpatient and outpatient ADP (p < 0.05). Receiving maternal milk at discharge was positively associated with cognitive (ß = 0.22, p < 0.05) and language scores (ß = 0.26, p < 0.05). CONCLUSION: Increased FFM is associated with improved cognitive, language, and gross motor testing. Maternal milk was positively associated with language and cognitive scores.

Placental Inflammation Significantly Correlates with Reduced Risk for Retinopathy of Prematurity.

Retinopathy of prematurity (ROP), a blinding condition affecting preterm infants, is an interruption of retinal vascular maturation that is incomplete when born preterm. Although ROP demonstrates delayed onset following preterm birth, representing a window for therapeutic intervention, there are no curative or preventative measures available for this condition. The in utero environment, including placental function, is increasingly recognized for contributions to preterm infant disease risk. The current study identified a protective association between acute placental inflammation and preterm infant ROP development using logistic regression, with the most significant association found for infants without gestational exposure to maternal preeclampsia and those with earlier preterm birth. Expression analysis of proteins with described ROP risk associations demonstrated significantly decreased placental high temperature requirement A serine peptidase-1 (HTRA-1) and fatty acid binding protein 4 protein expression in infants with acute placental inflammation compared with those without. Within the postnatal peripheral circulation, HTRA-1 and vascular endothelial growth factor-A demonstrated inverse longitudinal trends for infants born in the presence of, compared with absence of, acute placental inflammation. An agnostic approach, including whole transcriptome and differential methylation placental analysis, further identify novel mediators and pathways that may underly protection. Taken together, these data build on emerging literature showing a protective association between acute placental inflammation and ROP development and identify novel mechanisms that may inform postnatal risk associations in preterm infants.

Body Composition and "Catch-Up" Fat Growth in Healthy Small for Gestational Age Preterm Infants and Neurodevelopmental Outcomes.

To examine the growth and body composition of small for gestational age (SGA) and appropriate for gestational age (AGA) very low birth weight infants (VLBW) and their outpatient neurodevelopmental outcomes. From 2006-2012, VLBW infants (n = 57 of 92) admitted to the Neonatal Intensive Care Unit (NICU) had serial air displacement plethysmography (ADP) scans and were followed as outpatients. Serial developmental testing (CAT/CLAMS, Peabody Gross Motor Scales) and anthropometrics were obtained from n = 37 infants (29 AGA and 8 SGA) and analyzed via repeated measures analyses of variances. The percentage of body fat, percentage of lean mass, and weight gain were statistically significant between SGA and AGA groups at the first ADP assessment. There was no difference between the two groups in outpatient neurodevelopmental testing. Weight gain as "catch-up" body fat accrual occurs by 67 weeks of PMA. This catch-up growth is associated with normal SGA preterm neurodevelopment as compared to AGA preterm infants.

The Serine Protease HTRA-1 Is a Biomarker for ROP and Mediates Retinal Neovascularization.

Retinopathy of prematurity (ROP) is a blinding aberrancy of retinal vascular maturation in preterm infants. Despite delayed onset after preterm birth, representing a window for therapeutic intervention, we cannot prevent or cure ROP blindness. A natural form of ROP protection exists in the setting of early-onset maternal preeclampsia, though is not well characterized. As ischemia is a central feature in both ROP and preeclampsia, we hypothesized that angiogenesis mediators may underlie this protection. To test our hypothesis we analyzed peripheral blood expression of candidate proteins with suggested roles in preeclamptic and ROP pathophysiology and with a proposed angiogenesis function (HTRA-1, IGF-1, TGFß-1, and VEGF-A). Analysis in a discovery cohort of 40 maternal-infant pairs found that elevated HTRA-1 (high-temperature requirement-A serine peptidase-1) was significantly associated with increased risk of ROP and the absence of preeclampsia, thus fitting a model of preeclampsia-mediated ROP protection. We validated these findings and further demonstrated a dose-response between systemic infant HTRA-1 expression and risk for ROP development in a larger and more diverse validation cohort consisting of preterm infants recruited from two institutions. Functional analysis in the oxygen-induced retinopathy (OIR) murine model of ROP supported our systemic human findings at the local tissue level, demonstrating that HtrA-1 expression is elevated in both the neurosensory retina and retinal pigment epithelium by RT-PCR in the ROP disease state. Finally, transgenic mice over-expressing HtrA-1 demonstrate greater ROP disease severity in this model. Thus, HTRA-1 may underlie ROP protection in preeclampsia and represent an avenue for disease prevention, which does not currently exist.

Vitamin D insufficiency in neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Vitamin D has neuroprotective and immunomodulatory properties, and deficiency is associated with worse stroke outcomes. Little is known about effects of hypoxia-ischemia or hypothermia treatment on vitamin D status in neonates with hypoxic-ischemic encephalopathy (HIE). We hypothesized vitamin D metabolism would be dysregulated in neonatal HIE altering specific cytokines involved in Th17 activation, which might be mitigated by hypothermia. METHODS: We analyzed short-term relationships between 25(OH) and 1,25(OH)2 vitamin D, vitamin D binding protein, and cytokines related to Th17 function in serum samples from a multicenter randomized controlled trial of hypothermia 33 °C for 48 h after HIE birth vs. normothermia in 50 infants with moderate to severe HIE. RESULTS: Insufficiency of 25(OH) vitamin D was observed after birth in 70% of infants, with further decline over the first 72 h, regardless of treatment. 25(OH) vitamin D positively correlated with anti-inflammatory cytokine IL-17E in all HIE infants. However, Th17 cytokine suppressor IL-27 was significantly increased by hypothermia, negating the IL-27 correlation with vitamin D observed in normothermic HIE infants. CONCLUSION: Serum 25(OH) vitamin D insufficiency is present in the majority of term HIE neonates and is related to lower circulating anti-inflammatory IL-17E. Hypothermia does not mitigate vitamin D deficiency in HIE.

Customized versus population-based growth curves: prediction of low body fat percent at term corrected gestational age following preterm birth.

OBJECTIVE: Compare customized versus population-based growth curves for identification of small-for-gestational-age (SGA) and body fat percent (BF%) among preterm infants. METHODS: Prospective cohort study of 204 preterm infants classified as SGA or appropriate-for-gestational-age (AGA) by population-based and customized growth curves. BF% was determined by air-displacement plethysmography. Differences between groups were compared using bivariable and multivariable linear and logistic regression analyses. RESULTS: Customized curves reclassified 30% of the preterm infants as SGA. SGA infants identified by customized method only had significantly lower BF% (13.8 ± 6.0) than the AGA (16.2 ± 6.3, p = 0.02) infants and similar to the SGA infants classified by both methods (14.6 ± 6.7, p = 0.51). Customized growth curves were a significant predictor of BF% (p = 0.02), whereas population-based growth curves were not a significant independent predictor of BF% (p = 0.50) at term corrected gestational age. CONCLUSION: Customized growth potential improves the differentiation of SGA infants and low BF% compared with a standard population-based growth curve among a cohort of preterm infants.

Ultrasound assessment of intrauterine growth restriction: relationship to neonatal body composition.

OBJECTIVE: The objective of the study was to compare prenatal ultrasound parameters for intrauterine growth restriction (IUGR) with newborn percent body fat (%BF). STUDY DESIGN: This was a prospective study of 87 pregnancies followed with ultrasound. Subjects were categorized into 3 groups: estimated fetal weight (EFW) less than the 10th percentile, abdominal circumference (AC) less than the fifth percentile, and normal biometry. Neonatal %BF by air displacement plethysmography was compared between each group using multivariable analyses. RESULTS: The %BF in the EFW less than the 10th percentile group (5.1 ± 2.9%) was significantly lower than either AC less than the fifth percentile (9.5 ± 3.3%) or normal groups (11.6 ± 5.6%). EFW less than the 10th percentile best predicted %BF by regression model. Neonatal morbidity was not significantly higher in the EFW less than the 10th percentile group. CONCLUSION: Newborn %BF was significantly lower in infants with EFW less than the 10th percentile compared with AC less than the fifth percentile, an intermediate finding. An AC less than the fifth percentile on ultrasound does not reflect the same severity of IUGR as EFW less than the 10th percentile.

Caretaker perception of child vulnerability predicts behavior problems in NICU graduates.

This study explores parental perception of child vulnerability (PPCV) and parent overprotection (POP) and their relationship to neonatal medical problems, child development and behavior. Participants included 90 lower income parents of NICU graduates ages 22-81 months consecutively enrolled at a high-risk neonatal developmental follow-up clinic. Parents completed the Child Vulnerability Scale (CVS), the Parent Protection Scale (PPS) and the Child Behavior Checklist (CBCL) regarding their children. Step-wise regression analysis revealed the CVS as the sole predictor of child behavior, accounting for 13% of the variance in the CBCL Total T-score (R(2) =.13, $be =.86, p <.006). Neonatal medical problems, Child DQ, and most parental demographic variables did not correlate with CVS or PPS scores. A significant correlation between CVS and the separation subscale of the PPS was noted (r =.31, p <.01). We conclude that NICU graduates perceived vulnerable by their caretakers have significant behavioral difficulties compared to those perceived as not vulnerable. Future research should address early parental antecedents of PPCV, the persistence of PPCV, and its effects on behavioral outcomes.

Neonatal hair analysis for benzoylecgonine: a sensitive and semiquantitative biological marker for chronic gestational cocaine exposure.

Hair analysis for the major metabolite of cocaine, benzoylecgonine (BZE) was performed in a cohort of 251 predominantly African-American newborns utilizing a modified radioimmunoassay (RIA) (Abuscreen Roche Laboratories, Nutley, N.J., USA). Maternal drug intake was confirmed by positive urine drug screen for cocaine metabolites at the time of delivery. The BZE concentrations reported here are the composites of both the parent compound cocaine (hydrolyzed to BZE) and the native BZE metabolized by the patient and deposited in the hair follicle. Hair analysis as an indicator for gestational cocaine exposure had a sensitivity of 88%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 85%. The range of BZE was 99-23,300 ng/g of hair, with 79% having hair BZE levels <5,000 ng/g of hair. The BZE RIA was confirmed by gas chromatography and mass spectrometry (GC/MS). Of the 18 mother/infant pairs tested, the hair BZE ratio (maternal to neonatal) varied from 0.5 to 8.9 in 13 pairs. In spite of maternal high hair BZE levels, 5 newborns had no evidence of hair BZE, stressing the importance of the placental role for the cocaine transfer to the fetus. After controlling for gestational age, higher BZE levels significantly correlated with smaller head circumference (p < 0.03) and birth weight (p < 0.01).