Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial.

OBJECTIVES: To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). STUDY DESIGN: This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. RESULTS: In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7 mg/kg/d (IQR 2.1-5.8 mg/kg/d) at day 60, with a mean of 3.6 mg/kg/d in infants treated with placebo and 4.8 mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90 days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater. CONCLUSIONS: A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01378273.

Early Nutrition during Hospitalization in Relation to Bone Health in Preterm Infants at Term Age and Six Months Corrected Age.

AIM: to evaluate the potential association of macronutrient intake in the first postnatal weeks on bone mineral content (BMC) and bone mineral density (BMD) in extremely and very preterm infants. METHODS: fifty-eight extremely and very preterm infants were included. Daily macronutrient intake was calculated in g kg-1 day-1 from birth up to 36 weeks postmenstrual age. A dual-energy X-ray absorptiometry whole body scan was used to assess BMC and BMD in preterm infants at term corrected age (TCA) and six months corrected age (CA). RESULTS: fat intake (g kg-1 day-1) in the first four postnatal weeks was positively associated with BMC and BMD at TCA. At six months CA, protein and fat intake (g kg-1 day-1) in the first weeks of life were both individual predictors for BMD. Fat intake (g kg-1 day-1) in the first four postnatal weeks was significantly associated with BMC at six months CA. CONCLUSION: the association of macronutrient intake in the first postnatal weeks on BMC or BMD, at TCA and six months CA, suggest that early nutritional intervention immediately after birth and during early infancy is important for bone health in the first months of life.

Effects of Lactobacillus reuteri supplementation on the gut microbiota in extremely preterm infants in a randomized placebo-controlled trial.

Extremely low birth weight (ELBW) infants often develop an altered gut microbiota composition, which is related to clinical complications, such as necrotizing enterocolitis and sepsis. Probiotic supplementation may reduce these complications, and modulation of the gut microbiome is a potential mechanism underlying the probiotic effectiveness. In a randomized, double-blind, placebo-controlled trial, we assessed the effect of Lactobacillus reuteri supplementation, from birth to post-menstrual week (PMW)36, on infant gut microbiota. We performed 16S amplicon sequencing in 558 stool samples from 132 ELBW preterm infants at 1 week, 2 weeks, 3 weeks, 4 weeks, PMW36, and 2 years. Probiotic supplementation results in increased bacterial diversity and increased L. reuteri abundance during the 1st month. At 1 week, probiotic supplementation also results in a lower abundance of Enterobacteriaceae and Staphylococcaceae. No effects were found at 2 years. In conclusion, probiotics may exert benefits by modulating the gut microbiota composition during the 1st month in ELBW infants.

Association of early skin breaks and neonatal thalamic maturation: A modifiable risk?

OBJECTIVE: To test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (<28 weeks' gestation). METHODS: Two international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (<14 days) use of AL/CVL were scanned serially with MRI. General linear models were used to determine the association between skin breaks and thalamic volumes, accounting for clinical confounders and site differences. Children were assessed at preschool age on standardized tests of motor and cognitive function. Outcome scores were assessed in relation to neonatal thalamic growth. RESULTS: Prolonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35-84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, p = 0.001, 95% CI 48.48-195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003-0.001, p = 0.002) and motor scores (B = 0.01, 95% CI 0.001-0.10, p = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections. CONCLUSIONS: Prolonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment.

Macronutrient Intake from Human Milk, Infant Growth, and Body Composition at Term Equivalent Age: A Longitudinal Study of Hospitalized Very Preterm Infants.

The variable macronutrient content of human milk may contribute to growth deficits among preterm infants in the neonatal intensive care unit (NICU). In a longitudinal study of 37 infants < 32 weeks gestation, we aimed to (1) determine the between-infant variation in macronutrient intake from human milk and (2) examine associations of macronutrient intake with growth outcomes. We analyzed 1626 human milk samples (median, 43 samples/infant) with mid infrared spectroscopy. Outcomes at term equivalent age were weight, length, head circumference, fat mass, and fat-free mass. Median (range) intakes from human milk were: protein 1.37 (0.88, 2.43) g/kg/day; fat 4.20 (3.19, 5.82) g/kg/day; carbohydrate 8.94 (7.72, 9.85) g/kg/day; and energy 82.5 (68.7, 99.3) kcal/kg/day. In median regression models adjusted for birth size and gestational age, and other covariates, greater intakes of fat and energy were associated with higher weight (0.61 z-scores per g/kg/day fat, 95% CI 0.21, 1.01; 0.69 z-scores per 10 kcal/kg/day, 95% CI 0.28, 1.10), whereas greater protein intake was associated with greater body length (0.84 z-scores per g/kg/day protein, 95% CI 0.09, 1.58). Higher fat intake was also associated with higher fat mass and fat-free mass. Macronutrient intakes from human milk were highly variable and associated with growth outcomes despite routine fortification.

Efficacy of Supporting Play Exploration and Early Development Intervention in the First Months of Life for Infants Born Very Preterm: 3-Arm Randomized Clinical Trial Protocol.

OBJECTIVE: The aim of this project is to study the effect of a physical therapist intervention provided in the first months of life on developmental outcomes of infants born very preterm. Secondary aims are to investigate the impact of intervention timing on the efficacy and impact of the intervention on infants with and without cerebral palsy. METHODS: This study is a multisite longitudinal controlled trial comparing developmental outcomes from infants in the Supporting Play, Exploration, and Early Development Intervention (SPEEDI)_Late or SPEEDI_Early group to a usual care group. SETTINGS ARE URBAN: Urban and rural areas surrounding 2 academic medical centers. There will be 90 preterm infants enrolled in this study born at <29 weeks of gestation. SPEEDI is a developmental intervention provided by collaboration between a physical therapist and parent to support a child's motor and cognitive development. The primary outcome measure is the Bayley Scale of Infant and Toddler Development Cognitive and Gross Motor Scaled Scores. Secondary measures include behavioral coding of early problem solving skills, the Gross Motor Function Measure, and Test of Infant Motor Performance. IMPACT: More than 270,000 infants are born very preterm in the United States each year, 50% of whom will have neurological dysfunction that limits their ability to keep pace with peers who are typically developing. This study is a step toward understanding the impact that intensive developmental intervention could have in this population in the first months of life.

Nutritional interventions to reduce rates of infection, necrotizing enterocolitis and mortality in very preterm infants.

Observational studies demonstrating reduced rates of infections, necrotizing enterocolitis (NEC), and mortality in preterm infants fed their own mother's milk, as opposed to formula, have prompted endeavors to achieve similar effects with the right choice of food and food additives. In a systematic review of meta-analyses and randomized controlled trials (RCTs), we considered nutritional interventions aimed at reducing the rates of infections, NEC, or mortality in very preterm infants. The overall effects of particular interventions were presented as risk ratios with 95% confidence intervals. In RCTs, pasteurized human donor milk, as opposed to formula, reduced NEC but not infections or mortality. No differences emerged between infants receiving human or bovine milk-based fortifiers. Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections, NEC, or mortality. Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality. Enteral L-glutamine (six RCTs) lowered infection rates, and enteral L-arginine (three RCTs) reduced NEC. A meta-analysis sensitivity approach found multiple-strain (but not single-strain) probiotics to be highly effective in reducing NEC and mortality. Thus, selected food components may help to improve outcomes in preterm infants.

Very preterm infants who receive transitional formulas as a complement to human milk can achieve catch-up growth.

OBJECTIVE: To evaluate the growth of premature infants fed a postdischarge diet of human milk (HM) complemented with transitional formula (TF) as compared with those fed TF only. STUDY DESIGN: In this prospective cohort study, 51 infants' diets and anthropometrics were collected at discharge and at 12-15 months corrected gestational age. RESULTS: Post discharge, infants in both groups exhibited similar growth velocities and changes in z-scores. The duration of infants' HM consumption was not correlated with weight gain (r = -0.25, p = 0.26). The duration of complementary TF feeds also did not correlate with increased growth (r = -0.11, p = 0.44). Both groups achieved catch-up growth and displayed growth velocities that significantly exceeded the upper limit of the World Health Organization (WHO) weight growth standard (p < 0.001). CONCLUSIONS: Preterm infants receiving HM and complementary TF post discharge had growth velocities at or exceeding weight gain projected by the WHO growth standard for term infants.

Gut microbiota of preterm infants supplemented with probiotics: sub-study of the ProPrems trial.

BACKGROUND: The ProPrems trial, a multi-center, double-blind, placebo-controlled randomized trial, previously reported a 54% reduction in necrotizing enterocolitis (NEC) of Bell stage 2 or more from 4.4 to 2.0% in 1099 infants born before 32 completed weeks' gestation and weighing < 1500 g, receiving probiotic supplementation (with Bifidobacterium longum subsp. infantis BB-02, Streptococcus thermophilus TH-4 and Bifidobacterium animalis subsp. lactis BB-12). This sub-study investigated the effect of probiotic supplementation on the gut microbiota in a cohort of very preterm infants in ProPrems. RESULTS: Bifidobacterium was found in higher abundance in infants who received the probiotics (AOR 17.22; 95% CI, 3.49-84.99, p < 0.001) as compared to the placebo group, and Enterococcus was reduced in infants receiving the probiotic during the supplementation period (AOR 0.27; 95% CI, 0.09-0.82, p = 0.02). CONCLUSION: Probiotic supplementation with BB-02, TH-4 and BB-12 from soon after birth increased the abundance of Bifidobacterium in the gut microbiota of very preterm infants. Increased abundance of Bifidobacterium soon after birth may be associated with reducing the risk of NEC in very preterm infants.

Physiological Approach to Sodium Supplementation in Preterm Infants.

OBJECTIVE: To implement and evaluate a clinical practice algorithm to identify preterm infants with sodium deficiency and guide sodium supplementation based on urine sodium concentrations. STUDY DESIGN: Urine sodium concentration was measured in infants born at 260/7 to 296/7 weeks' gestation at 2-week intervals. Sodium supplementation was based on the urine sodium algorithm. Growth and respiratory outcomes in this cohort were compared with a matched cohort cared for in our neonatal intensive care unit prior to algorithm implementation (2014-2015 cohort). RESULTS: Data were compared for 50 infants in the 2014-2015 cohort and 40 infants in the 2016 cohort. Urine sodium concentration met criteria for supplementation in 75% of the 2016 cohort infants within the first 4 weeks after birth. Average daily sodium intake was greater in the 2016 cohort compared with the 2014-2015 cohort (p < 0.05). Caloric, protein, and total fluid intakes were similar between cohorts. The change in weight Z-score between 2 and 8 weeks of age was significantly greater in the 2016 versus 2014-2015 cohort (0.32 ± 0.05 vs. -0.01 ± 0.08; p < 0.01). No impact on respiratory status at 28 days of age or 36 weeks of postmenstrual age was identified. CONCLUSION: Institution of a clinical practice algorithm to instruct clinicians on sodium supplementation in preterm infants may improve growth outcomes.

Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates.

Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and N-acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development.SIGNIFICANCE STATEMENT Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates.

Assessing bone development in preterm infants using quantitative ultrasonography showed a decline in the early postnatal period.

AIM: Preterm infants have an insufficient bone mineral store at birth and this study explored their bone development during the early postnatal period. METHODS: The metacarpal speed of sound (mcSOS) and metacarpal bone transmission time (mcBTT) were used to assess bone development in 277 preterm infants, admitted to the neonatal intensive care unit of the VU University Medical Center, Amsterdam, the Netherlands from 2007-2012. RESULTS: During the first nine postnatal weeks, the mcSOS declined from 10 to 38 m per second per week and the mcBTT declined from 20 to 71 nanoseconds per week. The pattern of change in both of these measurements showed a significant difference between infants born before 32 weeks of gestation (p = 0.048) and those born between 28 and 32 weeks of gestation (p = 0.008). There was a borderline significant difference in the pattern of change of the mcBTT in infants with a protein intake below 2 g/kg per day versus a higher intake (p = 0.050). CONCLUSION: The mcSOS and mcBTT of preterm infants showed a small to moderate decline during the early postnatal period. Future studies should explore the clinical relevance of this decline and develop interventions to halt it.

Attention and Regional Gray Matter Development in Very Preterm Children at Age 12 Years.

OBJECTIVES: This study examines the selective, sustained, and executive attention abilities of very preterm (VPT) born children in relation to concurrent structural magnetic resonance imaging (MRI) measures of regional gray matter development at age 12 years. METHODS: A regional cohort of 110 VPT (≤32 weeks gestation) and 113 full term (FT) born children were assessed at corrected age 12 years on the Test of Everyday Attention-Children. They also had a structural MRI scan that was subsequently analyzed using voxel-based morphometry to quantify regional between-group differences in cerebral gray matter development, which were then related to attention measures using multivariate methods. RESULTS: VPT children obtained similar selective (p=.85), but poorer sustained (p=.02) and executive attention (p=.01) scores than FT children. VPT children were also characterized by reduced gray matter in the bilateral parietal, temporal, prefrontal and posterior cingulate cortices, bilateral thalami, and left hippocampus; and increased gray matter in the occipital and anterior cingulate cortices (family-wise error-corrected p<.05). Poorer sustained auditory attention was associated with increased gray matter in the anterior cingulate cortex (p=.04). Poor executive shifting attention was associated with reduced gray matter in the right superior temporal cortex (p=.04) and bilateral thalami (p=.05). Poorer executive divided attention was associated with reduced gray matter in the occipital (p=.001), posterior cingulate (p=.02), and left temporal (p=.01) cortices; and increased gray matter in the anterior cingulate cortex (p=.001). CONCLUSIONS: Disturbances in regional gray matter development appear to contribute, at least in part, to the poorer attentional performance of VPT children at school age. (JINS, 2017, 23, 539-550).

Timing for the Introduction of Cycled Light for Extremely Preterm Infants: A Randomized Controlled Trial.

Day-night cycled light improves health outcomes in preterm infants, yet the best time to institute cycled light is unclear. The hypothesis of this study was that extremely preterm infants receiving early cycled light would have better health and developmental outcomes than infants receiving late cycled light. Infants born at ≤28 weeks gestation were randomly assigned to early cycled light (ECL) starting at 28 weeks postmenstrual age [PMA] or late cycled light (LCL), starting at 36 weeks PMA. Daylight was 200-600 lux and night was 5-30 lux. Primary outcomes were weight over time and length of hospitalization. Secondary outcomes were hospital costs, sleep development, and neurodevelopment at 9, 18, and 24 months corrected age. Of 121 infants randomized, 118 were included in analysis. Weight gain in the two groups did not differ significantly but increased across time in both groups. In PMA weeks 36-44, the mean weight gain was 193.8 grams in the ECL group compared to 176.3 grams in the LCL group. Effect sizes for weight were Cohen d = 0.26 and 0.36 for 36 and 44 weeks PMA. Infants in the ECL group went home an average of 5.5 days earlier than the LCL group, but this difference was not statistically significant. There were no group differences on neurodevelopmental outcomes. Although statistically non-significant, clinically important differences of improved weight gain and decreased hospital stay were observed with ECL. The small observed effect sizes on weight during hospitalization should be considered in future cycled light research with extremely preterm infants. © 2017 Wiley Periodicals, Inc.

Longitudinal development in the preterm thalamus and posterior white matter: MRI correlations between diffusion weighted imaging and T2 relaxometry.

Infants born prematurely are at increased risk of adverse neurodevelopmental outcome. The measurement of white matter tissue composition and structure can help predict functional performance. Specifically, measurements of myelination and indicators of myelination status in the preterm brain could be predictive of later neurological outcome. Quantitative imaging of myelin could thus serve to develop biomarkers for prognosis or therapeutic intervention; however, accurate estimation of myelin content is difficult. This work combines diffusion MRI and multi-component T2 relaxation measurements in a group of 37 infants born very preterm and scanned between 27 and 58 weeks equivalent gestational age. Seven infants have longitudinal data at two time points that we analyze in detail. Our aim is to show that measurement of the myelin water fraction is achievable using widely available pulse sequences and state-of-the-art algorithmic modeling of the MR imaging procedure and that a multi-component fitting routine to multi-shell diffusion weighted data can show differences in neurite density and local spatial arrangement in grey and white matter. Inference on the myelin water fraction allows us to demonstrate that the change in diffusion properties of the preterm thalamus is not solely due to myelination (that increase in myelin content accounts for about a third of the observed changes) whilst the decrease in the posterior white matter T2 has no significant component that is due to myelin water content. This work applies multi-modal advanced quantitative neuroimaging to investigate changing tissue properties in the longitudinal setting. Hum Brain Mapp 37:2479-2492, 2016. © 2016 Wiley Periodicals, Inc.

Deep grey matter growth predicts neurodevelopmental outcomes in very preterm children.

We evaluated whether the volume and growth rate of critical brain structures measured by MRI in the first weeks of life following very preterm (<32/40 weeks) birth could predict subsequent neurodevelopmental outcomes at 4 years of age. A significant proportion of children born very prematurely have cognitive deficits, but these problems are often only detected at early school age. Structural T2-weighted magnetic resonance images were acquired in 96 very preterm neonates scanned within 2 weeks of birth and 70 of these at term-equivalent age. An automated 3D image analysis procedure was used to measure the volume of selected brain structures across all scans and time points. At 4 years of age, 53 children returned for neuropsychological assessments evaluating IQ, language and visual motor integration. Associations with maternal education and perinatal measures were also explored. Multiple regression analyses revealed that growth of the caudate and globus pallidus between preterm birth and term-equivalent age predicted visual motor integration scores after controlling for sex and gestational age. Further associations were found between caudate and putamen growth with IQ and language scores. Analyses at either preterm or term-equivalent age only found associations between normalized deep grey matter growth and visual motor integration scores at term-equivalent age. Maternal education levels were associated with measures of IQ and language, but not visual motor integration. Thalamic growth was additionally linked with perinatal measures and presence of white matter lesions. These results highlight deep grey matter growth rates as promising biomarkers of long-term outcomes following very preterm birth, and contribute to our understanding of the brain-behaviour relations in these children.

A.S.P.E.N. clinical guidelines: nutrition support of neonatal patients at risk for necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most devastating diseases in the neonatal population, with extremely low birth weight and extremely preterm infants at greatest risk. METHOD: A systematic review of the best available evidence to answer a series of questions regarding nutrition support of neonates at risk of NEC was undertaken and evaluated using concepts adopted from the Grading of Recommendations, Assessment, Development and Evaluation working group. A consensus process was used to develop the clinical guideline recommendations prior to external and internal review and approval by the A.S.P.E.N. Board of Directors. RESULTS/ CONCLUSIONS: (1) When and how should feeds be started in infants at high risk for NEC? We suggest that minimal enteral nutrition be initiated within the first 2 days of life and advanced by 30 mL/kg/d in infants ≥ 1, 000 g. (Weak) (2) Does the provision of mother's milk reduce the risk of developing NEC? We suggest the exclusive use of mother's milk rather than bovine-based products or formula in infants at risk for NEC. (Weak) (3) Do probiotics reduce the risk of developing NEC? There are insufficient data to recommend the use of probiotics in infants at risk for NEC. (Further research needed.) (4) Do nutrients either prevent or predispose to the development of NEC? We do not recommend glutamine supplementation for infants at risk for NEC (Strong). There is insufficient evidence to recommend arginine and/or long chain polyunsaturated fatty acid supplementation for infants at risk for NEC. (Further research needed.) (5) When should feeds be reintroduced to infants with NEC? There are insufficient data to make a recommendation regarding time to reintroduce feedings to infants after NEC. (Further research needed.).