Developmental coordination disorder in preterm children: A systematic review and meta-analysis.

This study aimed to review the prevalence of developmental coordination disorder (DCD) in individuals born preterm and systematically explore this prevalence according to gestational age and different assessment cut-offs and compare it to full-term peers. The eligibility criteria were observational and experimental studies reporting the prevalence of DCD in preterm individuals. A systematic search was performed in databases from inception until March 2022. Two independent reviewers performed the selection. Study quality assessment was performed using the checklists from Joanna Briggs Institute (JBI). Data analysis was performed on Excel and Review Manager Software 5.4. Among the 1774 studies identified, 32 matched the eligibility criteria. The pooled estimate rate of the DCD rate in preterm was 21% (95% confidence interval [CI] 17.8-24.3). The estimate rates were higher as gestational age decreased, and preterm children are two times more likely to have DCD than their full-term peers risk ratio (RR) 2.2 (95% CI 1.77-2.79). The limitation was high heterogeneity between studies; the assessment tools, cut-off points and age at assessment were diverse. This study provided evidence that preterm children are at higher risk for DCD than full-term children, and the risks increased as gestational age decreased.

Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil.

In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X-linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting.

Cytokine Levels in Neonates: Unveiling the Impact of Perinatal Inflammation on Prematurity.

OBJECTIVE: This study aimed to investigate the association between variations in cytokine levels in the first 72 hours of life and prematurity. STUDY DESIGN: In this prospective study, we examined the cytokine levels of 110 newborns in the first 72 hours of life. The participants were divided into two groups based on gestational age (66 very preterm and 44 term newborns), and cytokine levels (interleukin [IL]-6, IL-8, and IL-10, tumor necrosis factor-α [TNF-α], and transforming growth factor-ß [TGF-ß]) were evaluated. RESULTS: Premature newborns exhibited higher levels of IL-6, IL-8, and IL-10, while TNF-α and TGF-ß levels were lower comparing to term newborns. Even after adjusting for maternal and peripartum factors, the significant differences persisted. CONCLUSION: Our study underscores significant cytokine profile differences between full-term and very preterm newborns in early life. Elevated IL-6 and IL-8 levels in preterm infants suggest potential perinatal inflammation links to prematurity. KEY POINTS: · There is a direct association between cytokine levels and prematurity.. · Knowledge of the variation of cytokines in newborns enhances personalized interventions.. · Cytokine levels are early associated with gestational age.

Multivariate risk and clinical signs evaluations for early-onset sepsis on late preterm and term newborns and their economic impact.

There is an increasing evidence that strict evaluation of clinical signs is effective in detecting newborns at risk of early-onset sepsis (EOS) that require antibiotic therapy. In a retrospective case control design, we compared EOS antibiotic indication by clinical signs surveillance with multivariate risk analysis (EOSCalc), and estimate their costs. Newborns ≥ 34 weeks who received EOS antibiotics from June 2014 to December 2016 were studied. Were considered symptomatic those with three clinical signs within first 24 h or two signs and one risk factor present. Cost estimative was done using bottom-up hospital's perspective. Eight thousand three hundred twenty-one were born, 384 were included. Two hundred nineteen (57%) would receive antibiotics by EOSCalc and 64 (16.7%) by clinical signs (p < 0.001). All patients with blood cultures were detected and false-negatives were absent. Total cost was US$ 574,121, estimate US$ 415,576 by EOSCalc, and US$ 314,353 by clinical signs (p < 0.001).Conclusions: The use of EOSCalc and clinical signs surveillance seem to be safe and accurate methods in EOS management. Additionally, the two approaches have shown an economic advantage when compared with the hospital's current practice. What is Known: • EOSCalc is a useful method for screening of EOS in late preterm and term infants. • Presence of clinical signs and/or maternal risk factors are present newborns with EOS. What is New: • Rigorous observation of clinical signs is a more accurate method than EOSCalc to screen for EOS in late preterm and term newborns. • Rigorous observation of clinical signs is more economic than EOSCalc in managing EOS in late preterm and term neonates.

Outcome and Feasibility after 7 Years of Therapeutic Hypothermia in Southern Brazil.

OBJECTIVE: This study aimed to describe the experience with a protocol of therapeutic hypothermia (TH) in southern Brazil. STUDY DESIGN: Newborns with gestational age > 35 weeks with evidence of perinatal asphyxia plus moderate or severe encephalopathy were recruited between March 2011 and November 2017. Whole-body hypothermia for 72 hours, starting within the first 6 hours of life was used. Survivors underwent magnetic resonance imaging (MRI) and electroencephalogram (EEG). The primary outcome was death during hospitalization and neurodevelopment assessed using the Bayley Scales of Infant Development III (BSID III) at 12 months of age. RESULTS: A total of 72 newborns were treated (41 with moderate encephalopathy and 31 with severe encephalopathy), of whom 16 died. MRI was performed in 56 patients, and 24 presented some alterations. Fifty-three patients had an EEG: 11 normal, 20 mildly altered, 12 moderately altered, and 10 severely altered. Forty patients were evaluated through BSID III: 45% presented with some delay in neurodevelopment, 8 (20%) had motor retardation, 15 (37.5%) had language delay, and 13 (32.5%) had a delay in cognitive development. CONCLUSION: Mortality and adverse events were similar to those described in large randomized controlled trials. TH is a safe and an effective method of neurologic protection in asphyxiated newborns in a developing country when performed adequately.

Side Effects of Phototherapy on Neonates.

Phototherapy in neonates for treatment of pathological jaundice is an effective therapeutic tool that is widely used in neonatal units. Over the past years, a greater concern has emerged about the effects on the immune and inflammatory system and its potential genotoxic and side effects, especially the late ones, possibly associated with childhood diseases, showing that this treatment is not as harmless as previously believed. Numerous studies assessing these possible adverse effects of phototherapy on neonates have been published over the past years. Through this review, we seek to analyze what we know about the side effects of phototherapy in the neonatal period. The main causes of jaundice, phototherapy techniques, acute and late side effects, and effects on the immune and inflammatory system were reviewed. It was concluded that phototherapy is not a treatment free of side effects and further studies need to be conducted to elucidate its harmful effects on neonates.

The vaginal microbial communities of healthy expectant Brazilian mothers and its correlation with the newborn's gut colonization.

The female lower genital tract harbors a complex microbial community essential for homeostasis and health. During pregnancy, the female body undergoes unique hormonal changes that contribute to weight gain as well as modulations in immune function that can affect microbiota composition. Several studies have described the vaginal microbiota of pregnant women from the USA, Europe and Mexico. Here we expand our knowledge about the vaginal microbial communities during the third trimester to healthy expectant Brazilian mothers. Vaginal samples were collected from patients delivering at the Hospital de Clínicas de Porto Alegre, Brazil. Microbial DNA was isolated from samples and the V4 region of the 16S rRNA gene was amplified and sequenced using the PGM Ion Torrent. Brazilian pregnant women presented three distinct types of microbial community at the time of labor. Two microbial communities, Cluster 1 and Cluster 3, presented an overall dominance of Lactobacillus while Cluster 2 tended to present higher diversity and richness, with the presence of Pseudomonas, Prevotella and other vaginosis related bacteria. About half of the Brazilian mothers sampled here had dominance of L. iners. The proportion of mothers without dominance of any Lactobacillus was higher in Brazil (22%) compared to UK (2.4%) and USA, where this community type was not detected. The vaginal microbiota showed significant correlation with the composition of the babies' gut microbiota (p-value = 0.002 with a R2 of 15.8%). Mothers presenting different vaginal microbiota shared different microorganisms with their newborns, which would reflect on initial colonizers of the developing newborns' gut.

Early intervention program for very low birth weight preterm infants and their parents: a study protocol.

BACKGROUND: Preterm infants are high risk for delayed neurodevelopment. The main goal is to develop a program of early intervention for very preterm infants that allows families to apply it continuously at home, and quantify the results of early parental stimulation on improvement of cognition and motor skills. METHODS: Randomized clinical Trial including inborn preterm infants with gestational age less than 32 weeks or birth weight less than 1500 g at 48 h after birth. Eligible for begin the intervention up to 7 days after birth. Study Protocol approved by the Brazilian national Committee of ethics in Research and by the institutional ethics committee. Intervention group (IG): skin-to skin care by mother (kangaroo care) plus tactile-kinesthetic stimulation by mothers from randomization until hospital discharge when they receive a program of early intervention with 10 parents' orientation and a total of 10 home visits independently of the standard evaluation and care that will be performed. Systematic early intervention program will be according to developmental milestones, anticipating in a month evolutionary step acquisition of motor and / or cognitive expected for corrected age. Active comparator with a Conventional Group (CG): standard care according to the routine care of the NICU and their needs in the follow up program. Neurodevelopment outcome with blinded evaluations in both groups between 12 and 18 months by Bayley Scales of Infant and Toddler Development third edition and Alberta Motor Infant scale will be performed. All evaluations will be conducted in the presence of parents or caregivers in a safe room for the child move around during the evaluation. DISCUSSION: If we can show that a continuous and global early intervention at home performed by low income families is better than the standard care for very preterm infants, this kind of program may be applied elsewhere in the world. We received grants by Bill and Melinda Gates Foundation, DECIT, Cnpq and Health Ministry. Grand Challenges Brazil: All Children Thriving. TRIAL REGISTRATION: The study was restrospectively registered in ClinicalTrials.gov . in July 15 2016 ( NCT02835612 ).

Neurodevelopment and Growth of a Cohort of Very Low Birth Weight Preterm Infants Compared to Full-Term Infants in Brazil.

OBJECTIVE: The objective of this study was to investigate the neurodevelopment and growth of very low birth weight (BW) preterm infants, at 8 and 18 months corrected age (CA), compared with full term in Brazil. METHODS: Prospective cohort study including 83 preterm infants with BW ≤ 1,500 g and gestational age ≤ 32 weeks, and 52 full-term control infants. Preterm infants free from significant sensory and motor disability, and from congenital anomalies were included. Alberta infant motor scale (AIMS) and Brunet-Lèzini scale (BLS) were used to evaluate the neurodevelopment at 8 and 18 months. Anthropometric measurements were collected to evaluate the growth in both age groups. RESULTS: At 8 months CA, preterm infants scored significantly lower in total AIMS score (p = 0.001). At 18 months, they scored significantly lower on the stand subscale from AIMS (p = 0.040) and exhibited poor psychomotor development in the BLS (p = 0.006). The nutritional status showed significant differences between the groups, in both age groups (p < 0.001). There were positive correlations between nutritional status and AIMS (r = 0.420; p < 0.001) and BLS (r = 0.456; p < 0.001) at 8 months, and between head circumference and BLS (r = 0.235; p < 0.05) at 8 months and AIMS (r = 0.258; p < 0.05) at 18 months. CONCLUSION: Very low BW preterm infants at 8 and 18 months CA showed significant differences in the neurodevelopment and growth pattern when compared with their full-term peers.

Early Empiric Antibiotic Use Is Associated With Delayed Feeding Tolerance in Preterm Infants: A Retrospective Analysis.

The causative factors of neonatal feeding intolerance are poorly understood, but potentially related to clinical practices such as empiric antibiotic usage. The objective of this study was to evaluate whether early empiric antibiotic exposure negatively affects preterm infants' enteral feeding tolerance. Data from infants without risk factors for sepsis, 500 to 1499 g birth weight and 24 to 34 weeks gestational age were analyzed. The primary outcomes were the empiric antibiotic exposure effects on the infants' total parenteral nutrition usage duration and prevalence of necrotizing enterocolitis (NEC). Among the 901 infants included, 67 were exposed to early empiric antibiotic. A 50% increase in parenteral nutrition usage duration and a 4-fold greater prevalence of NEC was seen in the early empiric antibiotic-exposed neonates, when compared with control infants (P < 0.01). Early empiric antibiotic exposure appears to negatively influence preterm infant feeding tolerance and possibly contributes to NEC.

Association between Breast Milk and Bronchopulmonary Dysplasia: A Single Center Observational Study.

Introduction Bronchopulmonary dysplasia (BPD) is a frequent, long-term complication in very low-birth-weight (VLBW) newborns. Its etiology is multifactorial and the oxidative stress is one of its main causes. Breast milk (BM) reduces oxidative stress and provides antioxidant protection, therefore, BM may have a protective effect against BPD. Objectives This study aims to assess the possible protective effects of BM on BPD. Methods This is a cohort study including infants with a birth weight below 1,500 g and/or gestational age of less than 32 weeks, born between January 2011 and October 2014. BPD was defined as the need for supplementary oxygen for 28 days or more. Results The incidence of BPD was 29.1%. The median amount of BM received by the patients in the first 6 weeks of life was significantly higher in patients without BPD (10.8 mL/kg/day) than in those with BPD (2.3 mL/kg/day). The amount of BM received was inversely associated with the incidence of BPD, even after multivariate analysis. The cutoff point at which the protective effect emerged was an average amount of 7 mL/kg/day of BM during the first 42 days of life. Conclusion Feeding VLBW infants with BM is associated with a lower risk of developing BPD.

Vascular Endothelial Growth Factor/Placental Growth Factor Heterodimer Levels in Preterm Infants with Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with changes in pulmonary angiogenesis. However, the role of the vascular endothelial growth factor/placental growth factor (VEGF/PlGF) heterodimer, an antiangiogenic factor, remains unknown in this disease. OBJECTIVE: To compare VEGF/PlGF levels in preterm infants with and without BPD. METHODS: This study was approved by the Institutional Review Board. Preterm neonates with birth weight <2,000 g and gestational age ≤ 34 weeks were included. Exclusion criteria were: neonates transferred from other institutions after 72 hours of life; death before blood collection; presence of major congenital malformations, inborn errors of metabolism, and early sepsis; and mothers with multiple pregnancies, TORCH infections, HIV infection, or autoimmune diseases. BPD was defined as the need for oxygen therapy for a period equal to or greater than 28 days, accompanied by radiographic changes compatible with the disease. Blood was collected from neonates in the first 72 hours of life. VEGF/PlGF levels were measured using the enzyme-linked immunosorbent assay method. The chi-square test, t-test, Mann-Whitney test, analysis of variance, and Kruskal-Wallis test were used for statistical analysis. Variables found to be significant in the univariate analysis were included in the multivariate analysis. RESULTS: Seventy-three patients were included (19 with BPD, 43 without BPD, and 11 neonates who died in the first 28 days of life), with a mean (SD) gestational age of 30.32 (2.88) weeks and birth weight of 1,288 (462) g. Median VEGF/PlGF levels were higher in the groups with BPD and death in the first 28 days of life than in the group without BPD (16.46 [IQR, 12.19-44.57] and 20.64 [IQR, 13.39-50.22], respectively, vs. 9.14 [IQR, 0.02-20.64] pg/mL], p < 0.001). Higher VEGF/P1GF levels remained associated with BPD and death in the first 28 days of life in the multivariate analysis. CONCLUSION: Higher plasma VEGF/PlGF levels were found in preterm neonates with BPD and in those who died in the first 28 days of life, suggesting an important role of this substance in pulmonary vascular development.

Angiogenic and Antiangiogenic Factors in Preterm Neonates Born to Mothers with and without Preeclampsia.

BACKGROUND: Angiogenic and antiangiogenic factors are altered in pregnant women with preeclampsia (PE), but the pattern of expression of these factors in their newborns remains unknown. OBJECTIVE: This study aims to measure vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) levels in preterm neonates born to mothers with PE. METHODS: Neonates with birth weight<2,000 g and gestational age≤34 weeks were included and divided into the following two groups: born to mothers with PE and without PE. Blood was collected from neonates within the first 72 hours of life. VEGF and sFlt-1 levels were measured using the enzyme-linked immunosorbent assay method. RESULTS: A total of 88 neonates were included (37 born to mothers with PE and 51 born to mothers without PE), with a mean gestational age of 29.12±2.96 weeks and birth weight of 1,223.80±417.48 g. In the multivariate analysis, VEGF was 80% lower and sFlt-1 was 13.48 times higher in the group with PE. sFlt-1 concentration was higher in neonates small for gestational age (SGA) than in those appropriate for gestational age. CONCLUSION: Higher sFlt-1 and lower VEGF levels in the group with PE, as well as higher sFlt-1 levels in SGA neonates, reflect a predominance of antiangiogenic mechanisms in PE and growth restriction.

Prevalence and risk factors for iron-deficiency anemia in very-low-birth-weight preterm infants at 1 year of corrected age.

OBJECTIVE: To determine the prevalence of iron-deficiency anemia and iron deficiency at 1 year of corrected age (CA) in preterm very-low-birth-weight infants, and to identify risk factors for iron-deficiency anemia. METHODS: A cohort of infants with birth weight <1500 g and gestational age <34 weeks on iron prophylaxis were followed up to 12 months' CA. Anemia diagnosis was based on hemoglobin <11 g/dl. Iron deficiency was defined by ferritin levels <10 µg/l, transferrin saturation <10% and mean corpuscular volume <80 fl. Neonatal data and feeding at 6 and 12 months' CA (breastfeeding and/or cow's milk or infant formula); hospitalizations during the first year and weight, head circumference, body mass index and length at 12 months' CA were analyzed. RESULTS: Prevalence of anemia in 310 participants was 26.5% [95% confidence interval (CI) 21.8-31.6%] and of iron deficiency was 48% (95% CI 39.0-56.9%). Increased consumption of cow's milk at 6 months [relative risk (RR) 1.687; 95% CI 1.146-2.483], lower maternal age (RR 0.953; 95% CI 0.923-0.983), high number of pregnancies (RR 1.256; 95% CI 1.122-1.406) and being born small for gestational age (RR 1.578; 95% CI 1.068-2.331) were independently associated with anemia after adjustments. CONCLUSIONS: Prevalence of anemia is high at 1 year of CA. Dietary and environmental education strategies may help prevent anemia after discharge.

Administration time of caffeine in preterm infants: systematic review and meta-analysis.

To assess the ideal time for caffeine administration in preterms, identifying its effects and safety. Study Design: Meta-analysis conducted including preterms <32 weeks GA or BW < 1500 g, comparing caffeine administration time: <24 x ≥24HOL, <48 x ≥48HOL, <72 x ≥72HOL. 18 studies included 76.998 patients. The median age of starting caffeine was the first 24 HOL. In the overall comparisons, there was reduction in patent ductus arteriosus (OR 0.71 [0.55, 0. 92]; low evidence), retinopathy of prematurity (OR 0.71 [0.54, 0.93]; moderate evidence), severe brain injury (OR 0.79 [0.70, 0.91]; moderate evidence), bronchopulmonary dysplasia (BPD) (OR 0.69 [0.59, 0.81]; moderate evidence), composite outcome of BPD or death (OR 0.76 [0.66, 0.88]; moderate evidence). Mortality increase was found (OR 1.20 [1.12, 1.29], very low evidence).Caffeine in the first 24 HOL has benefits in reducing morbidities associated with prematurity. Mortality finding is potentially due to survival bias.

Bronchopulmonary dysplasia: temporal trend from 2010 to 2019 in the Brazilian Network on Neonatal Research.

OBJECTIVE: To evaluate the temporal trend of bronchopulmonary dysplasia (BPD) in preterm infants who survived to at least 36 weeks' post-menstrual age (PMA) and BPD or death at 36 weeks' PMA, and to analyse variables associated with both outcomes. DESIGN: Retrospective cohort with data retrieved from an ongoing national registry. SETTING: 19 Brazilian university public hospitals. PATIENTS: Infants born between 2010 and 2019 with 23-31 weeks and birth weight 400-1499 g. MAIN OUTCOME MEASURES: Temporal trend was evaluated by Prais-Winsten model and variables associated with BPD in survivors or BPD or death were analysed by logistic regression. RESULTS: Of the 11 128 included infants, BPD in survivors occurred in 22%, being constant over time (annual per cent change (APC): -0.80%; 95% CI: -2.59%; 1.03%) and BPD or death in 45%, decreasing over time (APC: -1.05%; 95% CI: -1.67%; -0.43%). Being male, small for gestational age, presenting with respiratory distress syndrome, air leaks, needing longer duration of mechanical ventilation, presenting with treated patent ductus arteriosus and late-onset sepsis were associated with an increase in the chance of BPD. For the outcome BPD or death, maternal bleeding, multiple gestation, 5-minute Apgar <7, late-onset sepsis, necrotising enterocolitis and intraventricular haemorrhage were added to the variables reported above as increasing the chance of the outcome. CONCLUSION: The frequency of BPD in survivors was constant and BPD or death decreased by 1.05% at each study year. These results show some improvement in perinatal care in Brazilian units which resulted in a reduction of BPD or death, but further improvements are still needed to reduce BPD in survivors.

Influence of perinatal nutrition and gestational age on neurodevelopment of very low-birth-weight preterm infants.

AIM: To assess the influence of gestational age and perinatal nutrition on development at 24 months' corrected age in a cohort of very low-birth-weight preterm infants. METHODS: One hundred twenty-five very low-birth-weight preterm infants admitted to a neonatal intensive care unit within the first 48 hours of life were studied. The infants were classified as born small for gestational age (SGA) and still SGA at discharge (SGA/SGA); born adequate for gestational age (AGA) and SGA at discharge (AGA/SGA); and born AGA and still AGA age at discharge (AGA/AGA). The Bayley Scales of Infant and Toddler Development III (BSID-III) were used for assessment of neurodevelopment at 24 months' corrected age. RESULTS: Fifty-six infants were classified as SGA/SGA, 55 as AGA/SGA, and 14 as AGA/AGA with no difference in BSID-III among the groups. By multiple linear regression analysis, the variables associated to better neurodevelopment outcome were higher gestational age and absence of grade III/IV periventricular/intraventricular hemorrhage. CONCLUSION: Immaturity is the most important variable associated with better neurodevelopment outcome in very preterm infants.

The Influence of Early Nutrition on Neurodevelopmental Outcomes in Preterm Infants.

Premature infants, given their limited reserves, heightened energy requirements, and susceptibility to nutritional deficits, require specialized care. AIM: To examine the complex interplay between nutrition and neurodevelopment in premature infants, underscoring the critical need for tailored nutritional approaches to support optimal brain growth and function. DATA SOURCES: PubMed and MeSH and keywords: preterm, early nutrition, macronutrients, micronutrients, human milk, human milk oligosaccharides, probiotics AND neurodevelopment or neurodevelopment outcomes. Recent articles were selected according to the authors' judgment of their relevance. Specific nutrients, including macro (amino acids, glucose, and lipids) and micronutrients, play an important role in promoting neurodevelopment. Early and aggressive nutrition has shown promise, as has recognizing glucose as the primary energy source for the developing brain. Long-chain polyunsaturated fatty acids, such as DHA, contribute to brain maturation, while the benefits of human milk, human milk oligosaccharides, and probiotics on neurodevelopment via the gut-brain axis are explored. This intricate interplay between the gut microbiota and the central nervous system highlights human milk oligosaccharides' role in early brain maturation. CONCLUSIONS: Individualized nutritional approaches and comprehensive nutrient strategies are paramount to enhancing neurodevelopment in premature infants, underscoring human milk's potential as the gold standard of nutrition for preterm infants.

Association between high cytokine levels with white matter injury in preterm infants with sepsis.

OBJECTIVE: To examine the association among interleukin-6, interleukin-8, tumor necrosis factor-α, interleukin-10, and interleukin-1ß and white matter injury in very-low-birth-weight infants with clinical sepsis and to help predict infants at risk for development of white matter injury. DESIGN: A prospective cohort study was carried out. SETTING: Neonatal intensive care unit. PATIENTS: Very low birth weight infants with clinical early-onset sepsis. Exclusion criteria were death before 14 days, major malformations, and congenital infections. INTERVENTION: Ultrasound brain scans were carried out on the third day and weekly until the sixth week of life or discharge and confirmed by a magnetic resonance image performed in the first year. Plasma was assayed for interleukin-6, interleukin-8, tumor necrosis factor-α, interleukin-10, and interleukin-1ß in the same sample collected for sepsis work-up. Mann-Whitney, chi-square, t tests, multiple regression, and receiver operating characteristic analysis were applied. MEASUREMENTS AND MAIN RESULTS: From July 2005 to October 2007 we studied 84 very-low-birth-weight infants, 27 (32%) with white matter injury, and 57 (68%) control subjects (with no white matter injury). Proven early-onset sepsis and necrotizing enterocolitis were high risk for white matter injury after adjustment for gestational age and birth weight (relative risk, 3.04; 1.93-4.80 and relative risk, 2.2; 1.31-3.74, respectively). Interleukin-6, interleukin-8, and tumor necrosis factor-α levels were higher in infants with white matter injury than in control subjects (p < .0001). Interleukin-1ß and interleukin-10 were similar. The areas under the curve for interleukin-6, interleukin-8, and tumor necrosis factor-α were 0.96 (0.92-0.99), 0.97 (0.94-1.0), and 0.93 (0.86-0.99), respectively. Interleukin-8 ≥100 pg/mL was the best predictor of white matter injury; the sensitivity and specificity were 96% and 83%, respectively, and negative predictive value was 98%. CONCLUSIONS: Very-low-birth-weight infants with proven early-onset sepsis, necrotizing enterocolitis, and high plasma levels of interleukin-6, interleukin-8, and tumor necrosis factor-α are at high risk for white matter injury.