Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?

OBJECTIVES: To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN: In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS: The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002). CONCLUSIONS: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.

Analysis of Factors Associated With Body Mass Index at Ages 18 and 36 Months Among Infants Born Extremely Preterm.

Importance: The development of neonatology has been associated with improved survival among infants born extremely preterm, and understanding their long-term outcomes is becoming increasingly important. However, there is little information on body mass index (BMI) among these children. Objective: To determine factors associated with BMI at ages 18 months and 36 months among infants born extremely preterm. Design, Setting, and Participants: This retrospective, multicenter cohort study was conducted using data from the Neonatal Research Network Japan database for 8838 infants born at gestational ages 23 to 28 weeks with data on BMI at 18 months and 36 months. Data were analyzed from April 2018 through June 2021. Exposures: BMI and BMI z score at ages 18 months and 36 months were regressed with gestational age, intrauterine growth restriction (IUGR) status, and complications during pregnancy and the neonatal period separately by presence of multiple pregnancy and sex. Main Outcomes and Measures: BMI and BMI z score at ages 18 months and 36 months. Results: Among 16 791 eligible infants born extremely preterm, 8838 infants were included in the analysis. There were 7089 infants born from single pregnancies (mean [SD] gestational age, 26.0 [1.6] weeks; 3769 [53.2%] boys; mean [SD] birth weight, 847 [228] g) and 1749 infants born from multiple pregnancies (mean [SD] gestational age, 26.3 [1.5] weeks; 903 [51.6%] boys; mean [SD] birth weight, 860 [217] g). In single pregnancies, every week of increased gestational age was associated with an increase in BMI of 0.21 (95% CI, 0.17-0.25) among boys and 0.20 (95% CI, 0.15-0.25) among girls at age 18 months and 0.21 (95% CI, 0.18-0.24) among boys and 0.21 (95% CI, 0.18-0.24) among girls at age 36 months. There was an interaction association between gestational age and IUGR among boys at age 36 months, with a decrease in the change associated with gestational age of 0.12 (95% CI, 0.05-0.19). Every week of increased gestational age in single pregnancies was associated with an increase in BMI z score of 0.14 (95% CI, 0.17-0.21) among boys and 0.17 (95% CI, 0.13-0.21) among girls at age 18 months and 0.19 (95% CI, 0.16-0.22) among boys and 0.17 (95% CI, 0.15-0.20) among girls at age 36 months. Among single pregnancies, IUGR was associated with a decrease in BMI among boys (0.59 [95% CI, 0.23-0.95]) and girls (0.75 [95% CI, 0.39-1.11]) and BMI z score among boys 0.85 [95% CI, 0.25-0.95)] and girls (0.67 [95% CI, 0.36-0.97] at age 18 months and BMI among boys (0.44 [95% CI, 0.17-0.18]) and girls (0.84 [95% CI, 0.55-1.12]) and BMI z score among boys (0.46 [95% CI, 0.21-0.71]) and girls (0.77 [95% CI, 0.53-1.01]) at age 36 months. In multiple pregnancies, IUGR was associated with a decrease in BMI z score at age 36 months among boys (0.26 [95% CI, 0.42-0.89]) and girls (0.29 [95% CI, 0.22-0.79]). In single pregnancies intraventricular hemorrhage (IVH) was associated with a decrease in BMI of 0.47 (95% CI, 0.21-0.73) among boys and 0.42 (95% CI, 0.13-0.71) among girls at age 18 months and 0.53 (95% CI, 0.32-0.74) among boys and 0.31 (95% CI, 0.07-0.54) among girls at age 36 months. IVH was associated with a decrease in BMI z score in single pregnancies of 0.63 (95% CI, 0.20-0.41) among boys and 0.35 (95% CI, 0.12-0.60) among girls at age 18 months and 0.53 (95% CI, 0.34-0.71) among boys and 0.30 (95% CI, 0.11-0.50) among girls at age 36 months. Similar associations were seen in multiple pregnancies. Conclusions and Relevance: This study found that gestational age, the presence of IUGR and multiple pregnancy, and IVH complications were associated with infant BMI at ages 18 months and 36 months. These findings suggest that these complicating factors should be considered when setting growth targets and nutrition strategies for infants born extremely preterm.

DNA Methylation Pattern of CALCA and CALCB in Extremely Premature Infants with Monochorionic Triplets after Single-Embryo Transfer.

Compared with full-term peers, premature infants are more likely to suffer from neonatal diseases and death. Variations in DNA methylation may affect these pathological processes. Calcitonin gene-related peptide (CGRP) plays a complex and diversified role in reproduction and chronic inflammation, and participates in the functional maintenance of vascular adaptation and trophoblast cells during pregnancy. Here, premature live births with single-chorionic triple embryos after single-embryo transfer were used as research objects, while full-term infants with double embryos and double-chorionic twins were used as controls. DNA was extracted from umbilical cord tissues for pyrosequencing to detect the methylation level of CpG island in CGRP promoter region. The average values of CGRP methylation in the umbilical cord tissues of very premature fetuses were higher than that of normal controls obtained from the databases. Immunofluorescence results showed that the expression of αCGRP was decreased in the blood vessel wall of the umbilical cord of monozygotic triplets, especially in death cases, while the ßCGRP had a compensatory expression. In conclusion, our findings suggest that hypermethylation of CGRP might be considered as an important cause of serious neonatal morbidities.

Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines.

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood. Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age. Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020. Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay. Main Outcomes and Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III). Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure. Conclusions and Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.

Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) and Ductus Arteriosus Closure After Premature Birth.

In preterm infants, a high risk of hemodynamically significant patent ductus arteriosus (PDA) exists and its persistence is associated with an increased risk of severe morbidity. Current pharmacological options include ibuprofen or indomethacin. However, treatment by indomethacin or ibuprofen of a large PDA was shown to reduce early pulmonary hemorrhage and later medical treatment but had no effect on neonatal death or morbidity. Early prophylactic treatment of ductus arteriosus by paracetamol seems to be an attractive opportunity to reduce life-threatening morbidity. However, there are currently no data regarding the pharmacokinetics (PK) and pharmacodynamics of paracetamol in preterm neonates in this potential new indication. In this study, we aimed to develop a population PK model for paracetamol and investigate the relationship between paracetamol exposure levels and time to contraction of the ductus. Data were modeled using Monolix software. A one-compartment model adequately described the paracetamol concentration-time course. A Weibull model adequately described the time to contraction of the ductus. Our results suggest that the dosage used in this study (i.e., first day 42.5 mg/kg, then 30 mg/kg/day) allows for reaching the maximum inhibition response from paracetamol regarding the time to close the ductus. However, this study pointed out a lower effect of paracetamol on extremely preterm neonates (below 27 weeks). Therefore, a dose-finding study focusing specifically on extremely preterm neonates with treatment efficacy and toxicity is strongly needed.

Maturational changes in sodium metabolism in periviable infants.

BACKGROUND: Sodium depletion results in impaired somatic growth. The sodium requirements of extremely preterm (periviable) infants early in life are not known. We therefore investigated sodium homeostasis in this population over the first 10 weeks following birth. METHODS: This was a longitudinal, observational study of sodium intake and urine sodium excretion in a convenience cohort of 23 infants born at 22 0/7-23 6/7-week gestation. RESULTS: Sodium intake ranged from 5.2 ± 0.4 to a maximum of 7.9 ± 0.5 mEq/kg/day at 2 and 8 weeks of postnatal age, respectively, while urinary sodium loss was 7.7 ± 1.0 mEq/kg/day and 6.9 ± 0.7 mEq/kg/day at these time points. Sodium balance (sodium intake - urine sodium output) was first positive at 6 weeks of age, though a positive sodium balance exceeding 1.4 mEq/kg/day (i.e., a balance associated with weight gain of 30 g/day) was not observed until 10 weeks. CONCLUSIONS: Infants born at 22-23-week gestational age have a prolonged period of high urinary losses of sodium and negative sodium balance. Sodium intakes greater than those currently recommended by the American Academy of Pediatrics are needed to achieve a significant positive sodium balance in this population.

Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm.

BACKGROUND: Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes. METHODS: We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS. RESULTS: Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case-control status. LIMITATIONS: The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited. CONCLUSIONS: Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.

Airway nitrite is increased in extremely preterm infants with bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and significantly contributes to mortality and morbidity with few predictive biomarkers. Given that nitrites have been implicated in pathways associated with lung disease, we hypothesized that nitrite levels would be altered in the airways of premature infants diagnosed with BPD. METHODS: This was a prospective cohort study of extremely low birth infants (< 28 weeks' gestation) at the University of Alabama at Birmingham. Nitrite levels from tracheal aspirates (TAs) were compared between intubated and ventilated infants with BPD and gestation matched full term (FT) controls. TA derived nitrite levels from day one after birth were also compared between preterm infants who did and did not develop BPD. RESULTS: Infants with BPD were found to have significantly elevated nitrite levels in their tracheal aspirates compared to gestation matched FT controls (p < 0.05). There was a trend for increased nitrite levels on postnatal day one in infants that developed BPD compared to infants that did not develop BPD (p = 0.05). CONCLUSIONS: In conclusion, nitrite levels are significantly increased in airways of infants with BPD. Data from a larger cohort are needed to further support the utility of nitrite for BPD prediction. TRIAL REGISTRATION: Not applicable.

Postnatal adaptations of phosphatidylcholine metabolism in extremely preterm infants: implications for choline and PUFA metabolism.

BACKGROUND: Lipid metabolism in pregnancy delivers PUFAs from maternal liver to the developing fetus. The transition at birth to diets less enriched in PUFA is especially challenging for immature, extremely preterm infants who are typically supported by total parenteral nutrition. OBJECTIVE: The aim was to characterize phosphatidylcholine (PC) and choline metabolism in preterm infants and demonstrate the molecular specificity of PC synthesis by the immature preterm liver in vivo. METHODS: This MS-based lipidomic study quantified the postnatal adaptations to plasma PC molecular composition in 31 preterm infants <28 weeks' gestational age. Activities of the cytidine diphosphocholine (CDP-choline) and phosphatidylethanolamine-N-methyltransferase (PEMT) pathways for PC synthesis were assessed from incorporations of deuterated methyl-D9-choline chloride. RESULTS: The concentration of plasma PC in these infants increased postnatally from median values of 481 (IQR: 387-798) µM at enrollment to 1046 (IQR: 616-1220) µM 5 d later (P < 0.001). Direct incorporation of methyl-D9-choline demonstrated that this transition was driven by an active CDP-choline pathway that synthesized PC enriched in species containing oleic and linoleic acids. A second infusion of methyl-D9-choline chloride at day 5 clearly indicated continued activity of this pathway. Oxidation of D9-choline through D9-betaine resulted in the transfer of 1 deuterated methyl group to S-adenosylmethionine. A very low subsequent transfer of this labeled methyl group to D3-PC indicated that liver PEMT activity was essentially inactive in these infants. CONCLUSIONS: This study demonstrated that the preterm infant liver soon after birth, and by extension the fetal liver, was metabolically active in lipoprotein metabolism. The low PEMT activity, which is the only pathway for endogenous choline synthesis and is responsible for hormonally regulated export of PUFAs from adult liver, strongly supports increased supplementation of preterm parenteral nutrition with both choline and PUFAs.

Hyperglycemia in Extremely Preterm Infants.

Hyperglycemia after birth is common in extremely preterm infants (<28 weeks of gestation). Lower gestational age, lower birthweight, presence of severe illness, and higher parenteral glucose intake increase the risk for hyperglycemia, while provision of higher amounts of amino acids and lipids in parenteral nutrition and early initiation and faster achievement of full enteral feeding decrease the risk. Hyperglycemia is associated with increased mortality and morbidity in the neonatal period. Limited data show an association with long-term adverse effects on growth, neurodevelopment, and cardiovascular and metabolic health. Lowering the glucose infusion rate and administration of insulin are the 2 treatment options. Lowering the glucose infusion could lead to calorie deficits and long-term adverse effects on growth and neurodevelopment. Conversely, insulin use increases the risk for hypoglycemia and requires close blood glucose monitoring and frequent adjustments to glucose infusion and insulin dosage. Randomized trials of varying strategies of nutrient provision and/or insulin therapy and long-term follow-up are needed to improve clinical care and overall health of extremely preterm infants with hyperglycemia.

Early angiogenic proteins associated with high risk for bronchopulmonary dysplasia and pulmonary hypertension in preterm infants.

Early pulmonary vascular disease in preterm infants is associated with the subsequent development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH); however, mechanisms that contribute to or identify infants with increased susceptibility for BPD and/or PH are incompletely understood. Therefore, we tested if changes in circulating angiogenic peptides during the first week of life are associated with the later development of BPD and/or PH. We further sought to determine alternate peptides and related signaling pathways with the risk for BPD or PH. We prospectively enrolled infants with gestational age <34 wk and collected blood samples during their first week of life. BPD and PH were assessed at 36 wk postmenstrual age. Samples were assayed for each of the 1,121 peptides included in the SOMAscan scan technology, with subsequent pathway analysis. Of 102 infants in the study, 82 had BPD, and 13 had PH. Multiple angiogenic proteins (PF-4, VEGF121, ANG-1, bone morphogenetic protein 10 [BMP10], hepatocyte growth factor (HGF), ANG-2) were associated with the subsequent diagnosis of BPD; and FGF-19, PF-4, connective tissue activating peptide (CTAP)-III, and PDGF-AA levels were associated with BPD severity. Early increases in BMP10 was strongly associated with the late risk for BPD and PH. We found that early alterations of circulating angiogenic peptides and others were associated with the subsequent development of BPD. We further identified peptides that were associated with BPD severity and BPD-associated PH, including BMP10. We speculate that proteomic biomarkers during the first week of life may identify infants at risk for BPD and/or PH to enhance care and research.

The Utility of Comprehensive Metabolic Panel Tests for the Prediction of Bronchopulmonary Dysplasia in Extremely Premature Infants.

BACKGROUND: Comprehensive metabolic panel tests (CMP) are routinely performed in extremely premature infants within the first days of life. The association between the parameters of first postnatal CMP and the risk of bronchopulmonary dysplasia (BPD) remains elusive. METHODS: A retrospective analysis was performed to evaluate the correlation between the parameters of first postnatal CMP and the risk of BPD in a cohort of extremely premature infants (born with a gestational age less than 28 weeks or a birth weight less than 1000 grams) at the neonatal intensive care unit, Shenzhen Maternity and Child Healthcare Hospital, from January 2016 to October 2018. A multivariant regression model was built to assess the association of the first postnatal CMP with the development of BPD. RESULTS: A total of 256 extremely premature infants were included in this study. BPD developed in 76 (29.7%) infants. The first CMP in these infants was performed at 5 to 8 days after birth. The levels of blood urea nitrogen (BUN) and magnesium were significantly higher in infants with BPD compared to infants with no BPD (10.2 versus 7.5 mmol/L, P < 0.001 and 0.9 versus 0.8 U/L, P = 0.001, respectively) whereas the level of alkaline phosphatase (ALP) and total protein was significantly lower in infants with BPD (215.5 versus 310.0 U/L, P = 0.002 and 41.2 versus 42.9 g/L, P = 0.037, respectively). Multiple analysis showed that a higher level of BUN (>8.18 mmol/L) was independently associated with BPD (OR 3.261, 95% CI 1.779-5.978). CONCLUSION: Our findings indicate that a higher postnatal BUN level (>8.18 mmol/L) may be a predictor for the development of BPD in extremely premature infants.

The Role of Melanin to Dissociate Oxygen from Water to Treat Retinopathy of Prematurity.

BACKGROUND: Retinopathy of Prematurity (ROP) is a potentially blinding disorder that commonly afflicts premature infants who are born prior to 31weeks of gestation or with a body weight less than 1250 grams (about 2.75 pounds). Another risk factor is excessive oxygen in incubators, which can lead to blindness. A compounding factor is that survival rates for premature infants are rising with concomitantly more cases of ROP. We have reported an unsuspected intrinsic property of melanin to dissociate water. This capability can be considered an alternative treatment option for adult and neonatal diseases. It is known that exogenous surfactant administration suppresses bronchopulmonary dysplasia and consequent death, randomized, controlled trials with various respiratory interventions did not show any significant reductions in morbidity and mortality rates. During a descriptive study about the three leading causes of blindness in the world, the ability of melanin to transform light energy into chemical energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link together our findings with the widely accepted metabolic pathways already described in molecular pathway databases, which have been developed to collect and organize the current knowledge on metabolism scattered across a multitude of scientific evidence. OBSERVATIONS: The current report demonstrates the main problems that afflict premature babies with an emphasis on the growth of abnormal vessels in the retina, the explanation for which is unknown until date. We also reported a case of a baby who suffered digestive and respiratory problems with a brain haemorrhage that was successfully treated by laser photocoagulation. We hypothesise that most likely this effect was due to the melanin level and melanin itself produces oxygen via dissociating with water molecules. CONCLUSION: We postulate that the intrinsic effect of melanin may easily convert visible and invisible light into chemical energy via a water dissociation reaction similar to the one in plant's chlorophyll, and markedly elevated with diagnosis and treatment of the complications related to premature babies.

Disrupted Maturation of the Microbiota and Metabolome among Extremely Preterm Infants with Postnatal Growth Failure.

Growth failure during infancy is a major global problem that has adverse effects on long-term health and neurodevelopment. Preterm infants are disproportionately affected by growth failure and its effects. Herein we found that extremely preterm infants with postnatal growth failure have disrupted maturation of the intestinal microbiota, characterized by persistently low diversity, dominance of pathogenic bacteria within the Enterobacteriaceae family, and a paucity of strictly anaerobic taxa including Veillonella relative to infants with appropriate postnatal growth. Metabolomic profiling of infants with growth failure demonstrated elevated serum acylcarnitines, fatty acids, and other byproducts of lipolysis and fatty acid oxidation. Machine learning algorithms for normal maturation of the microbiota and metabolome among infants with appropriate growth revealed a pattern of delayed maturation of the microbiota and metabolome among infants with growth failure. Collectively, we identified novel microbial and metabolic features of growth failure in preterm infants and potentially modifiable targets for intervention.

Growth, Feeding Tolerance and Metabolism in Extreme Preterm Infants under an Exclusive Human Milk Diet.

BACKGROUND: For preterm infants, human milk (HM) has to be fortified to cover their enhanced nutritional requirements and establish adequate growth. Most HM fortifiers are based on bovine protein sources (BMF). An HM fortifier based on human protein sources (HMF) has become available in the last few years. The aim of this study is to investigate the impact of an HMF versus BMF on growth in extremely low birth weight (ELBW, <1000 g) infants. METHODS: This was a retrospective, controlled, multicenter cohort study in infants with a birthweight below 1000 g. The HMF group received an exclusive HM diet up to 32+0 weeks of gestation and was changed to BMF afterwards. The BMF group received HM+BMF from fortifier introduction up to 37+0 weeks. RESULTS: 192 extremely low birth weight (ELBW)-infants were included (HMF n = 96, BMF n = 96) in the study. After the introduction of fortification, growth velocity up to 32+0 weeks was significantly lower in the HMF group (16.5 g/kg/day) in comparison to the BMF group (18.9 g/kg/day, p = 0.009) whereas all other growth parameters did not differ from birth up to 37+0 weeks. Necrotizing enterocolitis (NEC) incidence was 10% in the HMF and 8% in the BMF group. CONCLUSION: Results from this study do not support the superiority of HFM over BMF in ELBW infants.

Pharmacometabolomics of Respiratory Phenotypic Response to Dexamethasone in Preterm Infants at Risk for Bronchopulmonary Dysplasia.

A prospective cohort study was performed in preterm infants less than 32 weeks gestation at birth who were treated with dexamethasone for developing or established bronchopulmonary dysplasia (BPD). Respiratory phenotype (Respiratory Severity Score (RSS)), serum, and urine metabolomics were assessed before and after treatment. Ten infants provided nine matched serum and nine matched urine samples. There was a significant decrease in RSS with steroid treatment. Serum gluconic acid had the largest median fold change (140 times decreased, P = 0.008). In metabolite set enrichment analysis, in both serum and urine, the urea cycle, ammonia recycling, and malate-aspartate shuttle pathways were most significantly enriched when comparing pretreatment and post-treatment (P value < 0.05). In regression analyses, 6 serum and 28 urine metabolites were significantly associated with change in RSS. Urine gluconic acid lactone was the most significantly correlated with clinical response (correlational coefficient 0.915). Pharmacometabolomic discovery of drug response biomarkers in preterm infants may allow precision therapeutics in BPD treatment.

Third Trimester Cerebellar Metabolite Concentrations are Decreased in Very Premature Infants with Structural Brain Injury.

Advanced neuroimaging techniques have improved our understanding of microstructural changes in the preterm supratentorial brain as well as the cerebellum and its association with impaired neurodevelopmental outcomes. However, the metabolic interrogation of the developing cerebellum during the early postnatal period after preterm birth remains largely unknown. Our study investigates the relationship between cerebellar neurometabolites measured by proton magnetic spectroscopy (1H-MRS) in preterm infants with advancing post-menstrual age (PMA) and brain injury during ex-utero third trimester prior to term equivalent age (TEA). We prospectively enrolled and acquired high quality 1H-MRS at median 33.0 (IQR 31.6-35.2) weeks PMA from a voxel placed in the cerebellum of 53 premature infants born at a median gestational age of 27.0 (IQR 25.0-29.0) weeks. 1H-MRS data were processed using LCModel software to calculate absolute metabolite concentrations of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr). We noted positive correlations of cerebellar concentrations of NAA, Cho and Cr (Spearman correlations of 0.59, 0.64 and 0.52, respectively, p value < 0.0001) and negative correlation of Cho/Cr ratio (R -0.5, p value 0.0002) with advancing PMA. Moderate-to-severe cerebellar injury was noted on conventional magnetic resonance imaging (MRI) in 14 (26.4%) of the infants and were noted to have lower cerebellar NAA, Cho and Cr concentrations compared with those without injury (p value < 0.001). Several clinical complications of prematurity including necrotizing enterocolitis, systemic infections and bronchopulmonary dysplasia were associated with altered metabolite concentrations in the developing cerebellum. We report for the first time that ex-utero third trimester cerebellar metabolite concentrations are decreased in very preterm infants with moderate-to-severe structural cerebellar injury. We report increasing temporal trends of metabolite concentrations in the cerebellum with advancing PMA, which was impaired in infants with brain injury on MRI and may have early diagnostic and prognostic value in predicting neurodevelopmental outcomes in very preterm infants.

Telomere length and salivary cortisol stress reactivity in very preterm infants.

During the Neonatal Intensive Care Unit (NICU) stay, very preterm (VPT) infants are exposed to life-saving yet pain-inducing skin-breaking procedures (i.e., NICU pain-related stress) which contribute to the programming of hypo-responsive HPA axis development during the first months of life. Unfortunately, to date the mechanisms linking NICU pain-related stress and altered HPA axis regulation are only limitedly known. Telomere length (TL) regulation is an epigenetic mechanism previously shown to be affected by early stress exposures and capable of associating with HPA axis reactivity in children. In VPT infants, NICU pain-related stress was found to associate with decreased TL from birth to discharge, but there is no evidence for the association between TL and HPA axis in these infants. In this study, we prospectively examined the relationship between NICU pain-related stress and HPA axis reactivity to an age-appropriate socio-emotional condition (i.e., the Still-Face Procedure, SFP) in healthy VPT infants at 3-month corrected age. NICU pain-related stress was computed as the ratio between the number of skin-breaking procedures and length of NICU stay. A differential score (i.e., ∆TL) was obtained subtracting TL at birth from TL at discharge. A normalized (log10) cortisol reactivity index (CRI) was obtained by averaging post-stress (20 min after SFP) salivary cortisol sample on baseline value. A regression model controlling for neonatal and socio-demographic confounders showed that ∆TL was the only significant predictor of CRI. Although preliminary, these findings contribute to our knowledge of the mechanisms linking early exposures to adversity and later in life regulation of the HPA axis in VPT infants.

Early body composition changes are associated with neurodevelopmental and metabolic outcomes at 4 years of age in very preterm infants.

BACKGROUND: Very preterm (VPT) infants are at-risk for altered growth, slower speed of processing (SOP), and hypertension. This study assesses the relationship between postnatal body composition (BC), neurodevelopment (indexed by SOP), and blood pressure (BP) in VPT infants. METHODS: Thirty-four VPT infants underwent weekly measurements and BC testing until discharge and post-discharge at 4 mos CGA and 4 yrs. At post-discharge visits, SOP was assessed using visual evoked potentials and the NIH Toolbox; BP was also measured. RESULTS: In-hospital rate of weight, length and fat-free mass (FFM) gains were associated with faster SOP at 4 yrs. Higher rate of gains in weight and FFM from discharge to 4 mos CGA were associated with faster SOP at 4 mos CGA, while higher fat mass (FM) gains during the same time were positively associated with BP at 4 yrs. BC at 4 yrs nor gains beyond 4 mos CGA were associated with outcomes. CONCLUSIONS: In VPT infants, early FFM gains are associated with faster SOP, whereas post-discharge FM gains are associated with higher BPs at 4 yrs. This shows birth to 4 mos CGA is a sensitive period for growth and its relation to neurodevelopmental and metabolic outcomes. Close monitoring and early nutritional adjustments to optimize quality of gains may improve outcomes.

Cerebral oxygen saturation and peripheral perfusion in the extremely premature infant with intraventricular and/or pulmonary haemorrhage early in life.

Extremely preterm infants are at higher risk of pulmonary (PH) and intraventricular (IVH) haemorrhage during the transitioning physiology due to immature cardiovascular system. Monitoring of haemodynamics can detect early abnormal circulation that may lead to these complications. We described time-frequency relationships between near infrared spectroscopy (NIRS) cerebral regional haemoglobin oxygen saturation (CrSO2) and preductal peripheral perfusion index (PI), capillary oxygen saturation (SpO2) and heart rate (HR) in extremely preterm infants in the first 72 h of life. Patients were sub-grouped in infants with PH and/or IVH (N H = 8) and healthy controls (N C = 11). Data were decomposed in wavelets allowing the analysis of localized variations of power. This approach allowed to quantify the percentage of time of significant cross-correlation, semblance, gain (transfer function) and coherence between signals. Ultra-low frequencies (<0.28 mHz) were analyzed as slow and prolonged periods of impaired circulation are considered more detrimental than transient fluctuations. Cross-correlation between CrSO2 and oximetry (PI, SpO2 and HR) as well as in-phase semblance and gain between CrSO2 and HR were significantly lower while anti-phase semblance between CrSO2 and HR was significantly higher in PH-IVH infants compared to controls. These differences may reflect haemodynamic instability associated with cerebrovascular autoregulation and hemorrhagic complications observed during the transitioning physiology.