Race as social determinant of growth and body composition among infants born very preterm.

OBJECTIVE: Racism leads to disparities in health outcomes. Our objective was to determine if black race was independently associated with differences in fat accretion at discharge in a large cohort of very preterm infants (32 weeks of gestation or less). METHODS: De-identified demographic, anthropometric and body composition data were collected from seven neonatal units around the United States. Weight, length, and head circumference z-scores at birth and at the time of body composition assessment or hospital discharge were calculated. RESULTS: The median gestational age and birthweight for this cohort (n = 888) were 29 weeks [IQR, 27-30] and 1167 g [SD, 354], respectively. The study population included 53% black preterm infants. Birthweight was lower in black preterm infants compared with white infants (1112 ± 334 g vs. 1228 ± 366 g; p < 0.0001). After adjusting for birthweight, gestational age, and birthweight-for-age z-score, black preterm infants had more weight gain (adjusted mean difference: 0.5 g/kg/day; p = 0.03) but not higher BF% z-scores at hospital discharge (adjusted mean: 1.2 vs. 1.3; p = 0.14) than white infants. CONCLUSIONS: After adjusting for covariates, black race was associated with higher weight gain velocity but not higher BF% z-scores. IMPACT: This study presents findings from a large-scale multicenter cohort. Racial differences were observed in birth weight and the rate of weight gain; however, these differences were not associated with dissimilarities in body composition outcomes. Understanding nutrition and growth outcomes across racial groups is necessary to combat racial disparities in the neonatal intensive care unit (NICU).

Nutrient Composition of Donor Human Milk and Comparisons to Preterm Human Milk.

BACKGROUND: Human milk is the preferred diet for very low birth weight (VLBW, <1500 g) infants. When mother's own milk is unable to meet the needs of VLBW infants, donor human milk (DHM) is the preferred alternative. Unfortunately, the composition of DHM remains elusive and no comparative studies between preterm human milk and DHM have been performed previously. OBJECTIVES: We aimed to analyze the nutrient content of commercial pooled DHM and compare nutrient content in DHM with that of early and mature preterm human milk. METHODS: We analyzed nutrient content in 15 DHM samples provided from 7 commercial milk banks including calories, carbohydrate, fat, protein, sodium, chloride, potassium, zinc, calcium, phosphorus, magnesium, and vitamin D and compared each nutrient to early (7 d of life) and mature (28 d of life) preterm human milk samples (n = 28-36 per nutrient, gestational age = 28 ± 3 wk). Protein-to-energy ratio and carbohydrate-to-nonprotein energy ratio were calculated for each sample and compared. RESULTS: Mean values for all macro- and micronutrients in DHM are reported. In comparison to early or mature preterm human milk, DHM had significantly lower protein, sodium, chloride, potassium, and zinc content. Calorie, carbohydrate, calcium, phosphorus, magnesium, and vitamin D content did not differ statistically between DHM and early or mature preterm human milk. Fat content was modestly lower in early but not mature human milk when compared with DHM. CONCLUSIONS: We provide mean values for several macro- and micronutrients for DHM and identify key differences between DHM and preterm human milk, which may be considered when designing human milk-based feeding plans. This study was registered at clinicaltrials.gov as NCT05742815.

Body composition of extremely preterm infants fed protein-enriched, fortified milk: a randomized trial.

BACKGROUND: Critically ill extremely preterm infants fed human milk are often underrepresented in neonatal nutrition trials aimed to determine the effects of enteral protein supplementation on body composition outcomes. METHODS: Masked randomized trial in which 56 extremely preterm infants 25-28 weeks of gestation were randomized to receive either fortified milk enriched with a fixed amount of extensively hydrolyzed protein (high protein group) or fortified milk without additional protein (standard protein group). RESULTS: Baseline characteristics were similar between groups. In a longitudinal analysis, the mean percent body fat (%BF) at 30-32 weeks of postmenstrual age (PMA), 36 weeks PMA, and 3 months of corrected age (CA) did not differ between groups (17 ± 3 vs. 15 ± 4; p = 0.09). The high protein group had higher weight (-0.1 ± 1.2 vs. -0.8 ± 1.3; p = 0.03) and length (-0.8 ± 1.3 vs. -1.5 ± 1.3; p = 0.02) z scores from birth to 3 months CA. The high protein group also had higher fat-free mass (FFM) z scores at 36 weeks PMA (-0.9 ± 1.1 vs. -1.5 ± 1.1; p = 0.04). CONCLUSIONS: Increased enteral intake of protein increased FFM accretion, weight, and length in extremely preterm infants receiving protein-enriched, fortified human milk. IMPACT: Extremely preterm infants are at high risk of developing postnatal growth failure, particularly when they have low fat-free mass gains. Protein supplementation increases fat-free mass accretion in infants, but several neonatal nutrition trials aimed to determine the effects of enteral protein supplementation on body composition outcomes have systematically excluded critically ill extremely preterm infants fed human milk exclusively. In extremely preterm infants fed fortified human milk, higher enteral protein intake increases fat-free mass accretion and promotes growth without causing excessive body fat accretion.

The gut microbiome of extremely preterm infants randomized to the early progression of enteral feeding.

BACKGROUND: Early progression of feeding could influence the development of the gut microbiome. METHODS: We collected fecal samples from extremely preterm infants randomized to receive either early (feeding day 2) or delayed (feeding day 5) feeding progression. After study completion, we compared samples obtained at three different time points (week 1, week 2, and week 3) to determine longitudinal differences in specific taxa between the study groups using unadjusted and adjusted negative binomial and zero-inflated mixed models. Analyses were adjusted for a mode of delivery, breastmilk intake, and exposure to antibiotics. RESULTS: We analyzed 137 fecal samples from 51 infants. In unadjusted and adjusted analyses, we did not observe an early transition to higher microbial diversity within samples (i.e., alpha diversity) or significant differences in microbial diversity between samples (i.e., beta diversity) in the early feeding group. Our longitudinal, single-taxon analysis found consistent differences in the genera Lactococcus, Veillonella, and Bilophila between groups. CONCLUSIONS: Differences in single-taxon analyses independent of the mode of delivery, exposure to antibiotics, and breastmilk feeding suggest potential benefits of early progression of enteral feeding volumes. However, this dietary intervention does not appear to increase the diversity of the gut microbiome in the first 28 days after birth. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02915549. IMPACT: Early progression of enteral feeding volumes with human milk reduces the duration of parenteral nutrition and the need for central venous access among extremely preterm infants. Early progression of enteral feeding leads to single-taxon differences in longitudinal analyses of the gut microbiome, but it does not appear to increase the diversity of the gut microbiome in the first 28 days after birth. Randomization in enteral feeding trials creates appealing opportunities to evaluate the effects of human milk diets on the gut microbiome.

Orogastric Tube Insertion in Extremely Low Birth-Weight Infants.

BACKGROUND: Orogastric (OG) tube insertion is a frequent practice performed by nurses in the neonatal intensive care unit (NICU). Combining the nose-ear-mid-umbilicus (NEMU) method with a birth weight (BW)-based method to determine optimal insertion length of OG tubes could reduce misplacement in extremely low birth-weight (ELBW) infants. PURPOSE: The objective of this study was to determine whether combining the NEMU method with a BW-based method to determine insertion length of OG tubes reduces misplacement of OG tubes in ELBW infants younger than 6 hours. METHODS: The study included 129 ELBW infants in the NICU younger than 6 hours. We compared the frequency of OG tube misplacements in ELBW infants during 2 different time periods. In period I, the insertion length of OG tubes was estimated with the NEMU method alone. In period II, the insertion length of OG tubes was estimated by combining the NEMU method with a BW-based method. OG tubes were considered misplaced if the tip was above the diaphragm (high) or near the pylorus (low) in radiographs obtained after placement. RESULTS: Infants who had OG tubes placed by combining both methods were less likely to have low OG tubes (53% in period I vs 34% in period II; P < .05). The BW-based method alone predicted optimal OG tube insertion length in 57 of 89 infants (64%). IMPLICATIONS FOR PRACTICE AND RESEARCH: Combining the NEMU method with the BW-based method increases the probability of optimal OG tube placement in ELBW infants. Additional studies across multiple centers would validate the diagnostic accuracy of this method.Video abstract available athttps://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx .

Percent Body Fat Content Measured by Plethysmography in Infants Randomized to High- or Usual-Volume Feeding after Very Preterm Birth.

We measured percent body fat by air-displacement plethysmography in 86 infants born at <32 weeks of gestation randomized to receive either high-volume (180-200 mL/kg/day) or usual volume feeding (140-160 mL/kg/day). High-volume feeding increased percent body fat by ≤2% at 36 weeks of postmenstrual age (within a predefined range of equivalence). TRIAL REGISTRATION: ClincialTrials.gov: NCT02377050.

Growth Rates of Infants Randomized to Continuous Positive Airway Pressure or Intubation After Extremely Preterm Birth.

OBJECTIVE: To evaluate the effects of early treatment with continuous positive airway pressure (CPAP) on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (240/7-276/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks of postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks of PMA and follow-up outcomes at 18-22 months corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: Growth data were analyzed for 810 of 1316 infants enrolled in SUPPORT (414 in the intervention group, 396 in the control group). The median gestational age was 26 weeks, and the mean birth weight was 839 g. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between the 2 groups. In a regression model, growth rates between birth and 36 weeks of PMA, as well as growth rates during multiple intervals from birth to day 7, days 7-14, days 14-21, days 21-28, day 28 to 32 weeks PMA, and 32-36 weeks PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of having a Bayley-III cognitive score <85 at 18-22 months corrected age (P = .002). CONCLUSIONS: EPT infants randomized to early CPAP did not have higher in-hospital growth rates than infants randomized to early intubation.

Postnatal growth of preterm infants 24 to 26 weeks of gestation and cognitive outcomes at 2 years of age.

BACKGROUND: Weight z scores at 36 weeks of postmenstrual age (PMA) define postnatal growth failure (PGF) and malnutrition. This study aimed to determine weight z scores at 36 weeks PMA that are associated with adverse cognitive outcomes at 2 years of age. METHODS: In this retrospective cohort study, 350 infants 24-26 weeks of gestation born between 2006 and 2014 and followed at 2 years were included. Weight z scores at birth and at 36 weeks PMA were calculated using the INTERGROWTH-21st growth curves. The primary outcome was cognitive delay at 2 years of age (Bayley-III cognitive score < 85). RESULTS: Neither the traditional definition of PGF (z score below -1.3) nor the recently proposed definition of malnutrition (z score decline of 1.2 or greater) was associated with cognitive delay. Both a weight z score below -1.0 at 36 weeks PMA (RR: 1.65; 95% CI: 1.10-2.49; p < 0.05) and a decline below -1.0 in weight z score from birth to 36 weeks PMA (RR: 1.40; 95% CI: 1.00-1.94; p < 0.05) were associated with a higher risk of cognitive delay. CONCLUSION: With optimal cutoffs, INTERGROWTH-21st weight z scores can predict the risk of cognitive delay. IMPACT: New growth curves generated with longitudinal data could overcome some limitations of traditional growth curves generated with cross-sectional data. When these new growth curves are used to assess the growth of preterm infants, alternative definitions for postnatal growth alterations may be needed. This study examines the association between postnatal growth alterations defined by the INTEGROWTH-21st growth curves and adverse cognitive outcomes at 2 years of age. With alternative definitions of postnatal growth failure and malnutrition, the INTERGROWTH-21st growth curves can help establish the association between postnatal growth of extremely preterm infants and adverse neurodevelopmental outcomes in early childhood.

Higher- or Usual-Volume Feedings in Infants Born Very Preterm: A Randomized Clinical Trial.

OBJECTIVE: To determine whether higher-volume feedings improve postnatal growth among infants born very preterm. STUDY DESIGN: Randomized clinical trial with 1:1 parallel allocation conducted from January 2015 to June 2018 in a single academic medical center in the US. In total, 224 infants with a birth weight 1001-2500 g born at <32 weeks of gestation were randomized to higher-volume (180-200 mL/kg/d) or usual-volume (140-160 mL/kg/d) feedings after establishing full enteral feedings (≥120 mL/kg/d). The primary outcome was growth velocity (g/kg/d) from randomization to study completion at 36 weeks of postmenstrual age or hospital discharge if earlier. RESULTS: Growth velocity increased among infants in the higher-volume group compared with the usual-volume group (mean [SD], 20.5 [4.5] vs 17.9 [4.5] g/kg/d; P < .001). At study completion, all measurements were higher among infants in the higher-volume group compared with the usual-volume group: weight (2365 [324] g, z score -0.60 [0.73] vs 2200 [308] g, z score -0.94 [0.71]; P < .001); head circumference (31.9 [1.3] cm, z score -0.30 [0.91] vs 31.4 [1.3] cm, z score -0.53 [0.84]; P = .01); length (44.9 [2.1] cm, z score -0.68 [0.88] vs 44.4 [2.0], z score -0.83 [0.84]; P = .04); and mid-arm circumference (8.8 [0.8] cm vs 8.4 [0.8] cm; P = .002). Bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, or other adverse outcomes did not differ between groups. CONCLUSIONS: In infants born very preterm weighing 1001-2500 g at birth, higher-volume feedings increased growth velocity, weight, head circumference, length, and mid-arm circumference compared with usual-volume feedings without adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02377050.

Serial assessment of fat and fat-free mass accretion in very preterm infants: a randomized trial.

BACKGROUND: Clinicians could modify dietary interventions during early infancy by monitoring fat and fat-free mass accretion in very preterm infants. METHODS: Preterm infants were randomly assigned to either having reports on infant body composition available to the clinicians caring for them (intervention group) or not having reports available (control group). All infants underwent serial assessments of body composition by air-displacement plethysmography before 32 weeks of postmenstrual age (PMA) and at 36 weeks PMA. The primary outcome was percent body fat (%BF) at 3 months of corrected age (CA). RESULTS: Fifty infants were randomized (median gestational age: 30 weeks; mean ± SD birth weight: 1387 ± 283 g). The mean %BF increased from 7 ± 4 before 32 weeks PMA to 20 ± 5 at 3 months CA. The differences in mean %BF between the intervention group and the control group were not statistically significant at 36 weeks PMA (14.5 vs. 13.6) or 3 months CA (20.8 vs. 19.4). Feeding practices and anthropometric measurements during hospitalization did not differ between groups. CONCLUSIONS: Serial assessments of body composition in both intervention and control groups showed consistent increments in %BF. However, providing this information to clinicians did not influence nutritional practices or growth. IMPACT: Serial assessments of body composition in preterm infants at 32 and 36 weeks postmenstrual age show consistent increments in % body fat up to 3 months of corrected age. However, providing this information to the clinician did not influence nutritional practices or growth.

Transfusion-associated necrotizing enterocolitis in preterm infants: an updated meta-analysis of observational data.

BACKGROUND: The number of observational studies that report an association between packed red blood cell (PRBC) transfusions and necrotizing enterocolitis (NEC) has increased. The primary objective of this study was to evaluate the association between PRBC transfusions and NEC in observational studies. METHODS: Medline, Embase and Cochrane Library databases as well as the Pediatrics Academic Societies abstract archives were systematically searched to identify observational studies that investigated the association between PRBC transfusions and NEC. Key search terms included premature infant, blood transfusion and necrotizing enterocolitis. The generic inverse variance method with a random-effects model was used to meta-analyze selected studies. Odds ratios (ORs) and confidence intervals (CIs) were calculated. RESULTS: A meta-analysis of 17 observational studies that reported the association between PRBC transfusions and NEC was performed. The meta-analysis revealed no evidence of an association between PRBC transfusions and a higher risk of NEC (OR: 0.96; 95% CI: 0.53-1.71; P=0.88). The effect estimates that suggested an association between PRBC transfusion and NEC in matched case-control studies (OR: 1.20; 95% CI: 0.58-2.47; P=0.63) differed from those reported in cohort studies (OR: 0.51; 95% CI: 0.34-0.75; P=<0.01). CONCLUSIONS: This updated meta-analysis of predominantly low-to-moderate quality observational studies suggests that there is no significant association between PRBC transfusions and NEC. A higher quality of evidence on this topic is needed.

A Comparison of 3 Vitamin D Dosing Regimens in Extremely Preterm Infants: A Randomized Controlled Trial.

OBJECTIVE: To determine the optimal dose of vitamin D supplementation to achieve biochemical vitamin D sufficiency in extremely low gestational age newborns in a masked randomized controlled trial. STUDY DESIGN: 100 infants 23 0/7-27 6/7 weeks gestation were randomized to vitamin D intakes of placebo (n = 36), 200 IU (n = 34), and 800 IU/d (n = 30) (approximating 200, 400, or 1000 IU/d, respectively, when vitamin D routinely included in parenteral or enteral nutrition is included). The primary outcomes were serum 25-hydroxy vitamin D concentrations on postnatal day 28 and the number of days alive and off respiratory support in the first 28 days. RESULTS: At birth, 67% of infants had 25-hydroxy vitamin D <20 ng/mL suggesting biochemical vitamin D deficiency. Vitamin D concentrations on day 28 were (median [25th-75th percentiles], ng/mL): placebo: 22 (13-47), 200 IU: 39 (26-57), 800 IU: 84.5 (52-99); P < .001. There were no differences in days alive and off respiratory support (median [25th-75th percentiles], days): placebo: 1 (0-11), 200 IU: 0 (0-8), and 800 IU: 0.5 (0-22); P = .63, or other respiratory outcomes among groups. CONCLUSIONS: At birth, most extremely preterm infants have biochemical vitamin D deficiency. This biochemical deficiency is reduced on day 28 by supplementation with 200 IU/d and prevented by 800 IU/d. Larger trials are required to determine if resolution of biochemical vitamin D deficiency improves clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01600430.

Seasonal Variation in Solar Ultra Violet Radiation and Early Mortality in Extremely Preterm Infants.

BACKGROUND: Vitamin D production during pregnancy promotes fetal lung development, a major determinant of infant survival after preterm birth. Because vitamin D synthesis in humans is regulated by solar ultraviolet B (UVB) radiation, we hypothesized that seasonal variation in solar UVB doses during fetal development would be associated with variation in neonatal mortality rates. METHODS: This cohort study included infants born alive with gestational age (GA) between 23 and 28 weeks gestation admitted to a neonatal unit between 1996 and 2010. Three infant cohort groups were defined according to increasing intensities of solar UVB doses at 17 and 22 weeks gestation. The primary outcome was death during the first 28 days after birth. RESULTS: Outcome data of 2,319 infants were analyzed. Mean birth weight was 830 ± 230 g and median gestational age was 26 weeks. Mortality rates were significantly different across groups (p = 0.04). High-intensity solar UVB doses were associated with lower mortality when compared with normal intensity solar UVB doses (hazard ratio: 0.70; 95% confidence interval: 0.54-0.91; p = 0.01). CONCLUSION: High-intensity solar UVB doses during fetal development seem to be associated with risk reduction of early mortality in preterm infants. Prospective studies are needed to validate these preliminary findings.

Oronasopharyngeal suction versus wiping of the mouth and nose at birth: a randomised equivalency trial.

BACKGROUND: Wiping of the mouth and nose at birth is an alternative method to oronasopharyngeal suction in delivery-room management of neonates, but whether these methods have equivalent effectiveness is unclear. METHODS: For this randomised equivalency trial, neonates delivered at 35 weeks' gestation or later at the University of Alabama at Birmingham Hospital, Birmingham, AL, USA, between October, 2010, and November, 2011, were eligible. Before birth, neonates were randomly assigned gentle wiping of the face, mouth (implemented by the paediatric or obstetric resident), and nose with a towel (wipe group) or suction with a bulb syringe of the mouth and nostrils (suction group). The primary outcome was the respiratory rate in the first 24 h after birth. We hypothesised that respiratory rates would differ by fewer than 4 breaths per min between groups. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01197807. FINDINGS: 506 neonates born at a median of 39 weeks' gestation (IQR 38-40) were randomised. Three parents withdrew consent and 15 non-vigorous neonates with meconium-stained amniotic fluid were excluded. Among the 488 treated neonates, the mean respiratory rates in the first 24 h were 51 (SD 8) breaths per min in the wipe group and 50 (6) breaths per min in the suction group (difference of means 1 breath per min, 95% CI -2 to 0, p<0·001). INTERPRETATION: Wiping the nose and mouth has equivalent efficacy to routine use of oronasopharyngeal suction in neonates born at or beyond 35 weeks' gestation. FUNDING: None.

The value of Pa(CO2) in relation to outcome in congenital diaphragmatic hernia.

BACKGROUND: Postnatal assessment of disease severity is critical for analysis of mortality rates and development of future interventions in congenital diaphragmatic hernia (CDH). OBJECTIVE: The objective of this study was to stratify the risk of mortality based on arterial Paco 2. METHODS: Retrospective analysis of infants (n = 133) with CDH admitted to a regional extracorporeal membrane oxygenation (ECMO) center in two different periods: period I (1987-1996; n = 46) and period II (2002-2010; n = 87). RESULTS: The mortality rate (37%) was similar in both periods (p = 0.98). Paco 2 < 60 mm Hg in the first arterial blood gas (ABG) was an independent predictor of survival in both periods (p = 0.03). The predicted survival rate was 84% if initial Paco 2 was < 55 mm Hg. For infants with initial Paco 2 > 55 mm Hg treated with ECMO (n = 83), the predicted survival rate was 11% if the Paco 2 was > 88 mm Hg before the initiation of ECMO. CONCLUSION: Paco 2, a surrogate of lung hypoplasia, may be useful for risk stratification in CDH. Paco 2 < 60 mm Hg in the first ABG may indicate milder pulmonary hypoplasia. A Paco 2 > 80 mm Hg in the first ABG and/or before ECMO may indicate severe pulmonary hypoplasia.

Early and exclusive enteral nutrition in infants born very preterm.

OBJECTIVE: To characterise the effects of early and exclusive enteral nutrition with either maternal or donor milk in infants born very preterm (280/7-326/7 weeks of gestation). DESIGN: Parallel-group, unmasked randomised controlled trial. SETTING: Regional, tertiary neonatal intensive care unit. PARTICIPANTS: 102 infants born very preterm between 2021 and 2022 (51 in each group). INTERVENTION: Infants randomised to the intervention group received 60-80 mL/kg/day within the first 36 hours after birth. Infants randomised to the control group received 20-30 mL/kg/day (standard trophic feeding volumes). MAIN OUTCOME MEASURES: The primary outcome was the number of full enteral feeding days (>150 mL/kg/day) in the first 28 days after birth. Secondary outcomes included growth and body composition at the end of the first two postnatal weeks, and length of hospitalisation. RESULTS: The mean birth weight was 1477 g (SD: 334). Half of the infants were male, and 44% were black. Early and exclusive enteral nutrition increased the number of full enteral feeding days (+2; 0-2 days; p=0.004), the fat-free mass-for-age z-scores at postnatal day 14 (+0.5; 0.1-1.0; p=0.02) and the length-for-age z-scores at the time of hospital discharge (+0.6; 0.2-1.0; p=0.002). Hospitalisation costs differed between groups (mean difference favouring the intervention group: -$28 754; -$647 to -$56 861; p=0.04). CONCLUSIONS: In infants born very preterm, early and exclusive enteral nutrition increases the number of full enteral feeding days. This feeding practice may also improve fat-free mass accretion, increase length and reduce hospitalisation costs. TRIAL REGISTRATION NUMBER: NCT04337710.

Timing of Red Blood Cell Transfusions and Occurrence of Necrotizing Enterocolitis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Observational studies often report that anemia and red blood cell (RBC) transfusions are associated with a higher risk of necrotizing enterocolitis (NEC) among extremely low-birthweight (ELBW) infants. Objective: To evaluate whether there is a temporal association between 72-hour hazard periods of exposure to RBC transfusions and NEC among ELBW infants randomized to either higher or lower hemoglobin transfusion thresholds. Design, Setting, and Participants: This post hoc secondary analysis of 1690 ELBW infants who survived to postnatal day 10 enrolled in the Transfusion of Prematures (TOP) randomized multicenter trial between December 1, 2012, and April 12, 2017, was performed between June 2021 and July 2023. Exposures: First, the distribution of RBC transfusions and the occurrence of NEC up to postnatal day 60 were examined. Second, 72-hour posttransfusion periods were categorized as hazard periods and the pretransfusion periods of variable duration as control periods. Then, the risk of NEC in posttransfusion hazard periods was compared with that in pretransfusion control periods, stratifying the risk based on randomization group (higher or lower hemoglobin transfusion threshold group). Main Outcomes and Measures: The primary outcome was incidence of NEC stage 2 or 3. Secondary outcomes included the incidence rates of NEC within five 10-day intervals, taking into account the number of days at risk. Results: Of 1824 ELBW infants randomized during the TOP trial, 1690 were included in the present analysis (mean [SD] gestational age, 26.0 [1.5] weeks; 899 infants [53.2%] were female). After categorizing 4947 hazard periods and 5813 control periods, we identified 133 NEC cases. Fifty-nine of these cases (44.4%) occurred during hazard periods. Baseline and clinical characteristics of infants with NEC during hazard periods did not differ from those of infants with NEC during control periods. The risk of NEC was 11.9 per 1000 posttransfusion hazard periods and 12.7 per 1000 control periods (adjusted risk ratio, 0.95; 95% CI, 0.68-1.32; P = .74). This risk did not differ significantly between randomization groups, but the incidence rate of NEC per 1000 days peaked between postnatal days 20 and 29 in the lower hemoglobin transfusion threshold group. Conclusions and Relevance: The findings of this post hoc analysis suggest that, among ELBW infants with the hemoglobin ranges occurring in the TOP trial, exposure to RBC transfusions was not temporally associated with a higher risk of NEC during 72-hour posttransfusion hazard periods. Given that the incidence rate of NEC peaked between postnatal days 20 and 29 among infants with lower hemoglobin values, a more in-depth examination of this at-risk period using larger data sets is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Nutrition and the gut-brain axis in neonatal brain injury and development.

Early nutritional exposures, including during embryogenesis and the immediate postnatal period, affect offspring outcomes in both the short- and long-term. Alterations of these modifiable exposures shape the developing gut microbiome, intestinal development, and even neurodevelopmental outcomes. A gut-brain axis exists, and it is intricately connected to early life feeding and nutritional exposures. Here, we seek to discuss the (1) origins of the gut-brain access and relationship with neurodevelopment, (2) components of human milk (HM) beyond nutrition and their role in the developing newborn, and (3) clinical application of nutritional practices, including fluid management and feeding on the development of the gut-brain axis, and long-term neurodevelopmental outcomes. We conclude with a discussion on future directions and unanswered questions that are critical to provide further understanding and insight into how clinicians and healthcare providers can optimize early nutritional practices to ensure children not only survive, but thrive, free of neurodevelopmental impairment.