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.

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.

Predicting body fat percentage at 36 weeks of postmenstrual age in infants born preterm: A diagnostic accuracy study.

BACKGROUND: Current standards for assessing body composition can be costly and technically challenging. There is a need for a predictive equation that combines multiple clinical and anthropometric factors to predictbody composition outcomes at 36 weeks of postmenstrual age (PMA) or discharge. METHODS: To develop a widely applicable equation that predicts body fat percentage in preterm infants, we analyzed anthropometric data collected prospectively from a cohort of infants born very preterm between 2017 and 2018. We integrated clinical variables significantly associated with adiposity into a predictive equation using Bayesian linear regression models and leave-one-out cross-validation. RESULTS: We analyzed data from 86 infants born at 32 weeks of gestation or less (median gestational age, 30 weeks; mean birthweight, 1471 ± 270 g). Weight gain and increase in length per week from birth to 36 weeks of PMA, midarm circumference at 36 weeks of PMA, male sex, and higher enteral fluid intake (>180 ml/kg/day) were the strongest predictors of body fat percentage in the model with the highest predictive value (R2 = 0.65). The correlation between actual and predicted body fat percentage using this Bayesian model was high (r = 0.82). CONCLUSIONS: Weight gain and increase in length per week from birth to 36 weeks of PMA, midarm circumference at 36 weeks of PMA, male sex, and enteral fluid intake are significant predictors of body fat percentage at 36 weeks of PMA in very preterm infants.

Infant body composition: A comprehensive overview of assessment techniques, nutrition factors, and health outcomes.

Body composition assessment is a valuable tool for clinical assessment and research that has implications for long-term health. Unlike traditional measurements such as anthropometrics or body mass index, body composition assessments provide more accurate measures of body fatness and lean mass. Moreover, depending on the technique, they can offer insight into regional body composition, bone mineral density, and brown adipose tissue. Various methods of body composition assessment exist, including air displacement plethysmography, dual-energy x-ray absorptiometry, bioelectrical impedance, magnetic resonance imaging, D3 creatine, ultrasound, and skinfold thickness, each with its own strengths and limitations. In infants, several feeding practices and nutrition factors are associated with body composition outcomes, such as breast milk vs formula feeding, protein intake, breast milk composition, and postdischarge formulas for preterm infants. Longitudinal studies suggest that body composition in infancy predicts later body composition, obesity, and other cardiometabolic outcomes in childhood, making it a useful early marker of cardiometabolic health in both term and preterm infants. Emerging evidence also suggests that body composition during infancy predicts neurodevelopmental outcomes, particularly in preterm infants at high risk of neurodevelopmental impairment. The purpose of this narrative review is to provide clinicians and researchers with a comprehensive overview of body composition assessment techniques, summarize the links between specific nutrition practices and body composition in infancy, and describe the neurodevelopmental and cardiometabolic outcomes associated with body composition patterns in term and preterm infants.

Early Human Milk Fortification in Infants Born Extremely Preterm: A Randomized Trial.

OBJECTIVES: Enteral nutrition with unfortified human milk during the first 2 postnatal weeks often leads to cumulative protein and energy deficits among preterm infants. Fortified human milk administered soon after birth could increase fat-free mass (FFM) and improve growth in these infants. METHODS: This was a masked, randomized trial. Starting on feeding day 2, extremely preterm infants 28 weeks or younger fed maternal or donor milk were randomized to receive either a diet fortified with a human-based product (intervention group) or a standard, unfortified diet (control group). This practice continued until the feeding day when a standard bovine-based fortifier was ordered. Caregivers were masked. The primary outcome was FFM-for-age z score at 36 weeks of postmenstrual age (PMA). RESULTS: A total of 150 infants were randomized between 2020 and 2022. The mean birth weight was 795±250 g, and the median gestational age was 26 weeks. Eleven infants died during the observation period. The primary outcome was assessed in 105 infants (70%). FFM-for-age z scores did not differ between groups. Length gain velocities from birth to 36 weeks PMA were higher in the intervention group. Declines in head circumference-for-age z score from birth to 36 weeks' PMA were less pronounced in the intervention group. CONCLUSIONS: In infants born extremely preterm, human milk diets fortified soon after birth do not increase FFM accretion at 36 weeks' PMA, but they may increase length gain velocity and reduce declines in head circumference-for-age z scores from birth to 36 weeks' PMA.

The Practice of Enteral Nutrition: Clinical Evidence for Feeding Protocols.

Establishing full enteral nutrition in critically ill preterm infants with immature gastrointestinal function is challenging. In this article, we will summarize emerging clinical evidence from randomized clinical trials suggesting the feasibility and efficacy of feeding interventions targeting the early establishment of full enteral nutrition. We will also examine trial outcomes of higher volume feedings after the establishment of full enteral nutrition. Only data from randomized clinical trials will be discussed extensively. Future opportunities for clinical research will also be presented.

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.

Diagnostic accuracy of ASQ for screening of neurodevelopmental delays in low resource countries.

OBJECTIVE: The Bayley Scales of Infant Development (BSID) is the most used diagnostic tool to identify neurodevelopmental disorders in children under age 3 but is challenging to use in low-resource countries. The Ages and Stages Questionnaire (ASQ) is an easy-to-use, low-cost clinical tool completed by parents/caregivers that screens children for developmental delay. The objective was to determine the performance of ASQ as a screening tool for neurodevelopmental impairment when compared with BSID second edition (BSID-II) for the diagnosis of moderate-to-severe neurodevelopmental impairment among infants at 12 and 18 months of age in low-resource countries. METHODS: Study participants were recruited as part of the First Bites Complementary Feeding trial from the Democratic Republic of Congo, Zambia, Guatemala and Pakistan between October 2008 and January 2011. Study participants underwent neurodevelopmental assessment by trained personnel using the ASQ and BSID-II at 12 and 18 months of age. RESULTS: Data on both ASQ and BSID-II assessments of 1034 infants were analysed. Four of five ASQ domains had specificities greater than 90% for severe neurodevelopmental delay at 18 months of age. Sensitivities ranged from 23% to 62%. The correlations between ASQ communications subscale and BSID-II Mental Development Index (MDI) (r=0.38) and between ASQ gross motor subscale and BSID-II Psychomotor Development Index (PDI) (r=0.33) were the strongest correlations found. CONCLUSION: At 18 months, ASQ had high specificity but moderate-to-low sensitivity for BSID-II MDI and/or PDI <70. ASQ, when administered by trained healthcare workers, may be a useful screening tool to detect severe disability in infants from rural low-income to middle-income settings. TRIAL REGISTRATION NUMBER: NCT01084109.

Safety and Efficacy of Early Vitamin D Supplementation in Critically Ill Extremely Preterm Infants: An Ancillary Study of a Randomized Trial.

BACKGROUND: Despite substantial evidence that vitamin D deficiency is highly prevalent among infants born extremely preterm (≤28 weeks' of gestation), several consensus statements do not recommend vitamin D doses >400 IU/day for these infants. Safety remains a concern. OBJECTIVE: The study aim was to determine safety and efficacy profiles of enteral vitamin D in Black and White infants randomized to three different vitamin D doses soon after birth. DESIGN: Ancillary study of a masked randomized clinical trial. PARTICIPANTS/SETTING: Seventy-three infants born extremely preterm between 2012 and 2015 at a southern US academic neonatal unit (33' latitude) who had >90% compliance with the assigned intervention were included. INTERVENTION: Infants were randomized to receive placebo (placebo group), 200 IU/day vitamin D (200 IU group), or 800 IU/day vitamin D (800 IU group) during the first 28 days after birth. MAIN OUTCOME MEASURES: Safety outcomes included serum 25-hydroxy vitamin D (25[OH]D) and calcium concentrations. Efficacy outcomes included the predictive risk of bronchopulmonary dysplasia. STATISTICAL ANALYSIS: Per-protocol analysis using unadjusted, repeated-measures mixed models. RESULTS: Mean birth weight was 815 ± 199 g. Half were male and 56% were Black. Of 58 infants with 25(OH)D measurements at birth, 40 (69%) had vitamin D deficiency (<20 ng/mL). The mean difference in 25(OH)D in nanograms per milliliter between Postnatal Day 28 and Postnatal Day 1 was +9 in the placebo group, +23 in the 200 IU group, and +62 in the 800 IU group (P < 0.0001). The increase observed in 25(OH)D was more significant among Black infants. The predictive risk of severe bronchopulmonary dysplasia in the 200 IU and 800 IU groups was lower, but this difference did not reach statistical significance. No vitamin D or calcium toxicity was observed. CONCLUSIONS: A vitamin D dose of 800 IU/day safely corrected vitamin D deficiency by Postnatal Day 14.

Total Fluid Administration and Weight Loss during the First 2 Weeks in Infants Randomized to Early Enteral Feeding after Extremely Preterm Birth.

BACKGROUND: Randomized trials have not reported the effects of the early progression of feeding volumes on fluid balance and neurodevelopment among infants born extremely preterm (≤28 weeks). METHOD: Fluid, electrolyte, and neurodevelopment data of 60 extremely preterm infants randomly assigned to receive either 1 (early feeding group) or 4 days (late feeding group) of trophic feeding volumes at 20-24 mL/kg/day were analyzed. RESULTS: Infants randomized to the early feeding group received less parenteral fluids, generated lower urine volumes, and had less excessive weight loss during the first 14 days after birth. The 7-point difference in cognitive scores and the 0.5 difference in weight-for-age z-scores favoring the early feeding group did not reach statistical significance. CONCLUSIONS: In extremely preterm infants, early enteral feeding is associated with less total fluid administration and with less excessive weight loss during the first 2 weeks after birth. These short-term effects could have long-lasting benefits.

Improving Time to Independent Oral Feeding to Expedite Hospital Discharge in Preterm Infants.

BACKGROUND AND OBJECTIVES: Achievement of independent oral feedings remains the most common barrier to discharge in preterm infants. Early oral feeding initiation may be associated with a lower postmenstrual age (PMA) at independent oral feeding and discharge. In preterm infants born between 25 and 32 weeks' gestation, our aim was to decrease the PMA at independent oral feedings and discharge by 1 week between June 2019 and June 2020. METHODS: Following formation of a multidisciplinary team, the following plan-do-study-act cycles were targeted: (1) oral feeding initiation at <33 weeks' PMA, (2) cue-based feeding, and (3) practitioner-driven feeding in infants who had not yet achieved independent oral feedings by 36 weeks' PMA. Outcome measures included the PMA at independent oral feeding and discharge. Process measures included adherence to cue-based feeding assessments and PMA at oral feeding initiation. RESULTS: In total, 552 infants with a median gestational age of 30.3 weeks' (interquartile range 28.1-32.0) and birth weight of 1320 g (interquartile range 1019-1620) were included. The PMA at discharge decreased from 38.8 to 37.7 weeks during the first plan-do-study-act cycle, which coincided with an increase in the number of infants initiated on oral feeds at <33 weeks' PMA from 47% to 80%. The age at independent oral feeding decreased from 37.4 to 36.5 weeks' PMA. CONCLUSIONS: In preterm infants born between 25 and 32 weeks' gestation, earlier oral feeding initiation was associated with a decreased PMA at independent oral feeding and discharge.

Racial differences in growth rates and body composition of infants born preterm.

OBJECTIVE: To evaluate racial disparities in weight gain velocity and body composition among preterm infants. STUDY DESIGN: This observational study analyzed race differences in fat-free mass (FFM), fat mass (FM), percent body fat (%BF), and weight gain at discharge of infants born at 25-32 weeks of gestation. RESULTS: No racial differences in FFM, FM and %BF measurements were found between black and white preterm infants after adjusting for birth weight, gestational age, and the presence/absence of breastfeeding (n = 143). Black infants born preterm had lower birthweights and higher weight gain from birth to discharge in unadjusted and adjusted models (13 ± 3 vs. 11 ± 3 g/kg/day; <0.001). CONCLUSION: Black infants had higher weight gain from birth to discharge, but comparable body composition measurements at discharge. More research is needed to understand contributing factors and long-term implications of this finding.

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 .

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.

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.