Importance Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower–hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher–hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs −0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and Relevance In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia.

Background: Alloimmunization can be a significant barrier to red blood cell (RBC) transfusion. While alloantigen matching protocols hold promise in reducing alloantibody formation, transfusion-dependent patients can still experience RBC alloimmunization and associated complications even when matching protocols are employed. As a result, complementary strategies capable of actively preventing alloantibody formation following alloantigen exposure are warranted. Study Design and Methods: We examined whether pharmacological removal of macrophages using clodronate may provide an additional strategy to actively inhibit RBC alloimmunization using two preclinical models of RBC alloimmunization. To accomplish this, mice were treated with clodronate, followed by transfusion of RBCs expressing the HOD (HEL, OVA, and Duffy) or KEL antigens. On days 5 and 14 post transfusion, anti-HOD or anti-KEL IgM and IgG antibodies were evaluated. Results: Low dose clodronate effectively eliminated key marginal zone macrophage populations from the marginal sinus. Prior treatment with clodronate, but not empty liposomes, also significantly inhibited IgM and IgG anti-HOD alloantibody formation following transfusion of HOD RBCs. Similar exposure to clodronate inhibited IgM and IgG antibody formation following KEL RBC transfusion. Conclusions: Clodronate can inhibit anti-HOD and anti-KEL antibody formation following RBC transfusion in preclinical models. These results suggest that clodronate may provide an alternative approach to actively inhibit or prevent the development of alloantibodies following RBC transfusion, although future studies will certainly be needed to fully explore this possibility.

BACKGROUND: Enteral iron supplementation and RBC transfusions are routinely administered to very-low-birth-weight (VLBW) infants, although the potential risks of these exposures have not been adequately quantified. This study evaluated the association between the cumulative dose of enteral iron supplementation, total volume of RBCs transfused, and risk of bronchopulmonary dysplasia (BPD) in VLBW infants. STUDY DESIGN AND METHODS: Retrospective, multicenter observational cohort study in Atlanta, Georgia. Cumulative supplemental enteral iron exposure and total volume of RBCs transfused were measured until the age at assessment of BPD. Multivariable generalized linear models were used to control for confounding, and the reliability of the factors was assessed in 1000 bootstrap models. RESULTS: A total of 598 VLBW infants were studied. In multivariable analyses, a greater cumulative dose of supplemental enteral iron exposure was associated with an increased risk of BPD (adjusted relative risk per 50-mg increase, 1.07; 95% confidence interval [CI], 1.02–1.11; p = 0.002). Similarly, a greater volume of RBCs transfused was associated with a higher risk of BPD (adjusted relative risk per 20-mL increase, 1.05; 95% CI, 1.02–1.07; p < 0.001). Both factors were reliably associated with BPD (>50%). Volume of RBCs transfused was similar to gestational age in reliability as a risk factor for BPD (present in 100% of models) and was more reliable than mechanical ventilation at 1 week of age. CONCLUSION: The cumulative dose of supplemental enteral iron exposure and total volume of RBC transfusion are both independently associated with an increased risk of BPD in VLBW infants.

BACKGROUND: Prior studies have suggested an association between platelet transfusions (PTXs) and worse outcomes among infants with necrotizing enterocolitis (NEC), potentially mediated by proinflammatory factors released by platelets. However, the effects of storage on platelet proinflammatory factor release and the confounding role of illness severity on NEC outcomes have not been determined. STUDY DESIGN AND METHODS: First, neuropeptide Y (a potent splanchnic vasoconstrictor released by platelets) was measured by enzyme-linked immunosorbent assay in fresh frozen plasma and in the supernatant of leukoreduced apheresis-derived platelets at different times during storage. Next, we evaluated the relationship between PTX rates and death in a multicenter cohort of very-low-birth-weight infants with NEC, adjusting for illness severity. RESULTS: Neuropeptide Y levels increased over time in the supernatant of leukoreduced apheresis-derived platelets and were 4.4-fold and 8.9-fold higher than in fresh frozen plasma on Days 2 and 3 of storage, respectively (p < 0.001). Among 598 very-low-birth-weight infants, 44 developed NEC. In unadjusted analysis, PTX rate was 30.3 (95% confidence interval [CI], 11.5–80.1) per 100 infant-days among infants who died, compared to 6.0 (95% CI, 3.2–11.2) among survivors (incidence rate ratio, 5.1; 95% CI, 1.6–16.2; p = 0.006). In multivariable analysis, there was no association between PTX rate and mortality (incidence rate ratio, 3.0; 95% CI, 0.6–15.0; p = 0.18), although estimation was imprecise. CONCLUSION: Proinflammatory mediators accumulate in platelet suspensions during storage. Although PTX rates were not associated with increased mortality among infants with NEC in our study, our estimates suggest the potential for such an association that needs evaluation in larger studies.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in infants born prematurely. After birth, the neonatal gut must acquire a healthy complement of commensal bacteria. Disruption or delay of this critical process, leading to deficient or abnormal microbial colonization of the gut, has been implicated as key risk factor in the pathogenesis of NEC. Conversely, a beneficial complement of commensal intestinal microbiota may protect the immature gut from inflammation and injury. Interventions aimed at providing or restoring a healthy complement of commensal bacteria, such as probiotic therapy, are currently the most promising treatment to prevent NEC. Shifting the balance of intestinal microbiota from a pathogenic to protective complement of bacteria can protect the gut from inflammation and subsequent injury that leads to NEC. Herein, we review the relationship of intestinal microbiota and NEC in preterm infants.

Caffeine is one of the most commonly prescribed medications in preterm neonates and is widely used to treat or prevent apnea of prematurity. Caffeine therapy is safe, effectively decreases apnea, and improves short- and long-term outcomes in preterm infants. In this review, the authors summarize the role of caffeine therapy for preterm infants receiving noninvasive respiratory support. As caffeine is already widely used, recent data are summarized that may guide clinicians in optimizing the use of caffeine therapy, with a review of the timing of initiation, dose, and duration of therapy.

Objective:To evaluate early feeding factors associated with exclusive human milk (EHM) feeding at discharge in a cohort of human milk-fed infants admitted to the neonatal intensive care unit (NICU).Study Design:Retrospective cohort of consecutively discharged infants from two NICUs over a 12-month period who received any human milk during the 24 h before hospital discharge. We used logistic regression to evaluate early feeding factors associated with EHM feeding at discharge. Result:We evaluated a total of 264 infants. EHM-fed infants were twice as likely to receive human milk at the first feeding compared with partial human milk-fed infants (65% vs 32%; P<0.01). In multivariable analysis, including adjustment for race and type of maternal insurance, infants receiving human milk as the initial feeding, compared with formula, had a greater odds of EHM feeding at hospital discharge (adjusted odds ratio (OR)=3.41; 95% confidence interval (CI)=1.82 to 6.39; P<0.001). Conclusion:Among infants admitted to the NICU whose mothers provide human milk, those receiving human milk as the first feeding were more likely to receive EHM feeding at discharge.Journal of Perinatology advance online publication, 17 April 2014; doi:10.1038/jp.2014.63.

Background: Necrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality in premature infants. To date, no effective biomarkers exist to predict which premature infants will develop NEC, limiting targeted prevention strategies. Multiple observational studies have reported an association between the exposure to red blood cell (RBC) transfusion and/or anemia and the subsequent development of NEC; however, the underlying physiologic mechanisms of how these factors are independently associated with NEC remain unknown. Methods: In this paper, we outline our prospective, multicenter observational cohort study of infants with a birth weight ≤ 1250 g to investigate the associations between RBC transfusion, anemia, intestinal oxygenation and injury that lead to NEC. Our overarching hypothesis is that irradiation of RBC units followed by longer storage perturbs donor RBC metabolism and function, and these derangements are associated with paradoxical microvascular vasoconstriction and intestinal tissue hypoxia increasing the risk for injury and/or NEC in transfused premature infants with already impaired intestinal oxygenation due to significant anemia. To evaluate these associations, we are examining the relationship between prolonged irradiation storage time (pIST), RBC metabolomic profiles, and anemia on intestinal oxygenation non-invasively measured by near-infrared spectroscopy (NIRS), and the development of NEC in transfused premature infants. Discussion: Our study will address a critical scientific gap as to whether transfused RBC characteristics, such as irradiation and metabolism, impair intestinal function and/or microvascular circulation. Given the multifactorial etiology of NEC, preventative efforts will be more successful if clinicians understand the underlying pathophysiologic mechanisms and modifiable risk factors influencing the disease.

Objective: To evaluate if routine supplementation of Lactobacillus rhamnosus GG ATCC 53103 (LGG) is associated with a decreased risk of necrotizing enterocolitis in very low birth weight (VLBW) infants. Study design: Retrospective observational cohort study of VLBW (<1500 g) infants at a single center from 2008 to 2016. LGG supplementation with Culturelle at a dose of 2.5 to 5 × 10 9 CFU/day began in 2014. We used multivariable logistic regression to evaluate the association between LGG supplementation and necrotizing enterocolitis (modified Bell stage IIA or greater), after adjusting for potential confounders. We also compared changes in necrotizing enterocolitis incidence before and after implementation of LGG using a statistical process control chart. Results: We evaluated 640 VLBW infants with a median gestational age of 28.7 weeks (IQR 26.3-30.6); 78 (12%) developed necrotizing enterocolitis. The median age at first dose of LGG was 6 days (IQR 3-10), and duration of supplementation was 32 days (IQR 18-45). The incidence of necrotizing enterocolitis in the epoch before LGG implementation was 10.2% compared with 16.8% after implementation. In multivariable analysis, LGG supplementation was associated with a higher risk of necrotizing enterocolitis (aOR 2.10, 95 % CI 1.25-3.54, P =.005). We found no special cause variation in necrotizing enterocolitis after implementation of LGG supplementation. There were no episodes of Lactobacillus sepsis during 5558 infant days of LGG supplementation. Conclusions: In this study, routine LGG supplementation was not associated with a decreased risk of necrotizing enterocolitis. Our findings do not support the use of the most common probiotic preparation currently supplemented to VLBW infants in the US.

BACKGROUND Neonates receiving extracorporeal membrane oxygenation (ECMO) support are transfused large volumes of red blood cells (RBCs) and platelets (PLTs). Transfusions are often administered in response to specific, but largely unstudied thresholds. The aim of this study is to examine the relationship between RBC and PLT transfusion rates and mortality in neonates receiving ECMO support. STUDY DESIGN AND METHODS We retrospectively examined outcomes of neonates receiving ECMO support in the neonatal intensive care unit (NICU) for respiratory failure between 2010 and 2016 at a single quaternary-referral NICU. We examined the association between RBC and PLT transfusion rate (mL per kg per day) and in-hospital mortality, adjusting for confounding by using a validated composite baseline risk score (Neo-RESCUERS). RESULTS Among the 110 neonates receiving ECMO support, in-hospital mortality was 28%. The median RBC transfusion rate (mL/kg/d) after cannulation was greater among non-survivors, compared to survivors: 12.4 (IQR 9.3–16.2) versus 7.3 (IQR 5.1–10.3), p < 0.001. Similarly, PLT transfusion rate was greater among non-survivors: 22.9 (9.3–16.2) versus 12.1 (8.4–20.1), p = 0.02. After adjusting for baseline mortality risk, both RBC transfusion (adjusted relative risk per 5 mL/kg/d increase: 1.33; 95% Cl 1.05–1.69, p = 0.02) and PLT transfusion (adjusted relative risk per 5 mL/kg/d increase: 1.12; 95% Cl 1.02–1.23, p = 0.02) were both associated with in-hospital mortality. CONCLUSIONS RBC and PLT transfusion rates are associated with in-hospital mortality among neonates receiving ECMO. These data provide a basis for future studies evaluating more restrictive transfusion practices for neonates receiving ECMO support.