Evaluation of the impact of diagnostic blood loss and red blood cell transfusion in very-low-birth-weight anaemic neonates during hospitalization: A multi-centre retrospective clinical study.

BACKGROUND AND OBJECTIVES: Diagnostic blood loss is a significant factor in the development of anaemia in neonates with very low birth weight. This study aimed to assess the clinical efficacy of intervention approaches involving varying diagnostic blood loss and red blood cell transfusion volumes in neonates with very low birth weights experiencing anaemia during hospitalization. MATERIALS AND METHODS: A total of 785 newborns with anaemia weighing less than 1500 g were enrolled from 32 hospitals in China. The study involved monitoring diagnostic blood loss and red blood cell transfusion and evaluating relevant interventions such as red blood cell transfusion and clinical outcomes. Three intervention approaches were established based on the difference between blood loss and transfusion (Intervention Approaches 0, 1 and 2). The primary outcomes measured were unsatisfactory weight gain during hospitalization and neonatal mortality. The secondary outcomes included related complications. RESULTS: In the non-hospital-acquired anaemia group, Intervention Approach 2 had the highest incidence of below-normal weight gain (odds ratio [OR]: 3.019, 95% confidence interval [CI]: 1.081-8.431, p = 0.035). Multivariate analysis revealed that Intervention Approach 1 had a protective effect on weight gain. In the hospital-acquired anaemia group, Intervention Approach 2 had the highest incidence of below-normal weight gain (OR: 3.335, 95% CI: 1.785-6.234, p = 0.000) and mortality (OR: 5.341, 95% CI: 2.449-11.645, p = 0.000), while Intervention Approach 1 had the lowest incidence of intraventricular haemorrhage. Intervention Approach 1 demonstrated favourable outcomes in both anaemia groups. CONCLUSION: Intervention Approach 1 improved weight gain and reduced mortality and complications in both the non-hospital-acquired and hospital-acquired anaemia groups.

Trial-related blood sampling and red blood cell transfusions in preterm infants.

AIM: To determine if trial-related blood sampling increases the risk of later red blood cell (RBC) transfusion in very preterm infants, we compared the volume of clinical- and trial-related blood samples, in a specific trial and correlated to subsequent RBC transfusion. METHODS: For 193 very preterm infants, participating in the FortiColos trial (NCT03537365), trial-related blood volume drawn was in accordance with ethical considerations established by the European Commission. Medical records were reviewed to assess the number and accumulated volume (mL/kg) of blood samples (both clinical- and trial-related). Data were compared with the need of RBC transfusions during the first 28 days of life. RESULTS: Mean (SD) gestational age and birth weight was 28 ± 1 weeks and 1168 ± 301 g. In total, 11% of total blood volume was drawn for sampling (8.1 ± 5.1 mL/kg) and trial-related sampling accounted for 1.6 ± 0.6 mL/kg. Trial-related blood sampling had no impact on RBC transfusion (p = 0.9). CONCLUSION: Clinical blood sampling in very preterm infants is associated with blood loss and subsequent need for RBC transfusions. In a specific trial requiring blood samples, we found no additional burden of trial-related blood sampling. The study suggests that trial-related sampling is safe if European criteria are followed.

Erythrocyte transfusions are associated with retinopathy of prematurity in extremely low gestational age newborns.

AIM: Retinopathy of prematurity (ROP) is a major morbidity in preterm infants causing visual impairment including blindness. Prevention and timely treatment are critical. We investigated the potential role of red blood cell (RBC) transfusions as risk factor for ROP development. METHODS: Retrospective cohort study of data from 68 tertiary level neonatal intensive care units in Germany. Preterm infants born at 22 + 0 to 28 + 6 weeks of gestation between January 2009 and December 2021 were enrolled. RESULTS: We included n = 12 565 infants. Prevalence of any ROP was 49.2% with most infants being diagnosed with stage 1 (21.5%) and 2 disease (17.2%). ROP stage 3 was present in 10.2%, stage 4 in 0.3%, and ROP requiring treatment in 6.6%. Infants with ROP had significantly more frequently a history of RBC transfusions. Adjusting for confounders, RBC transfusions were associated with increased odds of ROP (OR 1.4, p < 0.001), ROP progression (OR 2.1, p < 0.01) and ROP requiring treatment (OR 3.6, p < 0.001). Restrictive transfusion approaches correlated with decreased (OR 0.7, p < 0.001), liberal regimes with increased odds (OR 1.2, p = 0.001). CONCLUSION: The present study confirmed an association of RBC transfusions and ROP. Our findings emphasise the need for anaemia prevention and critical re-evaluation of transfusion practices in preterm infants.

Perinatal outcome of pregnancy complicated by twin anemia-polycythemia sequence: systematic review and meta-analysis.

OBJECTIVE: To report the perinatal outcome of monochorionic diamniotic (MCDA) twin pregnancies complicated by twin anemia-polycythemia sequence (TAPS), according to the type of TAPS (spontaneous or postlaser) and the management option adopted. METHODS: MEDLINE, EMBASE and The Cochrane Library databases were searched for studies reporting on the outcome of twin pregnancies complicated by TAPS. Inclusion criteria were non-anomalous MCDA twin pregnancies with a diagnosis of TAPS. The primary outcome was perinatal mortality; secondary outcomes were neonatal morbidity and preterm birth (PTB). The outcomes were stratified according to the type of TAPS (spontaneous or following laser treatment for twin-twin transfusion syndrome) and the management option adopted (expectant, laser surgery, intrauterine transfusion (IUT) or selective reduction (SR)). Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Perinatal outcome was assessed according to whether TAPS occurred spontaneously or after laser treatment in 506 pregnancies (38 studies). Intrauterine death (IUD) occurred in 5.2% (95% CI, 3.6-7.1%) of twins with spontaneous TAPS and in 10.2% (95% CI, 7.4-13.3%) of those with postlaser TAPS, while the corresponding rates of neonatal death were 4.0% (95% CI, 2.6-5.7%) and 9.2% (95% CI, 6.6-12.3%), respectively. Severe neonatal morbidity occurred in 29.3% (95% CI, 25.6-33.1%) of twins after spontaneous TAPS and in 33.3% (95% CI, 17.4-51.8%) after postlaser TAPS, while the corresponding rates of severe neurological morbidity were 4.0% (95% CI, 3.5-5.7%) and 11.1% (95% CI, 6.2-17.2%), respectively. PTB complicated 86.3% (95% CI, 77.2-93.3%) of pregnancies with spontaneous TAPS and all cases with postlaser TAPS (100% (95% CI, 84.3-100%)). Iatrogenic PTB was more frequent than spontaneous PTB in both groups. Perinatal outcome was assessed according to the management option adopted in 417 pregnancies (21 studies). IUD occurred in 9.8% (95% CI, 4.3-17.1%) of twins managed expectantly and in 13.1% (95% CI, 9.2-17.6%), 12.1% (95% CI, 7.7-17.3%) and 7.6% (95% CI, 1.3-18.5%) of those treated with laser surgery, IUT and SR, respectively. Severe neonatal morbidity affected 27.3% (95% CI, 13.6-43.6%) of twins in the expectant-management group, 28.7% (95% CI, 22.7-35.1%) of those in the laser-surgery group, 38.2% (95% CI, 18.3-60.5%) of those in the IUT group and 23.3% (95% CI, 10.5-39.2%) of those in the SR group. PTB complicated 80.4% (95% CI, 59.8-94.8%), 73.4% (95% CI, 48.1-92.3%), 100% (95% CI, 76.5-100%) and 100% (95% CI, 39.8-100%) of pregnancies after expectant management, laser surgery, IUT and SR, respectively. CONCLUSIONS: The present meta-analysis provides pooled estimates of the risks of perinatal mortality, neonatal morbidity and PTB in twin pregnancies complicated by TAPS, stratified by the type of TAPS and the management option adopted. Although a direct comparison could not be performed, the results from this systematic review suggest that spontaneous TAPS may have a better prognosis than postlaser TAPS. No differences in terms of mortality and morbidity were observed when comparing different management options for TAPS, although these findings should be interpreted with caution in view of the limitations of the included studies. Individualized prenatal management, taking into account the severity of TAPS and gestational age, is currently the recommended strategy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Hemodynamics of different volumes of red blood cell transfusion in preterm infants.

BACKGROUND: Although many controversies exist regarding the risk of red blood cell (RBC) transfusions, half of preterm infants born at <32 weeks of gestational age receive such transfusions because of anemia of prematurity. Because of the costs and risks associated with multiple transfusions, it has been suggested that a large transfusion volume reduces the number of transfusions. However, there have been persistent concerns that RBC transfusion might lead to volume overload. METHODS: We examined the impacts of large (20 mL/kg) compared to standard volume (15 mL/kg) transfusions on the hemodynamic variables of stable, electively transfused, preterm infants, by serially measuring echocardiographic parameters and plasma B-type natriuretic peptide levels. RESULTS: A total of 39 infants born at <34 weeks of gestation and aged >2 weeks at the time of enrollment were randomly allocated to either a standard volume (15 mL/kg) or a large volume (20 mL/kg) group. Significant reductions in cardiac output and transient increases in plasma B-type natriuretic peptide levels were found after RBC transfusion in both the standard and large volume (20 mL/kg) groups. However, these changes were not significantly different between the two groups. CONCLUSIONS: Large-volume transfusions could be tolerable in stable preterm infants with anemia.

Anemia of Prematurity and Oral Feeding Milestones in Premature Infants.

OBJECTIVE: Anemia of prematurity (AOP) and oral feeding problems are common in premature infants. This study aimed to determine the influence of AOP on aerodigestive outcomes and the duration to full Per Oral (PO). STUDY DESIGN: Prospectively collected data on premature infants who initiated oral feeds at ≤ 34 weeks' postmenstrual age were examined. Infants were categorized into "AOP+" and "AOP-" based on hematocrit at initial PO, that is, < 29 or ≥ 29%. RESULTS: Forty-four infants in AOP+ compared with 74 in AOP-. AOP+ infants had lower birth gestation and weight (p < 0.001). The anthropometrics at initial PO were similar. AOP+ had lower mean hematocrit and higher oxygen need at initial PO, and at full PO (p < 0.05). AOP+ reached full PO at a later gestation and took longer days from initial PO to full PO (p < 0.01). BPD, intraventricular hemorrhage (IVH ≤ 2), and hospital stay were greater in the AOP+ (p < 0.05). After adjusting for covariates, initial PO hematocrit was not predictive of time to full PO [hazard ratio 1.3 (CI 0.88-2.0), p = 0.18]. CONCLUSION: AOP is not independently associated with the duration to full PO. Supplemental oxygen for associated comorbidities may have compensated for the underlying anemia.

Allogeneic cord blood transfusions prevent fetal haemoglobin depletion in preterm neonates. Results of the CB-TrIP study.

Repeated red blood cell (RBC) transfusions in preterm neonates are associated with poor outcome and increased risk for prematurity-associated diseases. RBC transfusions cause the progressive replacement of fetal haemoglobin (HbF) by adult haemoglobin (HbA). We monitored HbF levels in 25 preterm neonates until 36 weeks of post-menstrual age (PMA); patients received RBC units from allogeneic cord blood (cord-RBCs) or from adult donors (adult-RBCs), depending on whether cord-RBCs were available. Primary outcome was HbF level at PMA of 32 weeks. Twenty-three neonates survived until this age: 14 received no transfusions, two only cord-RBCs, three only adult-RBCs and four both RBC types. HbF levels in neonates transfused with cord-RBCs were significantly higher than in neonates receiving adult-RBCs (P < 0·0001) or both RBC types (P < 0·0001). Superimposable results were obtained at PMA of 36 weeks. Every adult-RBCs transfusion increased the risk for an HbF in the lowest quartile by about 10-fold, whereas this effect was not evident if combined adult- and cord-RBCs were evaluated. Overall, these data show that transfusing cord-RBCs can limit the HbF depletion caused by conventional RBC transfusions. Transfusing cord blood warrants investigation in randomised trials as a strategy to mitigate the severity of retinopathy of prematurity (NCT03764813).

Infantile Pyknocytosis: An Uncommon Cause of Newborn Hemolytic Anemia.

Infantile pyknocytosis is a rare cause of neonatal hemolytic anemia, which presents in the first few weeks of life. We report a classic case of infantile pyknocytosis that presented to our institution with rebound hyperbilirubinemia after receiving phototherapy. The infant was found to have a hemoglobin of 5.8 g/dL, requiring a total of 15 mL/kg of red blood cells (in 2 separate transfusions) before discharge. The diagnosis was ultimately made by a review of the peripheral blood smear. We review the literature and suggest pediatricians consider infantile pyknocytosis on their differential when hemolytic anemia presents in the newborn period.

Effects of blood transfusion on regional tissue oxygenation in preterm newborns are dependent on the degree of anaemia.

AIM: Most of the preterm infants are transfused at least once during their stay in the neonatal intensive care unit (NICU). The aims of this study were to demonstrate if packed red blood cell (pRBC) transfusion modulates regional (cerebral, abdominal, renal) tissue oxygen saturation measured by near-infrared spectroscopy (NIRS) and to demonstrate if we can use NIRS to guide transfusion decisions in neonates. METHODS: A multi-probe NIRS device was applied to anaemic preterm infants of gestational age <33 weeks for 30-60 min before and 24 h after pRBC transfusion. We evaluated the results separately in the subgroup with a pre-transfusion haemoglobin (Hb) < 8 g/dL. Cerebral, abdominal and renal tissue oxygen saturation (rSO2 ) and abdominal/cerebral, abdominal/renal and renal/cerebral rSO2 ratios before and 24 h after transfusion were compared. RESULTS: There was no significant difference in cerebral rSO2 and abdominal/renal rSO2 ratios before and 24 h after transfusion, but abdominal and renal rSO2 and abdominal/cerebral and renal/cerebral rSO2 ratios at the 24th h following transfusion increased significantly. This increase was observed in the subgroup with pre-transfusion Hb < 8 g/dL. Although statistically significant, the increase in renal oxygenation was within the limits of variability. CONCLUSIONS: The increase in tissue oxygenation in abdominal region after pRBC transfusion suggests decreased tissue oxygenation of intestines during severe anaemia despite cerebral oxygenation being maintained at that particular Hb level. The impact of the increase on renal oxygenation with pRBC transfusion is unclear and might need further investigation. Increase in abdominal rSO2 may cause reperfusion injury, oxidative damage and trigger necrotising enterocolitis.

Mortality and hospital readmissions in the first year of life after intra-uterine and neonatal blood product transfusions: A population data linkage study.

AIM: Blood product transfusions are a potentially life-saving therapy for fetal and neonatal anaemia, but there is limited population-based research on outcomes. We aimed to describe mortality, readmission and average hospital stay in the first year of life for infants with or without intra-uterine or neonatal blood product transfusions. METHODS: Linked birth, hospital and deaths data from New South Wales, Australia (January 2002-June 2014) were used to identify singleton infants (≥23 weeks' gestation, surviving to 29 days; n = 1 089 750) with intra-uterine or neonatal transfusion or no transfusion. Rates of mortality and readmission in the first year (29-365 days) and days in hospital were calculated. RESULTS: Overall, 68 (0.06/1000) infants had experienced intra-uterine transfusion and 4332 (3.98/1000) neonatal transfusion. Transfusion was more common among those born at earlier gestational ages requiring invasive ventilation. Mortality, readmissions and average days in hospital were higher among transfused than non-transfused infants. Over half of infants with intra-uterine and neonatal transfusion had ≥1 readmission in the first 29-365 days (55.9 and 51.8%, respectively), and around a quarter had ≥2 (20.6 and 28.5%, respectively) compared with 15.3% with ≥1 and 3.5% with ≥2 in the non-transfused group. CONCLUSION: Infants with a history of blood product transfusion, particularly those needing a neonatal transfusion, had higher mortality and more frequent contact with the hospital system in the first year of life than those infants with no history of transfusion.

Blood transfusion for anaemia of prematurity: Current practice in Australia and New Zealand.

AIM: To characterise the current transfusion practice among clinicians in Australasian neonatal units and factors that influence their decision-making. METHODS: Members of the Australia and New Zealand Neonatal Network (ANZNN) and practitioners at their local institutions were invited to participate in a 15-question web-based survey between 1 June and 31 July 2016. The survey was designed to assess (i) haemoglobin-based transfusion thresholds; (ii) presence of local guidelines; (iii) preference for a restrictive or liberal transfusion policy; (iv) perceived benefits and risks of transfusion; and (v) use of clinical adjuncts to assist decision-making. RESULTS: Overall, 130 participants responded to at least one question. Haemoglobin transfusion thresholds for anaemia of prematurity (AOP) varied significantly from <60 to <120 g/L. Of 103 participants, 36 (35%) reported that they do not have access to local transfusion guidelines. The majority utilise multiple clinical and haematological parameters to guide their decision-making, and approximately half (45/84, 54%) believe that tissue hypoxia detected by near-infrared spectroscopy (NIRS) may better inform transfusion thresholds. Of 102 participants, 51 (50%) support a restrictive rather than liberal transfusion policy. The most commonly reported perceived risks of transfusion for AOP were suppression of endogenous erythropoiesis and increased rates of necrotising enterocolitis. CONCLUSIONS: There is a significant variation in transfusion practice in Australasian neonatal units. Quality and safety initiatives may assist with improved consistency of transfusion practice across the ANZNN. However, further research is required to better define optimal transfusion thresholds, quantify potential risks of transfusion and determine clinical utility of newer adjuncts such as NIRS.

The contribution of red blood cell transfusion to neonatal morbidity and mortality.

Anaemia of prematurity will affect 90% of all very preterm infants, resulting in at least one red blood cell (RBC) transfusion. A significant proportion of preterm infants require multiple transfusions over the course of hospital admission. Growing evidence supports an association between transfusion exposure and adverse neonatal outcomes. In adults, transfusion-associated sepsis, transfusion-related acute lung injury and haemolytic reactions are the leading causes of transfusion-related morbidity and mortality; however, these are seldom recognised in newborns. The association between transfusion and adverse outcomes remains inconclusive. However, the evidence from preclinical studies demonstrates that RBC products can directly modulate immune cell function, a pathway termed transfusion-related immunomodulation (TRIM), which may provide a mechanism linking transfusion exposure with neonatal morbidities. Finally, we discuss the impact of TRIM on transfusion medicine, how we may address these issues and the emerging areas of research aimed at improving the safety of transfusions in this vulnerable population.

Updates in Red Blood Cell and Platelet Transfusions in Preterm Neonates.

Anemia and thrombocytopenia occur frequently in preterm neonates and the majority of them require at least one blood transfusion during the first few weeks of life. However, there is no international consensus on optimal transfusion management neither for red blood cell nor for platelet transfusions, resulting in large worldwide variations in transfusion practices between neonatal intensive care units. In the past decade, several studies performed in adults, infants as well as neonates showed that restrictive transfusion guidelines are just as safe as liberal guidelines. In fact, some studies even showed that liberal guidelines could be associated with an increased risk of morbidity and mortality, suggesting that too many transfusions may have a deleterious effect. In a recent randomized trial in preterm neonates with thrombocytopenia, the liberal transfusion group (receiving more platelet transfusions) had a significantly higher rate of death or major bleeding than the restrictive group (receiving less transfusions). In preterm neonates with anemia, the available evidence is also limited and controversial. Two large randomized controlled trials (ETTNO and TOP) are currently assessing the safety and effectiveness of liberal versus restrictive red blood cell transfusions. Results of these large two studies, including the long-term neurodevelopment outcome, are eagerly awaited. Until then, reduction of anemia of prematurity by implementation of effective preventive measures, such as delayed cord clamping and minimization of iatrogenic blood loss, remain of paramount importance.

Case Report of Anemia Following Fetal-Maternal Hemorrhage.

BACKGROUND: Any maternal history of blood loss, ABO or Rh incompatibility, and hydrops fetalis often leads to suspicion of neonatal anemia postnatally. When maternal history consists only of decreased fetal movement, recognition of neonatal anemia can be problematic. CLINICAL FINDINGS: This case was a transported late preterm neonate who presented initially with persistent hypoxia unresponsive to usual respiratory support. On examination, mild paleness was noted. PRIMARY DIAGNOSIS: Anemia caused by fetal-maternal hemorrhage was the ultimate diagnosis confirmed by a Kleihauer-Betke test on maternal serum examining fetal cells. INTERVENTIONS: Neonatal resuscitation included positive pressure ventilation, oxygen, and intubation. However, oxygenation did not improve prompting consultation with the neonatologist. Sedation and a paralytic were given. A chest radiograph ruled out pneumothoraces and pleural effusions as causative. Initiation of inhaled nitric oxide produced a mild response. Eventually, the transport nurse obtained a complete blood count indicating severe anemia, which prompted an emergent blood transfusion. The accepting neonatology team consulted with the obstetrician and a Kleihauer-Betke test was performed on mother's blood confirming a large fetal-maternal hemorrhage. OUTCOMES: This neonate responded well to blood transfusions, a pressor, and respiratory support and was discharged home at 7 days of life. PRACTICE RECOMMENDATIONS: Recognition of postnatal anemia is vital to sustaining life and this can occur in the transport environment. When maternal history is nonspecific and a neonate is hypoxic, uncommon causes of hypoxia can be identified with consultation and a complete blood count.

Immunoglobulin for alloimmune hemolytic disease in neonates.

BACKGROUND: Exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological complications. Because of the risks and burdens of exchange transfusion, intravenous immunoglobulin (IVIg) has been suggested as an alternative therapy for alloimmune hemolytic disease of the newborn (HDN) to reduce the need for exchange transfusion. OBJECTIVES: To assess the effect and complications of IVIg in newborn infants with alloimmune HDN on the need for and number of exchange transfusions. SEARCH METHODS: We performed electronic searches of CENTRAL, PubMed, Embase (Ovid), Web of Science, CINAHL (EBSCOhost), Academic Search Premier, and the trial registers ClinicalTrials.gov and controlled-trials.com in May 2017. We also searched reference lists of included and excluded trials and relevant reviews for further relevant studies. SELECTION CRITERIA: We considered all randomized and quasi-randomized controlled trials of IVIg in the treatment of alloimmune HDN. Trials must have used predefined criteria for the use of IVIg and exchange transfusion therapy to be included. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane and its Neonatal Review Group. We assessed studies for inclusion and two review authors independently assessed quality and extracted data. We discussed any differences of opinion to reach consensus. We contacted investigators for additional or missing information. We calculated risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) for categorical outcomes. We calculated mean difference (MD) for continuous variables. We used GRADE criteria to assess the risk of bias for major outcomes and to summarize the level of evidence. MAIN RESULTS: Nine studies with 658 infants fulfilled the inclusion criteria. Term and preterm infants with Rh or ABO (or both) incompatibility were included. The use of exchange transfusion decreased significantly in the immunoglobulin treated group (typical RR 0.35, 95% CI 0.25 to 0.49; typical RD -0.22, 95% CI -0.27 to -0.16; NNTB 5). The mean number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (MD -0.34, 95% CI -0.50 to -0.17). However, sensitivity analysis by risk of bias showed that in the only two studies in which the treatment was masked by use of a placebo and outcome assessment was blinded, the results differed; there was no difference in the need for exchange transfusions (RR 0.98, 95% CI 0.48 to 1.98) or number of exchange transfusions (MD -0.04, 95% CI -0.18 to 0.10). Two studies assessed long-term outcomes and found no cases of kernicterus, deafness or cerebral palsy. AUTHORS' CONCLUSIONS: Although overall results show a significant reduction in the need for exchange transfusion in infants treated with IVIg, the applicability of the results is limited because of low to very low quality of evidence. Furthermore, the two studies at lowest risk of bias show no benefit of IVIg in reducing the need for and number of exchange transfusions. Based on these results, we have insufficient confidence in the effect estimate for benefit of IVIg to make even a weak recommendation for the use of IVIg for the treatment of alloimmune HDN. Further studies are needed before the use of IVIg for the treatment of alloimmune HDN can be recommended, and should include blinding of the intervention by use of a placebo as well as sufficient sample size to assess the potential for serious adverse effects.

Does red blood cell irradiation and/or anemia trigger intestinal injury in premature infants with birth weight ≤ 1250 g? An observational birth cohort study.

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. TRIAL REGISTRATION: Our study is registered in ClinicalTrials.gov Identifier: NCT02741648 .

Do feeding practices during transfusion influence the risk of developing necrotising enterocolitis in preterm infants?

Our evidence-based review set out to answer the clinical question 'In a preterm infant (patient) with anaemia of prematurity, do feeding practices (intervention) during blood transfusion reduce the risk of developing transfusion-associated necrotising enterocolitis (outcome)'? We found limited evidence that withholding feeding during red blood cell transfusion in preterm infants may reduce the risk of development of transfusion-associated necrotising enterocolitis. As clinical equipoise seemingly exists, it seems reasonable for individual units to make their own decisions regarding whether to withhold or continue enteral feeds during red blood cell transfusion until further evidence is available. The UK-based Withholding Enteral Feeds Around Transfusion (WHEAT) trial, a nation-wide multi-centre 'opt-out' randomised controlled study, hopefully will definitively answer our clinical question. Further research in other areas of neonatal care, using this innovative study design, is needed and it is exciting to see such a study underway.

Multiple red blood cell transfusions and iron overload in very low birthweight infants.

BACKGROUND AND OBJECTIVES: To estimate the risk of iron overload in very low birthweight (VLBW) infants who receive more than two red blood cell (RBC) transfusions, in comparison with those who receive two or less during their hospital stay. MATERIALS AND METHODS: Prospective open cohort study in VLBW infants with >2 (exposed) and ≤2 (non-exposed) RBC transfusions. Ferritin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured at birth and after each RBC transfusion. The incidence of iron overload was determined. Risk factors were analysed using a logistic regression model. RBC transfusion volume correlations with ferritin, ALT and AST were calculated with Spearman's rank correlation coefficient, as well as correlations between ferritin and aminotransferases. RESULTS: A total of 63 patients were enrolled, 18 of which were exposed and 45 non-exposed. Twelve patients developed severe iron overload, eight exposed (44·5%) vs. four (8·8%) non-exposed (RR: 5, 95% CI: 1·7-14·6). Multivariate analysis showed that the number of transfusions increased the risk of iron overload (OR: 2·07, 95% CI: 1·36-2·14) while a higher one-minute Apgar score was associated with a lower risk (OR: 0·56, 95% CI: 0·32-0·99). Severe iron overload mainly occurred with a transfusion volume higher than 120 ml/kg. There was a positive correlation between ferritin and transfusion (r = 0·53; P < 0·001). CONCLUSION: There was a higher risk of iron overload in exposed infants in comparison with non-exposed infants. Severe iron overload in VLBW infants may occur with a total transfusion volume >120 ml/kg.

Effects of Red Blood Cell Transfusions on the Risk of Developing Complications or Death: An Observational Study of a Cohort of Very Low Birth Weight Infants.

Background The aim of this study was to evaluate the association between red blood cell (RBC) transfusions on the risk of death, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. Study Design and Methods This is an observational study. Data were entered prospectively into the study database at the time of the first transfusion. Clinical characteristics, adverse events, and outcomes of the patients transfused in the first 28 days of life were compared with the population of VLBW infants not transfused during the same period. The association among birth weight, gestational age, comorbidities, and the number of transfusions was estimated with a Poisson regression model. The association between the composite outcome and the occurrence of death, ROP, or BPD separately considered and a set of covariates was estimated with a logistic regression model. Results We enrolled 641 VLBW infants, 42% of whom were transfused. Transfusions were associated with the risk of developing the composite outcome, independently from other conditions; this risk correlated with several transfusions ≥ 3 (odds ratio: 5.88, 95% confidence interval: 2.74-12.6). ROP and BPD were associated with several transfusions ≥ 3. Conclusion We observed an association between RBC transfusions and the composite risk of death or ROP, BPD, and NEC.