The short-term effects of RBC transfusions on intestinal injury in preterm infants.

BACKGROUND: Anemic preterm infants may require red blood cell (RBC) transfusions to maintain sufficient oxygen supply to vital organs. Transfusion treatment, however, may have adverse intestinal effects. We aimed to investigate the short-term effects of RBC transfusions, hypothesizing to find signs of oxidative stress and intestinal injury, possibly related to levels of splanchnic (re-)oxygenation. METHODS: We prospectively included preterm infants (gestational age < 32 weeks). We measured urinary biomarkers for oxidative stress (8-isoprostane) and intestinal cell injury (intestinal fatty acid-binding protein, I-FABP) shortly before and after RBC transfusion. Splanchnic oxygen saturation (rsSO2) and rsSO2 variability were assessed simultaneously. RESULTS: Twenty-nine preterm infants received 58 RBC transfusions at various postnatal ages. Six of them developed necrotizing enterocolitis (NEC) after transfusion. Urinary 8-isoprostane and I-FABP increased following RBC transfusion (median 282-606 pg/ml and 4732-6968 pg/ml, p < 0.01), more pronounced in infants who developed NEC. Change in I-FABP correlated with change in 8-isoprostane (rho = 0.623, p < 0.01). Lower rsSO2 variability, but not higher mean rsSO2 was associated with higher 8-isoprostane and I-FABP levels after transfusion. CONCLUSIONS: Preterm RBC transfusions are associated with concomitant signs of oxidative stress and intestinal injury, parallel with lower variability in splanchnic oxygenation. This may represent the early pathogenetic process of transfusion-associated NEC. IMPACT: Red blood cell (RBC) transfusions in preterm infants are associated with a near 2-fold increase in urinary biomarkers for oxidative stress (8-isoprostane) and intestinal cell injury (intestinal fatty acid-binding protein, I-FABP). Magnitude of change in I-FABP strongly correlated with the magnitude of 8-isoprostane change, suggesting a role for oxidative stress in the pathogenesis of intestinal injury. Lower splanchnic oxygen saturation variability following RBC transfusion was associated with higher 8-isoprostane and I-FABP levels. Loss of splanchnic variability after RBC transfusion may result from increased oxidative stress and its concomitant intestinal injury, possibly representing the early pathogenetic process of transfusion-associated necrotizing enterocolitis.

Neonatal anemia relates to intestinal injury in preterm infants.

BACKGROUND: Anemia is associated with decreased tissue oxygenation in preterm infants and may contribute to developing necrotizing enterocolitis (NEC). We aimed to investigate whether hemoglobin level is associated with intestinal injury, by comparing anemic infants 10 days prior to red blood cell (RBC) transfusion with non-anemic controls. METHODS: A nested case-control study in which we matched anemic preterms (gestational age (GA) < 32 weeks) with non-anemic controls (1:1), based on GA, birth weight (BW), and postnatal age. We measured urinary intestinal fatty acid-binding protein, I-FABP, marker for intestinal injury, twice weekly. Simultaneously, we assessed splanchnic oxygen saturation (rsSO2) and rsSO2 variability. RESULTS: Thirty-six cases and 36 controls were included (median GA 27.6 weeks, BW 1020 grams). Median I-FABP level was higher in cases from 6 days to 24-h before transfusion (median ranging: 4749-8064 pg/ml versus 2194-3751 pg/ml). RsSO2 and rsSO2 variability were lower in cases than controls shortly before transfusion. Hemoglobin levels correlated negatively with rsSO2 and rsSO2 variability in cases, and negatively with I-FABP in cases and controls together. CONCLUSIONS: Urinary I-FABP levels were higher in anemic infants before RBC transfusion than in non-anemic matched controls, suggesting intestinal injury associated with anemia. This may predispose to NEC in some anemic preterm infants. IMPACT: Anemia is a common comorbidity in preterm infants and may lead to impaired splanchnic oxygen saturation and intestinal tissue hypoxia, a proposed mechanism for NEC. Lower hemoglobin level is associated with higher urinary I-FABP levels, a marker for intestinal injury, both in anemic preterm infants and in cases and controls together. Lower splanchnic oxygen saturation and reduction of its variability are associated with higher urinary I-FABP levels in anemic preterm infants before their first RBC transfusion. These results support the hypothesis that anemia in very preterm infants results in intestinal cell injury, which may precede NEC development in some.

Neonatal Hemoglobin Levels in Preterm Infants Are Associated with Early Neurological Functioning.

BACKGROUND: Neonatal anemia may compromise oxygen transport to the brain. The effects of anemia and cerebral oxygenation on neurological functioning in the early neonatal period are largely unknown. OBJECTIVE: This study aimed to determine the association between initial hemoglobin levels (Hb) and early neurological functioning in preterm infants by assessing their general movements (GMs). METHODS: A retrospective analysis of prospectively collected data on preterm infants born before 32 weeks of gestation was conducted. We excluded infants with intraventricular hemorrhage > grade II. On day 8, we assessed infants' GMs, both generally as normal/abnormal and in detail using the general movement optimality score (GMOS). We measured cerebral tissue oxygen saturation (rcSO2) on day 1 using near-infrared spectroscopy. RESULTS: We included 65 infants (median gestational age 29.9 weeks [IQR 28.2-31.0]; median birth weight 1,180 g [IQR 930-1,400]). Median Hb on day 1 was 10.3 mmol/L (range 4.2-13.7). Lower Hb on day 1 was associated with a higher risk of abnormal GMs (OR = 2.3, 95% CI: 1.3-4.1) and poorer GMOSs (B = 0.9, 95% CI: 0.2-1.7). Hemoglobin strongly correlated with rcSO2 (rho = 0.62, p < 0.01). Infants with lower rcSO2 values tended to have a higher risk of abnormal GMs (p = 0.06). After adjusting for confounders, Hb on day 1 explained 44% of the variance of normal/abnormal GMs and rcSO2 explained 17%. Regarding the explained variance of the GMOS, this was 25% and 16%, respectively. CONCLUSIONS: In preterm infants, low Hb on day 1 is associated with impaired neurological functioning on day 8, which is partly explained by low cerebral oxygenation.

Blood group AB is associated with poor outcomes in infants with necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a neonatal disease associated with necrosis and perforation of the bowel. We investigated the association between blood group and NEC outcomes and the potential contribution of fetal-maternal blood group incompatibility. METHODS: Retrospective study including all preterm-born infants with NEC (≥ Bell's stage IIa) admitted to our NICU between January 2008 and October 2019. We analyzed the association between infants' blood groups and fetal-maternal blood group incompatibility with Bell stage severity, need for surgery, and mortality due to NEC. RESULTS: We included 237 NEC patients. In univariable analyses both AB blood group and fetal-maternal blood group incompatibility increased infants' risk of severe outcomes, with odds ratios (OR) ranging from 6.57 to 12.06 and 1.97 to 2.38, respectively. When adjusted for gestational age only AB blood group remained significant with OR 7.47 (95% confidence interval, 1.95-28.53, P = 0.003), 12.37 (2.63-58.20, P = 0.001), and 8.16 (2.28-29.14, P = 0.001) for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively. Blood group incompatibility adjusted for gestational age was not related to worse outcomes with OR 1.84 (0.87-3.89, P = 0.11, 2.08 (0.98-4.41, P = 0.06) 1.52 (0.68-3.42, P = 0.31), for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively. CONCLUSION: Our data confirm an association between blood group AB and worse outcomes in NEC infants, but this is not based on fetal-maternal blood group incompatibility.

Anemia and Red Blood Cell Transfusions, Cerebral Oxygenation, Brain Injury and Development, and Neurodevelopmental Outcome in Preterm Infants: A Systematic Review.

Background: Anemia remains a common comorbidity of preterm infants in the neonatal intensive care unit (NICU). Left untreated, severe anemia may adversely affect organ function due to inadequate oxygen supply to meet oxygen requirements, resulting in hypoxic tissue injury, including cerebral tissue. To prevent hypoxic tissue injury, anemia is generally treated with packed red blood cell (RBC) transfusions. Previously published data raise concerns about the impact of anemia on cerebral oxygen delivery and, therefore, on neurodevelopmental outcome (NDO). Objective: To provide a systematic overview of the impact of anemia and RBC transfusions during NICU admission on cerebral oxygenation, measured using near-infrared spectroscopy (NIRS), brain injury and development, and NDO in preterm infants. Data Sources: PubMed, Embase, reference lists. Study Selection: We conducted 3 different searches for English literature between 2000 and 2020; 1 for anemia, RBC transfusions, and cerebral oxygenation, 1 for anemia, RBC transfusions, and brain injury and development, and 1 for anemia, RBC transfusions, and NDO. Data Extraction: Two authors independently screened sources and extracted data. Quality of case-control studies or cohort studies, and RCTs was assessed using either the Newcastle-Ottawa Quality Assessment Scale or the Van Tulder Scale, respectively. Results: Anemia results in decreased oxygen-carrying capacity, worsening the burden of cerebral hypoxia in preterm infants. RBC transfusions increase cerebral oxygenation. Improved brain development may be supported by avoidance of cerebral hypoxia, although restrictive RBC transfusion strategies were associated with better long-term neurodevelopmental outcomes. Conclusions: This review demonstrated that anemia and RBC transfusions were associated with cerebral oxygenation, brain injury and development and NDO in preterm infants. Individualized care regarding RBC transfusions during NICU admission, with attention to cerebral tissue oxygen saturation, seems reasonable and needs further investigation to improve both short-term effects and long-term neurodevelopment of preterm infants.

Regional splanchnic oxygen saturation for preterm infants in the first week after birth: reference values.

BACKGROUND: Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rsSO2), but solid reference values are scarce. We aimed to establish reference values of rsSO2 for preterm infants during the first week after birth, both crude and modeled based on predictors. METHODS: We included infants with gestational age (GA) <32 weeks and/or birth weight <1200 g. We excluded infants who developed necrotizing enterocolitis or sepsis or who died. In the first week after birth, we determined a daily 2-h mean of rsSO2 to assess its associations with sex, GA, postnatal age (PNA), small-for-gestational age (SGA) status, patent ductus arteriosus, hemoglobin, nutrition, and head circumference at birth and translated those into a prediction model. RESULTS: We included 220 infants. On day 1, the mean ± SD rsSO2 value was 48.2% ± 16.6. The nadir of rsSO2 was on day 4 (38.7% ± 16.6 smoothed line) to 5 (37.4%±17.3, actual data), after which rsSO2 increased to 44.2% ± 16.6 on day 7. The final model of the reference values of rsSO2 included the following coefficients: rsSO2 = 3.2 - 7.0 × PNA + 0.8 × PNA2 - 4.0 × SGA + 1.8 × GA. CONCLUSIONS: We established reference values of rsSO2 for preterm infants during the first week after birth. GA, PNA, and SGA affect these values and need to be taken into account. IMPACT: Regional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study.

Predicting intestinal recovery after necrotizing enterocolitis in preterm infants.

BACKGROUND: Intestinal recovery after NEC is difficult to predict in individuals. We evaluated whether several biomarkers predict intestinal recovery after NEC in preterm infants. METHODS: We measured intestinal tissue oxygen saturation (rintSO2) and collected urinary intestinal-fatty acid binding protein (I-FABPu) levels 0-24 h and 24-48 h after NEC onset, and before and after the first re-feed. We assessed intestinal recovery in two ways: time to full enteral feeding (FEFt; below or equal/above group's median) and development of post-NEC complications (recurrent NEC/post-NEC stricture). We determined whether the rintSO2, its range, and I-FABPu differed between groups. RESULTS: We included 27 preterm infants who survived NEC (Bell's stage ≥ 2). Median FEFt was 14 [IQR: 12-23] days. Biomarkers only predicted intestinal recovery after the first re-feed. Mean rintSO2 ≥ 53% combined with mean rintSO2range ≥ 50% predicted FEFt < 14 days with OR 16.7 (CI: 2.3-122.2). The rintSO2range was smaller (33% vs. 51%, p < 0.01) and I-FABPu was higher (92.4 vs. 25.5 ng/mL, p = 0.03) in case of post-NEC stricture, but not different in case of recurrent NEC, compared with infants without complications. CONCLUSION: The rintSO2, its range, and I-FABPu after the first re-feed after NEC predicted intestinal recovery. These biomarkers have potential value in individualizing feeding regimens after NEC.

Perinatal Anemia is Associated with Neonatal and Neurodevelopmental Outcomes in Infants with Moderate to Severe Perinatal Asphyxia.

BACKGROUND: Perinatal anemia may cause perinatal asphyxia. Its pathophysiology and neurodevelopmental effects are theoretically different from other causes of perinatal asphyxia. OBJECTIVE: The study aimed to determine whether perinatal anemia results in different short-term and long-term outcomes than other causes of perinatal asphyxia treated with therapeutic hypothermia. METHODS: We retrospectively included infants with moderate to severe hypoxic-ischemic encephalopathy, born between May 2009 and October 2015. During follow-up, we assessed cognitive and motor development at 2-3 years of age, using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III). Neurodevelopmental outcome (NDO) was classified as abnormal in case of cerebral palsy with Gross Motor Function Classification System ≥III and/or a BSID-III composite score < 85. Outcomes of infants with perinatal anemia (initial hemoglobin < 7 mmol/L) were compared to infants born with perinatal asphyxia due to other causes. RESULTS: In total, 111 infants were included of whom 30 infants (27%) died during the neonatal period. Infants with anemia (n = 23) had a higher mortality risk, OR 3.33, 95% CI 1.27-8.72, p = 0.01. None of the surviving infants with anemia (n = 12) had an abnormal NDO, in contrast to 26/69 (38%) with neurodevelopmental impairments, particularly motor problems, in the non-anemic group, p < 0.01. CONCLUSIONS: Perinatal anemia causing moderate to severe perinatal asphyxia is associated with a higher risk for neonatal mortality. All survivors with perinatal anemia, however, showed a normal NDO in contrast to children who were born asphyxiated due to other causes. The underlying pathophysiological mechanism for the favorable NDO in the perinatal anemia group needs further elucidation.

Red Blood Cell Transfusions Affect Intestinal and Cerebral Oxygenation Differently in Preterm Infants with and without Subsequent Necrotizing Enterocolitis.

OBJECTIVE: To assess intestinal and cerebral oxygenation during and after red blood cell (RBC) transfusions in preterms with or without subsequent transfusion-associated necrotizing enterocolitis (TANEC). STUDY DESIGN: In preterms of < 32 weeks' gestational age, we measured intestinal and cerebral regional tissue oxygen saturation (rintSO2, rcSO2) and their variabilities using near-infrared spectroscopy during and after transfusions. We compared eight infants who developed TANEC 6 to 48 hours after RBC transfusions with 16 controls. RESULTS: In TANEC infants, rcSO2 was lower during and after RBC transfusions than in controls, median (interquartile range) 55% (50-62) versus 72% (65-75), p < 0.01. There were no differences regarding rintSO2. Individual rintSO2 and rcSO2 ranges were smaller after transfusions in TANEC infants, 28% (9-36) versus 49% (40-65), p < 0.01, and 17% (14-33) versus 36% (26-57), p = 0.01, as was short-term rintSO2 variability. For each 10% higher rcSO2, the risk of developing TANEC decreased (odds ratio 0.09; 95% confidence interval 0.01-0.63). The smaller the rintSO2 range after transfusion, the higher the risk of developing TANEC. CONCLUSION: In preterm infants lower rcSO2, but not rintSO2, values during and after RBC transfusions are associated with TANEC. Lower rintSO2 and rcSO2 variabilities after RBC transfusions may represent a diminished capacity for vascular adaptation, possibly leading to TANEC.