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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 (r s SO 2 ) and r s SO 2 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 r s SO 2 variability, but not higher mean r s SO 2 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., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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 (r s SO 2 ) and r s SO 2 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). R s SO 2 and r s SO 2 variability were lower in cases than controls shortly before transfusion. Hemoglobin levels correlated negatively with r s SO 2 and r s SO 2 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., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (r s SO 2 ), but solid reference values are scarce. We aimed to establish reference values of r s SO 2 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 r s SO 2 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 r s SO 2 value was 48.2% ± 16.6. The nadir of r s SO 2 was on day 4 (38.7% ± 16.6 smoothed line) to 5 (37.4%±17.3, actual data), after which r s SO 2 increased to 44.2% ± 16.6 on day 7. The final model of the reference values of r s SO 2 included the following coefficients: r s SO 2  = 3.2 - 7.0 × PNA + 0.8 × PNA 2  - 4.0 × SGA + 1.8 × GA., Conclusions: We established reference values of r s SO 2 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., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

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 (r int SO 2 ) and collected urinary intestinal-fatty acid binding protein (I-FABP u ) 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 r int SO 2 , its range, and I-FABP u 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 r int SO 2  ≥ 53% combined with mean r int SO 2range  ≥ 50% predicted FEFt < 14 days with OR 16.7 (CI: 2.3-122.2). The r int SO 2range was smaller (33% vs. 51%, p < 0.01) and I-FABP u 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 r int SO 2 , its range, and I-FABP u after the first re-feed after NEC predicted intestinal recovery. These biomarkers have potential value in individualizing feeding regimens after NEC.

Objectives: Congenital heart disease (CHD) has been associated with reduced fetal head circumference (HC), although the underlying pathophysiology remains undetermined. We aimed to define trends in fetal growth and cerebroplacental Doppler flow, and to investigate their relationship, in fetuses with CHD., Methods: This was a retrospective study in two fetal medicine units in The Netherlands. We included all fetuses with CHD in whom Doppler flow patterns (middle cerebral artery (MCA) pulsatility index (PI), umbilical artery (UA) PI and cerebroplacental ratio (CPR)) and biometry (HC and abdominal circumference (AC)) had been measured serially after 19 weeks' gestation between January 2010 and November 2016. Fetuses were categorized into three groups based on the expected cerebral arterial oxygen saturation of their particular type of CHD: normal; mild to moderately reduced; severely reduced. Trends over time in Z-scores were analyzed using a linear mixed-effects model., Results: A total of 181 fetuses fulfilled the inclusion criteria. Expected cerebral arterial oxygen saturation in CHD was classified as normal in 44 cases, mild to moderately reduced in 84 and severely reduced in 53. In the cohort overall, average trends over time were significant for both HC and AC Z-scores. HC Z-scores showed a tendency to decrease until 23 weeks, then to increase until 33 weeks, followed by another decrease in the late third trimester. AC Z-scores increased progressively with advancing gestation. MCA-PI and UA-PI Z-scores showed significant trends throughout pregnancy, but CPR Z-scores did not. There were no associations between expected cerebral arterial oxygen saturation and fetal growth. Average trends in MCA-PI Z-scores were significantly different between the three subgroups, whereas those in UA-PI Z-scores and in CPR Z-scores were similar between the subgroups. There was no significant association between MCA-PI and HC Z-scores., Conclusions: Fetal biometry and Doppler flow patterns are within normal range in fetuses with CHD, but show trends over time. Head growth in fetuses with CHD is not associated with cerebral blood flow pattern or placental function and HC is not influenced by the cerebral arterial oxygen saturation. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology., (© 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.)

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 (r int SO 2 , r c SO 2 ) 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, r c SO 2 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 r int SO 2 . Individual r int SO 2 and r c SO 2 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 r int SO 2 variability. For each 10% higher r c SO 2 , the risk of developing TANEC decreased (odds ratio 0.09; 95% confidence interval 0.01-0.63). The smaller the r int SO 2 range after transfusion, the higher the risk of developing TANEC., Conclusion: In preterm infants lower r c SO 2 , but not r int SO 2 , values during and after RBC transfusions are associated with TANEC. Lower r int SO 2 and r c SO 2 variabilities after RBC transfusions may represent a diminished capacity for vascular adaptation, possibly leading to TANEC., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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., (© 2018 The Author(s) Published by S. Karger AG, Basel.)