Sex Differences in the Association of Pretransfusion Hemoglobin Levels with Brain Structure and Function in the Preterm Infant

Benavides, Amanda; Bell, Edward F.; Conrad, Amy L.; Feldman, Henry A.; Georgieff, Michael; Josephson, Cassandra D.; Koscik, Timothy R.; Stowell, Sean R.; Sola‐Visner, Martha; Nopoulos, Peg

doi:10.1016/j.jpeds.2021.12.051

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…This explains the results of our decision tree, i.e., an early Hb threshold of >15.2 would have no independent impact at 24 months on a population that is said to be less at risk (female, VP, >26 weeks), which naturally has a higher sex-related Hb fetal threshold [26]. A recent study confirms this sex-specific association between an early marker of anemia and cognitive function at age 12 months of age and white matter volume [27].…”

Section: Discussionmentioning

confidence: 65%

Impact of Early Hemoglobin Levels on Neurodevelopment Outcomes of Two-Year-Olds in Very Preterm Children

et al. 2023

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Objective: To evaluate, in very preterm infants, the hemoglobin (Hb) levels during the first 24 h and the neurodevelopment outcomes at 24 months of corrected age. Design, setting, and patients: We conducted a secondary analysis of the French national prospective and population-based cohort EPIPAGE-2. The eligible study participants were live-born singletons who were born before 32 weeks of gestational age, with early Hb levels who were admitted to the neonatal intensive care unit. Main outcome measures: The early Hb levels for an outcome survival at 24 months of corrected age without neurodevelopmental impairment were measured. The secondary outcomes were survival at discharge and without severe neonatal morbidity. Results: Of the 2158 singletons of <32 weeks with mean early Hb levels of 15.4 (±2.4) g/dL, 1490 of the infants (69%) had a follow-up at two years of age. An early Hb of 15.2 g/dL is the minimum receiving operating characteristic curve at the 24 months risk-free level, but the area under the curve at 0.54 (close to 50%) indicates that this rate was not informative. In logistic regression, no association was found between early Hb levels and outcomes at two years of age (aOR 0.966; 95% CI [0.775–1.204]; p = 0.758) but rather there was a correlation found with severe morbidity (aOR 1.322; 95% CI [1.003–1.743]; p = 0.048). A risk stratification tree showed that male newborns of >26 weeks with Hb of <15.5 g/dL (n = 703) were associated with a poor outcome at 24 months (OR 1.9; CI: [1.5–2.4] p < 0.01). Conclusions: Early low Hb levels are associated with major neonatal morbidities in VP singletons, but not with neurodevelopment outcomes at two years of age, except in male infants of >26 Weeks GA.

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Section: Discussionmentioning

confidence: 65%

Impact of Early Hemoglobin Levels on Neurodevelopment Outcomes of Two-Year-Olds in Very Preterm Children

et al. 2023

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“…Although Hgb 12.5 mg/dL or greater was an associated variable from the CART analysis, infants with Hgb 12.5 mg/dL or greater received more transfusions outside of study protocol than other infants and may have intentionally been kept at a higher Hgb level due to severity of illness, inherently placing them at higher risk for adverse outcomes. However, the possibility that higher Hgb levels are detrimental in specific circumstances should also be considered …”

Section: Discussionmentioning

confidence: 99%

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants

Chock,

Kirpalani,

Bell

et al. 2023

JAMA Netw Open

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ImportancePreterm 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsNear-infrared spectroscopy monitoring of Csat and Msat.Main Outcomes and MeasuresPrimary 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 &lt;85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment.ResultsA 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 RelevanceIn 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.Trial RegistrationClinicalTrials.gov Identifier: NCT01702805

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“…Together, these studies suggest that RBC transfusions have a pro-inflammatory effect that might be more pronounced in premature female infants, with the potential to affect long-term neurodevelopmental outcomes. Interestingly, among male preterm infants randomized to liberal or restrictive transfusion thresholds (in the same subset of TOP infants), lower pretransfusion Hb levels were associated with lower cerebral white matter volume at discharge, suggesting that the male brain might be more sensitive to anemia while the female brain may be more sensitive to the pro-inflammatory effects of transfusions [18].…”

Section: Red Blood Cell Transfusions In Neonatesmentioning

confidence: 99%

Immunologic effects of red blood cell and platelet transfusions in neonates

Davenport

Sola‐Visner²

2022

Current Opinion in Hematology

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Purpose of ReviewPremature neonates are frequently transfused red blood cells (RBCs) or platelets to raise hemoglobin or platelet counts. However, these transfusions may have unintended effects on the immune system. This review will summarize the newest discoveries on the immunologic effects of RBC and platelet transfusions in neonates, and their potential impact on neonatal outcomes. Recent FindingsNeonatal RBC transfusions are associated with increases in plasma pro-inflammatory cytokines, but recent findings suggest sex-specific differential responses. At least one cytokine (monocyte chemoattractant protein-1) rises in females receiving RBC transfusions, but not in males. These inflammatory responses correlate with poorer neurodevelopmental outcomes in heavily transfused female infants, while preterm male infants seem to be more sensitive to severe anemia. Platelet transfusions in preterm neonates are associated with increased neonatal mortality and morbidity. The underlying mechanisms are unknown, but likely related to the immune/inflammatory effects of transfused platelets. Adult platelets are different from neonatal platelets, with the potential to be more pro-inflammatory. Early preclinical data suggest that platelet transfusions alter the neonatal systemic inflammatory response and enhance immune cell migration. SummaryRBC and platelet transfusions alter neonatal immune and inflammatory responses. Their pro-inflammatory effects might worsen neonatal disease or affect neurodevelopmental outcomes.

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Sex Differences in the Association of Pretransfusion Hemoglobin Levels with Brain Structure and Function in the Preterm Infant

Cited by 7 publications

References 35 publications

Impact of Early Hemoglobin Levels on Neurodevelopment Outcomes of Two-Year-Olds in Very Preterm Children

Impact of Early Hemoglobin Levels on Neurodevelopment Outcomes of Two-Year-Olds in Very Preterm Children

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants

Immunologic effects of red blood cell and platelet transfusions in neonates

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