Clinical Practice Guideline for Red Blood Cell Transfusion Thresholds in Very Preterm Neonates.

Importance: Red blood cell (RBC) transfusion is a common medical intervention to treat anemia in very preterm neonates; however, best transfusion practices, such as thresholds, remain uncertain. Objective: To develop recommendations for clinicians on the use of RBC transfusions in very preterm neonates. Evidence Review: An international steering committee reviewed evidence from a systematic review of 6 randomized clinical trials (RCTs) that compared high vs low hemoglobin-based or hematocrit-based transfusion thresholds. The steering committee reached consensus on certainty-of-evidence ratings and worked with a panel from stakeholder organizations on reviewing the evidence. With input from parent representatives and the stakeholder panel, the steering committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to develop recommendations. Findings: A systematic review of 6 RCTs encompassing 3483 participants (1759 females [51.3%]; mean [SD] age range, 25.9-29.8 [1.5-3.0] weeks) was used as the basis of the recommendations. The ranges for higher hemoglobin concentration (liberal) vs lower hemoglobin concentration (restrictive) threshold study arms were similar across the trials. However, specific thresholds differed based on the severity of illness, which was defined using variable criteria in the trials. There was moderate certainty of evidence that low transfusion thresholds likely had little to no difference in important short-term and long-term outcomes. The recommended hemoglobin thresholds varied on the basis of postnatal week and respiratory support needs. At postnatal weeks 1, 2, and 3 or more, for neonates on respiratory support, the recommended thresholds were 11, 10, and 9 g/dL, respectively; for neonates on no or minimal respiratory support, the recommended thresholds were 10, 8.5, and 7 g/dL, respectively (to convert hemoglobin to grams per liter, multiply by 10.0). Conclusions and Relevance: This consensus statement recommends a restrictive RBC transfusion strategy, with moderate certainty of evidence, for preterm neonates with less than 30 weeks' gestation.

Sex differences in the association of pretransfusion haemoglobin and cognition in preterm infants.

OBJECTIVES: To assess sex-specific differences in the association between pre-transfusion haemoglobin values and early neurodevelopmental function. DESIGN: Observational follow-up of infants with birth weights <1000 g and gestational ages 22-28 weeks who were enrolled in the NICHD Neonatal Research Network Transfusion of Prematures (TOP) Trial at 19 U.S. sites, 2012-2017. MAIN OUTCOME MEASURES: Pretransfusion haemoglobin values were obtained longitudinally through 36 weeks' postmenstrual age. The infant's mean pretransfusion haemoglobin was used as a marker of degree of anaemia (n=1655 measures). Measures of brain function were obtained at 22-26 months' corrected age using the Bayley Scales of Infant & Toddler Development, third edition (BSID-III) (n=1290 BSID-III scores). Sex-specific estimates for the linear relation between pretransfusion haemoglobin and BSID-III scores were obtained from repeated-measures regression analysis, adjusted for gestational age, birth weight, study site, clinical characteristics, and demographic covariates. RESULTS: The relation of pretransfusion haemoglobin with 24-month BSID-III scores showed significant, independent interactions with both (1) sex (p=0.046) and (2) retinopathy of prematurity (ROP; p=0.004). In 614 males, BSID-III scores were higher by 1.07 points per g/dL (95% CI 1.58 to 4.33; p=0.008), not differing significantly among the three subscales (cognitive, language and motor; p=0.94). In 247 infants with ROP, BSID-III scores were higher by 2.95 points per g/dL (95% CI 0.28 to 1.87; p<0.0001), uniformly across subscales (p=0.73). These associations were non-significant in 676 females (p=0.96) and 1043 infants without ROP (p=0.81). CONCLUSIONS: This study demonstrates sex-specific associations between mean pretransfusion haemoglobin (a marker of the severity of anaemia throughout the neonatal intensive care unit [NICU] hospitalisation) and early neurodevelopmental function at 22-26 months' corrected age.

Blood Donor Sex and Outcomes in Transfused Infants.

Red blood cell transfusion is common in neonatal intensive care. Multiple trials have evaluated different thresholds for when to administer red blood cell transfusion. In contrast, there has been less focus on studies of the characteristics of red blood cells transfused into neonates. In this review, the authors summarize the emerging literature on the potential impact of the sex of blood donors on outcomes in transfused neonates using a systematic search strategy. The authors review the uncertainty generated from studies with conflicting findings and discuss considerations regarding the impact of blood donor sex and other characteristics on neonatal outcomes.

Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy.

BACKGROUND: Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. METHODS: We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. RESULTS: A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). CONCLUSION: We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. IMPACT: Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research Network Induced Hypothermia trial.

Antiseizure medication at discharge in infants with hypoxic-ischaemic encephalopathy: an observational study.

OBJECTIVES: To assess variability in continuation of antiseizure medication (ASM) at discharge and to evaluate if continuation of ASM at discharge is associated with death or disability among infants with hypoxic-ischaemic encephalopathy (HIE) and seizures. DESIGN: Retrospective study of infants enrolled in three National Institute of Child Health and Human Development Neonatal Research Network Trials of therapeutic hypothermia. SETTING: 22 US centres. PATIENTS: Infants with HIE who survived to discharge and had clinical or electrographic seizures treated with ASM. EXPOSURES: ASM continued or discontinued at discharge. OUTCOMES: Death or moderate-to-severe disability at 18-22 months, using trial definitions. Multivariable logistic regression evaluated the association between continuation of ASM at discharge and the primary outcome, adjusting for severity of HIE, hypothermia trial treatment arm, use of electroencephalogram, discharge on gavage feeds, Apgar Score at 5 min, birth year and centre. RESULTS: Of 302 infants included, 61% were continued on ASMs at discharge (range 13%-100% among 22 centres). Electroencephalogram use occurred in 92% of the cohort. Infants with severe HIE comprised 24% and 22% of those discharged with and without ASM, respectively. The risk of death or moderate-to-severe disability was greater for infants continued on ASM at discharge, compared with those infants discharged without ASM (44% vs 28%, adjusted OR 2.14; 95% CI 1.13 to 4.05). CONCLUSIONS: In infants with HIE and seizures, continuation of ASM at discharge varies substantially among centres and may be associated with a higher risk of death or disability at 18-22 months of age.

Long-term outcomes and life-impacts of necrotizing enterocolitis: A survey of survivors and parents.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease that primarily affects premature infants. Necrotizing enterocolitis is associated with adverse two-year outcomes, yet limited research has evaluated the impact of NEC on long-term complications and quality of life in children older than two years. We conducted a survey to characterize the long-term impact of NEC on physical and mental health, social experiences, and quality of life as self-reported by adult NEC survivors and parents of children who survived NEC. To our knowledge, this is the first study that describes the lived experience of NEC survivors and parents of children affected by NEC to understand their experience years after the original diagnosis. Our survey results describe that NEC survivors and parents of children affected by NEC experience long-term complications that impact their physical and mental health, social experiences, and quality of life.

Probiotics for prevention of necrotizing enterocolitis: Where do we stand?

In this review, we provide a historical perspective on probiotic use in preterm infants. We review recent data on the treatment effects of probiotics on necrotizing enterocolitis, sepsis, and mortality. We highlight guidance statements from professional societies and organizations, discussing key points within the context of the currently available evidence from both randomized trials and cohort studies. Finally, we summarize experiences from several North American centers that have reported on the routine use of probiotics, including our center. Our goal is to highlight some of the considerations and complexities surrounding routine probiotics use in preterm infants.

Pulmonary Hypertension in Preterm Infants Treated With Laser vs Anti-Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity.

Importance: Anti-vascular endothelial growth factor (VEGF) therapy for retinopathy of prematurity (ROP) has potential ocular and systemic advantages compared with laser, but we believe the systemic risks of anti-VEGF therapy in preterm infants are poorly quantified. Objective: To determine whether there was an association with increased risk of pulmonary hypertension (PH) in preterm infants with ROP following treatment with anti-VEGF therapy as compared with laser treatment. Design, Setting, and Participants: This multicenter retrospective cohort study took place at neonatal intensive care units of 48 children's hospitals in the US in the Pediatric Health Information System database from 2010 to 2020. Participants included preterm infants with gestational age at birth 22 0/7 to 31 6/7 weeks who had ROP treated with anti-VEGF therapy or laser photocoagulation. Exposures: Anti-VEGF therapy vs laser photocoagulation. Main Outcomes and Measures: New receipt of pulmonary vasodilators at least 7 days after ROP therapy was compared between exposure groups, matched using propensity scores generated from preexposure variables, and adjusted for birth year and hospital. The odds of receiving an echocardiogram after 30 days of age was also included to adjust for secular trends and interhospital variation in PH screening. Results: Among 1577 patients (55.9% male) meeting inclusion criteria, 689 received laser photocoagulation and 888 received anti-VEGF treatment (95% bevacizumab, 5% ranibizumab). Patients were first treated for ROP at median 36.4 weeks' postmenstrual age (IQR, 34.6-38.7). A total of 982 patients (491 in each group) were propensity score matched. Good covariate balance was achieved, as indicated by a model variance ratio of 1.15. More infants who received anti-VEGF therapy were treated for PH, but when adjusted for hospital and year, this was no longer statistically significant (6.7%; 95% CI, 2.6-6.9 vs 4.3% 95% CI, 4.4-10.2; adjusted odds ratio, 1.62; 95% CI, 0.90-2.89; P = .10). Conclusions and Relevance: Anti-VEGF therapy was not associated with greater use of pulmonary vasodilators after adjustment for hospital and year. Our findings suggest exposure to anti-VEGF may be associated with PH, although we cannot exclude the possibility of residual confounding based on systemic comorbidities or hospital variation in practice. Future studies investigating this possible adverse effect seem warranted.

Neonatal and Obstetric Provider Perceptions and Management at 22 Weeks' Gestation.

OBJECTIVE: Active treatment for periviable infants may be influenced by neonatal and obstetric provider perceptions of prognosis. The two aims of this study are to (1) quantify prognostic discordance between provider and data-driven survival estimates and (2) evaluate if prognostic discordance is associated with the threshold probability of survival at which neonatal providers recommend active treatment or obstetric providers recommend antenatal corticosteroids. STUDY DESIGN: Provider survival estimates and threshold probabilities of survival for active treatment and antenatal steroid use were obtained from a case-based survey for an infant or pregnancy at 22 weeks' gestation that was administered at two Atlanta hospitals. Data-driven survival estimates, including ranges, were acquired through the National Institute of Child Health and Human Development Extremely Preterm Birth Outcomes Tool. Prognostic discordance was calculated as the difference between a provider and data-driven estimates and classified as pessimistic (provider estimate below data-driven estimate range), accurate (within range), or optimistic (above range). The association between prognostic discordance and the threshold probability of survival was evaluated using nonparametric tests. RESULTS: We had 137 neonatal respondents (51% response rate) and 57 obstetric responses (23% response rate). The overall median prognostic discordance was 1.5% (interquartile range: 17, 13) and 52 (27%) of all respondents were pessimistic, 100 (52%) were accurate, and 42 (22%) were optimistic. The survival threshold above which neonatal and obstetric providers recommended active treatment or antenatal corticosteroids was 30% (20-45%) and 10% (0-20%), respectively. Thresholds did not significantly differ among the three prognostic discordance groups (p = 0.45 for neonatal and p = 0.53 for obstetric providers). There was also no significant correlation between the magnitude of prognostic discordance and thresholds. CONCLUSION: Prognostic discordance exists among both neonatal and obstetric providers. However, this discordance is not associated with the threshold probability of survival at which providers recommend active treatment or antenatal corticosteroids at 22 weeks' gestation. KEY POINTS: · Prognostic discordance at 22 weeks' gestation exists for neonatal and obstetric providers.. · Prognostic discordance is not associated with survival thresholds for neonatal active treatment.. · Prognostic discordance is not associated with survival thresholds for the use of antenatal corticosteroids..

Association of Antenatal Steroid Exposure at 21 to 22 Weeks of Gestation With Neonatal Survival and Survival Without Morbidities.

Importance: The provision of antenatal corticosteroids to pregnant patients at gestational age (GA) 22 6/7 weeks or less remains controversial and lacks support from randomized clinical trials. Objective: To compare rates of survival and survival without major morbidities among infants born at GA 22 0/7 to 23 6/7 weeks after exposure to antenatal steroids at 22 6/7 weeks' gestation or less vs no exposure to antenatal steroids. Design, Setting, and Participants: This cohort study enrolled infants born at GA 22 0/7 to 23 6/7 weeks between January 1, 2016, and December 31, 2019, at centers in the National Institute of Child Health and Human Development Neonatal Research Network. Infants who did not receive intensive care and infants with antenatal steroid exposure after GA 22 6/7 weeks were excluded. Exposure: Infants were classified as having no, partial, or complete exposure to antenatal steroids. Main Outcomes and Measures: The primary outcome was survival to discharge. The main secondary outcome was survival without major neonatal morbidity. The associations of differential exposures to antenatal steroids with outcomes were evaluated using logistic regression, adjusting for GA, sex, race, maternal education, small for GA status, mode of delivery, multiple birth, prolonged rupture of membranes, year of birth, and Neonatal Research Network center. Results: A total of 431 infants (mean [SD] GA, 22.6 [0.5] weeks; 232 [53.8%] boys) were included, with 110 infants (25.5%) receiving no antenatal steroids, 80 infants (18.6%) receiving partial antenatal steroids, and 241 infants (55.9%) receiving complete antenatal steroids. Seventeen infants were exposed to antenatal steroids at GA 21 weeks. Among infants exposed to complete antenatal steroids, 130 (53.9%) survived to discharge, compared with 30 infants (37.5%) with partial antenatal steroid exposure and 239 infants (35.5%) with no antenatal steroids. Infants born after complete antenatal steroid exposure, compared with those without antenatal steroid exposure, were more likely to survive to discharge (adjusted odds ratio [aOR], 1.95 [95% CI, 1.07-3.56]) and to survive without major morbidity (aOR, 2.74 [95% CI, 1.19-6.30]). Conclusions and Relevance: In this retrospective cohort study, among infants born between GA 22 0/7 and 23 6/7 weeks who received intensive care, exposure to a complete course of antenatal steroids at GA 22 6/7 weeks or less was independently associated with greater odds of survival and survival without major morbidity. These data suggest that the use of antenatal steroids in patients at GA 22 6/7 weeks or less could be beneficial when active treatment is considered.

Patterns of acute kidney and hepatic injury and association with adverse outcomes in infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

OBJECTIVE: To describe patterns of renal and hepatic injury in infants with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Retrospective cohort of infants receiving therapeutic hypothermia for HIE was classified into groups based on organ injury: neither acute kidney injury (AKI) nor acute hepatic injury (AHI), isolated AKI, isolated AHI, or both AKI/AHI. Biomarkers and outcomes were described and analyzed. RESULTS: Among 188 infants, 55% had no AKI nor AHI, 7% had only AKI, 22% had only AHI and 16% had both AKI and AHI. Infants with both AKI/AHI had the highest mortality (47%) and worse outcomes, compared to other injury groups, although AKI/AHI was not significantly associated with mortality (hazard ratio 2.5; 95% CI 0.9-6.9), after accounting for severity of HIE. For surviving infants, biomarkers of organ injury, on average, normalized by discharge. CONCLUSION: Infants with HIE with both AKI/AHI have worse outcomes than infants with AKI or AHI alone.

The center-effect on outcomes for infants born at less than 25 weeks.

Marked variation exists in the care of infants born at <25 weeks' gestation. The center or location where a fetus or infant is cared for influences outcomes at very early gestational ages. Understanding this "center-effect," including characteristics associated with centers that have high survival of births at <25 weeks' gestation, may inform future studies and guide care practices to improve outcomes. This review focuses on the impact that the location or center of birth has on survival and other important outcomes for infants born at <25 weeks' gestation. We review potential sources of variation in care practices and other factors that might explain the "center-effect."

Caffeine for preterm infants: Fixed standard dose, adjustments for age or high dose?

Caffeine is an effective treatment for apnea of prematurity and has several important benefits, including decreasing respiratory morbidity and motor impairment. In this article, we focus on the dose of caffeine. We review the evidence regarding the efficacy and safety of standard caffeine dosing and alternative dosing approaches, including the use of high dose caffeine and routine dose adjustments for age. Current evidence suggests high dose caffeine may provide additional benefit in reducing the risk of bronchopulmonary dysplasia and extubation failure, but may also increase the risk of cerebellar hemorrhage and seizures. Increasing the standard caffeine citrate dose every 1-2 weeks to a goal dose of 8 mg per kilogram every 24 h may help maintain therapeutic effect. We conclude by highlighting the need for additional trials before high dose caffeine is routinely used.

Defining necrotizing enterocolitis: current difficulties and future opportunities.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in hospitalized infants. First classified through Bell staging in 1978, a number of additional definitions of NEC have been proposed in the subsequent decades. In this review, we summarize eight current definitions of NEC, and explore similarities and differences in clinical signs and radiographic features included within these definitions, as well as their limitations. We highlight the importance of a global consensus on defining NEC to improve NEC research and outcomes, incorporating input from participants at an international NEC conference. We also highlight the important role of patient-families in helping to redefine NEC.

Transfusion-related Gut Injury and Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) accounts for 10% of deaths in neonatal intensive care units. Several causal mechanisms are likely to lead to a final common disease phenotype. This article summarizes recent data on NEC following red blood cell (RBC) transfusion, with a focus on the most recent literature and ongoing trials. It highlights potential mechanisms from preclinical and human physiologic studies. It also discusses the role of feeding during RBC transfusion and the risk of NEC. Ongoing randomized trials will provide important data on how liberal or conservative approaches to RBC transfusion influence the risk of NEC.

Blood product transfusion and mortality in neonatal extracorporeal membrane oxygenation.

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% CI 1.05-1.69, p = 0.02) and PLT transfusion (adjusted relative risk per 5 mL/kg/d increase: 1.12; 95% CI 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.