Association between intermittent hypoxemia and neurodevelopmental outcomes in extremely premature infants: A single-center experience.

OBJECTIVE: To describe the association between intermittent hypoxemic events (IHEs) and severe neurodevelopmental impairment (SNDI) or death in extremely premature infants. STUDY DESIGN: Retrospective study of extremely premature infants 230/7-276/7 weeks gestational age (GA) and birthweight (BW) ≤1250 grams (g) admitted to a level IV neonatal intensive care unit (NICU) from 2013 to 2017. IHEs, defined as events with SpO2 ≤ 80 % lasting 10 s to 5 min, were algorithmically identified using data extracted from bedside monitors at 2 s intervals (0.5 Hz). The primary outcome was SNDI at 18-24 months corrected age (CA), defined as a Bayley-III motor, language or cognitive composite score ≤69, or death before discharge while the secondary outcome was SNDI alone. We used mixed-effects regression models to evaluate the relationship between mean daily IHE rate per postnatal week of life for the first 12 weeks and the outcomes, and logistic regression models to assess the association between outcomes and summary measures of hypoxic burden for the entire NICU hospitalization. RESULTS: The mortality rate was 7 % (18/249) during NICU hospitalization. Of 249 infants born during this time period, IHE and neurodevelopmental outcome data were fully available for 65 infants (mean GA 26 ± 1.4 weeks, mean birth weight (BW) 738 ± 199 g. The outcome of SNDI alone occurred in 34 % (22/65) with a majority demonstrating motor or language delay on the Bayley-III. Although mean daily IHE rate/week was not associated with SNDI or death, total IHE duration was associated with increased odds of SNDI (OR (95 % CI) 1.03 (1.01, 1.05), p = 0.008) in models adjusted for GA. CONCLUSIONS: In a cohort of extremely premature infants 23-27 weeks GA, each hour of total IHE duration (SpO2 ≤ 80 %) was associated with a 2.7 % (0.7 %, 4.8 %) increase in the odds of SNDI at 18-24 months CA.

Low nephron endowment increases susceptibility to renal stress and chronic kidney disease.

Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated potentially novel mouse models with a 30%-70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy, followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared with controls with normal nephron number. Mice with low nephron number had reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.

Intracranial ultrasound abnormalities and mortality in preterm infants with and without fetal growth restriction stratified by fetal Doppler study results.

OBJECTIVE: To evaluate whether fetal growth restriction (FGR) with or without abnormal Dopplers is associated with intracranial abnormalities and death in premature infants. STUDY DESIGN: Premature infants with and without FGR born between 2016 and 2019 were included. Primary outcome was death, severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Groups were compared using standard bivariate testing and multivariable regression. RESULTS: Among 168 FGR and 560 non-FGR infants, FGR infants with abnormal Dopplers had an increased incidence of death, severe IVH or PVL compared to non-FGR infants (13% (16/123) vs. 7% (41/560); p = 0.03) while FGR infants with normal Dopplers had a nonsignificant decrease. In a logistic regression model, FGR with abnormal Dopplers was associated with more than three times higher odds of death, severe IVH or PVL (OR 3.2, 95% CI 1.54,6.49; p < 0.001). CONCLUSIONS: Growth-restricted infants with abnormal Dopplers had an increased risk of death, intracranial abnormalities, and prematurity-related morbidities.

Outcomes after neonatal cardiac surgery: The impact of a dedicated neonatal cardiac program.

OBJECTIVES: Prematurity is a risk factor for in-hospital mortality after cardiac surgery. The structure of intensive care unit models designed to deliver optimal care to neonates including those born preterm with critical congenital heart disease is unknown. The objective of this study was to evaluate in-hospital outcomes after cardiac surgery across gestational ages in an institution with a dedicated neonatal cardiac program. METHODS: This study is a single-center, retrospective review of infants who underwent cardiac surgical interventions from our dedicated neonatal cardiac intensive care program between 2006 and 2017. We evaluated in-hospital mortality and morbidity rates across all gestational ages. RESULTS: A total of 1238 subjects met inclusion criteria over a 11-year period. Overall in-hospital mortality after cardiac surgery was 6.1%. The mortality rate in very preterm infants (n = 68; <34 weeks' gestation at birth) was 17.6% (odds ratio, 3.52 [1.4-8.53]), versus 4.3% in full-term (n = 563; 39-40 weeks) referent/control infants. Very preterm infants with isolated congenital heart disease (without evidence of other affected organ systems) experienced a mortality rate of 10.5% after cardiac surgery. Neither the late preterm (34-36 6/7 weeks) nor the early term (37-38 6/7) groups had significantly increased odds of mortality compared with full-term infants. Seventy-eight percent of very preterm infants incurred a preoperative or postoperative complication (odds ratio, 4.78 [2.61-8.97]) compared with 35% of full-term infants. CONCLUSIONS: In this study of a single center with a dedicated neonatal cardiac program, we report some of the lowest mortality and morbidity rates after cardiac surgery in preterm infants in the recent era. The potential survival advantage of this model is most striking for very preterm infants born with isolated congenital heart disease.

The Prevalence and Clinical Significance of Congenital Anomalies of the Kidney and Urinary Tract in Preterm Infants.

Importance: The prevalence and importance of congenital anomalies of the kidney and urinary tract (CAKUT) in preterm infants is unknown. Objective: To determine the prevalence of CAKUT in preterm infants and association with in-hospital morbidity and mortality. Design, Setting, and Participants: This cohort study included infants cared for in neonatal intensive care units managed by a large US network of hospitals and doctors. Eligible participants were infants born at 23 to 33 weeks' gestation between 2000 and 2020. Infants transferred from or to other health care facilities prior to discharge or death were excluded in analysis of outcomes. Data were analyzed from December 2021 until May 2022. Exposures: The presence of anomalies of the kidneys, ureters, bladder, or urethra was assessed. Covariates were discharge year, exposure to antenatal steroids, sex, maternal race, gestational age, birthweight, mechanical ventilation in first 72 hours of life, genetic disorders, and extrarenal anomalies. Main Outcomes and Measures: Death or in-hospital severe illness (acute kidney injury, kidney failure, intracranial hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, bacterial sepsis, or administration of inotrope or vasopressor). Results: In this cohort of 409 704 infants, 191 105 (46.6%) were girls, mean (SD) gestational age was 30.1 (2.84) weeks, and mean (SD) birth weight was 1.49 (0.53) kg. A total of 8093 infants (2.0%) had CAKUT, with urinary tract dilation comprising the majority of cases (5669 [70.0%]). The presence of CAKUT correlated with earlier gestational age and was associated with genetic disorders and extrarenal anomalies. Analysis of 323 957 infants after exclusions demonstrated an adjusted odds ratio of 3.96 (95% CI, 3.70-4.24) of death or severe illness. This risk was found across all forms of CAKUT including isolated urinary tract dilation. Conclusions and Relevance: The findings of this cohort study suggest that clinicians caring for preterm infants should have higher suspicion for CAKUT and consider screening, particularly those with extrarenal anomalies or genetic disorders, as preterm infants with CAKUT appear to be at significantly higher risk of death or severe illness. Detection of CAKUT can inform risk stratification and clinical decision making, and should also prompt clinicians to consider a genetic evaluation.

The impact of a Donor Human Milk Program on the provision of mothers' own milk at discharge in very low birth weight infants.

OBJECTIVE: Examine the effect of a donor human milk (DHM) program on mothers' own milk feedings at discharge for very low birth weight (VLBW) infants. STUDY DESIGN: A single center retrospective analysis of feeding outcomes in preterm infants. Data were assigned as: (1) pre DHM era (2) Bridge DHM era (3) Full DHM era. Each era was divided into infants <1500 g (n = 724) or ≥1500 g (n = 784). RESULTS: Both the percentage of mothers' own milk feeds and percent of infants exclusively receiving mothers' own milk at discharge were increased in the <1500 g (p = 0.003, p = 0.002) and the ≥1500 g group (p = 0.007, p = 0.004) respectively, following the introduction of DHM for VLBW infants. CONCLUSION: Practice changes that accompany a donor milk program likely play a prominent role in the provision of mothers' own milk and exclusivity of breast milk feedings at discharge for very low birth weight infants.

Revisiting the definition of bronchopulmonary dysplasia in premature infants at a single center quaternary neonatal intensive care unit.

OBJECTIVE: To compare the incidence of bronchopulmonary dysplasia (BPD) based on the 1988 Vermont Oxford Network (VON) criteria, National Institutes of Health (NIH) 2001 definition, and NIH 2018 definition. METHODS: BPD incidence by each definition was compared in premature infants born at a single center between 2016 and 2018. Comorbidities were compared between those with and without BPD according to the newest definition. RESULTS: Among 352 survivors, BPD incidence was significantly different at 9%, 28% and 34% according to VON, NIH 2001 and NIH 2018 definitions, respectively (p < 0.05). According to the newest definition, any grade of BPD was associated with more co-morbidities than those without BPD (P < 0.001). CONCLUSION: At a center that emphasizes use of early noninvasive respiratory support, the incidence of BPD was significantly higher according to the NIH 2018 definition compared to other two definitions. The relationship between BPD diagnosis and long-term clinical outcomes remains unclear.

Patterns of Urinary Neutrophil Gelatinase-Associated Lipocalin and Acute Kidney Injury in Neonates Receiving Cardiopulmonary Bypass.

Elevated urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts acute kidney injury (AKI) in children following cardiopulmonary bypass (CPB) during cardiac surgery, but little is known about uNGAL's predictive ability in neonates in this setting. We sought to determine the relationship between AKI and post-CPB uNGAL in neonates in the first 72 post-operative hours. METHODS: Urine samples for uNGAL analysis were collected at preoperative baseline and serially post-operatively from 76 neonates undergoing CPB. Mixed-effects regression models and logistic models assessed associations between uNGAL and AKI (controlling for sex, gestational age, CPB time, surgical complexity, and age at surgery). Receiver-operator curves were applied to define optimal uNGAL cut-off values for AKI diagnosis. RESULTS: Between 0 and 4 h post-operatively, uNGAL values did not differ between neonates with and without AKI. After 4 h until 16 h post-operatively, significant time-wise separation occurred between uNGAL values of neonates with AKI and those without AKI. Odds ratios at each time point significantly exceeded unity, peaking at 10 h post-operatively (3.48 (1.58, 8.71)). Between 4 and 16 h post-operatively, uNGAL discriminated AKI from no-AKI, with a sensitivity of 0.63 (0.49, 0.75) and a specificity of 0.68 (0.62, 0.74) at a cut-off value of 100 ng/mL. CONCLUSION: After 4 h until 16 h post-operatively, elevated uNGAL is associated with AKI in neonates receiving CPB during cardiac surgery; however, this relationship is more complex than in older children.

Patent ductus arteriosus is associated with acute kidney injury in the preterm infant.

BACKGROUND: This study aimed to test the hypothesis that a patent ductus arteriosus (PDA) is independently associated with acute kidney injury (AKI) in neonates ≤ 28 weeks gestation. METHODS: Preterm infants with echocardiographic diagnosis of moderate-large PDA at age ≤ 30 days were studied retrospectively. AKI, the primary outcome, was defined and staged according to serum creatinine using Kidney Disease Improving Global Outcomes (KDIGO) neonatal criteria. Its association with the timing and duration of PDA, non-steroidal anti-inflammatory drugs (NSAIDs) and other nephrotoxic exposures, gestational age, and other covariates was evaluated using mixed-effects logistic regression models. RESULTS: Acute Kidney Injury occurred in 49% (101/206) of infants. Moderate-to-large PDA was associated with any-stage AKI (OR 5.31, 95% CI 3.75 to 7.53), stage 1 (mild) AKI (OR 4.86, 95% CI 3.12 to 7.56), and stages 2-3 (severe) AKI (OR 10.9, 95% CI 5.70 to 20.8). NSAID treatment added additional risk for mild AKI (OR 2.45, 95% CI 1.61 to 3.71). Severe AKI was less likely when NSAID treatment was effective (OR 0.45, 95% CI 0.21 to 0.97) but not when ineffective (OR 1.63, 95% CI 0.76 to 3.50). CONCLUSIONS: Moderate-to-large PDA was strongly associated with all stages of AKI in preterm infants ≤ 28 weeks of gestational age. Effective NSAID treatment decreased the risk of severe but not mild AKI. These differential effects reflect the balance between the renal benefits of PDA closure and the risk of NSAID toxicity.

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia.

On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine ("7+3") in 309 patients 60-75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% confidence interval, 0.52-0.90; P = 0.005) with an estimated median overall survival of 9.6 months compared with 5.9 months for the "7+3" control arm. The toxicity profile of Vyxeos was similar to that seen with standard "7+3" with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.

Effect of red blood cell storage time on markers of hemolysis and inflammation in transfused very low birth weight infants.

BackgroundProlonged storage of transfused red blood cells (RBCs) is associated with hemolysis in healthy adults and inflammation in animal models. We aimed to determine whether storage duration affects markers of hemolysis (e.g., serum bilirubin, iron, and non-transferrin-bound iron (NTBI)) and inflammation (e.g., interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1) in transfused very low birth weight (VLBW) infants.MethodsBlood samples from 23 independent transfusion events were collected by heel stick before and 2-6 h after transfusion.ResultsSerum iron, total bilirubin, NTBI, and MCP-1 levels were significantly increased after transfusion of RBCs (P<0.05 for each comparison). The storage age of transfused RBCs positively correlated with increases in NTBI following transfusion (P<0.001; R2=0.44). No associations between storage duration and changes in the other analytes were observed.ConclusionTransfusion of RBCs into VLBW infants is associated with increased markers of hemolysis and the inflammatory chemokine MCP-1. RBC-storage duration only correlated with increases in NTBI levels following transfusion. NTBI was only observed in healthy adults following 35 days of storage; however, this study suggests that VLBW infants are potentially more susceptible to produce this pathological form of iron, with increased levels observed after transfusion of only 20-day-old RBCs.

Vital signs and their cross-correlation in sepsis and NEC: a study of 1,065 very-low-birth-weight infants in two NICUs.

BACKGROUND: Subtle changes in vital signs and their interactions occur in preterm infants prior to overt deterioration from late-onset septicemia (LOS) or necrotizing enterocolitis (NEC). Optimizing predictive algorithms may lead to earlier treatment. METHODS: For 1,065 very-low-birth-weight (VLBW) infants in two neonatal intensive care units (NICUs), mean, SD, and cross-correlation of respiratory rate, heart rate (HR), and oxygen saturation (SpO2) were analyzed hourly (131 infant-years' data). Cross-correlation (cotrending) between two vital signs was measured allowing a lag of ± 30 s. Cases of LOS and NEC were identified retrospectively (n = 186) and vital sign models were evaluated for ability to predict illness diagnosed in the ensuing 24 h. RESULTS: The best single illness predictor within and between institutions was cross-correlation of HR-SpO2. The best combined model (mean SpO2, SDHR, and cross-correlation of HR-SpO2,) trained at one site with ROC area 0.695 had external ROC area of 0.754 at the other site, and provided additive value to an established HR characteristics index for illness prediction (Net Reclassification Improvement: 0.205; 95% confidence interval (CI): 0.113, 0.328). CONCLUSION: Despite minor inter-institutional differences in vital sign patterns of VLBW infants, cross-correlation of HR-SpO2 and a 3-variable vital sign model performed well at both centers for preclinical detection of sepsis or NEC.

Is urinary neutrophil gelatinase-associated lipocalin able to predict acute kidney injury episodes in very low birth weight infants in clinical settings?

BACKGROUND: We evaluated the potential utility of elevated urinary neutrophil gelatinase-associated lipocalin (UNGAL) concentration as a screening test for early identification of acute kidney injury (AKI) in very low birth weight (VLBW) newborns. METHODS: Urine for UNGAL analysis was collected prospectively daily until 32 wk postmenstrual age in 91 VLBW newborns, yielding 2,899 specimens. UNGAL values > 50 ng/ml were considered elevated. AKI was defined as two or more consecutive elevations in s[Cr] above the 95th percentile adjusted for gestational age and chronological age within a 48 h period. We compared UNGAL values taken during the 5 d prior to AKI onset (pre-AKI) to values taken during non-AKI days. RESULTS: Overall, 15 episodes of AKI were identified in 13 infants. UNGAL was available in 44 pre-AKI days and 969 non-AKI days. UNGAL > 50 ng/ml occurred more often in pre-AKI days than in non-AKI days (risk ratio 3.48 (1.89, 6.40)). Positive and negative likelihood ratios were 1.92 (1.52, 2.41) and 0.52 (0.34, 0.78), respectively. CONCLUSION: Although UNGAL elevation > 50 ng/ml discriminates between pre-AKI and non-AKI days, high false positive and false negative rates limit utility as a screening test in VLBW newborns.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

Urinary neutrophil gelatinase-associated lipocalin: potential biomarker for late-onset sepsis.

BACKGROUND: To assess the ability of urinary neutrophil gelatinase-associated lipocalin (UNGAL) to discriminate between culture-positive vs. culture-negative late-onset sepsis evaluations. METHODS: This is a prospective observational study of 136 neonates who underwent ≥1 sepsis evaluation at >72 h of age. Urine was obtained at the time of sepsis evaluation to measure UNGAL concentration. Using generalized estimating equations controlling for gender, gestational and postnatal age, acute kidney injury, and within-patient correlations, pair-wise contrasts between mean log UNGAL concentrations of infants with negative sepsis evaluations vs. culture-positive sepsis and presumed sepsis were assessed. Discrimination characteristics at several UNGAL cutoff concentrations were assessed using receiver-operating characteristic curves. RESULTS: The predicted mean log UNGAL values of culture-positive sepsis and presumed sepsis vs. negative sepsis evaluations differed significantly (P < 0.001 and P = 0.02, respectively). At a cutoff ≥ 50 ng/ml, UNGAL discriminated between culture-positive sepsis and culture-negative sepsis evaluations with sensitivity = 86%, specificity = 56%, positive predictive value = 41%, negative predictive value = 92%, and number needed to treat = 3. CONCLUSION: UNGAL is a noninvasive biomarker with high negative predictive value at the time of late-onset sepsis evaluation in neonates and could be a useful adjunct to traditional components of sepsis evaluations.

Serum creatinine concentration in very-low-birth-weight infants from birth to 34-36 wk postmenstrual age.

BACKGROUND: Serum creatinine (s[Cr]) reference ranges for very-low-birth-weight (VLBW) infants must account for physiologic changes in the first months of life. METHODS: We retrospectively identified a sample of 218 appropriate-for-gestational age (GA) VLBW infants without risk factors for renal impairment, and classified into one of three GA groups: 25-27, 28-29, and 30-33 wk. We observed three phases of s[Cr] change (initial, decline, and equilibrium), whose characteristics varied by GA group. We used mixed-effects regression models to estimate mean and upper 95th prediction interval of s[Cr] for each GA group from birth to 34-36 wk post menstrual age (PMA). RESULTS: In phase I, s[Cr] increased after birth, then returned slowly to baseline. The duration of phase I and the magnitude of s[Cr] rise decreased with increasing GA. In phase II, s[Cr] declined abruptly at a rate that increased with GA. A gradual transition to phase III, a steady-state equilibrium with similar s[Cr] among GA groups, began at approximately 34-36 wk PMA. We constructed GA group-specific nomograms depicting s[Cr] behaviour across the three phases. CONCLUSION: The reference ranges derived from a sample of infants without risk factors for renal impairment provide a context for quantitative interpretation of s[Cr] trends in VLBW infants.