Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Variability in Practice and Implementation of Oxygen Target Saturation Policies in United States' Neonatal Intensive Care Units.

OBJECTIVE: This study aimed to describe target oxygen saturation (SpO2) ranges used for premature infants in United States' neonatal intensive care units (NICUs) and to describe if these target SpO2 ranges have changed in recent years. STUDY DESIGN: A 29-question survey focused on target SpO2 practices and policies was distributed via the NICU medical directors listservs for the American Academy of Pediatrics Section of Neonatal-Perinatal Medicine and Pediatrix Medical Group between August and October of 2021. Results were collected via Research Electronic Data Capture (REDCap). RESULTS: We received responses representing 170 unique, levels 2, 3, and 4 NICUs from 36 states. Most NICUs (130, 78%) have recently changed their SpO2 targets in response to target SpO2 clinical trials. Over time, the most commonly reported target SpO2 range has shifted from 88-92% to 90-95%. Of NICUs that changed limits, the most common lower SpO2 limits increased from 88 to 90% and the upper SpO2 limits changed from 92 to 95%. The interquartile range for lower SpO2 limit shifted from 85-88% to 88-90% and the IQR for upper SpO2 limit decreased from 92-95% to 94-95%. Most NICUs had designated conditions that would allow for deviations from standard target SpO2 ranges. These most commonly include pulmonary hypertension (152, 95%), severe bronchopulmonary dysplasia (81, 51%), and retinopathy of prematurity (51, 32%). CONCLUSION: Oxygen saturation limits have changed over time with an overall increase in targeted SpO2. However, there remains considerable interunit variation in SpO2 policies. There is a need to achieve consensus to optimize clinical outcomes. KEY POINTS: · What are the SpO2 ranges in United States' NICUs?. · There is a shift in SpO2 ranges for preterm infants in NICUs across United States.. · Variability still persists in SpO2 ranges for preterm infants in United States' NICUs..

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns.

BACKGROUND: The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS: A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS: Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS: We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Current Patterns of Probiotic Use in U.S. Neonatal Intensive Care Units: A Multi-Institution Survey.

OBJECTIVE: Probiotic supplementation is associated with health benefits in preterm infants. The 2021 American Academy of Pediatrics (AAP) statement on probiotic use advised caution, citing heterogeneity and absence of federal regulation. We assessed the impact of the AAP statement and current institution-wide patterns of probiotic use across neonatal intensive care units (NICU) across the United States. STUDY DESIGN: A cross-sectional web-based institutional survey using REDCap was emailed to 430 Children's Hospital Neonatal Consortium (CHNC) and Pediatrix Medical Group institutions. The survey captured data on probiotic formulations, supplementation, initiation and cessation criteria, reasons for discontinuation, interest in initiating, and AAP statement's impact. RESULTS: Ninety-five (22.1%) hospitals, including 42/46 (91%) CHNC and 53/384 (14%) Pediatrix institutions, completed the survey. Thirty-seven (39%) currently use probiotics. Fourteen different probiotic formulations were reported. The common criteria for initiation were birth weight <1,500 g and gestational age <32 weeks. Parental consent or assent was obtained at only 30% of institutions. Five hospitals (11%) with prior probiotic use discontinued solely due to the AAP statement. Overall, 23 (24%) of hospitals indicated that the AAP statement significantly influenced their decision regarding probiotic use. Nineteen of 51 nonusers (37%) are considering initiation. CONCLUSION: Probiotic use in preterm infants is likely increasing in NICUs across the United States, but significant variability exists. The 2021 AAP statement had variable impact on NICUs' decision regarding probiotic use. The growing interest in adopting probiotics and the significant interhospital variability highlight the need for better regulation and consensus guidelines to ensure standardized use. KEY POINTS: · Probiotic use in preterm infants is likely increasing in U.S. NICUs, but clinical variability exists.. · The AAP statement on probiotic use in preterm infants had a modest impact on current practices.. · There's a need for better product regulation and consensus guidelines to ensure standardized use..

Low Rate of Spontaneous Closure in Premature Infants Discharged with a Patent Ductus Arteriosus: A Multicenter Prospective Study.

OBJECTIVES: To assess the rate of spontaneous closure and the incidence of adverse events in infants discharged home with a patent ductus arteriosus. STUDY DESIGN: In a prospective multicenter study, we enrolled 201 premature infants (gestational age of 23-32 weeks at birth) discharged home with a persistently patent ductus arteriosus (PDA) and followed their PDA status at 6-month intervals through 18 months of age. The primary study outcome was the rate and timing of spontaneous ductal closure. Secondary outcomes included rate of assisted closure and the incidence of serious adverse events. RESULTS: Spontaneous ductal closure occurred in 95 infants (47%) at 12 months and 117 infants (58%) by 18 months. Seventeen infants (8.4%) received assisted closure with surgical ligation or device assisted occlusion. Three infants died (1.5%). Although infants with spontaneous closure had a higher mean birth weight and gestational age compared with infants with a persistent PDA or assisted closure, we did not identify other factors predictive of spontaneous closure. CONCLUSIONS: Spontaneous closure of the PDA occurred in slightly less than one-half of premature infants discharged with a patent ductus by 1 year, lower than prior published reports. The high rate of assisted closure and/or adverse events in this population warrants close surveillance following discharge. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02750228.

Mild hypoxic-ischemic encephalopathy (HIE): timing and pattern of MRI brain injury.

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a risk factor for neonatal brain injury. We examined the timing and pattern of brain injury in mild HIE. METHODS: This retrospective cohort study includes infants with mild HIE treated at 9 hospitals. Neonatal brain MRIs were scored by 2 reviewers using a validated classification system, with discrepancies resolved by consensus. Severity and timing of MRI brain injury (i.e., acute, subacute, chronic) was scored on the subset of MRIs that were performed at or before 8 days of age. RESULTS: Of 142 infants with mild HIE, 87 (61%) had injury on MRI at median age 5 (IQR 4-6) days. Watershed (23%), deep gray (20%) and punctate white matter (18%) injury were most common. Among the 125 (88%) infants who received a brain MRI at ≤8 days, mild (44%) injury was more common than moderate (11%) or severe (4%) injury. Subacute (37%) lesions were more commonly observed than acute (32%) or chronic lesions (1%). CONCLUSION: Subacute brain injury is common in newborn infants with mild HIE. Novel neuroprotective treatments for mild HIE will ideally target both subacute and acute injury mechanisms. IMPACT: Almost two-thirds of infants with mild HIE have evidence of brain injury on MRI obtained in the early neonatal period. Subacute brain injury was seen in 37% of infants with mild HIE. Neuroprotective treatments for mild HIE will ideally target both acute and subacute injury mechanisms.

Changing Tocolytic Exposures among Neonatal Intensive Care Unit Admitted Preterm Infants.

OBJECTIVE: Since 2010, the American College of Obstetrics and Gynecology have released three committee opinions to recommend and reaffirm the utility of magnesium sulfate for neuroprotection and later for tocolysis to achieve antenatal steroid course completion in preterm labor. We sought to determine changes in antenatal magnesium sulfate exposure and other tocolytic agents for pregnancies resulting in neonatal intensive care unit (NICU)-admitted preterm infants. STUDY DESIGN: Using the Pediatrix Clinical Data Warehouse, we evaluated all inborn infants delivered between 22 and 33 weeks' gestation and admitted to the intensive care units from 2009 to 2018. We classified patients based on antenatal exposure to tocolytic medications: calcium channel blockers (nifedipine and amlodipine), betamimetics (terbutaline, theophylline, and ritodrine), prostaglandin inhibitors (indomethacin), and magnesium sulfate. RESULTS: A total of 229,781 patients met inclusion criteria. During the study period, magnesium sulfate exposure increased from 27.6 to 57.7% of births while betamimetic exposure decreased from 10.2 to 5.2%. Increasing magnesium sulfate exposure over time was seen at all gestational ages examined and magnesium exposure was most common between 23 and 31 weeks' gestation. By 2017 to 2018, 70.5% of 24 to 29 weeks' gestation NICU infants received exposure to at least one tocolytic agent while this remained at 53.7% of 32 to 33 weeks' NICU admitted infants. Antenatal steroid exposure increased from 74.8 to 87.4% during the study period. CONCLUSION: For NICU-admitted preterm infants, prenatal exposure patterns to tocolytic agents has shifted since 2009 with prenatal magnesium sulfate exposure increasing significantly. Antenatal steroid exposure has risen concurrently. Exposure to tocolytic agents is the highest among preterm infants born between 24 and 29 weeks' gestation. KEY POINTS: · Exposure to magnesium sulfate significantly increased from 2009 to 2018 for NICU admitted infants.. · Concurrently, the use of other tocolytics decreased significantly.. · The use of antenatal steroids has been rising over time..

Parental Enrollment Decision-Making for a Neonatal Clinical Trial.

OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. STUDY DESIGN: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. RESULTS: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. CONCLUSIONS: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02811263.

Utilization of Erythropoietin within the United States Neonatal Intensive Care Units from 2008 to 2017.

OBJECTIVE: Little data are available regarding erythropoietin (Epo) utilization patterns within neonatal intensive care units (NICUs). We sought to describe the trends in Epo utilization across a large cohort of U.S. NICUs. STUDY DESIGN: This is a retrospective cohort study of infants discharged from 2008 to 2017 using the Pediatrix Clinical Data Warehouse. RESULTS: We identified 704,159 eligible infants from 358 sites, of whom 9,749 (1.4%) had Epo exposure. For extremely low gestational age newborns (ELGANs), Epo exposure ranged from 7.6 to 13.5%. We found significant site variability in Epo utilization in ELGANs. Among the 299 NICUs caring for ELGANs during the study period, 184 (61.5%) never used Epo for this population, whereas 21 (7%) utilized Epo in 50% or more of eligible infants. Epo was initiated at a median of 25 days in ELGANs. For infants with hypoxic-ischemic encephalopathy (HIE), Epo exposure remained ≤1% through 2014 then increased fourfold to 3.4% by 2017. The median day of Epo initiation was the day of birth for infants diagnosed with HIE. CONCLUSION: Epo is utilized in ELGANs more commonly than for other NICU populations. Utilization patterns appear to indicate the treatment of established anemia for ELGANs and more recently for neuroprotection in patients diagnosed with HIE.

Longitudinal Survey of COVID-19 Burden and Related Policies in U.S. Neonatal Intensive Care Units.

OBJECTIVE: This study aimed to determine the prevalence of confirmed novel coronavirus disease 2019 (COVID-19) disease or infants under investigation among a cohort of U.S. neonatal intensive care units (NICUs). Secondarily, to evaluate hospital policies regarding maternal COVID-19 screening and related to those infants born to mothers under investigation or confirmed to have COVID-19. STUDY DESIGN: Serial cross-sectional surveys of MEDNAX-affiliated NICUs from March 26 to April 3, April 8 to April 19, May 4 to May 22, and July 13 to August 2, 2020. The surveys included questions regarding COVID-19 patient burden and policies regarding infant separation, feeding practices, and universal maternal screening. RESULTS: Among 386 MEDNAX-affiliated NICUs, responses were received from 153 (42%), 160 (44%), 165 (45%), 148 (38%) across four rounds representing an active patient census of 3,465, 3,486, 3,452, and 3,442 NICU admitted patients on the day of survey completion. Confirmed COVID-19 disease in NICU admitted infants was rare, with the prevalence rising from 0.03 (1 patient) to 0.44% (15 patients) across the four survey rounds, while the prevalence of patients under investigation increased from 0.8 to 2.6%. Hospitals isolating infants from COVID-19-positive mothers fell from 46 to 20% between the second and fourth surveys, while centers permitting direct maternal breastfeeding increased 17 to 47% over the same period. Centers reporting universal severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) screening for all expectant mothers increased from 52 to 69%. CONCLUSION: Among a large cohort of NICU infants, the prevalence of infants under investigation or with confirmed neonatal COVID-19 disease was low. Policies regarding universal maternal screening for SARS-CoV-2, infant isolation from positive mothers, and direct maternal breastfeeding for infants born to positive mothers are rapidly evolving. As universal maternal screening for SARS-CoV-2 becomes more common, the impact of these policies requires further investigation. KEY POINTS: · In this cohort, neonatal COVID-19 is rare.. · Policies regarding isolation and breastfeeding for infants are rapidly evolving.. · Most hospitals are now providing universal screening for expectant mothers for SARS-CoV-2..

Factors Associated with Outpatient Therapy Utilization in Extremely Preterm Infants.

OBJECTIVE: Factors influencing utilization of outpatient interventional therapies for extremely low gestational age newborns (ELGANs) after discharge remain poorly characterized, despite a significant risk of neurodevelopmental impairment. We sought to assess the effects of maternal, infant, and environmental characteristics on outpatient therapy utilization in the first 2 years after discharge using data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial. STUDY DESIGN: This is a secondary analysis of 818, 24 to 27 weeks gestation infants enrolled in the PENUT trial who survived through discharge and completed at least one follow-up call or in-person visit between 4 and 24 months of age. Utilization of a state early intervention (EI) program, physical therapy (PT), occupational therapy (OT), and speech therapy (ST) was recorded. Odds ratios and cumulative frequency curves for resource utilization were calculated for patient characteristics adjusting for gestational age, treatment group, and birth weight. RESULTS: EI was not accessed by 37% of infants, and 18% did not use any service (PT/OT/ST/EI). Infants diagnosed with severe morbidities (intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis), discharged with home oxygen, or with gastrostomy placement experienced increased utilization of PT, OT, and ST compared with peers. However, substantial variation in service utilization occurred by the state of enrollment and selected maternal characteristics. CONCLUSIONS: ELGANs with severe medical comorbidities are more likely to utilize services after discharge. Therapy utilization may be impacted by maternal characteristics and state of enrollment. Outpatient therapy services remain significantly underutilized in this high-risk cohort. Further research is required to characterize and optimize the utilization of therapy services following NICU discharge of ELGANs. KEY POINTS: · Outpatient therapy is underutilized in ELGANs.. · Medical comorbidities may impact therapy use.. · Maternal characteristics may impact therapy use.. · State of enrollment may impact therapy use..

The Characteristics and Outcomes of Cardiopulmonary Resuscitation within the Neonatal Intensive Care Unit Based on Gestational Age and Unit Level of Care.

OBJECTIVES: This study aimed to describe the variation of in-neonatal intensive care unit (NICU) cardiopulmonary resuscitation (CPR) characteristics and outcomes across different gestational ages and levels of NICU care. STUDY DESIGN: This is a retrospective cohort study of in-NICU CPR events across 10 NICUs in San Antonio, TX from 2012 through 2017. RESULTS: We identified 140 patients experiencing a total of 210 in-NICU CPR events. CPR was performed in 0.23% of Level III and 0.85% of Level IV NICU admissions. Gestational age was inversely related to CPR incidence. The median age at in-NICU CPR was lower for preterm versus term infants (6 vs. 28 days, p = 0.002). With regression modeling, each added minute of chest compression decreased the odds of return to spontaneous circulation by 11%. CONCLUSION: In-NICU CPR incidence rises with decreasing gestational age and increasing level of NICU care. The rate of return of spontaneous circulation decreases significantly with increasing duration of chest compressions. Further study is needed to identify patient factors associated with adverse outcome.

Two-Year Outcomes of Infants with Stage 2 or Higher Retinopathy of Prematurity: Results from a Large Multicenter Registry.

OBJECTIVE: To define the incidence of ophthalmologic morbidities in the first 2 years of life among infants diagnosed with stage 2 or higher retinopathy of prematurity (ROP). STUDY DESIGN: We prospectively enrolled premature infants with stage 2 or higher ROP. The infants were followed up for 2 years, and we report on data collected from outpatient ophthalmology and primary care visits. RESULTS: We enrolled 323 infants who met inclusion criteria, of which 112 (35%) received treatment with laser surgery (90) or bevacizumab (22). Two-year follow-up was available for 292 (90%) of the cohort. The most common ophthalmologic conditions at follow-up were hyperopia (35%), astigmatism (30%), strabismus (21.9%), myopia (19.2%), anisometropia (12%), and amblyopia (12%). Severe ophthalmologic morbidities such as retinal detachment and cataracts were rare, but occurred in both treated and untreated infants. Overall, 22.6% of the infants were wearing glasses at 2 years, including 8.5% of the untreated infants. CONCLUSION: Patients with stage 2 or higher ROP remain at significant risk for ophthalmological morbidity through 2 years of age. Infants with regression of subthreshold ROP who do not require treatment represent an underrecognized population at long-term ophthalmological risk. CLINICALTRIALS. GOV IDENTIFIER: NCT01559571.

Improved Outcomes in Preterm Infants Fed a Nonacidified Liquid Human Milk Fortifier: A Prospective Randomized Clinical Trial.

OBJECTIVE: To compare growth, feeding tolerance, and clinical and biochemical evaluations in human milk-fed preterm infants randomized to receive either an acidified or a nonacidified liquid human milk fortifier. STUDY DESIGN: This prospective, controlled, parallel, multicenter growth and tolerance study included 164 preterm infants (≤32 weeks of gestation, birth weight 700-1500 g) who were randomized to acidified or nonacidified liquid human milk fortifier from study day 1, the first day of fortification, through study day 29 or until hospital discharge. RESULTS: There was no difference in the primary outcome of weight gain from study days 1 to 29 (acidified liquid human milk fortifier, 16.4 ± 0.4 g/kg/day; nonacidified liquid human milk fortifier, 16.9 ± 0.4 g/kg/day). However, in both the intention-to-treat and the protocol evaluable analyses, infants fed nonacidified liquid human milk fortifier had significantly greater weight gain from study days 1 to 15 (17.9 g/kg/day vs 15.2 g/kg/day; P = .001). Infants fed with acidified liquid human milk fortifier received more protein (4.26 vs g/kg/day 4.11 g/kg/day, P = .0099) yet had lower blood urea nitrogen values (P = .010). The group fed acidified liquid human milk fortifier had more vomiting (10.3% vs 2.4%; P = .018), gastric residuals (12.8% vs 3.7%; P = .022), and metabolic acidosis (27% vs 5%; P < .001) in the intention-to-treat analysis and more abdominal distension (14.0% vs 1.7%; P = .015) in the protocol evaluable analysis. CONCLUSIONS: Infants fed an acidified liquid human milk fortifier had higher rates of metabolic acidosis and poor feeding tolerance compared with infants fed a nonacidified liquid human milk fortifier. Initial weight gain was poorer with the acidified liquid human milk fortifier. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02307760.

Neonatal Intensive Care Unit Resource Use for Infants at 22 Weeks' Gestation in the US, 2008-2021.

Importance: During the past decade, clinical guidance about the provision of intensive care for infants born at 22 weeks' gestation has changed. The impact of these changes on neonatal intensive care unit (NICU) resource utilization is unknown. Objective: To characterize recent trends in NICU resource utilization for infants born at 22 weeks' gestation compared with other extremely preterm infants (≤28 weeks' gestation) and other NICU-admitted infants. Design, Setting, and Participants: This is a serial cross-sectional study of 137 continuously participating NICUs in 29 US states from January 1, 2008, through December 31, 2021. Participants included infants admitted to the NICU. Data analysis was performed from October 2022 to August 2023. Exposures: Year and gestational age at birth. Main Outcomes and Measures: Measures of resource utilization included NICU admissions, NICU bed-days, and ventilator-days. Results: Of 825 112 infants admitted from 2008 to 2021, 60 944 were extremely preterm and 872 (466 [53.4%] male; 18 [2.1%] Asian; 318 [36.5%] Black non-Hispanic; 218 [25.0%] Hispanic; 232 [26.6%] White non-Hispanic; 86 [9.8%] other or unknown) were born at 22 weeks' gestation. NICU admissions at 22 weeks' gestation increased by 388%, from 5.7 per 1000 extremely preterm admissions in 2008 to 2009 to 27.8 per 1000 extremely preterm admissions in 2020 to 2021. The number of NICU admissions remained stable before the publication of updated clinical guidance in 2014 to 2016 and substantially increased thereafter. During the study period, bed-days for infants born at 22 weeks increased by 732%, from 2.5 per 1000 to 20.8 per 1000 extremely preterm NICU bed-days; ventilator-days increased by 946%, from 5.0 per 1000 to 52.3 per 1000 extremely preterm ventilator-days. The proportion of NICUs admitting infants born at 22 weeks increased from 22.6% to 45.3%. Increases in NICU resource utilization during the period were also observed for infants born at less than 22 and at 23 weeks but not for other gestational ages. In 2020 to 2021, infants born at less than or equal to 23 weeks' gestation comprised 1 in 117 NICU admissions, 1 in 34 of all NICU bed-days, and 1 in 6 of all ventilator-days. Conclusions and Relevance: In this serial cross-sectional study of 137 US NICUs from 2008 to 2021, an increasing share of resources in US NICUs was allocated to infants born at 22 weeks' gestation, corresponding with changes in national clinical guidance.

Trends in COVID-19 diagnoses and outcomes in infants hospitalized in the neonatal intensive care unit.

OBJECTIVE: Characterize the prevalence of coronavirus disease 2019 (COVID-19) diagnosis among mothers with infants hospitalized in 294 neonatal intensive care units (NICUs), and demographics and outcomes of infants with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure in utero. STUDY DESIGN: Cohort study of infants discharged from NICUs 01/2020-09/2021. We defined groups based on infant diagnosis, infant testing, and maternal SARS-CoV-2 infection status. We compared demographics, clinical characteristics, and outcomes. RESULTS: Of 150,924 infants, 94% had no COVID-related diagnosis or test; 247 (0.2%) infants tested positive for COVID-19 and were more likely to require mechanical ventilation. Infants with unknown maternal status and negative testing were more commonly premature, outborn, and had longer hospitalizations. CONCLUSION: In this large cohort of hospitalized infants, most had no known exposure to COVID-19. Adverse outcomes and mortality were rare. Further studies are needed to evaluate the long-term effects of COVID-19 in this population.