Gastric Aspirate Phosphatidylcholine Species in Preterm Neonates Receiving Aerosolized Surfactant.

OBJECTIVE: To characterize phosphatidylcholine (PC) molecular species in serial gastric aspirates as biomarkers for lung maturity, delivery of aerosolized surfactant (AS), and need for intubation. METHODS: In a phase II clinical trial of aerosolized surfactant in preterm neonates with respiratory distress syndrome receiving noninvasive ventilation, infants received a maximum of 2 doses of nebulized beractant. Gastric aspirates were collected before and after each dose and were analyzed for PCs using liquid chromatography mass spectrometry. RESULTS: Of 149 infants enrolled, gastric aspirates were obtained before (n = 91) and after (n = 94) dose 1, and before (n = 56) and after (n = 57) dose 2 of nebulized beractant. The mean ± SD values of birthweight, gestational age, and age at collection of baseline gastric aspirate were 1.7 ± 0.6 kg, 31.7 ± 2.8 weeks, and 5.5 ± 1.7 hours, respectively. The most abundant PC in beractant and gastric aspirates was PC(16:0/16:0). Advancing gestational age and number of antenatal corticosteroid doses predicted increased gastric aspirate PC(16:0/16:0), whereas maternal diabetes predicted a decrease. Several PCs increased significantly (P < .05) after nebulized beractant, consistent with effective aerosol delivery. Infants who received intubation within 72 hours of birth were more likely to have lower PC(16:0/16:0) levels in baseline gastric aspirates compared with those who did not (P = .024). CONCLUSIONS: PC molecular species in gastric aspirates of preterm neonates are potentially novel and precise biomarkers to assess lung maturity, aerosol delivery, and need for endotracheal intubation.

Aerosolized Beractant in neonatal respiratory distress syndrome: A randomized fixed-dose parallel-arm phase II trial.

PURPOSE: There is increasing research into novel techniques of administering surfactant to preterm infants (PTIs) with respiratory distress syndrome (RDS) receiving non-invasive respiratory support (NIRS). Although aerosolized surfactant (AS) is promising in PTIs receiving NIRS, the optimal surfactant dose and formulation, drug-device combination and patient profile is not known. The objective of this randomized clinical trial was to investigate the feasibility, safety, efficacy and impact of four dosing schedules of AS using two nebulizers in PTIs with RDS stratified by gestational age (GA). METHODS: PTIs with RDS receiving pre-defined NIRS for ≤8 h were assigned to 4 A S dosing schedules and 2 nebulizers within three GA strata (I = 240/7-286/7, II = 290/7-326/7, III = 330/7-366/7 weeks). There was no contemporaneous control group; at the recommendation of the Data Monitoring Committee, data was collected retrospectively for control infants. RESULTS: Of 149 subjects that received AS, the median age at initiation of the 1st dose and duration was 5.5 and 2.4 h respectively. There were 29 infants in stratum I, and 60 each in strata II and III. Of infants <32 weeks GA, 94% received caffeine prior to AS. Fifteen infants (10%) required intubation within 72 h; the rates were not significantly different between GA strata, dosing schedules and nebulizers for infants who received aerosolized surfactant. Compared to retrospective controls, infants who received AS were less likely to need intubation within 72 h in both the intention-to-treat (32% vs. 11%) and the per-protocol (22% vs. 10%) analyses (p < 0.05) with GA stratum specific differences. AS was well tolerated by infants and clinical caregivers. Commonest adverse events included surfactant reflux from nose and mouth (18%), desaturations (11%), and increased secretions (7%). CONCLUSIONS: We have demonstrated the feasibility, absence of serious adverse events and short-term efficacy of four dosing schedules of AS in the largest Phase II clinical trial of PTIs 24-36 weeks' GA with RDS receiving NIRS (ClinicalTrials.gov NCT02294630). The commonest adverse events noted were surfactant reflux and desaturations; no serious adverse effects were observed. Infants who received AS were less likely to receive intubation within 72 h compared to historical controls. AS is a promising new therapy for PTIs with RDS.

Chronic Inflammatory Placental Lesions Correlate With Bronchopulmonary Dysplasia Severity in Extremely Preterm Infants.

OBJECTIVE: Correlation of BPD with placental pathology is important for clarification of the multifactorial pathogenesis of BPD; however, previous reports have yielded varying results. We report placental findings in no/mild BPD compared to moderate/severe BPD, and with and without pulmonary hypertension (PH). METHODS: Eligible infants were 230/7-276/7 weeks gestational age. BPD was defined by the need for oxygen at ≥28 days with severity based on need for respiratory support at ≥36 weeks. Acute and chronic inflammatory placental lesions and lesions of maternal and fetal vascular malperfusion were examined. RESULTS: Of 246 eligible infants, 146 (59%) developed moderate/severe BPD. Thirty-four (23%) infants developed PH, all but 1 being in the moderate/severe BPD group. Chronic deciduitis (32% vs 16%, P = .003), chronic chorioamnionitis (23% vs 12%, P = .014), and ≥ 2 chronic inflammatory lesions (13% vs 3%, P = .007) were more frequent in the moderate/severe BPD group. Development of PH was associated with placental villous lesions of maternal vascular malperfusion (30% vs 15%, P = .047). CONCLUSIONS: The association of chronic inflammatory placental lesions with BPD severity has not been previously reported. This supports the injury responsible for BPD as beginning before birth in some neonates, possibly related to cytokines associated with these chronic inflammatory lesions.

Pulmonary Hypertension Associated with Hypoxic-Ischemic Encephalopathy-Antecedent Characteristics and Comorbidities.

OBJECTIVE: To determine the characteristics of term infants with persistent pulmonary hypertension of the newborn (PPHN) associated with moderate or severe hypoxic ischemic encephalopathy (HIE). METHODS: We compared infants with and without PPHN enrolled in 2 randomized trials of therapeutic hypothermia: the induced hypothermia trial of cooling to 33.5°C for 72 hours vs normothermia, and the "usual-care" arm (33.5°C for 72 hours) of the optimizing cooling trial. RESULTS: Among 303 infants with HIE from these 2 studies, 67 (22%) had PPHN and 236 (78%) did not. We compared infants with PPHN with those without PPHN. The proportion of patients treated with therapeutic hypothermia was similar in PPHN and no-PPHN groups (66% vs 65%). Medication use during resuscitation (58% vs 44%), acidosis after birth (pH: 7.0 ± 0.2 vs 7.1 ± 0.2), severe HIE (43% vs 28%), meconium aspiration syndrome (39% vs 7%), pulmonary hemorrhage (12% vs 3%), culture-positive sepsis (12% vs 3%), systemic hypotension (65% vs 28%), inhaled nitric oxide therapy (64% vs 3%), and extracorporeal membrane oxygenation (12% vs 0%) were more common in the PPHN group. Length of stay (26 ± 21 vs 16 ± 14 days) and mortality (27% vs 16%) were higher in the PPHN group. CONCLUSIONS: PPHN is common among infants with moderate/severe HIE and is associated with severe encephalopathy, lung disease, sepsis, systemic hypotension, and increased mortality. The prevalence of PPHN was not different between those infants receiving therapeutic hypothermia at 33.5°C in these 2 trials (44/197 = 22%) compared with infants receiving normothermia in the induced hypothermia trial (23/106 = 22%).

Antenatal magnesium sulfate exposure and acute cardiorespiratory events in preterm infants.

OBJECTIVE: Antenatal magnesium (anteMg) is used for various obstetric indications including fetal neuroprotection. Infants exposed to anteMg may be at risk for respiratory depression and delivery room (DR) resuscitation. The study objective was to compare the risk of acute cardiorespiratory events among preterm infants who were and were not exposed to anteMg. STUDY DESIGN: This was a retrospective analysis of prospective data collected in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Generic Database from April 1, 2011, through March 31, 2012. The primary outcome was DR intubation or respiratory support at birth or on day 1 of life. Secondary outcomes were invasive mechanical ventilation, hypotension treatment, neonatal morbidities, and mortality. Logistic regression analysis evaluated the risk of primary outcome after adjustment for covariates. RESULTS: We evaluated 1544 infants <29 weeks' gestational age (1091 in anteMg group and 453 in nonexposed group). Mothers in the anteMg group were more likely to have higher education, pregnancy-induced hypertension, and antenatal corticosteroids, while their infants were younger in gestation and weighed less (P < .05). The primary outcome (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.88-1.65) was similar between groups. Hypotension treatment (OR, 0.70; 95% CI, 0.51-0.97) and invasive mechanical ventilation (OR, 0.54; 95% CI, 0.41-0.72) were significantly less in the anteMg group. CONCLUSION: Among preterm infants age <29 weeks' gestation, anteMg exposure was not associated with an increase in cardiorespiratory events in the early newborn period. The safety of anteMg as measured by the need for DR intubation or respiratory support on day 1 of life was comparable between groups.

Screening Cranial Imaging at Multiple Time Points Improves Cystic Periventricular Leukomalacia Detection.

OBJECTIVE: The aim of this study is to determine whether the cystic periventricular leukomalacia (cPVL) detection rate differs between imaging studies performed at different time points. DESIGN: We retrospectively reviewed the prospectively collected data of 31,708 infants from the NICHD Neonatal Research Network. Inclusion criteria were infants < 1,000 g birth weight or < 29 weeks' gestational age who had cranial imaging performed using both early criterion (cranial ultrasound [CUS] < 28 days chronological age) and late criterion (CUS, magnetic resonance imaging, or computed tomography closest to 36 weeks postmenstrual age [PMA]). We compared the frequency of cPVL diagnosed by early and late criteria. RESULTS: About 664 (5.2%) of the 12,739 infants who met inclusion criteria had cPVL using either early or late criteria; 569 using the late criterion, 250 using the early criterion, and 155 patients at both times. About 95 (14.3%) of 664 cPVL cases seen on early imaging were no longer visible on repeat screening closest to 36 weeks PMA. Such disappearance of cPVL was more common in infants < 26 weeks' gestation versus infants of 26 to 28 weeks' gestation (18.5 vs. 11.5%; p = 0.013). CONCLUSIONS: Cranial imaging at both < 28 days chronological age and closest to 36 weeks PMA improves cPVL detection, especially for more premature infants.

Target ranges of oxygen saturation in extremely preterm infants.

BACKGROUND: Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. METHODS: We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. RESULTS: The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. CONCLUSIONS: A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

Early CPAP versus surfactant in extremely preterm infants.

BACKGROUND: There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS: We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS: A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS: The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

MicroRNA dysregulation in the heart and lung of infants with bronchopulmonary dysplasia.

BACKGROUND AND OBJECTIVES: Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth, resulting in significant morbidity and mortality. Recent studies have suggested that microRNA (miRNA) dysregulation is involved in the pathogenesis of BPD and may serve as biomarkers for early detection. We conducted a directed search for dysregulated miRNAs in lung and heart autopsy samples of infants with histologic BPD. METHODS: We used archived lung and heart samples from BPD (13 lung, 6 heart) and control (24 lung, 5 heart) subjects. To measure miRNA expression, RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue specimens then reverse-transcribed, labeled, and hybridized to miRNA microarrays. The microarrays were scanned, and data were quantile normalized. Statistical analysis with a moderated t-test and control of the false discovery rate (5%) was used to compare normalized miRNA expression values between clinical categories. RESULTS: With our set of 48 samples, 43 miRNAs had a significant difference in expression comparing BPD to non-BPD controls. Among the most statistically significant miRNAs, miR-378b, miRNA-184, miRNA-3667-5p, miRNA-3976, miRNA-4646-5p, and miRNA-7846-3p were all consistently upregulated in both the heart and lung tissues of BPD subjects. The cellular pathway predicted to be most affected by these miRNAs is the Hippo signaling pathway. CONCLUSIONS: This study identifies miRNAs that are similarly dysregulated in postmortem lung and heart samples in subjects with histologic BPD. These miRNAs may contribute to the pathogenesis of BPD, have potential as biomarkers, and may provide insight to novel approaches for diagnosis and treatment.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS).

Importance: Preterm 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. Objective: To 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 Participants: This 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. Interventions: Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures: Primary 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 <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results: A 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 Relevance: In 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 Registration: ClinicalTrials.gov Identifier: NCT01702805.

Cytokine profiles of preterm neonates with fungal and bacterial sepsis.

BACKGROUND: Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight (ELBW) infants, is lacking. We hypothesized that cytokine profiles in the first 21 d of life in ELBW infants with FS differ from those with bacterial sepsis (BS) or no sepsis (NS). METHODS: In a secondary analysis of the National Institute of Child Health and Human Development Cytokine study, three groups were defined-FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3 ± 1, 7 ± 2, 14 ± 3, and 21 ± 3 and sepsis group was explored. RESULTS: Of 1,066 infants, 89 had FS and 368 had BS. As compared with BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (P < 0.05). Analyses controlling for covariates showed significant group differences over time for interferon-γ (IFN-γ), interleukin (IL)-10, IL-18, transforming growth factor-ß (TGF-ß), and tumor necrosis factor-α (TNF-α) (P < 0.05). CONCLUSION: Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-ß, and TNF-α in FS, BS, or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.

Aerosol delivery during high frequency jet ventilation: an MRI evaluation.

BACKGROUND: We have previously demonstrated aerosol delivery during conventional and high frequency oscillatory (HFOV) ventilation using magnetic resonance imaging (MRI) in piglets. There are no reports on aerosol delivery during high frequency jet ventilation (HFJV). OBJECTIVE: To compare delivery of aerosolized gadopentetate dimeglumine (Gd-DTPA) in 3 neonatal ventilator circuits: conventional mechanical ventilation, HFOV, and HFJV. METHODS: Aerosols of Gd-DTPA (0.025 mol/L) generated using a jet nebulizer placed in the inspiratory limb of each ventilator were delivered into an in vitro lung model simultaneously. Multi-slice T1-weighted spin-echo sequence scans were obtained prior to and after 10 and 20 min of cumulative aerosol delivery. Gd-DTPA concentration was calculated from signal intensity changes, and the total amount of Gd-DTPA was estimated. RESULTS: Gd-DTPA was visualized in the lung model at 10 and 20 min for all 3 ventilators. Gd-DTPA delivery was highest with conventional mechanical ventilation (1.92 µmol at 10 min, 2.89 µmol at 20 min), followed by HFJV (1.59 µmol at 10 min, 1.98 µmol at 20 min) and HFOV (0.79 µmol at 10 min, 1.00 µmol at 20 min). CONCLUSIONS: This is the first report of effective aerosol delivery in a neonatal HFJV circuit. Future studies are needed for more accurate quantification of aerosol deposition.

Early histological changes of bronchopulmonary dysplasia and pulmonary hypertension may precede clinical diagnosis in preterm infants.

Bronchopulmonary Dysplasia (BPD), the commonest complication of prematurity, is defined by treatment with oxygen for ≥28 days. Pulmonary hypertension (PH) often coexists with BPD and is associated with increased mortality. In 42 autopsies, histological changes of BPD and PH were demonstrated in 25 % and 65 % respectively of preterm infants <28 days of age, highlighting the need for early diagnosis and treatment.

Considerations in the Determination of Medical Necessity in Children: Application to Contractual Language.

Through this policy statement, the American Academy of Pediatrics advocates that all health care insurers adopt consistent medical necessity definitions that reflect the needs of infants, children, adolescents, and young adults (hereafter noted as "children") as a function of developmental, epidemiologic, dependency, demographic, and cost-related factors that change over the pediatric continuum and that differ from adults. Optimally, the scope of benefits defined in health care contracts should address the complete spectrum of health care needs of children and families, but in reality, many plans offer a limited scope of benefits for children. Even if a proposed intervention falls within the scope of benefits or is not specifically excluded from coverage, the health plan may still deny the intervention. In such cases, contractual language may allow an appeal to succeed if the provider demonstrates medical necessity. With the assistance of experienced pediatric physicians and other providers with pediatric expertise, health care payers and agencies should clearly detail the processes that define, evaluate, and determine medical necessity and through which providers may appeal decisions. A basic requirement for any medical necessity process is the consideration of input from the physician(s) caring for a pediatric patient for whom a medical necessity determination is necessary.

Expression of eNOS in the lungs of neonates with pulmonary hypertension.

BACKGROUND: Neonatal hypoxemic respiratory failure (NHRF) is usually associated with reversible persistent pulmonary hypertension (PPHN). Congenital diaphragmatic hernia (CDH), a cause of refractory NHRF, is associated with irreversible pulmonary hypertension. Nitric oxide (NO) generated in the pulmonary vascular endothelium by endothelial nitric oxide synthase (eNOS) plays a pivotal role in perinatal circulatory adaptation. OBJECTIVE: To compare the expression of eNOS using IHC in postmortem lung tissue from newborns diagnosed clinically with PPHN and CDH. DESIGN/METHODS: Formalin-fixed lung tissue from infants who died following treatment for PPHN (n=12) or CDH (n=8) and age and gender matched controls who died from non-respiratory causes (Control, n=14) was evaluated for expression and staining intensity (1-4 scale) of eNOS using IHC. RESULTS: Mean gestational and postnatal age was comparable across groups. Histological evidence of chronic lung disease, pulmonary hypoplasia and pulmonary hypertension were seen more frequently in CDH compared to PPHN and control infants. eNOS expression was increased in arteriolar media of PPHN infants compared to Controls (p=0.027). CDH infants had increased intensity of staining for eNOS in the arteriolar endothelium (p=0.022) compared to control and PPHN infants and in the alveolar lining (p=0.002) compared to Controls. CONCLUSIONS: Upregulation of eNOS was seen both in infants with CDH and PPHN but was more marked in infants with CDH. These findings may have implications for understanding disease pathophysiology in cases with fatal outcome and development of novel therapies for neonatal pulmonary hypertension.

Changes in Clinical Care of the Newborn During COVID-19 Pandemic: From the Womb to First Newborn Visit.

COVID-19 has afflicted the health of children and women across all age groups. Since the outbreak of the pandemic in December 2019, various epidemiologic, immunologic, clinical, and pharmaceutical studies have been conducted to understand its infectious characteristics, pathogenesis, and clinical profile. COVID-19 affects pregnant women more seriously than nonpregnant women, endangering the health of the newborn. Changes have been implemented to guidelines for antenatal care of pregnant women, delivery, and newborn care. We highlight the current trends of clinical care in pregnant women and newborns during the COVID-19 pandemic.

Perinatal systemic inflammatory response syndrome and retinopathy of prematurity.

Fetal and neonatal inflammation is associated with several morbidities of prematurity. Its relationship to retinopathy of prematurity (ROP) has not been investigated. Our objective was to determine the relationship between cytokine levels and ROP in the first 3 postnatal wks. Data for this study were derived from the NICHD Cytokine Study. Dried blood spots (DBS) were obtained from infants <1000 g on days 0-1, 3 +/- 1, 7 +/- 2, 14 +/- 3, and 21 +/- 3. Infants were classified into three groups-no, mild, and severe ROP. Multiplex Luminex assay was used to quantify 20 cytokines. Temporal profiles of cytokines were evaluated using mixed-effects models after controlling for covariates. Of 1074 infants enrolled, 890 were examined for ROP and 877 included in the analysis. ROP was associated with several clinical characteristics on unadjusted analyses. Eight cytokines remained significantly different across ROP groups in adjusted analyses. IL-6 and IL-17 showed significant effects in early time periods (D0-3); TGF-beta, brain-derived neurotrophic factor (BDNF), and regulated on activation, normal T cell expressed and secreted (RANTES) in later time periods (D7-21) and IL-18, C-reactive protein (CRP), and neurotrophin-4 (NT-4) in both early and later time periods. We conclude that perinatal inflammation may be involved in the pathogenesis of ROP.

Effective aerosol delivery during high-frequency ventilation in neonatal pigs.

BACKGROUND AND OBJECTIVE: Pulmonary delivery of aerosols during high-frequency oscillatory ventilation (HFOV) has not been studied in vivo. This study investigated the pulmonary delivery of aerosolized gadopentetate dimeglumine (Gd-DTPA) in a HFOV circuit in piglets using MRI to visualize contrast excretion in the kidneys. METHODS: Four ventilated piglets (3-7 days old, 1.7-2.4 kg at birth) received aerosolized Gd-DTPA in a HFOV circuit for different durations of time (60, 30, 20 and 10 min). Aerosols were generated using the MiniHeart jet nebulizer. As MR-compatible HFOV was not available, aerosolized Gd-DTPA was administered in the HFOV circuit outside the MR suite followed by MRI 10-20 min later. T1-weighted spin echo sequences were obtained using the Bruker/Siemens 4T MR scanner. RESULTS: Enhancement of the kidneys was observed 10 min after aerosol initiation in piglets who received Gd-DTPA aerosol for 60, 30 and 20 min in the HFOV circuit but not in the piglet who received aerosol for 10 min. Renal concentration of Gd-DTPA, determined from the signal intensity, increased linearly with time until 40 min post Gd-DTPA delivery. CONCLUSIONS: Effective pulmonary aerosol delivery during HFOV was confirmed by contrast visualization in the kidneys within 30 min of aerosol initiation reflecting, alveolar absorption, glomerular filtration and renal concentration.

Early prediction of moderate to severe bronchopulmonary dysplasia in extremely premature infants.

BACKGROUND: Bronchopulmonary Dysplasia (BPD) is the commonest morbidity in extremely preterm infants (PTIs). Risk factors for BPD have been described in the era before the widespread availability of non-invasive ventilation (NIV) in the delivery room (DR). The objective of this study is to identify risk factors for Moderate/Severe BPD in an era of widespread availability of NIV in the DR. METHODS: Detailed antenatal and postnatal data were abstracted for PTIs, 230/7-276/7 weeks GA. Multivariate logistic regression and classification and regression tree analyses (CART) identified predictors for the primary outcome of Moderate/Severe BPD. RESULTS: Of 263 eligible infants, 59% had Moderate/Severe BPD. Moderate/Severe BPD was significantly associated with birthweight, gender, DR intubation and surfactant compared to No/Mild BPD. Of infants not intubated in the DR, 40% with No/Mild BPD and 80% with Moderate/Severe BPD received intubation by 48 hours (p < 0.05). Infants with Moderate/Severe BPD received longer duration of oxygen and mechanical (MV). On logistic regression, birthweight, gender, oxygen concentration, cumulative duration of oxygen and MV, surfactant, and blood transfusions predicted Moderate/Severe BPD. Both CART analysis and logistic regression showed duration of oxygen and MV to be the most important predictors for Moderate/Severe BPD. CONCLUSIONS: In an era of increasing availability of NIV in the DR, lower birthweight, male gender, surfactant treatment, blood transfusions and respiratory support in the first 2-3 weeks after birth predict Moderate/Severe BPD with high sensitivity and specificity. The majority of these infants received intubation within 48 hours of birth (97%). These data suggest that early failures of NIV represent opportunities for improvement of NIV techniques and of non-invasive surfactant to avoid intubation in the first 48 hours. Furthermore, these risk factors may allow earlier identification of infants most likely to benefit from interventions to prevent or decrease severity of BPD.

Effect of aerosolized PGE(1) on the ductus arteriosus of neonatal swine.

BACKGROUND: Inhaled PGE(1) (IPGE(1)) is a potential pulmonary vasodilator in neonatal respiratory failure. However, its effect on the patency of the ductus arteriosus (DA) has not been described. OBJECTIVE: To investigate the effect of IPGE(1) on the DA in healthy piglets. DESIGN/METHODS: IPGE(1) (1200ng/kg/min) [Study] or nebulized saline [Control] was administered using a jet nebulizer. Transthoracic echocardiography (TTE) was performed prior to (T0) and after 24h of aerosol therapy (T24). The DA was also evaluated histomorphologically at autopsy. RESULTS: Fifteen piglets, 1-9 days old (study=9; control=6), were evaluated for DA patency. Study piglets received IPGE(1) for 12-24h. TTE was performed on 12 piglets at T0. Nine animals showed no ductal flow and 3 (1 study, 2 control) had a small DA. TTE at T24 in 5 animals showed no change in DA. At autopsy, the ductal diameter and histologic maturity stage were comparable in study and control animals. CONCLUSIONS: High dose IPGE(1) given for 12-24h does not exert significant effect on the DA of healthy term piglets as evaluated by echocardiography and histomorphology. We conclude that ductal patency in neonates is influenced not only by prostaglandins but also by factors like hypoxemia, prematurity, and heart disease.