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Background: Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 240/7–276/7 weeks’ gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation. Methods: This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24–276/7 weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO2 ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks’ postmenstrual age, discharge, death, or transfer. Discussion: The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites. Trial registration: , trial identifier , registered July 6, 2022. [ABSTRACT FROM AUTHOR]

Objectives: Inhaled nitric oxide (iNO) is an effective pulmonary vasodilator. However, the efficacy of iNO in former premature infants with established bronchopulmonary dysplasia (BPD) has not been studied. This study aimed to determine the efficacy of iNO in reducing pulmonary artery pressure in infants with severe BPD as measured by echocardiography. Study Design: Prospective, observational study enrolling infants born at less than 32 weeks gestation and in whom (1) iNO therapy was initiated after admission to our institution, or (2) at the outside institution less than 48 h before transfer and received an echocardiogram prior to iNO initiation, and (3) had severe BPD. Data were collected at three time-points: (1) before iNO; (2) 12–48 h after initiation of iNO; and (3) 48–168 h after initiation of iNO. The primary outcome was the effect of iNO on pulmonary artery pressure measured by echocardiography in patients with severe BPD between 48 and 168 h after initiating iNO therapy. Results: Of 37 enrolled, 81% had echocardiographic evidence of pulmonary arterial hypertension (PAH) before iNO and 56% after 48 h of iNO (p = 0.04). FiO2 requirements were significantly different between time-points (1) and (3) (p = 0.05). There were no significant differences between Tricuspid Annular Plane Systolic Excursion (TAPSE) Z-Scores, time to peak velocity: right ventricular ejection time (TPV:RVET), and ventilator changes. Conclusions: Although we found a statistically significant reduction of PAH between time-point (1) and (3), future trials are needed to further guide clinical care. [ABSTRACT FROM AUTHOR]

Introduction: The early acute phase of the coronavirus disease 2019 pandemic created rapid adaptation in health care delivery. Methods: Using electronic medical record data from two different institutions located in two different states, we examined how telemedicine was integrated into obstetric care. Results: With no telemedicine use prior, both institutions rapidly incorporated telemedicine into prenatal care (PNC). There were significant patient-level and institutional-level differences in telemedicine use. Telemedicine users initiated PNC earlier and had more total visits, earlier timing of ultrasounds, and earlier diabetes screening during pregnancy compared with nonusers. There were no significant differences in delivery mode or stillbirth associated with telemedicine use at either institution. Conclusions: Rapid adoption of obstetric telemedicine maintained adequate prenatal care provision during the early pandemic, but implementation varied across institutions. [ABSTRACT FROM AUTHOR]

Background The antibiotic use rate (AUR) has emerged as a potential metric for neonatal antibiotic use, but reported center-level AURs are limited by differences in case mix. The objective of this study was to identify patient characteristics associated with AUR among a large cohort of preterm infants. Methods Retrospective observational study using the Optum Neonatal Database, including infants born from January 1, 2010 through November 30, 2016 with gestational age 23–34 weeks admitted to neonatal units across the United States. Exposures were patient-level characteristics including length of stay, gestational age, sex, race/ethnicity, bacterial sepsis, necrotizing enterocolitis, and survival status. The primary outcome was AUR, defined as days with ≥ 1 systemic antibiotic administered divided by length of stay. Descriptive statistics, univariable comparative analyses, and generalized linear models were utilized. Results Of 17 910 eligible infants, 17 836 infants (99.6%) from 1090 centers were included. Median gestation was 32.9 (interquartile range [IQR], 30.3–34) weeks. Median length of stay was 25 (IQR, 15–46) days and varied by gestation. Overall median AUR was 0.13 (IQR, 0–0.26) and decreased over time. Gestational age, sex, and race/ethnicity were independently associated with AUR (P   <  .01). AUR and gestational age had an unexpected inverse parabolic relationship, which persisted when only surviving infants without bacterial sepsis or necrotizing enterocolitis were analyzed. Conclusions Neonatal AURs are influenced by patient-level characteristics besides infection and survival status, including gestational age, sex, and race/ethnicity. Neonatal antibiotic use metrics that account for patient-level characteristics as well as morbidity case mix may allow for more accurate comparisons and better inform neonatal antibiotic stewardship efforts. [ABSTRACT FROM AUTHOR]

Objective: Compare rates of hypoxaemia during transpyloric and gastric feedings in very preterm infants with severe bronchopulmonary dysplasia.Design: N-of-1 multiple crossover trials with individual patient and pooled data analyses.Setting: Level IV intensive care nursery.Patients: Infants receiving positive airway pressure between 36 and 55 weeks postmenstrual age were enrolled between December 2014-July 2016.Intervention: N-of-1 trial consisting of two blocks, each with a 4-day gastric and 4-day transpyloric feeding period assigned in random order.Main Outcome Measures: The primary outcome was the frequency of daily intermittent hypoxaemic events (SpO2 ≤80% lasting 10-180 s). Secondary outcomes included the daily proportion of time with an SpO2 ≤80% and mean daily fraction of inspired oxygen.Results: Of 15 infants, 13 completed the trial and 2 stopped early for transient worsening in respiratory status during gastric feedings. In the intention-to-treat analyses, transpyloric feedings resulted in increased rates of intermittent hypoxaemia in five infants, greater time per day in hypoxaemia in three infants and more supplemental oxygen use in three infants. One infant received more supplemental oxygen during gastric feedings. The remaining study outcomes were similar between the feeding routes in all other infants. Pooling all data, transpyloric feedings resulted in a higher frequency of intermittent hypoxaemic events (median 7.5/day (IQR 1-23.5) vs 3/day (1-11); adjusted incidence rate ratio 1.8, 95% CI 1.3 to 2.5) and a greater proportion of daily hypoxaemia time (median 0.8% (IQR 0.1-2.3) vs 0.4% (0.07-1.8); adjusted mean difference 1.6, 95% CI 1.1 to 2.5).Conclusions: Transpyloric compared with gastric feedings modestly increased rates of hypoxaemia among study participants.Trial Registration Number: NCT02142621. [ABSTRACT FROM AUTHOR]

Rationale: Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately predict childhood morbidity.Objectives: To determine which of 18 prespecified, revised definitions of bronchopulmonary dysplasia that variably define disease severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks' postmenstrual age best predicts death or serious respiratory morbidity through 18-26 months' corrected age.Methods: We assessed infants born at less than 32 weeks of gestation between 2011 and 2015 at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.Measurements and Main Results: Of 2,677 infants, 683 (26%) died or developed serious respiratory morbidity. The diagnostic criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks' postmenstrual age, regardless of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (n = 773); grade 1, nasal cannula ≤2 L/min (n = 1,038); grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure (n = 617); and grade 3, invasive mechanical ventilation (n = 249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33-79%) was observed for death or neurodevelopmental impairment.Conclusions: The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks' postmenstrual age, regardless of supplemental oxygen use. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to determine the accuracy and validity of the Ultrasonic Cardiac Output Monitor (USCOM) measurements of cardiac output (CO) compared to echocardiography in newborn infants, and the inter-rater agreement of USCOM measurements. Methods: In a single-center study we prospectively evaluated neonates undergoing an echocardiographic evaluation. USCOM measurements of CO were obtained at the pulmonary and aortic valve by 2 physicians blinded to the echocardiographic results. All echocardiographic measurements were performed blinded to USCOM measurements. We first enrolled an ascertainment cohort which was subsequently validated in an independent new cohort. Agreement between echocardiography and USCOM methods was assessed by Bland-Altman analysis. Intra-class correlation coefficients (ICC) assessed the agreement between the 2 operators. The ascertainment cohort correction factors were applied in a second validation cohort and agreement of the calibrated measures evaluated with repeat Bland-Altman comparisons. Results: A total of 50 infants were enrolled in the initial cohort and 15 in the validation cohort. There was a high degree of correlation between the USCOM operators (ICC = 0.975). USCOM measurements of CO were significantly higher compared to echocardiography (left ventricular output bias 95 ± 52 mL/kg/min and right ventricular output bias 64 ± 30 mL/kg/min). There was no difference in the subgroup of infants with and without a ductus arteriosus. After the correction was applied to the validation cohort, there was no longer a significant difference between the measures. Conclusions: CO measured by USCOM consistently overestimated the results obtained from echocardiography. USCOM is not adequate to provide absolute estimates of CO. However, it may allow longitudinal hemodynamic assessment of sick neonates. [ABSTRACT FROM AUTHOR]

Objective: To characterise the excess risk for death, grade 3-4 intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD) and stage 3-5 retinopathy of prematurity independently associated with birth small for gestational age (SGA) among very preterm infants, stratified by completed weeks of gestation.Methods: Retrospective cohort study using the Optum Neonatal Database. Study infants were born <32 weeks gestation without severe congenital anomalies. SGA was defined as a birth weight <10th percentile. The excess outcome risk independently associated with SGA birth among SGA babies was assessed using adjusted risk differences (aRDs).Results: Of 6708 infants sampled from 717 US hospitals, 743 (11.1%) were SGA. SGA compared with non-SGA infants experienced higher unadjusted rates of each study outcome except grade 3-4 IVH among survivors. The excess risk independently associated with SGA birth varied by outcome and gestational age. The highest aRD for death (0.27; 95% CI 0.13 to 0.40) occurred among infants born at 24 weeks gestation and declined as gestational age increased. In contrast, the peak aRDs for BPD among survivors (0.32; 95% CI 0.20 to 0.44) and the composites of death or BPD (0.35; 95% CI 0.24 to 0.46) and death or major morbidity (0.35; 95% CI 0.24 to 0.45) occurred at 27 weeks gestation. The risk-adjusted probability of dying or developing one or more of the evaluated morbidities among SGA infants was similar to that of non-SGA infants born approximately 2-3 weeks less mature.Conclusion: The excess risk for neonatal morbidity and mortality associated with being born SGA varies by adverse outcome and gestational age. [ABSTRACT FROM AUTHOR]

Key points: Bronchopulmonary dysplasia is a disease of extreme prematurity that occurs when the immature lung is exposed to gas ventilation. We designed a novel ‘artificial womb’ system for supporting extreme premature lambs (called EXTEND) that obviates gas ventilation by providing oxygen via a pumpless arteriovenous circuit with the lamb submerged in sterile artificial amniotic fluid. In the present study, we compare different arteriovenous cannulation strategies on EXTEND, including carotid artery/jugular vein (CA/JV), carotid artery/umbilical vein (CA/UV) and umbilical artery/umbilical vein (UA/UV). Compared to CA/JV and CA/UV cannulation, UA/UV cannulation provided significantly higher, physiological blood flows to the oxygenator, minimized flow interruptions and supported significantly longer circuit runs (up to 4 weeks). Physiological circuit blood flow in UA/UV lambs made possible normal levels of oxygen delivery, which is a critical step toward the clinical application of artificial womb technology. Abstract: EXTEND (EXTra‐uterine Environment for Neonatal Development) is a novel system that promotes physiological development by maintaining the premature lamb in a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit. During the development of EXTEND, different cannulation strategies evolved with the aim of improving circuit flow. The present study examines how different cannulation strategies affect EXTEND circuit haemodynamics in extreme premature lambs. Seventeen premature lambs were cannulated at gestational ages 105–117 days (term 145–150 days) and supported on EXTEND for up to 4 weeks. Experimental groups were distinguished by cannulation strategy: carotid artery outflow and jugular vein inflow (CA/JV; n = 4), carotid artery outflow and umbilical vein inflow (CA/UV; n = 5) and double umbilical artery outflow and umbilical vein inflow (UA/UV; n = 8). Circuit flows and pressures were measured continuously. As we transitioned from CA/JV to CA/UV to UA/UV cannulation, mean duration of circuit run and weight‐adjusted circuit flows increased (P < 0.001) and the frequency of flow interruptions declined (P < 0.05). Umbilical vessels generally accommodated larger‐bore cannulas, and cannula calibre was directly correlated with circuit pressures and indirectly correlated with flow:pressure ratio (a measure of post‐membrane resistance). We conclude that UA/UV cannulation in fetal lambs on EXTEND optimizes circuit flow dynamics and flow stability and also supports circuit flows that closely approximate normal placental flow. [ABSTRACT FROM AUTHOR]

Objective We compared the accuracy of serum intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and phosphate (phos) levels for diagnosing severe metabolic bone disease (MBD) in very low-birth-weight (VLBW) infants with severe bronchopulmonary dysplasia (BPD). Study Design Retrospective analysis of VLBW infants with severe BPD admitted between 2010 and 2012 and with ≥ 1 iPTH, ALP, and phos level collected within a similar 72-hour period. MBD severity was classified by serial radiography. Results Laboratory values were available for 65 infants, of whom 24 (36.9%) developed severe MBD. A maximum ALP > 660 IU/L was the most accurate for diagnosing severe MBD (area under the curve: 88.4%; 95% confidence interval [CI]: 77.2-94.5%). Maximum iPTH was the least accurate (optimal cut point > 130 pg/mL; area under the curve: 70.5%; 95% CI: 58.2-81.4). Conclusion Maximum ALP was more accurate than iPTH or phos for diagnosing severe MBD among preterm infants with severe BPD. [ABSTRACT FROM AUTHOR]

Objective Bacterial colonization of the airway may contribute to the development of bronchopulmonary dysplasia. Whether airway colonization increases risk for later adverse respiratory outcomes is less clear. We described tracheal aspirate culture results obtained from preterm infants receiving mechanical ventilation at 36 weeks postmenstrual age (PMA) and evaluated the association between bacteria type and the risk for prolonged supplemental oxygen use. Study Design We conducted a retrospective, single-center cohort study comparing infants (1) with and without a tracheal aspirate culture that grew a Gram-negative rod (GNR) and (2) with and without a culture that grew a Gram-positive cocci (GPC). Results Among 121 infants, 65 (53.7%) and 51 (42.2%) had a tracheal aspirate culture that grew a potentially pathogenic GNR and GPC prior to 36 weeks PMA, respectively. GNR were associated with increased risk for death or use of supplemental oxygen at discharge (adjusted odds ratio [aOR], 6.2; 95% confidence interval [CI], 1.8-21.1), and use of supplemental oxygen at discharge among survivors (aOR, 5.5; 95% CI, 1.6-19.0). GPC did not affect the risk for any study outcomes. Conclusion GNR but not GPC in the airways of preterm infants receiving mechanical ventilation at 36 weeks PMA is associated with increased risk for prolonged supplemental oxygen use. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in very low-birth-weight (VLBW) infants managed successfully on continuous positive airway pressure (CPAP) versus mechanical ventilation on the first day of life (DOL). Study Design This is a retrospective analysis of the Alere neonatal database for infants born between January 2009 and December 2014, weighing ≤ 1,500 g. Baseline demographics, clinical characteristics, and outcomes were compared between the two groups. Multivariable regression analysis was performed to control the variables that differ in bivariate analysis. Results In this study, 4,629 infants (birth weight 1,034 ± 290 g, gestational age 28.1 ± 2.5 weeks) met the inclusion criteria. The successful use of early CPAP was associated with a significant reduction in BPD or death (p < 0.001), as well as days to room air, decreased oxygen use at discharge, lower risk for severe intraventricular hemorrhage, and patent ductus arteriosus requiring surgical ligation (p < 0.001 for all outcomes). Conclusion Successful use of early CPAP on the first DOL in VLBW infants is associated with a reduced risk of BPD or death. [ABSTRACT FROM AUTHOR]

More than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS. Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine. Large, urban, tertiary care hospital. Twenty-four term infants requiring pharmacological treatment for NAS. Outcomes were neonatal safety, length of treatment and length of hospitalization. Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of treatment compared to 38 days for those treated with morphine ( P = 0.01), representing a 40% reduction. Length of hospital stay in the buprenorphine group was reduced 24%, from 42 to 32 days ( P = 0.05). Sublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine. [ABSTRACT FROM AUTHOR]

We compared survival and outcomes in process of care in female versus male infants born <=32 weeks gestational age (GA). Data were obtained from the Alere database for infants born <=32 weeks GA. Females were compared with males for demographics, complications, and care processes. Univariate and multivariate analysis was conducted using chi-square analysis, analysis of variance, or logistic regression. Of the infants included, 6086 female and 6721 males were included. Mean GA did not differ, males were born larger than females, and females were more likely to be born SGA. Males received more surfactant, developed more CLD, received more steroids, and more often required oxygen at discharge. Females were more likely to develop a patent ductus arteriosus. After controlling for body weight, GA, and small-for-GA status, females were more likely to survive (95.4% versus 93.6%, odds ratio 1.63, P < 0.01). Male sex did not play a role in other processes of care except for weaning to a crib. Male infants born <=32 weeks GA have a decreased rate of survival and an increased rate of respiratory morbidity in spite of higher birth weight distributions. Sex did not play a role in other processes of care. [ABSTRACT FROM AUTHOR]

Objective: To report 3 patients who developed anti-N-methyl-D-aspartate receptor encephalitis during pregnancy. Design: Case reports. Setting: University hospitals. Patients: Three young women developed at 14, 8, and 17 weeks of gestation acute change of behavior, prominent psychiatric symptoms, progressive decrease of consciousness, seizures, dyskinesias, and autonomic dysfunction. Main Outcome Measures: Clinical, radiological, and immunological findings. Results: The 3 patients had cerebrospinal fluid pleocytosis, normal magnetic resonance imaging, and electroencephalogram showing slow activity. All had higher antibody titers in cerebrospinal fluid than in serum and 2 had ovarian teratomas that were removed. The pregnancy was terminated in 1 patient with recurrent bilateral teratomas. All patients had substantial neurological recoveries, and the 2 newborns were normal. Results of extensive antibody testing in 1 of the babies were negative. Conclusion: The current study shows that anti-NMDAR encephalitis during pregnancy can have a good outcome for the mother and newborn. [ABSTRACT FROM AUTHOR]

We examined if very low-birth-weight (VLBW) infants of multiple gestation pregnancies experience more complications and take longer to achieve clinical milestones compared with similar singletons. We performed a retrospective analysis of all infants less than 1500 g at birth in a large neonatal database. Singletons were compared with twins and higher-order multiples for demographic, morbidities, and process milestones including feeding, respiratory, thermoregulation, and length of stay. Multivariable regression analyses were performed to control for potential confounding variables. A total of 5507 infants were included: 3792 singletons, 1391 twins, and 324 higher-order multiples. There were no differences in Apgar scores, small for gestational age status, and incidence of necrotizing enterocolitis, severe retinopathy of prematurity, severe intraventricular hemorrhage, sepsis, bronchopulmonary dysplasia, or the need for surgery. Multiples had higher rates of apnea and patent ductus arteriosus than singletons. VLBW multiples achieved milestones at similar rates in most areas compared with singletons except for the achievement of full oral feedings. Length of stay, after controlling for confounding variables, did not differ between the groups. Compared with singletons, VLBW multiples had similar morbidity and achieved most feeding and thermoregulation milestones at similar rates. [ABSTRACT FROM AUTHOR]

Objective: We determined the effect of preterm delivery on the course of neonatal abstinence syndrome (NAS) in infants born to mothers participating in a methadone maintenance program. Study design: A retrospective cohort study was conducted in which infant and maternal data were collected from the medical records of 53 preterm and 66 term infants. Infants were selected from all infants admitted to Thomas Jefferson University hospital born between 1998 and 2002 whose mothers were enrolled in the methadone maintenance program. All infants were managed by a standard protocol utilizing the Neonatal Abstinence Scoring System (NASS) and neonatal opiate solution (NOS). Preterm and term infants were compared. Results: Preterm infants had shorter lengths of stay, treatment courses and required less medication than did term infants during the same time period. Conclusion: These data indicate that following exposure to maternal methadone, preterm infants have a different neonatal course than do infants born at term. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/ncomms15112 [ABSTRACT FROM AUTHOR]

In the developed world, extreme prematurity is the leading cause of neonatal mortality and morbidity due to a combination of organ immaturity and iatrogenic injury. Until now, efforts to extend gestation using extracorporeal systems have achieved limited success. Here we report the development of a system that incorporates a pumpless oxygenator circuit connected to the fetus of a lamb via an umbilical cord interface that is maintained within a closed 'amniotic fluid' circuit that closely reproduces the environment of the womb. We show that fetal lambs that are developmentally equivalent to the extreme premature human infant can be physiologically supported in this extra-uterine device for up to 4 weeks. Lambs on support maintain stable haemodynamics, have normal blood gas and oxygenation parameters and maintain patency of the fetal circulation. With appropriate nutritional support, lambs on the system demonstrate normal somatic growth, lung maturation and brain growth and myelination. [ABSTRACT FROM AUTHOR]