OBJECTIVE:Evaluate whether minimally invasive surfactant therapy (MIST) reduces respiratory support duration in infants born at 28-37 weeks' gestation with respiratory distress syndrome (RDS). STUDY DESIGN:Retrospective cohort study of infants with RDS born between 28- 36 6/7 weeks' gestation at a single center level III NICU between 2016-2024. MIST was implemented in 2020. Primary outcome was total days of respiratory support. Secondary outcomes included intubation rates, length of stay, corrected gestational age (cGA) at discharge, and incidence of bronchopulmonary dysplasia (BPD). RESULTS:Of 218 infants with RDS, the post MIST group had fewer days of respiratory support (8.8 vs 11 days), significantly lower rate of intubation (39% vs 100%), and shorter NICU stay (35.5 vs 41.2 days). BPD among infants <32 weeks' gestation decreased from 43% to 29%. CONCLUSION:MIST was associated with reduced respiratory support and hospitalization duration in this population.

Importance:The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective:To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants:Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions:Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures:The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results:Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance:In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration:anzctr.org.au Identifier: ACTRN12611000916943.

This randomized clinical trial investigates whether withholding the standard 48 hours of intravenous empirical antibiotics immediately after birth in preterm infants protects the developing microbiome and improves clinical outcomes.

In the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of intubation. However, in infants requiring intubation for >= 10 days, prolonged PDA exposure (>= 11 days) was associated with an increased risk of moderate/severe BPD.

Objective To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns < 28 weeks. Methods We performed a secondary analysis of the multi-center PDA-TOLERATE trial (NCT01958320). Infants with moderate-to-large PDAs were randomized 1:1 at 8.1 ± 2.1 days to either Drug treatment ( n = 104) or Conservative management ( n = 98). Drug treatments were assigned by center rather than within center (acetaminophen: 5 centers, 27 infants; ibuprofen: 7 centers, 38 infants; indomethacin: 7 centers, 39 infants). Results Indomethacin produced the greatest constriction (compared with spontaneous constriction during Conservative management): RR (95% CI) = 3.21 (2.05–5.01)), followed by ibuprofen = 2.03 (1.05–3.91), and acetaminophen = 1.33 (0.55–3.24). The initial rate of acetaminophen-induced constriction was 27%. Infants with persistent moderate-to-large PDA after acetaminophen were treated with indomethacin. The final rate of constriction after acetaminophen ± indomethacin was 60% (similar to the rate in infants receiving indomethacin-alone (62%)). Conclusion Indomethacin was more effective than acetaminophen in producing ductus constriction.

Objective To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. Study design A total of 202 neonates of < 28 weeks of gestation age (mean, 25.8 +/- 1.1 weeks) with moderateto-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 +/- 2.2 days) into an exploratory randomized controlled trial. Results At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT, 19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were >= 26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT, 6%) and death (ERT, 16%; CT, 2%). Conclusions In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at >= 26 weeks of gestation.

Neonates born very preterm (before 32 weeks' gestational age), are a significant public health concern because of their high-risk of mortality and life-long disability. In addition, caring for very preterm neonates can be expensive, both during their initial hospitalization and their long-term cost of permanent impairments. To address these issues, national and regional neonatal networks around the world collect and analyse data from their constituents to identify trends in outcomes, and conduct benchmarking, audit and research. Improving neonatal outcomes and reducing health care costs is a global problem that can be addressed using collaborative approaches to assess practice variation between countries, conduct research and implement evidence-based practices. The International Network for Evaluating Outcomes (iNeo) of neonates was established in 2013 with the goal of improving outcomes for very preterm neonates through international collaboration and comparisons. To date, 10 national or regional population-based neonatal networks/datasets participate in iNeo collaboration. The initiative now includes data on >200,000 very preterm neonates and has conducted important epidemiological studies evaluating outcomes, variations and trends. The collaboration has also surveyed >320 neonatal units worldwide to learn about variations in practices, healthcare service delivery, and physical, environmental and manpower related factors and support services for parents. The iNeo collaboration serves as a strong international platform for Neonatal-Perinatal health services research that facilitates international data sharing, capacity building, and global efforts to improve very preterm neonate care.

OBJECTIVE:To assess decisional conflict and knowledge about prematurity among mothers facing extreme premature delivery when the counseling clinicians were randomized to counsel using a validated decision aid compared with usual counseling. STUDY DESIGN:In this randomized trial, clinicians at 5 level III neonatal intensive care units in the US were randomized to supplement counseling using the decision aid or to counsel mothers in their usual manner. We enrolled mothers with threatened premature delivery at 220/7 to 256/7 weeks of gestation within 7 days of their counseling. The primary outcome was the Decisional Conflict Scale (DCS) score. One hundred mothers per group were enrolled to detect a clinically relevant effect size of 0.4 in the Decisional Conflict Scale. Secondary outcomes included knowledge about prematurity; scores on the Preparedness for Decision Making scale; and acceptability. RESULTS:Ninety-two clinicians were randomized and 316 mothers were counseled. Of these, 201 (64%) mothers were enrolled. The median gestational age was 24.1 weeks (IQR 23.7-24.9). In both groups, DCS scores were low (16.3 ± 18.2 vs 16.8 ± 17, P = .97) and Preparedness for Decision Making scores were high (73.4 ± 28.3 vs 70.5 ± 31.1, P = .33). There was a significantly greater knowledge score in the decision aid group (66.2 ± 18.5 vs 57.2 ± 18.8, P = .005). Most clinicians and parents found the decision aid useful. CONCLUSIONS:For parents facing extremely premature delivery, use of a decision aid did not impact maternal decisional conflict, but it significantly improved knowledge of complex information. A structured decision aid may improve comprehension of complex information. TRIAL REGISTRATION:Clinicaltrials.gov: NCT01713894.

The PDA: TO LEave it alone or Respond And Treat Early trial compared the effects of 2 strategies for treatment of patent ductus arteriosus (PDA) in infants <28(0/7) weeks of gestation; however 137 potentially eligible infants were not recruited and received treatment of their PDA outside the PDA-TOLERATE trial due to "lack-of-physician-equipoise" (LPE). Despite being less mature and needing more respiratory support, infants with LPE had lower rates of mortality than enrolled infants. Infants with LPE treated before day 6 had lower rates of late respiratory morbidity than infants with LPE treated >= day 6.

A male infant is born at 29 5/7 weeks’ gestation via vaginal delivery to a 35-year-old gravida 2 para 1 mother with limited prenatal care. His mother initially presents at a referring hospital in preterm labor, where she is given a dose of betamethasone and then transferred. On admission, prenatal laboratory tests are performed. Labor is augmented due to a 7-cm dilation. The infant’s birth measurements are as follows: weight, 1,530 g (68th percentile); length, 35 cm (3rd percentile); and head circumference, 27.5 cm (45th percentile). His Apgar scores are 8 at 1 minute and 9 at 5 minutes. His physical examination findings are notable for musculoskeletal abnormalities, including limited extension at the elbows bilaterally and an internally rotated left shoulder. He is also noted to have slightly anteverted nares and a depressed nasal bridge. On abdominal examination, he has slight distention but no hepatosplenomegaly. No skin rashes are noted. After delivery, he has intermittent respiratory distress that improves with stimulation. Due to his low oxygen saturation values and increased work of breathing, he is first started on continuous positive airway pressure and then undergoes intubation to improve saturations. Laboratory evaluation consists of a complete blood cell (CBC) count and liver function tests, which show the following: white blood cell (WBC) count, 30.9/μL (0.03 × 109/L); hemoglobin, 11.4 g/dL (114 g/L); hematocrit, 35% (0.35); platelets, 106 × 103/μL (106 × 109/L); alkaline phosphatase, 301 U/L (5.03 μkat/L); alanine aminotransferase, 15 U/L (0.25 μkat/L); aspartate aminotransferase, 65 U/L (1.09 μkat/L); and direct bilirubin, 1.4 mg/dL (24 μmol/L). A lumbar puncture is …

One of the central, unanswered questions in perinatology is why preterm infants continue to have such poor long-term neurodevelopmental, cognitive and learning outcomes, even though severe brain injury is now rare. There is now strong clinical evidence that one factor underlying disability may be infection, as well as nonspecific inflammation, during fetal and early postnatal life. In this review, we examine the experimental evidence linking both acute and chronic infection/inflammation with perinatal brain injury and consider key experimental determinants, including the microglia response, relative brain and immune maturity and the pattern of exposure to infection. We highlight the importance of the origin and derivation of the bacterial cell wall component lipopolysaccharide. Such experimental paradigms are essential to determine the precise time course of the inflammatory reaction and to design targeted neuroprotective strategies to protect the perinatal brain from infection and inflammation. (C) 2015 S. Karger AG, Basel

Cerebral palsy (CP) has a significant impact on both patients and society, but therapy is limited. Human umbilical cord blood cells (HUCBC), containing various stem and progenitor cells, have been used to treat various brain genetic conditions. In small animal experiments, HUCBC have improved outcomes after hypoxic-ischemic (HI) injury. Clinical trials using HUCBC are underway, testing feasibility, safety and efficacy for neonatal injury as well as CP. We tested HUCBC therapy in a validated rabbit model of CP after acute changes secondary to HI injury had subsided. Following uterine ischemia at 70% gestation, we infused HUCBC into newborn rabbit kits with either mild or severe neurobehavioral changes. Infusion of high-dose HUCBC (5 × 10(6) cells) dramatically altered the natural history of the injury, alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test, however, showed that joint function did not restore to naïve control function in either group. Tracing HUCBC with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. This is the first study to show that HUCBC improve motor performance in a dose-dependent manner, perhaps by improving compensatory repair processes.

Rabbits, like humans, are perinatal brain developers. We have developed a model of fetal hypoxia-ischemia that results in postnatal rabbit kits with a phenotype analogous to that observed in humans with cerebral palsy. This chapter gives a practical approach to performing the model and shows the range methods available for study using the model.

We hypothesized that a deficiency in the descending serotonergic input to spinal cord may underlie postnatal muscle hypertonia after global antenatal hypoxic‐ischemic injury in a rabbit model of cerebral palsy. Neurotransmitter content was determined by HPLC in the spinal cord of newborns with and without muscle hypertonia after fetal global hypoxic‐ischemic brain injury and naïve controls. Contrary to our hypothesis, serotonin levels in both cervical and lumbar expansions and norepinephrine in cervical expansion were increased in hypertonic kits relative to non‐hypertonic kits and controls, with unchanged number of serotonergic cells in caudal raphe by stereological count. Serotonergic fiber length per unit of volume was also increased in hypertonic kits’ cervical and lumbar spinal cord, both in dorsal and ventral horns. Gene expression of serotonin transporter was increased and 5‐HTR2 receptors were decreased in hypertonic kits relative to controls in cervical and lumbar cord. Intrathecal administration of non‐selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic kits only. Conversely, intrathecal administration of serotonin solution increased muscle tone only in non‐hypertonic kits. We speculate that maturation of serotonergic system in spinal cord may be directly affected by decreased corticospinal connectivity after antenatal hypoxic‐ischemic brain injury.

ObjectiveWhite matter (WM) injury due to myelination defects is believed to be responsible for the motor deficits seen in cerebral palsy. We tested the hypothesis that the predominant injury is to functional electrical connectivity in unmyelinated WM fibers by conducting a longitudinal study of central WM tracts in newborn rabbit kits with hypertonia in our model of cerebral palsy.MethodsPregnant rabbits at 70% gestation underwent 40‐minute uterine ischemia. Motor deficits in newborn kits, including muscle hypertonia, were assessed by neurobehavioral testing. Major central WM tracts, including internal capsule, corpus callosum, anterior commissure, and fimbria hippocampi, were investigated for structural and functional injury using diffusion tensor magnetic resonance imaging (MRI), electrophysiological recordings of fiber conductivity in perfused brain slices, electron microscopy, and immunohistochemistry of oligodendrocyte lineage.ResultsMotor deficits were observed on postnatal day 1 (P1) when WM tracts were unmyelinated. Myelination occurred later and was obvious by P18. Hypertonia was associated with microstructural WM injury and unmyelinated axon loss at P1, diagnosed by diffusion tensor MRI and electron microscopy. Axonal conductivity from electrophysiological recordings in hypertonic P18 kits decreased only in unmyelinated fibers, despite a loss in both myelinated and unmyelinated axons.InterpretationMotor deficits in cerebral palsy were associated with loss of unmyelinated WM tracts. The contribution of injury to myelinated fibers that was observed at P18 is probably a secondary etiological factor in the motor and sensory deficits in the rabbit model of cerebral palsy. Ann Neurol 2014;75:533–541

Anisotropy indices derived from diffusion tensor imaging (DTI) are being increasingly used as biomarkers of central WM structural maturation, myelination and even functional development. Our hypothesis was that the rate of functional changes in central WM tracts directly reflects rate of changes in structural development as determined by DTI indices. We examined structural and functional development of four major central WM tracts with different maturational trajectories, including internal capsule (IC), corpus callosum (CC), fimbria hippocampi (FH) and anterior commissure (AC). Rabbits were chosen due to perinatal brain development being similar to humans, and four time points were studied: P1, P11, P18 and adults. Imaging parameters of structural maturation included fractional anisotropy (FA), mean and directional diffusivities derived from DTI, and T2 relaxation time. Axonal composition and degree of myelination were confirmed on electron microscopy. To assess functional maturation, conduction velocity was measured in myelinated and non-myelinated fibers by electrophysiological recordings of compound action potential in perfused brain slices. Diffusion indices and T2 relaxation time in rabbits followed a sigmoid curve during development similar to that for humans, with active changes even at premyelination stage. The shape of the developmental curve was different between the fiber tracts, with later onset but steeper rapid phase of development in IC and FH than in CC. The structural development was not directly related to myelination or to functional development. Functional properties in projection (IC) and limbic tracts (FH) matured earlier than in associative and commissural tracts (CC and AC). The rapid phase of changes in diffusion anisotropy and T2 relaxation time coincided with the development of functional responses and myelination in IC and FH between the second and third weeks of postnatal development in rabbits. In these two tracts, MRI indices could serve as surrogate markers of the early stage of myelination. However, the discordance between developmental change of diffusion indices, myelination and functional properties in CC and AC cautions against equating DTI index changes as biomarkers for myelination in all tracts.

Tetrahydrobiopterin (BH4) is important for normal brain development as congenital BH4 deficiencies manifest movement disorders at various childhood ages. BH4 transitions from very low levels in fetal brains to higher "adult" levels postnatally, with the highest levels in the thalamus. Maternal supplementation with the BH4 precursor sepiapterin reduces postnatal motor deficits and perinatal deaths after 40-min fetal hypoxia-ischemia (HI) at 70% gestation, suggesting that brain BH4 is important in improving function after HI. We tested the hypothesis that the intrinsically low concentrations of BH4 made fetal neurons vulnerable to added insults. Brains were obtained from naïve fetal rabbits or after 40-min HI, at 70% (E22) and 92% gestation (E29). Neuronal cultures were prepared from basal ganglia, cortex, and thalamus, regions with different intrinsic levels of BH4. Cultures were grown with or without added BH4 for 48h. Cell survival and mitochondrial function were determined by flow cytometry. At E22, thalamic cells had the lowest survival rate in a BH4-free milieu, in both control and HI groups, whereas BH4 supplementation ex vivo increased neuronal survival only in HI cells. Neuronal survival was similar in all regions without BH4 at E29. BH4 supplementation increased cell survival and cells with intact mitochondrial membrane potential, from basal ganglia and cortex, but not thalamus. After E29 HI, however, the benefit of BH4 was limited to cortical neurons. We conclude that BH4 is important for fetal neuronal survival after HI especially in the premature thalamus. Supplementation of BH4 has a greater benefit at an earlier gestational age.

Objective To test the hypothesis that infants who are just being introduced to enteral feedings will advance to full enteral nutrition at a faster rate if they receive "trophic" (15 mL/kg/d) enteral feedings while receiving indomethacin or ibuprofen treatment for patent ductus arteriosus.Study design Infants were eligible for the study if they were 23(1/7) -30(6/7) weeks' gestation, weighed 401-1250 g at birth, received maximum enteral volumes <= 60 mL/kg/d, and were about to be treated with indomethacin or ibuprofen. A standardized "feeding advance regimen" and guidelines for managing feeding intolerance were followed at each site (N = 13).Results Infants (N = 177, 26.3 +/- 1.9 weeks' mean +/- SD gestation) were randomized at 6.5 +/- 3.9 days to receive "trophic" feeds ("feeding" group, n = 81: indomethacin 80%, ibuprofen 20%) or no feeds ("fasting [ nil per os]" group, n = 96: indomethacin 75%, ibuprofen 25%) during the drug administration period. Maximum daily enteral volumes before study entry were 14 +/- 15 mL/kg/d. After drug treatment, infants randomized to the "feeding" arm required fewer days to reach the study's feeding volume end point (120 mL/kg/d). Although the enteral feeding end point was reached at an earlier postnatal age, the age at which central venous lines were removed did not differ between the 2 groups. There were no differences between the 2 groups in the incidence of infection, necrotizing enterocolitis, spontaneous intestinal perforation, or other neonatal morbidities.Conclusion Infants required less time to reach the feeding volume end point if they were given "trophic" enteral feedings when they received indomethacin or ibuprofen treatments.