Antenatal Glucocorticoid Administration Promotes Cardiac Structure and Energy Metabolism Maturation in Preterm Fetuses.

Although the rate of preterm birth has increased in recent decades, a number of preterm infants have escaped death due to improvements in perinatal and neonatal care. Antenatal glucocorticoid (GC) therapy has significantly contributed to progression in lung maturation; however, its potential effects on other organs remain controversial. Furthermore, the effects of antenatal GC therapy on the fetal heart show both pros and cons. Translational research in animal models indicates that constant fetal exposure to antenatal GC administration is sufficient for lung maturation. We have established a premature fetal rat model to investigate immature cardiopulmonary functions in the lungs and heart, including the effects of antenatal GC administration. In this review, we explain the mechanisms of antenatal GC actions on the heart in the fetus compared to those in the neonate. Antenatal GCs may contribute to premature heart maturation by accelerating cardiomyocyte proliferation, angiogenesis, energy production, and sarcoplasmic reticulum function. Additionally, this review specifically focuses on fetal heart growth with antenatal GC administration in experimental animal models. Moreover, knowledge regarding antenatal GC administration in experimental animal models can be coupled with that from developmental biology, with the potential for the generation of functional cells and tissues that could be used for regenerative medical purposes in the future.

Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale.

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005-1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS.

A successful treatment of tadalafil in incontinentia pigmenti with pulmonary hypertension.

We describe a female infant with incontinentia pigmenti complicated by severe pulmonary arterial hypertension that was markedly improved by tadalafil administration. The infant was referred to our institution because of neonatal seizures and generalized skin rash at the age of 1 day. She was diagnosed with incontinentia pigmenti on skin biopsy findings. In addition to incontinentia pigmenti, she had pulmonary arterial hypertension without structural heart disease. The pulmonary hypertension rapidly worsened at the age of 2 months and was confirmed by cardiac catheterization. The pulmonary artery pressure was equal to systemic pressure but it decreased in response to nitric oxide inhalation. We, therefore, initiated treatment with tadalafil of 1 mg/kg/day. The follow-up cardiac catheterization performed at 9 months revealed dramatic improvement in the pulmonary artery pressure. An IKBKG mutation with deletion of exons 4-10 was detected in the blood of both the patient and her mother. Our experience indicates that tadalafil may be beneficial in treating pulmonary arterial hypertension associated with incontinentia pigmenti.

A Novel System for Spinal Muscular Atrophy Screening in Newborns: Japanese Pilot Study.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by SMN1 gene deletion/mutation. The drug nusinersen modifies SMN2 mRNA splicing, increasing the production of the full-length SMN protein. Recent studies have demonstrated the beneficial effects of nusinersen in patients with SMA, particularly when treated in early infancy. Because nusinersen treatment can alter disease trajectory, there is a strong rationale for newborn screening. In the current study, we validated the accuracy of a new system for detecting SMN1 deletion (Japanese patent application No. 2017-196967, PCT/JP2018/37732) using dried blood spots (DBS) from 50 patients with genetically confirmed SMA and 50 controls. Our system consists of two steps: (1) targeted pre-amplification of SMN genes by direct polymerase chain reaction (PCR) and (2) detection of SMN1 deletion by real-time modified competitive oligonucleotide priming-PCR (mCOP-PCR) using the pre-amplified products. Compared with PCR analysis results of freshly collected blood samples, our system exhibited a sensitivity of 1.00 (95% confidence interval [CI] 0.96-1.00) and a specificity of 1.00 (95% CI 0.96-1.00). We also conducted a prospective SMA screening study using DBS from 4157 Japanese newborns. All DBS tested negative, and there were no screening failures. Our results indicate that the new system can be reliably used in SMA newborn screening.

Development of a neonatal adverse event severity scale through a Delphi consensus approach.

BACKGROUND: Assessment of the seriousness, expectedness and causality are necessary for any adverse event (AE) in a clinical trial. In addition, assessing AE severity helps determine the importance of the AE in the clinical setting. Standardisation of AE severity criteria could make safety information more reliable and comparable across trials. Although standardised AE severity scales have been developed in other research fields, they are not suitable for use in neonates. The development of an AE severity scale to facilitate the conduct and interpretation of neonatal clinical trials is therefore urgently needed. METHODS: A stepwise consensus process was undertaken within the International Neonatal Consortium (INC) with input from all relevant stakeholders. The consensus process included several rounds of surveys (based on a Delphi approach), face-to-face meetings and a pilot validation. RESULTS: Neonatal AE severity was classified by five grades (mild, moderate, severe, life threatening or death). AE severity in neonates was defined by the effect of the AE on age appropriate behaviour, basal physiological functions and care changes in response to the AE. Pilot validation of the generic criteria revealed κ=0.23 and guided further refinement. This generic scale was applied to 35 typical and common neonatal AEs resulting in the INC neonatal AE severity scale (NAESS) V.1.0, which is now publicly available. DISCUSSION: The INC NAESS is an ongoing effort that will be continuously updated. Future perspectives include further validation and the development of a training module for users.

Stat-3 is required for pulmonary homeostasis during hyperoxia.

Acute lung injury syndromes remain common causes of morbidity and mortality in adults and children. Cellular and physiologic mechanisms maintaining pulmonary homeostasis during lung injury remain poorly understood. In the present study, the Stat-3 gene was selectively deleted in respiratory epithelial cells by conditional expression of Cre-recombinase under control of the surfactant protein C gene promoter. Cell-selective deletion of Stat-3 in respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function. However, exposure of adult Stat-3-deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress. Epithelial cell injury and inflammatory responses were increased in the Stat-3-deleted mice. Surfactant proteins and lipids were decreased or absent in alveolar lavage material. Intratracheal treatment with exogenous surfactant protein B improved survival and lung histology in Stat-3-deleted mice during hyperoxia. Expression of Stat-3 in respiratory epithelial cells is not required for lung formation, but plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury.

Effects of the early administration of sivelestat sodium on bronchopulmonary dysplasia in infants: A retrospective cohort study.

BACKGROUND: Chorioamnionitis, or infiltration of the chorioamnion by neutrophils, is a risk factor associated with the development of bronchopulmonary dysplasia. Increased neutrophil elastase levels are observed in the tracheal aspirates of these patients. AIMS: To examine the effects of early administration of the selective neutrophil elastase inhibitor sivelestat, which is used to treat acute lung injury in adults, on bronchopulmonary dysplasia in extremely premature infants. STUDY DESIGN: Retrospective cohort study. SUBJECTS: This study included extremely low-birth-weight infants born at a gestational age<28weeks. Patients were divided into groups based on the receipt of sivelestat. OUTCOME MEASURES: The primary outcome was the rate of bronchopulmonary dysplasia-free survival at a postmenstrual age of 36weeks, and the secondary outcomes included various clinically significant factors of neonatal mortality and morbidity and adverse events. RESULTS: Of the 1031 included neonates, 124 (12.0%) were treated with sivelestat. Significant differences between the groups were noted for gestational age, delivery method, fetal number, the frequency of chorioamnionitis, immunoglobulin M levels, and WBC counts. No differences were identified concerning the bronchopulmonary dysplasia-free survival rate at a postmenstrual age of 36weeks (adjusted odds ratio for sivelestat to control, 0.83; 95% confidence interval=0.53-1.30). Secondary outcomes did not significantly differ between the groups. CONCLUSIONS: In extremely premature infants, early sivelestat use was not associated with an improved rate of survival without bronchopulmonary dysplasia at a postmenstrual age of 36weeks.

Functional hemispheric specialization in processing phonemic and prosodic auditory changes in neonates.

This study focuses on the early cerebral base of speech perception by examining functional lateralization in neonates for processing segmental and suprasegmental features of speech. For this purpose, auditory evoked responses of full-term neonates to phonemic and prosodic contrasts were measured in their temporal area and part of the frontal and parietal areas using near-infrared spectroscopy (NIRS). Stimuli used here were phonemic contrast /itta/ and /itte/ and prosodic contrast of declarative and interrogative forms /itta/ and /itta?/. The results showed clear hemodynamic responses to both phonemic and prosodic changes in the temporal areas and part of the parietal and frontal regions. In particular, significantly higher hemoglobin (Hb) changes were observed for the prosodic change in the right temporal area than for that in the left one, whereas Hb responses to the vowel change were similarly elicited in bilateral temporal areas. However, Hb responses to the vowel contrast were asymmetrical in the parietal area (around supra marginal gyrus), with stronger activation in the left. These results suggest a specialized function of the right hemisphere in prosody processing, which is already present in neonates. The parietal activities during phonemic processing were discussed in relation to verbal-auditory short-term memory. On the basis of this study and previous studies on older infants, the developmental process of functional lateralization from birth to 2 years of age for vowel and prosody was summarized.

FGF signaling is required for pulmonary homeostasis following hyperoxia.

To assess the role of fibroblast growth factor (FGF) signaling in pulmonary function in the postnatal period, we generated transgenic mice in which a soluble FGF receptor (FGFR-HFc) was conditionally expressed in respiratory epithelial cells of the mouse lung, thereby inhibiting FGF activity. Although FGFR-HFc did not alter postnatal lung morphogenesis, male FGFR-HFc transgenic mice were more susceptible to hyperoxia and failed to recover when ambient oxygen concentrations were normalized. Inflammation, alveolar-capillary leak, and mortality were increased following exposure to 95% Fi(O(2)). Expression of surfactant protein (SP)-A and SP-B were significantly decreased in association with decreased immunostaining for thyroid transcription factor-1. FGF signaling is required for maintenance of surfactant homeostasis and lung function during hyperoxia in vivo, mediated, at least in part, by its role in the maintenance of SP-B expression.

Prenatal, but not postnatal, inhibition of fibroblast growth factor receptor signaling causes emphysema.

Although fibroblast growth factor (FGF) signaling is required for the formation of the lung in the embryonic period, it is unclear whether FGF receptor activity influences lung morphogenesis later in development. We generated transgenic mice expressing a soluble FGF receptor (FGFR-HFc) under conditional control of the lung-specific surfactant protein C promoter (SP-C-rtTA), to inhibit FGF activity at various times in late gestation and postnatally. Although expression of FGFR-HFc early in development caused severe fetal lung hypoplasia, activation of the transgene in the postnatal period did not alter alveolarization, lung size, or histology. In contrast, expression of the transgene at post-conception day E14.5 decreased lung tubule formation before birth and caused severe emphysema at maturity. FGFR-HFc caused mild focal emphysema when expressed from E16.5 but did not alter alveolarization when expressed after birth. Although FGF signaling was required for branching morphogenesis early in lung development, postnatal alveolarization was not influenced by FGFR-HFc.

A congenital anterior diaphragmatic hernia with massive pericardial effusion requiring neither emergency pericardiocentesis nor operation. A case report and review of the literature.

UNLABELLED: All previously reported cases of anterior, diaphragmatic hernia with massive pericardial effusion were treated by pericardiocentesis and radical surgery during the early neonatal period. However, we initially followed the course of our patient in the neonatal period. Subsequently, elective surgery was performed at 70 days of age. Including our case, cardiac tamponade has not been observed in any previously reported cases of congenital anterior diaphragmatic hernia with massive pericardial effusion. CONCLUSION: Emergency pericardiocentesis and surgery are not always required immediately after birth, even when the presence of this condition is suspected by prenatal diagnosis. Our observation may be beneficial to preterm low birth weight infants with this condition.

Temporal effects of Sprouty on lung morphogenesis.

Paracrine signaling mediated by FGF-10 and the FGF-R2IIIb receptor is required for formation of the lung. To determine the temporal requirements for FGF signaling during pulmonary morphogenesis, Sprouty-4 (Spry-4), an intracellular FGF receptor antagonist, was expressed in epithelial cells of the fetal lung under control of a doxycycline-inducible system. Severe defects in lobulation and severe lung hypoplasia were observed when Spry-4 was expressed throughout fetal lung development (E6.5-E18.5) or from E6.5 until E13.5. Effects of Spry-4 on branching were substantially reversed by removal of doxycycline from the dam at E12.5, but not at E13.5. In contrast, when initiated late in development (E12.5 to birth), Spry-4 caused less severe pulmonary hypoplasia. Expression of Spry-4 from E16.5 to E18.5 reduced lung growth and resulted in perinatal death due to respiratory failure. Expression of Spry-4 during the saccular and alveolar stages, from E18.5 to postnatal day 21, caused mild emphysema. These findings demonstrate that the embryonic-pseudoglandular stage is a critical time period during which Spry-sensitive pathways are required for branching morphogenesis, lobulation, and formation of the peripheral lung parenchyma.