Comparison between two doses of betamethasone administration with 12 hours vs. 24 hours intervals on prevention of respiratory distress syndrome: a randomised trial.

The purpose of the present study was to compare the effect of a two-dose administration of betamethasone with 12 hours interval vs. 24 hours interval on neonatal respiratory distress syndrome (RDS). The study was performed as a randomised clinical trial on 201 pregnant women with a gestational age of 26-34 weeks. In one group 12 mg of betamethasone every 12 hours for two doses and in the other group 12 mg of betamethasone every 24 hours for two doses were prescribed intramuscularly. There were no significant differences between the two groups according to maternal age, parity, gravidity, BMI, neonatal sex, need to surfactant, NICU admission, NICU stay, neonatal death, neonatal sepsis and Apgar score at minutes 1 and 5, but the gestational age at the beginning of the study and delivery receiving complete course of betamethasone and neonatal weight were lower in 24 hours group. RDS, necrotising enterocolitis, intra-ventricular haemorrhage and chorioamnionitis were more in the 24 hours' group. Multiple regression analysis showed that RDS and IVH (p = .022, RR = 0.07, CI95% 0.006-0.96 and p = .013; RR = 0.9, CI95% 0.1-0.89, respectively) were more in the 24 hours group and neonatal death (p = .034, RR = 4.7, CI95% 1.07-16.2) and NEC (p = 0.038, RR = 2.5, CI95% 1.7-3.7), were more in the 12 hours group. In conclusion, it seems that 12 hours interval betamethasone therapy may be considered as an alternative treatment in the case of preterm labour for acceleration of lung maturity; however, it is suggested that more studies should be performed on this issue and various morbidities. IMPACT STATEMENT What is already known on this subject: Administration of a single course of corticosteroids in all women with a gestational age of 24-34 weeks of pregnancy who are at risk for preterm labour and delivery has been recommended. The accepted regimen by National Institutes of Health (NIH) is an injection of betamethasone for two doses with 24 hours interval. What do the results of this study add: Twelve hours interval betamethasone therapy may be considered as an alternative treatment in the cases of preterm labour for acceleration of lung maturity. What are the implications of these findings for clinical practice and/or further research: Prescription of two doses (complete regimen) is more important than the interval between two doses for obtaining the maximum effect in a preterm birth.

Neonatal Respiratory Failure with Retarded Perinatal Lung Maturation in Mice Caused by Reticulocalbin 3 Disruption.

Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum lumen protein localized to the secretory pathway. As a Ca2t-binding protein of 45 kDa (Cab45)/Rcn/ER Ca2t-binding protein of 55 kDa (ERC45)/calumenin (CREC) family member, Rcn3 is reported to function as a chaperone protein involved in protein synthesis and secretion; however, the biological role of Rcn3 is largely unknown. The results presented here, for the first time, depict an indispensable physiological role of Rcn3 in perinatal lung maturation by using an Rcn3 gene knockout mouse model. These mutant mice die immediately at birth owing to atelectasis-induced neonatal respiratory distress, although these embryos are produced with grossly normal development. This respiratory distress results from a failure of functional maturation of alveolar epithelial type II cells during alveogenesis. This immaturity of type II cells is associated with a dramatic reduction in surfactant protein A and D, a disruption in surfactant phospholipid homeostasis, and a disorder in lamellar body. In vitro studies further show that Rcn3 deficiency blunts the secretion of surfactant proteins and phospholipids from lung epithelial cells, suggesting a decrease in availability of surfactants for their surface activity. Collectively, these observations indicate an essential role of Rcn3 in perinatal lung maturation and neonatal respiratory adaptation as well as shed additional light on the mechanism of neonatal respiratory distress syndrome development.

Alveolar development and disease.

Gas exchange after birth is entirely dependent on the remarkable architecture of the alveolus, its formation and function being mediated by the interactions of numerous cell types whose precise positions and activities are controlled by a diversity of signaling and transcriptional networks. In the later stages of gestation, alveolar epithelial cells lining the peripheral lung saccules produce increasing amounts of surfactant lipids and proteins that are secreted into the airspaces at birth. The lack of lung maturation and the associated lack of pulmonary surfactant in preterm infants causes respiratory distress syndrome, a common cause of morbidity and mortality associated with premature birth. At the time of birth, surfactant homeostasis begins to be established by balanced processes involved in surfactant production, storage, secretion, recycling, and catabolism. Insights from physiology and engineering made in the 20th century enabled survival of newborn infants requiring mechanical ventilation for the first time. Thereafter, advances in biochemistry, biophysics, and molecular biology led to an understanding of the pulmonary surfactant system that made possible exogenous surfactant replacement for the treatment of preterm infants. Identification of surfactant proteins, cloning of the genes encoding them, and elucidation of their roles in the regulation of surfactant synthesis, structure, and function have provided increasing understanding of alveolar homeostasis in health and disease. This Perspective seeks to consider developmental aspects of the pulmonary surfactant system and its importance in the pathogenesis of acute and chronic lung diseases related to alveolar homeostasis.

Amniotic lamellar body count: predicting and distinguishing neonatal respiratory complications in twin pregnancies.

BACKGROUND: Twin pregnancies have a higher rate of preterm births, making precise prediction of neonatal respiratory disorders essential. We herein examined the amniotic lamellar body count (LBC) and found it to be an accurate predictor of respiratory disorders in twin pregnancies. METHODS: Five hundred fourteen amniotic fluid samples, comprising 132 dichorionic twin (DCT) and 125 monochorionic twin (MCT) gestations, were obtained at cesarean section performed at 29 to 38 gestational weeks. Samples were analyzed immediately without centrifugation. RESULTS: There were 26 neonates (5.1%) with respiratory distress syndrome (RDS) and 43 (8.4%) with transient tachypnea of the newborn (TTN). The LBC in neonates with TTN (5.12×10(4)/µl) was between the counts in RDS (1.26×10(4)/µl) and controls (10.6×10(4)/µl), which differed significantly. Twin concordance rates were significantly higher for TTN in MCT gestations than DCT gestations (p=0.003) and delta LBC value was significantly smaller in MCT (3.15±0.4×10(4)/µl) than DCT (5.17±0.5×10(4)/µl) gestations (p=0.003). CONCLUSIONS: The amniotic LBC is useful for predicting respiratory disorders, including RDS and TTN, in twin pregnancies. The data in this study may indicate a genetic predisposition to TTN among MCTs.

Acceleration time-to-ejection time ratio in fetal pulmonary artery predicts the development of neonatal respiratory distress syndrome: a prospective cohort study.

OBJECTIVE: This study investigates whether fetal pulmonary artery Doppler waveforms can predict the subsequent development of respiratory distress syndrome (RDS). STUDY DESIGN: A prospective cohort study was performed in women with impending preterm birth. Pulsatility index, resistance index, systolic-to-diastolic ratio, peak systolic velocity, and acceleration time-to-ejection time (At/Et) ratio were measured in the main pulmonary artery of fetus just before delivery. RESULTS: Neonates who developed RDS (n = 11) had significantly lower gestational age at birth than those without RDS (n = 31; median: 28.7 [range: 24.7 to 34.9] versus 32.9 [range: 25.7 to 36.0] weeks; p = 0.003); there was no difference in antenatal corticosteroid administration. Pulmonary artery At/Et ratio was significantly higher in fetuses that developed RDS compared with those that did not (median: 0.37 [range: 0.26 to 0.41] versus median: 0.30 [range: 0.21 to 0.44]; p = 0.008). RDS prediction score (=a hundredfold At/Et ratio) is significantly associated with the subsequent development of RDS after controlling for gestational age by logistic regression analysis (odds ratio = 1.31, 95% confidence interval 1.05 to 1.63, p = 0.017). CONCLUSION: An elevated At/Et ratio in the fetal pulmonary artery is independently associated with the development of RDS in preterm infants. These data suggest that fetal pulmonary artery Doppler velocimetry may provide a reliable noninvasive technique to evaluate fetal lung maturity, similar to the way in which middle cerebral artery Doppler has replaced amniocentesis for the assessment of fetal anemia.

Antenatal steroids and the IUGR fetus: are exposure and physiological effects on the lung and cardiovascular system the same as in normally grown fetuses?

Glucocorticoids are administered to pregnant women at risk of preterm labour to promote fetal lung surfactant maturation. Intrauterine growth restriction (IUGR) is associated with an increased risk of preterm labour. Hence, IUGR babies may be exposed to antenatal glucocorticoids. The ability of the placenta or blood brain barrier to remove glucocorticoids from the fetal compartment or the brain is compromised in the IUGR fetus, which may have implications for lung, brain, and heart development. There is conflicting evidence on the effect of exogenous glucocorticoids on surfactant protein expression in different animal models of IUGR. Furthermore, the IUGR fetus undergoes significant cardiovascular adaptations, including altered blood pressure regulation, which is in conflict with glucocorticoid-induced alterations in blood pressure and flow. Hence, antenatal glucocorticoid therapy in the IUGR fetus may compromise regulation of cardiovascular development. The role of cortisol in cardiomyocyte development is not clear with conflicting evidence in different species and models of IUGR. Further studies are required to study the effects of antenatal glucocorticoids on lung, brain, and heart development in the IUGR fetus. Of specific interest are the aetiology of IUGR and the resultant degree, duration, and severity of hypoxemia.

Pathophysiology of neonatal transition and meaningful measures for the initial stabilisation of extremely premature neonates.

This report discusses the physiological aspects of neonatal transition from breathing liquid to air. Further, we discuss reasonable medical interventions to actively assist a gentle transition, and focus on team aspects of preparing both the perinatal team and parents for the challenging situation of preterm labour and delivery. Our aim is to critically evaluate current concepts on the physiology of neonatal transition and the current assessment of the newborn infant, to present means to facilitate non-traumatic pulmonary aeration and ways to foster successful teamwork and professional parental guidance in the delivery room. The authors report on their own work and on that of other research groups, as recently published in peer reviewed medical journals. When born, the newborn needs to rapidly clear his/her lungs from fluid to establish breathing. Active fluid transport and passive resorption help to establish the pulmonary functional residual capacity (FRC). Prenatal administration of corticosteroids helps to form and maintain the FRC of the newborn. Many very low gestational age neonates (ELGAN) will breathe at birth but require medical assistance. This is best done by giving distending positive airway pressure at levels of 5 cmH(2)O, or greater. Monitoring of these infants should be by peripheral pulse oximetry. Some ELGANs may require non-invasive ventilation and/or exogenous Surfactant replacement, and even fewer may require intubation and mechanical ventilation. The obstetric and neonatal teams need to coordinate their joined efforts to secure a safe delivery for mother and child. Ways of communication between teams and parents are presented. Many neonatal teams use video recording as a tool to assess and improve their work. We give insights into the use of video as a means to improve teamwork and patient care alike.

Distribution of antioxidant enzymes in developing human lung, respiratory distress syndrome, and bronchopulmonary dysplasia.

We studied cell-specific protein expression of all the major antioxidant enzymes (AOEs) and related proteins, such as copper-zinc superoxide dismutase (CuZnSOD), manganese SOD (MnSOD), extracellular SOD (ECSOD), catalase, the heavy and light chains of gamma-glutamylcysteine synthetase (gamma-GCS-l and gamma-GCS-h, also called glutamate cysteine ligase), the rate-limiting enzyme in glutathione synthesis, hemeoxygenase-1 (HO-1), and thioredoxin (Trx), in developing human lung, respiratory distress syndrome, and bronchopulmonary dysplasia by immunohistochemistry. Generally, after 17 weeks of gestational age, MnSOD was predominantly expressed in bronchial epithelium, alveolar epithelium, and macrophages, CuZnSOD was expressed in bronchial epithelium, ECSOD was expressed in bronchial epithelium, vascular endothelium, and the extracellular matrix, catalase was expressed in bronchial epithelium and alveolar macrophages, gamma-GCS-h was expressed in bronchial epithelium and endothelium, and gamma-GCS-l was expressed in bronchial epithelium. Trx was restricted to bronchial epithelium and to a lesser extent to alveolar macrophages, and HO-1 found in alveolar macrophages. Basically, the expression of these enzymes was similar in normal and diseased lung. It can be concluded that various AOEs and related proteins differ in their distribution and expression in lung before term, but generally it seems that infants are better adapted to high oxygen tension than might be expected.

Defective lung vascular development and fatal respiratory distress in endothelial NO synthase-deficient mice: a model of alveolar capillary dysplasia?

Endothelium-derived NO plays a critical role in the regulation of cardiovascular function and structure, as well as acting as a downstream mediator of the angiogenic response to numerous vascular growth factors. Although endothelial NO synthase (eNOS)-deficient mice are viable, minor congenital cardiac abnormalities have been reported and homozygous offspring exhibit high neonatal mortality out of proportion to the severity of these defects. The aim of the present report was to determine whether abnormalities of the pulmonary vascular development could contribute to high neonatal loss in eNOS-deficient animals. We now report that eNOS-deficient mice display major defects in lung morphogenesis, resulting in respiratory distress and death within the first hours of life in the majority of animals. Histological and molecular examination of preterm and newborn mutant lungs demonstrated marked thickening of saccular septae, with evidence of reduced surfactant material. Lungs of eNOS-deficient mice also exhibited a striking paucity of distal arteriolar branches and extensive regions of capillary hypoperfusion, together with misalignment of pulmonary veins, which represent the characteristic features of alveolar capillary dysplasia. We conclude that eNOS plays a previously unrecognized role in lung development, which may have relevance for clinical syndromes of neonatal respiratory distress.

Lung morphometry after repetitive antenatal glucocorticoid treatment in preterm sheep.

Antenatal glucocorticoids are thought to be less effective when delivery occurs more than 7 d after initiation of treatment; therefore, repeat courses are often administered. We examined lung structure after single or repetitive antenatal glucocorticoid injections in fetal sheep. Pregnant ewes received single or repetitive doses of 0.5 mg/kg betamethasone at 7-d intervals by maternal or fetal injection, beginning at D104 or D114 with delivery at D125, D135, or D146 gestation (term = 150 d). Changes in lung structure were more pronounced after repetitive versus single injections. Repetitive fetal or maternal injections beginning at D104 (delivery at D125) resulted in comparable structural changes: alveolar volume increased by 50 to 80%, alveolar numerical density decreased by 30 to 40%, and pleural and interlobular septal volumes decreased by as much as 70%. Similar changes were seen in animals delivered at D135 after repetitive maternal injections beginning at D114. There were no structural differences between control and repetitive betamethasone animals when delivery was delayed until D146, indicating that betamethasone induced structural changes were reversible.

[Lung hypoplasia: an underestimated diagnosis?]. / Die Lungenhypoplasie: eine unterschätzte Diagnose?

BACKGROUND: Lung hypoplasia is a complex disease which is probably an underestimated problem in newborns. The diagnosis may be missed since the clinical features are highly varying. Histologic counting of alveoli is necessary to ensure the diagnosis. PATHOGENESIS: Risk factors for lung hypoplasia are oligohydramnios, absent fetal breathing movements, and thoracal tumors. Under these conditions physical stimuli are absent on which lung growth mainly depends. In the case of preterm rupture of membranes the gestational age and the degree of oligohydramnios are decisive for the risk of hypoplasia. Postnatal growth can compensate in less severe cases. However, in severe cases persistent pulmonary hypertension is associated with a poor outcome. THERAPY AND DIAGNOSIS: New therapeutic options for persistent pulmonary hypertension are currently under evaluation. Prenatal measurement of lung volume and flow profile in pulmonary vessels are new issues to improve prenatal diagnosis. CONCLUSIONS: Lung hypoplasia is usually not adequately taken into account. High clinical suspicion is necessary in order to understand this disease and to develop therapeutic strategies.

Lung disease in premature neonates: impact of new treatments and technologies.

Advances in perinatal medicine and neonatology have dramatically changed clinical outcomes for premature neonates and have ushered in a new era of radiological complexity. "Portable" chest radiographs continue to be the mainstay in diagnostic imaging of fragile newborns, but radiologists may be confronted with new and unexpected radiological expressions of once-familiar disease processes. Familiarity with the radiological impact of emerging treatments in premature neonates is essential for accurate film interpretation.

The relationship of sonographic placental grading, biochemical pulmonary maturity and neonatal outcome in pregnancy-induced hypertension.

In a prospective study, the accuracy of placental grade in predicting pulmonary maturity was evaluated in 50 cases of pregnancy-induced hypertension (PIH) between 28 and 41 weeks of gestation. Pulmonary maturity was measured by lecithin/sphingomyelin (L/S) ratio and phosphatidylglycerol (PG) in amniotic fluid and by clinical development of respiratory distress syndrome (RDS) in the neonates. Fifty normotensive healthy primigravidae, who were matched for age and period of gestation, served as control. No difference (p > 0.05) in the placental grading was observed between normotensive and hypertensive pregnancies. The advancement of placental grade was found to be associated with an increase in L/S ratio and PG level in amniotic fluid. A mature placental grade (grade III) identified by real-time sonography corresponded to foetal lung maturity (L/S > or = 2.0, PG > or = 0.36 mg/dl) and absence of RDS in all cases. Hence, in PIH a grade III placenta appeared to be a reliable predictor of foetal lung maturity in the population examined.

Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation.

The role of the glucocorticoid receptor (GR) in glucocorticoid physiology and during development was investigated by generation of GR-deficient mice by gene targeting. GR -/- mice die within a few hours after birth because of respiratory failure. The lungs at birth are severely atelectatic, and development is impaired from day 15.5 p.c. Newborn livers have a reduced capacity to activate genes for key gluconeogenic enzymes. Feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocorticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Accordingly, adrenal glands are enlarged because of hypertrophy of the cortex, resulting in increased expression of key cortical steroid biosynthetic enzymes, such as side-chain cleavage enzyme, steroid 11 beta-hydroxylase, and aldosterone synthase. Adrenal glands lack a central medulla and synthesize no adrenaline. They contain no adrenergic chromaffin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. These results suggest that the adrenal medulla may be formed from two different cell populations: adrenergic-specific cells that require glucocorticoids for proliferation and/or survival, and a smaller noradrenergic population that differentiates normally in the absence of glucocorticoid signaling.

Clinical implementation of a rapid, automated assay for assessing fetal lung maturity.

We retrospectively determined cutoff levels and implemented the use of the TDxFLx assay in assessing the likelihood or absence of respiratory distress syndrome or fetal lung maturity (FLM) in a high-risk obstetric setting when compared to the lecithin/sphingomyelin (L/S) ratio and disaturated lecithin (DSL) measurements. Using a mature TDxFLx cutoff value of > or = 50 mg/g and an immature cutoff value of < 20 mg/g, 88% of L/S ratio and DSL measurements could be eliminated without compromise to the patient. The > or = 50 mg/g TDxFLx cutoff value resulted in a sensitivity of 100% and specificity of 88%. We also recommend the use of the TDxFLx assay as a screening test in diabetic pregnancies. More timely patient care occurred when the rapid TDxFLx assay was implemented by the laboratory and used by clinicians.

[Prenatal prevention of respiratory distress syndrome in newborn infants]. / Prenatal forebygging av åndenødssyndrom hos nyfødte.

This article reviews the embryology, pathophysiology, clinical aspects and prophylactic treatment of respiratory distress syndrome (RDS). Prenatal prophylaxis with corticosteroids is indicated for gestational ages between 24 and 32 weeks, even if the effect of prophylaxis is uncertain before the 28th week. Prophylactic treatment is less important between the 32nd and 34th gestational week. Hypertension is not considered a contraindication, but premature rupture of the membranes is a relative contraindication. Corticosteroid treatment may be given, however, in combination with antibiotic prophylaxis.