Acceleration Of Lung Maturation Research Articles

The effect of steroid administration on fetal diaphragm function

BackgroundAntenatal steroid administrations lead to not only accelerated lung maturation, improved blood gas measurements but also lung dynamics and lung compliance. This study aimed to investigate structural and functional changes in diaphragm after antenatal steroid administration.MethodsThe 79 volunteers were divided into 2 groups according to presence of preterm delivery. Betamethasone (CelestoneR) 12 mg intramuscularly was routinely administered to pregnancies complicated with preterm delivery between 28th -34th weeks of gestation. Same dose was repeated 24 h later. In all patients, diaphragm thickness, diaphragmatic excursion and costophrenic angle were measured in both the inspirium and expirium stage of respiration. This is an observational cross-sectional study.ResultsDiaphragm thickness, diaphragmatic excursion and diaphragm thickening fraction parameters were improved but costophrenic angle was not different 7 days after steroid administration. Diaphragm thickness, diaphragmatic excursion and costophrenic angle changes during inspiration and expiration stage after 7 days of betamethasone treatment reflects the effect of steroid administration on diaphragm muscle. Comparisons of the differences that occur after steroid rescue protocol were done by subtracting the diaphragm thickness, diaphragmatic excursion and costophrenic angle parameters before the treatment from the diaphragm thickness, diaphragmatic excursion and costophrenic angle parameters 7 days after steroid treatment respectively.ConclusionDiaphragm became more mobile in patients with preterm labor, 7 days after steroid administration. This situation reflects positive effect of steroid administration on diaphragm function.

Antenatal corticosteroids prior to planned caesarean at term for improving neonatal outcomes.

Antenatal corticosteroids prior to planned caesarean at term for improving neonatal outcomes.

Antenatal Infections and Respiratory Outcome in Preterm Infants.

Fetal exposure to infection and inflammation can result in accelerated lung maturation and simultaneously altered lung development. This alteration is characterized by reduced alveolar and vascular formation that is one of the hallmarks of the changes observed in animal models and in infants with bronchopulmonary dysplasia (BPD). These opposite effects on maturation and on lung development can explain the reduced severity of respiratory distress syndrome (RDS) but increased incidence of BPD observed in infants exposed to antenatal infections. This also explains why infants born to mothers with chorioamnionitis or colonized with ureaplasma urealitycum have an increased risk of lung injury and BPD. Despite the negative effects of infection on lung development, there is no clear evidence that antibiotic therapy improves the respiratory course in these infants. While the administration of azithromycin to ureaplasma colonized infants is effective in eradicating airway colonization, the effect on BPD is inconclusive. One of the few interventions that have been shown to improve respiratory outcome and reduce BPD in infants with severe RDS is the modulation of inflammation by the administration of systemic or intratracheal steroids early after birth. KEY POINTS: · Antenatal infection can reduce RDS.. · Fetal exposure to infection can alter lung development and increase BPD.. · The detrimental effect of infection is enhanced by mechanical ventilation..

Antenatal PPAR-γ agonist pioglitazone stimulates fetal lung maturation equally in males and females.

Antenatal steroids (ANS) accelerate fetal lung maturation and reduce the incidence of respiratory distress syndrome. However, sex specificity, i.e., being less effective in males, and potential long-term neurodevelopmental sequelae, particularly with repeated courses, remain significant limitations. The differential sex response to ANS is likely mediated via the inhibitory effect of fetal androgens on steroid's stimulatory effect on alveolar epithelial-mesenchymal interactions. Since peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists accelerate lung maturation by stimulating alveolar epithelial-mesenchymal interactions, independent of fetal sex, we hypothesized that the effect of PPAR-γ agonist pioglitazone (PGZ) would be sex-independent. Pregnant Sprague-Dawley rat dams were intraperitoneally administered dexamethasone (DEX) or PGZ on embryonic day (e) 18 and e19. At e20, pups were delivered by cesarean section, and fetal lungs and brains were examined for markers of lung maturation and apoptosis, respectively. Mixed epithelial-fibroblast cell cultures were examined to gain mechanistic insights. Antenatal PGZ increased alveolar epithelial and mesenchymal maturation markers equally in males and females; in contrast, antenatal DEX had sex-specific effects. Additionally, unlike DEX, antenatal PGZ did not increase hippocampal apoptosis. We conclude that PPAR-γ agonist administration is an effective, and probably even a superior, alternative to ANS for accelerating fetal lung maturity equally in both males and females.

Bone marrow stem cells accelerate lung maturation and prevent the LPS-induced delay of morphological and functional fetal lung development in the presence of ErbB4.

ErbB4 is a regulator in lung development and disease. Prenatal infection is an important risk factor for the delay of morphologic lung development, while promoting the maturation of the surfactant system. Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to prevent lung injury. We hypothesized that BMSCs in comparison with hematopoietic control stem cells (HPSCs) minimize the lipopolysaccharide (LPS)-induced lung injury only when functional ErbB4 receptor is present. We injected LPS and/or murine green fluorescent protein-labeled BMSCs or HPSCs into the amniotic cavity of transgenic ErbB4heart mothers at gestational day 17. Fetal lungs were analyzed 24h later. BMSCs minimized significantly LPS-induced delay in morphological lung maturation consisting of a stereologically measured increase in mesenchyme and septal thickness and a decrease of future airspace and septal surface. This effect was more prominent and significant in the ErbB4heart+/- lungs, suggesting that the presence of functioning ErbB4 signaling is required. BMSC also diminished theLPS induced increase in surfactant protein (Sftp)amRNA and decrease inSftpcmRNA is only seen if ErbB4 is present. The reduction of morphological delay of lung development and of levels of immune-modulating Sftp was more pronounced in the presence of the ErbB4 receptor. Thus, ErbB4 may be required for the protective signaling of BMSCs.

Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term.

Infants born at term by elective caesarean section are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications. The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual management without corticosteroids, in reducing neonatal respiratory morbidity and admission to special care with respiratory complications. We searched Cochrane Pregnancy and Childbirth's Trials Register (14 June 2017), and reference lists of retrieved studies. Randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation). Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. We included four trials (3956 women and 3893 neonates) at a moderate risk of bias, comparing prophylactic administration of betamethasone or dexamethasone versus placebo or usual treatment without steroids in term elective caesarean section. Women randomised to treatment group received either two intramuscular doses of betamethasone in the 48 hours before delivery, or intramuscular dexamethasone (two or four doses) prior to delivery (at 37 weeks' gestation or 48 hours before delivery), and were compared to the control group who received a saline placebo or treatment as usual.Prophylactic antenatal corticosteroid administration appeared to decrease the risk of respiratory distress syndrome (RDS) (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.87; 4 studies; 3817 participants; low-quality evidence), transient tachypnoea of the neonate (TTN) (RR 0.43; 95% CI 0.29 to 0.65; 4 studies; 3821 participants; low-quality evidence), admission to the neonatal intensive care unit (NICU) for respiratory morbidity (RR 0.42; 95% CI 0.22 to 0.79; 3 studies; 3441 participants), and admission to neonatal special care (all levels) for respiratory complications (RR 0.45; 95% CI 0.22 to 0.90; 1 study; 942 participants; low-quality evidence). Administration of antenatal corticosteroids also appeared to reduce admission to neonatal special care (RR 0.62; 95% CI 0.43 to 0.89; 2 studies; 2169 participants) and neonatal intensive care (RR 0.14; 95% CI 0.03 to 0.61; 1 study; 452 participants) for any indication, compared to placebo or usual care. Finally, prophylactic antenatal corticosteroids also appeared to reduce the length of stay in NICU by 2.70 days (mean difference (MD) -2.70; 95% CI -2.76 to -2.64; 2 studies; 32 participants).No reduction was found in the need for mechanical ventilation (RR 0.67; 95% CI 0.27 to 1.68; 3 studies; 3441 participants; very-low quality), perinatal death (RR 0.67; 95% CI 0.11 to 4.10; 4 studies; 3893 participants) or neonatal sepsis (RR 1.00; 95% CI 0.06 to 15.95; 2 studies; 2214 participants) .There were no reported events of neonatal respiratory complications (other than RDS and tachypnoea of the newborn (TTN)), chronic lung disease, duration of mechanical ventilation or maternal postpartum infection, therefore results on these outcomes are non-estimable. The studies did not provide data on other pre-defined outcomes.The quality of evidence, as assessed using GRADE was low for the outcomes of RDS, TTN and admission to NICU for respiratory morbidity, indicating that the true effect could potentially be substantially different from our estimate of effect. The results from the four trials are promising, but more high-quality studies with larger sample sizes that are adequately powered to detect the effect of prophylactic antenatal corticosteroids on outcomes of respiratory morbidity are needed, given the potential of the current studies for bias. Consideration should be given to the balance between statistical significance and clinical significance, particularly in view of the low event rates of significant respiratory morbidity (RDS or admission to NICU for respiratory complications) in this population. In addition, further trials on the long-term outcomes of these infants are needed to identify any potential harms and complications of antenatal corticosteroid administration at term.

A Combination of the Aerosolized PPAR-γ Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats

Background: Despite improvements in perinatal care, bronchopulmonary dysplasia (BPD) in extremely premature infants has not decreased. Postnatal surfactant therapy provides symptomatic relief from respiratory distress syndrome, but does not translate into a reduction in BPD. Therefore, the search for effective interventions to prevent BPD continues. Objectives: Since PPAR-γ agonists have been demonstrated to promote neonatal lung maturation and injury repair, we hypothesized that a formulation of a PPAR-γ agonist, pioglitazone (PGZ) and a synthetic lung surfactant (a surfactant protein B peptide mimic, B-YL) combined would stimulate lung maturation and block hyperoxia-induced neonatal lung injury more effectively than either modality alone. Methods: One-day-old Sprague-Dawley rat pups were administered PGZ + B-YL via nebulization every 24 h for up to 72 h. The pups were exposed to either 21 or 95% O₂, and then sacrificed. Their lungs were examined for markers of lung maturation (levels of PPAR-γ, SP-C and choline-phosphate cytidylyltransferase [CCT-α] and [³H]triolein uptake) and injury repair (bronchoalveolar lavage cell count and protein content, and levels of LEF-1, fibronectin, ALK5, and β-catenin) by Western blot analysis. Results: Markers of alveolar epithelial/mesenchymal maturation (PPAR-γ, SP-C, CCT-α, and triolein uptake) increased significantly in the PGZ + B-YL group, more than with either drug alone. Similarly, markers of hyperoxia-induced lung injury were blocked effectively with PGZ + B-YL treatment. Conclusions: Nebulized PPAR-γ agonist PGZ with a synthetic lung surfactant accelerates lung maturation and prevents neonatal hyperoxia-induced lung injury more than either modality alone, with the potential to provide more effective prevention of BPD.

Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia

BackgroundLung and pulmonary vascular maldevelopment in congenital diaphragmatic hernia (CDH) results in significant morbidity and mortality. Retinoic acid (RA) and imatinib have been shown to improve pulmonary morphology following prenatal administration in the rat nitrofen-induced CDH model. It remains unclear if these changes translate into improved function. We evaluated the effect of prenatal RA and imatinib on postnatal lung function, structure, and pulmonary artery (PA) blood flow in the rat CDH model. MethodsOlive oil or nitrofen was administered alone or in combination with RA or imatinib to pregnant rats. Pups were assessed for PA blood flow by ultrasound and pulmonary function/morphology following delivery, intubation, and short-term ventilation. ResultsNeither RA nor imatinib had a negative effect on lung and body growth. RA accelerated lung maturation indicated by increased alveoli number and thinner interalveolar septa and was associated with decreased PA resistance and improved oxygenation. With the exception of a decreased PA pulsatility index, no significant changes in morphology and pulmonary function were noted following imatinib. ConclusionPrenatal treatment with RA but not imatinib was associated with improved pulmonary morphology and function, and decreased pulmonary vascular resistance. This study highlights the potential of prenatal pharmacologic therapies, such as RA, for management of CDH.

Avoiding the prenatal programming effects of glucocorticoids: are there alternative treatments for the induction of antenatal lung maturation?

The long-term outcomes of antenatal glucocorticoids (GCs) vary between reports, and have generated controversy in terms of repeated and single-course events, causing irreversible effects on endocrine set points. This study aimed to assess the effects of alternative therapeutic agents other than synthetic glucocorticoid GC administration for fetal lung maturation. A review of literature from PubMed, EMBASE, Cochrane Library, and Google Scholar was conducted to assess the use of alternative therapies to synthetic GCs using recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). End points included the rates of respiratory distress syndrome (RDS), mRNA expression for pneumocyte type II, concentration of surfactant proteins in alveolar lavage, morphological differences, histological proof of lung maturation, and angiogenesis or quantification of the surfactant pool. In all 41 studies examined, we found that ambroxol showed positive effects on lung maturation, but it has yet to be analyzed with sufficient significance in humans. Interleukins and TNF-alpha produce accelerated lung maturation, but have only been evaluated in basic research/experimental studies. Growth factors promote structural and functional growth in all phases of lung maturation, but little is known about their reciprocal effects and exact mechanisms as therapeutics. Thyroid releasing hormone or vitamin A cause detrimental side effects or were less effective for lung maturation. The efficacy and safety of these alternative agents are differentiated and none up to now can be recommended as an alternative to GCs.

My tribute to Mary ellen avery.

My tribute to Mary ellen avery.

The effects of betamethasone on allopregnanolone concentrations and brain development in preterm fetal sheep

The risk of preterm delivery often means that the fetus will be exposed to exogenous synthetic glucocorticoids to accelerate fetal lung maturation, but effects on other organs, particularly the brain, are not understood. The neurosteroid allopregnanolone (AP) is a GABAA receptor agonist that influences fetal brain development and has neuroprotective properties. In this study we determined the impact of maternal glucocorticoid (betamethasone) administration on brain development and AP synthesis in preterm fetal sheep. Pregnant ewes underwent surgery at 105 days gestation for implantation of fetal catheters. Ewes received either betamethasone (BM; 11.4 mg; n = 10) or vehicle (saline; n = 5) by i.m injection on days five (BM1) and six (BM2) following surgery. Five fetuses of the BM treated ewes received an infusion of alfaxalone (20 mg) over 48 h commencing 30 min prior to BM1. All animals were euthanased on day 7, and the fetal brains collected to determine AP concentrations and histopathology. BM significantly reduced AP levels in the fetal brain and placental cotyledons, and also in fetal plasma without altering progesterone concentrations. There was a significant decrease in the number of myelinating cells in subcortical white matter, but no change to total oligodendrocyte number. Co-administration of the AP analogue analog alfaxalone with BM prevented this change in MBP expression. BM, given at a dose clinically prescribed to accelerate lung maturation, adversely affects neurosteroid levels in the preterm fetal brain, and affects the maturational profile of white matter development; these effects were mitigated by the co-administration of alfaxolone.

Glucocorticoid Induced Cerebellar Toxicity in the Developing Neonate: Implications for Glucocorticoid Therapy during Bronchopulmonary Dysplasia

Prematurely born infants commonly suffer respiratory dysfunction due to the immature state of their lungs. As a result, clinicians often administer glucocorticoid (GC) therapy to accelerate lung maturation and reduce inflammation. Unfortunately, several studies have found GC therapy can also produce neuromotor/cognitive deficits and selectively stunt the cerebellum. However, despite its continued use, relatively little is known about how exposure to this hormone might produce neurodevelopmental deficits. In this review, we use rodent and human research to provide evidence that GC therapy may disrupt cerebellar development through the rapid induction of apoptosis in the cerebellar external granule layer (EGL). The EGL is a transient proliferative region responsible for the production of over 90% of the neurons in the cerebellum. During normal development, endogenous GC stimulation is thought to selectively signal the elimination of the EGL once production of new neurons is complete. As a result, GC therapy may precociously eliminate the EGL before it can produce enough neurons for normal cerebellar function. It is hoped that this review may provide information for future clinical research in addition to translational guidance for the safer use of GC therapy.

Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-β signaling

There is no effective intervention to prevent or treat bronchopulmonary dysplasia (BPD). Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-γ (PPARγ), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-β. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O(2) for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPARγ, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPARγ and ADRP) and increase (α-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-β signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O(2) for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPARγ, ADRP, fibronectin, TGF-β receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-β activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxia-induced neonatal lung injury, possibly by blocking TGF-β activation, suggesting that it is a potential intervention against BPD.

Programming Effects of Antenatal Corticosteroids Exposure in Male Sexual Behavior

Brain regions implicated in sexual behavior begin to differentiate in the last trimester of gestation. Antenatal therapy with corticosteroids is often used in clinical practice during this period to accelerate lung maturation in preterm-risk pregnancies. Clinical and animal studies highlighted major behavioral impairments induced later in life by these treatments, especially when synthetic corticosteroids are used. To evaluate the implications of acute prenatal treatment with natural vs. synthetic corticosteroids on adult male rat sexual behavior and its neurochemical correlates. Twelve pregnant Wistar rats were injected with dexamethasone (DEX-1 mg/kg), corticosterone (CORT-25 mg/kg), or saline on late gestation (pregnancy days 18 and 19). Following this brief exposure to corticosteroids, we assessed the sexual behavior of the adult male progeny and subsequently associated these behaviors with the levels of catecholamines and mRNA of dopamine and androgen receptors (AR) in brain regions relevant for sexual behavior. Sexual behavior of adult male offspring was assessed by exposure to receptive females. This was associated with serum testosterone levels and levels of catecholamines (determined by high-performance liquid chromatography) and dopamine and AR mRNA expression (real-time polymerase chain reaction [PCR]) in brain regions implicated in sexual behavior. Prenatal DEX exposure resulted in a decreased number and increased mounts and intromissions latencies in adulthood. These findings were associated with decreased levels of serum testosterone and increased hypothalamic expression of AR mRNA. DEX animals also displayed lower dopamine levels and higher dopamine receptor mRNA expression both in hypothalamus and nucleus accumbens (NAcc). The milder phenotype of CORT animals was associated only with decreased dopamine levels in NAcc. Antenatal corticotherapy programs adult male sexual behavior through changes in specific neuronal and endocrine mediators. Importantly, equipotent doses of CORT trigger less detrimental consequences than DEX, emphasizing the differential impact of activation of the different corticosteroid receptors.

Transient in utero nicotine exposure stimulates mechanosensory-dependent lung development

ABSTRACTNicotine receptors are present in the developing lung yet their function is unknown. The transient role of nicotine receptors in lung development has not been addressed. In this study, nicotine's direct effect on smooth muscle contraction, necessary for mechanosensory-dependent fetal lung development, is examined after transient nicotine stimulation to determine the relationship between nicotine exposure, smooth muscle contraction, and fetal lung development. Rat fetuses at 16 days’ gestation were exposed in utero to 5 different concentrations of nicotine or control injected directly into the amniotic fluid. Specific concentrations of in utero nicotine increased the phosphorylated Western blot analysis and immunohistochemistry of muscle contraction proteins. Respiratory function tests on nicotine-exposed rat pups showed a statistically significant decrease in airway resistance earlier in life compared to control and an upward shift of the pressure-volume curve pointing towards a structural maturation of the in utero nicotine-exposed lung. These results are consistent with transient nicotine exposure during intrauterine life stimulating stretch-induced lung organogenesis by altering phosphorylation of muscle contraction proteins. The increase in smooth muscle phosphorylation may stimulate stretch-induced lung organogenesis, which affects lung development and accelerates lung maturation in rats.

Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

The physiological development and homeostasis of the lung alveolus is determined by the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) by the interstitial lipofibroblast. We have recently shown (Dasgupta C et al., Am J Physiol Lung Cell Mol Physiol 296: L1031-L1041, 2009.) that PPAR-γ agonists administered postnatally accelerate lung maturation and prevent hyperoxia-induced lung injury. However, whether the same occurs antenatally is not known. The objective of this study was to test the hypothesis that the potent PPAR-γ agonist rosiglitazone (RGZ), administered antenatally, enhances fetal lung maturation and protects against hyperoxia-induced neonatal lung injury. Sprague-Dawley rat dams were administered either diluent or RGZ (3 mg/kg), at late gestation, to determine its effect on lung maturation and on hyperoxia (95% O(2) exposure for 24 h)-induced neonatal lung injury. The lungs were examined for the expression of specific markers of alveolar development (surfactant proteins A and B, cholinephosphate cytidylyltransferase-α, leptin receptor, triglyceride uptake, and [(3)H]choline incorporation into saturated phosphatidylcholine) and injury/repair, in particular, the markers of transforming growth factor-β signaling (activin receptor-like kinase-5, SMAD3, lymphoid enhancer factor-1, fibronectin, and calponin). Overall, antenatal RGZ accelerated lung maturation and blocked the inhibition of alveolar sacculation and septal wall thinning by hyperoxia. RGZ specifically stimulated the development of the alveolar epithelial type II cell, the lipofibroblast, and the vasculature. The increased expression of the transforming growth factor-β intermediates, such as SMAD3 and lymphoid enhancer factor-1, implicated in hyperoxic lung injury, was also blocked by antenatal RGZ treatment. In conclusion, PPAR-γ agonists can enhance fetal lung maturation and can effectively prevent hyperoxia-induced neonatal lung injury.

The Effect of Intrauterine Growth Restriction on Circulating Surfactant Protein D Concentrations in the Perinatal Period

The aim of this study was to investigate possible alterations in circulating concentrations of surfactant protein D (SP-D)-an important component of the innate immune system that is upregulated in pulmonary diseases-in appropriate for gestational age (AGA) and intrauterine growth-restricted (IUGR) pregnancies, because the latter are characterized by structural lung immaturity, impaired immunocompetence, and increased risk of respiratory infections and chronic obstructive lung disease in later life. Serum SP-D concentrations were determined in 40 mothers and their 20 IUGR and 20 AGA full-term fetuses-neonates on postnatal day 1 (N1) and 4 (N4). Fetal SP-D concentrations were higher in the IUGR group (b = 18.16, 95% CI: 6.86-29.47, P = .002) and negatively correlated with infants' customized centiles and gestational age (r = -.326, P = .04, and r = -.446, P = .004, respectively). In both groups, fetal SP-D concentrations were lower than N1 and N4 ones (P <or= .015 in all cases). In the IUGR group, N1 SP-D concentrations were higher in vaginal deliveries (P = .032). Higher SP-D concentrations in IUGR fetuses may reflect structural lung immaturity, leading to increased alveolar-vascular permeability and protein leakage into the circulation. Alternatively, SP-D production may be increased due to intrauterine glucocorticoid exposure, leading to accelerated lung maturation. Surfactant protein D concentrations postnatally increase and are higher in neonates born vaginally, probably as a consequence of lung liquid reabsorption, concomitant with initiation of breathing and delivery stress. A progressive decrease in placental function may result in downregulated SP-D production, accounting for the negative correlation between fetal SP-D concentrations and gestational age.

Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term

Infants born at term by elective caesarean delivery are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications. The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual management without corticosteroids, in reducing neonatal respiratory morbidity and admission to special care with respiratory complications. We searched the Cochrane Pregnancy and Chilbirth Group's Trials Register (30 June 2009). Randomised and quasi-randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation). The co-authors assessed the results of the only available trial independently to retrieve data on perinatal outcomes. Results were expressed as risk ratio (RR) or mean differences (MD), together with their 95% confidence intervals (CI). One study comparing prophylactic administration of betamethasone (N = 467) versus usual treatment without steroids (N = 475) in term elective caesarean section was included in the review. Women randomised to treatment group received two intramuscular doses of betamethasone in the 48 hours before delivery, whereas the control group received treatment as usual.Prophylactic betamethasone appeared to significantly decrease the risk of admission to the neonatal intensive care unit for respiratory morbidity (RR 0.15; 95% CI 0.03 to 0.64). However, no statistically significant reduction was found in the incidence of neonatal respiratory distress syndrome (RR 0.32; 95% CI 0.07 to 1.58), transient tachypnoea of the newborn (RR 0.52; 95% CI 0.25 to 1.11), need for mechanical ventilation (RR 4.07; 95% CI 0.46 to 36.27) and length of stay in neonatal intensive care unit (MD) -2.14 days; 95% CI -5.58 to 1.30).There were no reported events of neonatal sepsis, perinatal deaths or maternal trauma infection, therefore results on these outcomes are non-estimable. The study did not provide data on other pre-defined outcomes. The results from the single trial are promising, but more studies with larger samples are needed to investigate the effect of prophylactic steroids in the incidence of neonatal complications per se. Also more data and longer follow up would be needed for potential harms and complications.

Maternal Endotoxin-Induced Preterm Birth in Mice: Fetal Responses in Toll-Like Receptors, Collectins, and Cytokines

Major cause of prematurity is spontaneous preterm birth (PTB) associated with intrauterine inflammation. Our aim was to establish a model of endotoxin Lipopolysaccharide-induced PTB of live-born pups and to study early immune activation in fetal and maternal compartments. Expression of several proteins that bind microbes (Toll-like receptors TLR4, TLR2; surfactant proteins SP-A, SP-D) was analyzed. At 16 or 17 d of gestation, C57BL/6 dams received a single dose of intraperitoneal LPS, leading to PTB within 17 h. Cytokine levels increased in maternal serum, followed by a modest increase in fetal serum and in amniotic fluid. In uterus, placenta, and fetal membranes, LPS mostly increased the expressions of TLR, SPs, and cytokines. The number of TLR2-positive macrophages increased in labyrinthine placenta. In fetal lung, intestine, liver, and brain there were modest changes in cytokine expressions. In fetal lung, SP and TLR mRNAs decreased and TLR2-positive macrophages redistributed around vessels. LPS-induced fetal deaths associated with early age (16 d gestation) rather than with proinflammatory activation. Here we propose that maternal LPS response leads to PTB and acute decrease of immune proteins in epithelial lining of fetal lung. Instead, acceleration of lung maturity has been previously observed in intraamniotic inflammation.

Pathophysiology and Prevention of Bronchopulmonary Dysplasia

BPD is the major respiratory complication of preterm delivery and is typified by chronic oxygen dependency and respiratory insufficiency beyond 36 weeks postconceptional age. It is caused by a combination of insults on the developing lung precipitated by preterm birth and its subsequent respiratory management. The common pathway linking the various causative factors is inflammation, which may be initiated prior to birth in the setting of maternal chorioamnionitis, or after birth by mechanical ventilation, infection or oxidative stress. Inflammation in the developing lung induces airways remodeling which adversely affects lung function. Multiple inflammatory mediators are implicated in this process and modifying the course of the disease has proven difficult. The emphasis of management should be directed towards prevention with strategies aimed at minimizing early lung injury and oxidative stress. These include delivery room stabilization and mechanical ventilation techniques that aim to avoid volutrauma and atelectotrauma. Drugs may also influence BPD progression and can broadly be divided into three categories; those administered prenatally to accelerate lung maturation, those administered postnatally to reduce initiation of inflammatory stimuli and those to modify any established inflammatory response. In this review we have examined recent evidence for each of these ventilatory and therapeutic strategies to prevent BPD. A better understanding of the pathophysiology of airways remodeling in BPD could have significant implications for future potential targeted interventions.