Glucocorticoids, sodium transport mediators, and respiratory distress syndrome in preterm infants.

BACKGROUND: Antenatal glucocorticoids (GCs) reduce respiratory distress syndrome (RDS) in preterm infants and are associated with reduced lung liquid content. Our aim was to assess whether airway gene expression of mediators of pulmonary epithelial sodium and liquid absorption, and further, respiratory morbidity, associate with cord blood GC concentrations. METHODS: The study included 64 infants delivered <32 weeks gestation. Cortisol and betamethasone in umbilical cord blood were quantified with liquid chromatography-tandem mass spectrometry. The total GC concentration was calculated. Gene expression of the epithelial sodium channel (ENaC), Na,K-ATPase, and serum- and GC-inducible kinase 1 at <2 h and at 1 day postnatally in nasal epithelial cell samples was quantified with reverse transcription-polymerase chain reaction. The mean oxygen supplementation during the first 72 h was calculated. RESULTS: Concentrations of cord blood betamethasone and total GC were significantly lower in infants with RDS and correlated with mean oxygen supplementation. Expression of αENaC and α1- and ß1Na,K-ATPase at <2 h correlated with betamethasone and total GC concentrations. Expression of Na,K-ATPase was lower in infants with RDS. CONCLUSION: Enhancement of lung liquid absorption via increased expression of sodium transporters may contribute to the beneficial pulmonary effects of antenatal GCs. IMPACT: RDS is related to lower umbilical cord blood GC concentrations and lower airway expression of sodium transporters. In addition to the timing of antenatal GC treatment, resulting concentrations may be of importance in preventing RDS. Induction of sodium transport may be a factor contributing to the pulmonary response to antenatal GCs.

Randomised trial of early neonatal hydrocortisone demonstrates potential undesired effects on neurodevelopment at preschool age.

AIM: We evaluated the neurodevelopment and growth of five- to seven-year-old children who had participated in a randomised trial of early low-dose hydrocortisone treatment to prevent bronchopulmonary dysplasia. METHODS: The 51 infants in the original study had birthweights of 501-1250 g and gestational ages of 23-30 weeks, required mechanical ventilation during the first 24 hours and received hydrocortisone or a placebo for 10 days. The majority (80%) of the 90% who survived to five- to seven years of age participated in this follow-up study and their growth, neuromotor, cognitive and speech development were evaluated. RESULTS: Some neurodevelopment impairment was observed in 61% of the hydrocortisone group and 39% of the placebo group, ranging from minor neurological dysfunction to severe neurological conditions (p = 0.182). The mean full-scale intelligence quotient (IQ) was 87.8 (15.3) in the hydrocortisone group and 95.7 (15.0) in the placebo group (p = 0.135), and the mean performance IQ was 88.3 (14.5) and 99.1 (14.0) (p = 0.034), respectively. A fifth (22%) of the hydrocortisone group required physiotherapy, but none of the placebo group did (p = 0.034). The age-standardised growth was comparable between both groups. CONCLUSION: Early hydrocortisone treatment may have undesired effects on neurodevelopment at preschool age, and further safety studies are required.

A study of genes encoding cytokines (IL6, IL10, TNF), cytokine receptors (IL6R, IL6ST), and glucocorticoid receptor (NR3C1) and susceptibility to bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease associated with very preterm birth. The major risk factors include lung inflammation and lung immaturity. In addition, genetic factors play an important role in susceptibility to moderate-to-severe BPD. In this study, the aim was to investigate whether common polymorphisms of specific genes that are involved in inflammation or differentiation of the lung have influence on BPD susceptibility. METHODS: Genes encoding interleukin-6 (IL6) and its receptors (IL6R and IL6ST), IL-10 (IL10), tumor necrosis factor (TNF), and glucocorticoid receptor (NR3C1) were assessed for associations with moderate-to-severe BPD susceptibility. Five IL6, nine IL6R, four IL6ST, one IL10, two TNF, and 23 NR3C1 single nucleotide polymorphisms (SNPs) were analyzed in very preterm infants born in northern Finland (56 cases and 197 controls) and Canada (58 cases and 68 controls). IL-6, TNF and gp130 contents in umbilical cord blood, collected from very preterm infants, were studied for associations with the polymorphisms. Epistasis (i.e., interactions between SNPs in BPD susceptibility) was also examined. SNPs showing suggestive associations were analyzed in additional replication populations from Finland (39 cases and 188 controls) and Hungary (29 cases and 40 controls). RESULTS: None of the studied SNPs were associated with BPD nor were the IL6, TNF or IL6ST SNPs associated with cord blood IL-6, TNF and gp130, respectively. However, epistasis analysis suggested that SNPs in IL6ST and IL10 were associated interactively with risk of BPD in the northern Finnish population; however, this finding did not remain significant after correction for multiple testing and the finding was not replicated in the other populations. CONCLUSIONS: We conclude that the analyzed SNPs within IL6, IL6R, IL6ST, IL10, TNF, and NR3C1 were not associated with BPD. Furthermore, there was no evidence that the studied SNPs directly contribute to the cord blood protein contents.

Repeated antenatal corticosteroid treatment: a systematic review and meta-analysis.

OBJECTIVE: To systematically review the efficacy and safety of repeated antenatal corticosteroid on neonatal morbidity, growth and later development. DESIGN: MEDLINE, Cochrane database and a bibliography of identified articles were searched for English language studies. Design. Meta-analysis of randomized controlled trials. SAMPLE: Randomized, controlled trials studying the efficacy and safety of repeat antenatal corticosteroid treatment on neonatal morbidity and early childhood development. MAIN OUTCOME MEASURES: Respiratory distress syndrome, intrauterine growth, neurodevelopment. METHODS: Two reviewers independently assessed titles, abstracts and full studies, extracted data and assessed quality. Meta-analyses were performed, calculating risk ratios and weighted differences of means with 95% confidence intervals using a random-effects model. RESULTS: Eight trials were included. Repeated betamethasone treatment decreased the risk of respiratory distress syndrome (relative risk 0.85, 95% confidence interval 0.77-0.93). Trials involving weekly or biweekly repeated betamethasone and those involving a single rescue dose decreased the risk of respiratory distress syndrome. Intrauterine growth was significantly restricted among preterm infants exposed to weekly or biweekly repeated betamethasone. A single rescue course did not affect growth. Four follow-up studies did not reveal any disturbances in neurodevelopment or growth at two years of corrected age. CONCLUSIONS: Repeated corticosteroid treatment decreased the risk of respiratory distress syndrome among preterm infants. Weekly or biweekly repeated betamethasone restricted intrauterine growth, which raises concerns about long-term consequences on neurodevelopment and metabolism. More follow-up studies are needed to confirm the long-term safety of repeated betamethasone.

Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene.

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10-6). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10-4) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10-5), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.

Exhaled nitric oxide at school age in prematurely born infants with neonatal chronic lung disease.

Prematurely born infants with neonatal chronic lung disease (CLD) have increased respiratory morbidity and bronchial obstruction at school age. To evaluate the possible inflammatory basis of lung function abnormalities, we studied 40 children, 7.5-9.6 years of age, born very prematurely (birth weights, 600-1,575 g) and 14 nonatopic term-born controls, using flow-volume spirometry and exhaled nitric oxide (eNO) measurements. In children born prematurely, eNO was significantly higher in atopics than in nonatopics (respective means, 14.8 vs. 6.3 ppb, P = 0.02). Nonatopic prematurely born infants did not differ significantly from controls (means, 6.3 vs. 6.4 ppb, P = ns). Of the 27 nonatopic children not on regular glucocorticoid inhalations, 9 had a history of CLD. Spirometry indicated bronchial obstruction and values that were significantly lower in prematurely born infants with or without CLD than in controls, and they were lower in the CLD than the non-CLD group. However, no significant differences were observed in eNO levels between CLD, non-CLD, and control groups (means, 6.8, 5.9, and 6.4 ppb, P = ns). In nonatopic schoolchildren born very prematurely and with a history of CLD, we found no evidence of airway inflammation associated with increased eNO concentrations. Neither were eNO levels associated with severity of chronic lung disease, as determined by conventional lung function tests. eNO levels were higher in atopic children born prematurely than in controls.

Enhancing functional maturity before preterm birth.

Enhancing functional maturity of the high-risk preterm fetus is aimed at decreasing the life-threatening neonatal disorders that increase the burden of chronic disease. A course of antenatal glucocorticoids before 35 weeks of pregnancy substitutes endogenous activation of the hypothalamic-adrenal axis that spontaneously enhances functional maturity and augments cytokine-induced preterm lung maturity. It is the main fetal therapy that decreases the functional prematurity-related neonatal morbidity in the era of surfactant therapy. Tocolytic agents potentiate the effect of glucocorticoids on the fetus. Repeating an antenatal glucocorticoid course may be recommended if the preterm fetus remains undelivered for more than 7 days and very preterm birth is imminent. However, the follow-up results are still incomplete, and available preliminary studies warn against adverse neurological and metabolic consequences following several antenatal repeat courses of glucocorticoids. Administration of glucocorticoids after 34 weeks of pregnancy may be considered in selected high-risk cases, preferably with documented lung immaturity. We recommend delaying elective delivery in low-risk pregnancies without established lung maturity until 40 weeks, unless labor starts earlier. In a selected high-risk population 17alpha-hydroxyprogesterone acetate decreases the prematurity rate. However, this drug has a limited impact on functional maturity of the preterm fetus and its effects on the development of the child remain to be studied further.

Expression of airway epithelial sodium channel in the preterm infant is related to respiratory distress syndrome but unaffected by repeat antenatal beta-methasone.

BACKGROUND: The airway epithelial sodium channel (ENaC) is rate limiting for postnatal alveolar fluid clearance. Increased lung water content is a feature of respiratory distress syndrome (RDS), which is reduced by antenatal corticosteroid treatment in preterm infants. OBJECTIVES: Since corticosteroids also induce ENaC gene expression, we studied whether a repeat dose of antenatal beta-methasone affects postnatal expression of airway ENaC. METHODS: 17 pregnant women with imminent preterm birth were randomized to receive a single repeat dose of beta-methasone (12 mg) or placebo (repeat beta-methasone: 8 infants, gestational age (GA) 30.8 +/- 2.2 weeks; placebo: 14 infants, GA 30.4 +/- 2.7 weeks). Expression of alpha-, beta- and gammaENaC subunits in nasal epithelium 1-5 and 20-29 h postnatally was analyzed with reverse transcription-PCR. RESULTS: There were no differences between the study groups in RDS incidence or ENaC subunit expression (all p > 0.38). Regression coefficients for association of alphaENaC expression at 1-5 h with GA in infants with and without RDS differed significantly (p = 0.023). At 20-29 h, alphaENaC expression was lower in infants with RDS (p = 0.048). CONCLUSIONS: A single repeat dose of antenatal beta-methasone did not increase ENaC expression, which may in part explain the absence of reduction in RDS incidence.

Trial of early neonatal hydrocortisone: two-year follow-up.

BACKGROUND: Dexamethasone treatment is associated with an increased risk of cerebral palsy (CP). Early hydrocortisone (HC) treatment may decrease the incidence of bronchopulmonary dysplasia; however, the long-term effects are still under evaluation. Follow-up of randomized studies concerning early HC treatment is essential to confirm the long-term safety. OBJECTIVE: We hypothesized that early HC treatment in very preterm infants does not impair the neurologic outcome. METHODS: We report follow-up data from a randomized trial of early HC given for 10 days. Before the HC or placebo treatment, serum cortisol levels were measured. Receiver-operating characteristic was defined. Values below the median were classified as low endogenous cortisol and those above the median as high endogenous cortisol. A meta-analysis was performed. RESULTS: Altogether 98% of the 46 surviving infants participated in a follow-up study at a corrected age of 2 years. The growth characteristics were similar between the study groups. The developmental quotients (DQs) of the children with high endogenous cortisol and placebo treatment shortly after birth (100 +/- 13) and those with low endogenous cortisol and HC (97 +/- 7) were not lower than the DQs of the children with high endogenous cortisol and HC (92 +/- 3) or low cortisol and placebo (96 +/- 2). According to a meta-analysis of three available trials (411 children), the rate of CP and survival without neurosensory or cognitive impairment was not influenced by HC. CONCLUSION: Early low-dose HC administration had no adverse effects at 2 years of age. Further studies are required to define the target group for neonatal HC.

Antenatal betamethasone and fetal growth in prematurely born children: implications for temperament traits at the age of 2 years.

OBJECTIVE: We explored whether repeated dose of antenatal betamethasone and variation in intrauterine growth of prematurely born children predict temperament characteristics at the age of 2 years. PATIENTS AND METHODS: The patients (n = 142) were prematurely born children (mean gestational age: 31.0 weeks; range: 24.6-35.0 weeks) who participated in a randomized and blinded trial testing the effects of a repeated dose of antenatal betamethasone in imminent preterm birth. Fetal growth was estimated as weight, length, and head circumference in SDs according to Finnish growth charts. Parents assessed their toddlers' temperament with 201 items of the Early Childhood Temperament Questionnaire (mean child corrected age: 2.1 years). RESULTS: No significant main effects of repeated betamethasone on toddler temperament existed. However, a significant interaction between study group and duration of exposure to betamethasone emerged; those exposed to a repeated dose for >24 hours before delivery were more impulsive. One-SD increases in weight, length, and head circumference at birth were associated with 0.14- to 0.19-SD lower levels of negative affectivity (fearfulness, anger proneness, and sadness); 1-SD increases in length, weight, and head circumference at birth were associated with 0.14- to 0.18-SD higher levels of effortful control (self-regulation). CONCLUSIONS: Repeated antenatal betamethasone did not induce alterations in toddler temperament. The results, however, suggest that a longer duration of exposure is associated with higher impulsivity scores. Regardless of betamethasone exposure, slower fetal growth exerted influences on temperament. Our findings indicate prenatal programming of psychological development and imply that more attention is needed to support the development of infants born at the lower end of the fetal growth distribution.

Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth.

BACKGROUND: A single dose of prenatal betamethasone treatment decreases neonatal morbidity rates when administered within 7 days before preterm delivery. A single repeat dose or booster dose of betamethasone before delivery has been proposed to be effective, but its efficacy has not been subjected to a randomized, blinded trial. METHODS: Women with imminent delivery before 34.0 gestational weeks were eligible if they remained without delivery for >7 days after a single course of betamethasone. After stratification, a single repeat dose of betamethasone (12 mg) or placebo was administered. The primary outcome was survival without respiratory distress syndrome or severe intraventricular hemorrhage (grade 3 or 4). RESULTS: A total of 249 mothers had been enrolled by the time the study was discontinued. All of the 159 infants in the betamethasone group and 167 in the placebo group were born before 36 weeks of gestation. The intact survival rate was unaffected and was lower than anticipated, because the gestational age-adjusted incidence of respiratory distress syndrome was higher than the population incidence. The requirement for surfactant therapy in respiratory distress syndrome was increased in the betamethasone group. According to posthoc analysis of the data for 206 infants who were delivered within 1 to 24 hours, the betamethasone booster tended to increase the risk of respiratory distress syndrome and to decrease intact survival rates. CONCLUSIONS: According to this study, a single booster dose of betamethasone just before preterm birth may perturb respiratory adaptation. These results caution against uncontrolled use of a repeat dose of glucocorticoid in high-risk pregnancies.

Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants.

OBJECTIVES: To investigate the effect of hydrocortisone treatment on survival without bronchopulmonary dysplasia (BPD) and to study whether serum cortisol concentrations predict the response. STUDY DESIGN: We performed a randomized, placebo-controlled trial on infants with gestation < or =30 weeks, body weight of 501 to 1250 g, and respiratory failure. Hydrocortisone was started before 36 hours of age and given for 10 days at doses from 2.0 to 0.75 mg/kg per day. Shortly before hydrocortisone treatment, basal and stimulated (ACTH, 0.1 microg/kg) serum cortisols were measured. RESULTS: The study was discontinued early, because of gastrointestinal perforations in the hydrocortisone group (4/25 vs 0/26, P = .05); 3 of the 4 had received indomethacin/ibuprofen. The incidence of BPD (28% vs placebo 42%, P = 0.28) tended to be lower, and patent ductus arteriosus (36% vs 73%, P = .01) was lower in the hydrocortisone group. The hydrocortisone-treated infants with serum cortisol concentrations above the median had a high risk of gastrointestinal perforation. In infants with cortisol values below the median, hydrocortisone treatment increased survival without BPD. CONCLUSIONS: Serum cortisol concentrations measured shortly after birth may identify those very high-risk infants who may benefit from hydrocortisone supplementation.