M. Anneli Kari

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.

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.

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.

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 17α-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.

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

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.

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

BackgroundBronchopulmonary 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.MethodsGenes 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).ResultsNone 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.ConclusionsWe 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.

Expression of Airway Epithelial Sodium Channel in the Preterm Infant Is Related to Respiratory Distress Syndrome but Unaffected by Repeat Antenatal β-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 β-methasone affects postnatal expression of airway ENaC. Methods: 17 pregnant women with imminent preterm birth were randomized to receive a single repeat dose of β-methasone (12 mg) or placebo (repeat β-methasone: 8 infants, gestational age (GA) 30.8 ± 2.2 weeks; placebo: 14 infants, GA 30.4 ± 2.7 weeks). Expression of α-, β- and γENaC 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 αENaC expression at 1–5 h with GA in infants with and without RDS differed significantly (p = 0.023). At 20–29 h, αENaC expression was lower in infants with RDS (p = 0.048). Conclusions: A single repeat dose of antenatal β-methasone did not increase ENaC expression, which may in part explain the absence of reduction in RDS incidence.

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.