Outi Peltoniemi

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.

Two-year follow-up of a randomised trial with repeated antenatal betamethasone

Background: Weekly repeated antenatal corticosteroid treatment improves respiratory outcome but decreases fetal growth and may impair neurodevelopmental outcome. We have previously reported that a single repeat betamethasone (BM) dose neither decreased fetal growth nor improved the outcome of preterm infants during the first hospitalisation. Objective: To study prospectively whether a single repeat dose of BM influences neurodevelopment and growth within 2 years. Design: Women with imminent delivery before 34.0 gestational weeks were eligible if they remained undelivered for >7 days after a single course of antenatal BM. After stratification, a single repeat dose of BM (12 mg) or placebo was given. The children underwent neurological and psychometric examinations and a speech evaluation at a corrected age of 2 years. Setting: Prospective, blinded evaluation following the randomised multicentre trial. Patients: 259 (82%) surviving infants completed the 2-year follow-up, 120 in the BM group and 139 in the placebo group. Results: The rate of survival without severe neurodevelopmental impairment was similar in both groups (BM 98%, placebo 99%). The risk of cerebral palsy (BM 2%, placebo 1%), growth or re-hospitalisation rates (BM 60%, placebo 50%) did not differ between the groups. Conclusions: A single repeat dose of antenatal BM tended not to influence physical growth or neurodevelopment at 2 years of age.

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.

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.

Repeat prenatal corticosteroid prior to preterm birth: a systematic review and individual participant data meta-analysis for the PRECISE study group (prenatal repeat corticosteroid international IPD study group: assessing the effects using the best level of evidence) - study protocol

BackgroundThe aim of this individual participant data (IPD) meta-analysis is to assess whether the effects of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their babies are modified in a clinically meaningful way by factors related to the women or the trial protocol.Methods/DesignThe Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE) Group will conduct an IPD meta-analysis. The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis. The primary study outcomes for the infants will be serious neonatal outcome (defined by the PRECISE International IPD Study Group as one of death (foetal, neonatal or infant); severe respiratory disease; severe intraventricular haemorrhage (grade 3 and 4); chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular leukomalacia); use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory support); and birth weight (Z-scores). For the children, the primary study outcomes will be death or any neurological disability (however defined by trialists at childhood follow up and may include developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness (for example, corrected visual acuity worse than 6/60 in the better eye) or deafness (for example, hearing loss requiring amplification or worse)). For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics; or postnatal pyrexia).DiscussionData analyses are expected to commence in 2011 with results publicly available in 2012.

Early Neonatal Hydrocortisone: Study Rather Than Treat

Hydrocortisone at doses corresponding or exceeding the endogenous corticosteroid secretion during stress has been studied in randomized trials since the early 1970s.1 Lately, the aim has been to stabilize very low blood pressure or decrease the risk of bronchopulmonary dysplasia (BPD).2,3 According to experimental studies, the beneficial hemodynamic effects are largely a result of an increase in myocardial smooth muscle contractility.4 Corticosteroids increase cardiovascular adrenergic receptors and enhance the microvascular endothelial barrier function, and hydrocortisone has a mineralocorticoid-mediated effect on cardiac muscle. Closure of patent ductus arteriosus (PDA) is promoted by corticosteroid, which also decreases the synthesis of prostaglandins and endothelial nitric-oxide synthetase.5 The blood pressure is just one function that, together with perfusion resistance and oxygen carrying capacity of the blood, determine the oxygen delivery to the tissue. The pressure-passive cerebral perfusion evident in some very preterm infants argues for interventions that increase and stabilize the perfusion pressures. Beneficial hemodynamic effects of hydrocortisone have been observed in randomized, placebo-controlled trials. In a single-center randomized trial of 48 preterm infants (mean gestational age: 26.6 weeks; birth weight [BW]: <1500 g [mean: 920 g]), hydrocortisone was given at 3 mg/kg per day, divided into 3 intravenous injections for 4 days, starting during the first week (a mean of 11 hours after birth) for treatment of refractory hypotension.3 Despite an increase in mean blood pressure, there was a decrease in the requirement for dopamine, dobutamine, and saline infusions and no detectable effects on PDA or other outcomes. In 3 randomized trials in which the influence of early neonatal hydrocortisone on survival without BPD was studied, the acute hemodynamic changes … Address correspondence to Mikko Hallman, MD, PhD, Department of Pediatrics, University of Oulu, PO Box 5000, University of Oulu, FIN-90014 Oulu, Finland. E-mail: mikko.hallman{at}oulu.fi

Blood glucose level in preterm infants after antenatal exposure to glucocorticoid.

Aim: To determine the impact of antenatal glucocorticoid on neonatal glucose homeostasis.

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.

Expressive Language Skills in Finnish Two-Year-Old Extremely- and Very-Low-Birth-Weight Preterm Children

Objective: Preterm children with low birth weight are at greater risk of experiencing speech and language difficulties than full-term children. The aim of the current study was to investigate expressive language skills of Finnish-speaking preterm children with low birth weight [extremely-low-birth-weight (ELBW) children: n = 8; very-low-birth-weight (VLBW) children: n = 10] at 2 years of corrected age and to compare their language results with full-term controls (n = 18), using spontaneous speech samples. Methods: The children were video recorded in semistructured free-play sessions with their mothers. From these video samples, expressive vocabulary size and maximum sentence length (MSL) were analyzed. In addition, the possible effect of children’s gender on language measures as well as associations between different language measures were examined. Results: The results showed that there was no statistically significant difference between the preterm and full-term groups in the size of expressive vocabulary. In contrast, the MSL, which measures morphosyntactic skills, was significantly shorter in preterm children. A positive correlation was found between MSL and expressive vocabulary. Children’s gender was not associated with language skills measured. Conclusion: The findings indicate that Finnish-speaking preterm children, especially ELBW children, experience difficulties in morphosyntactic skills.