Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis.

BACKGROUND: Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors. METHODS AND FINDINGS: Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach. Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference -0.12, 95%CI -0.18 to -0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2-5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes. CONCLUSIONS: In this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg.

Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis.

OBJECTIVE: To assess the effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone on survival without bronchopulmonary dysplasia (BPD) in very preterm infants using an individual patient data meta-analysis. STUDY DESIGN: All existing randomized controlled trials testing the efficacy of the prophylaxis of early adrenal insufficiency using low-dose hydrocortisone on survival without BPD were considered for inclusion when data were available. The primary outcome was the binary variable survival without BPD at 36 weeks of postmenstrual age. RESULTS: Among 5 eligible studies, 4 randomized controlled trials had individual patient data available (96% of participants identified; n = 982). Early low-dose hydrocortisone treatment for 10-15 days was associated with a significant increase in survival without BPD (OR, 1.45; 95% CI, 1.11-1.90; P = .007; I2 = 0%), as well as with decreases in medical treatment for patent ductus arteriosus (OR, 0.72; 95% CI, 0.56-0.93; P = .01; I2 = 0%) and death before discharge (OR, 0.70; 95% CI, 0.51-0.97; P = .03; I2 = 0%). The therapy was associated with an increased risk of spontaneous gastrointestinal perforation (OR, 2.50; 95% CI, 1.33-4.69; P = .004; I2 = 31.9%) when hydrocortisone was given in association with indomethacin exposure. The incidence of late-onset sepsis was increased in infants exposed to hydrocortisone (OR, 1.34; 95% CI, 1.02-1.75; P = .04; I2 = 0%), but no adverse effects were reported for either death or 2-year neurodevelopmental outcomes as assessed in an aggregate meta-analysis. CONCLUSIONS: This individual patient data meta-analysis showed that early low-dose hydrocortisone therapy is beneficial for survival without BPD in very preterm infants.

Pediatric Intensive Care in PICUs and Adult ICUs: A 2-Year Cohort Study in Finland.

OBJECTIVES: To investigate the association between the type of ICU and mortality for children treated at PICUs and adult ICUs. DESIGN: This was a national multicenter cohort study. Data were collected from electronic critical care data management systems at 3 units and from national intensive care registries at 26 units. SETTING: We assessed the incidence of admissions, length of stay at ICUs, main diagnoses, and mortality for children at ICUs. Units were categorized as PICUs or as adult ICUs located at university hospitals or at non-academic central hospitals. PATIENTS: Children younger than 17 years of age treated at ICUs in Finland. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: There were 4,876 admissions from 2009 to 2010, and 98.9% of patients survived until unit discharge. The mean length of stay was 3.0 ± 7.4 days; 1,395 patients (35%) required mechanical ventilation at PICUs versus 167 (35%) at adult university hospital ICUs versus 79 (19%) at central hospital ICUs (p < 0.001). The odds for mortality in univariate regression analysis were emergency admission (odds ratio, 3.99; 95% CI, 1.82-8.76), cardiovascular (odds ratio, 7.84; 95% CI, 3.49-22.88), gastrointestinal (odds ratio, 5.37; 95% CI, 1.45-19.88), acute infections (odds ratio, 2.83; 95% CI, 1.23-6.48), hematologic/oncologic disease (odds ratio, 10.32; 95% CI, 3.14-33.86), and nonsurgical trauma (odds ratio, 3.53; 95% CI, 1.19-10.41). Treatment at adult ICUs had higher odds of mortality compared with PICUs (university hospital: odds ratio, 3.93; 95% CI, 1.85-8.35 and central hospital: odds ratio, 3.91; 95% CI, 1.69-9.05), adjusted for readmission less than 48 hours after discharge, emergency admission, mechanical ventilation, and diagnostic group. CONCLUSIONS: Pediatric patients treated at PICUs showed lower mortality. Requirement of mechanical ventilation, emergency admission, and readmission less than 48 hours after discharge and cardiovascular, gastrointestinal, acute infections, hematologic/oncologic disease, and nonsurgical trauma were associated with higher risk of mortality.

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.

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.

BACKGROUND: The 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/DESIGN: The 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). DISCUSSION: Data analyses are expected to commence in 2011 with results publicly available in 2012.

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.

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.

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.

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.