Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial.

BACKGROUND: Bronchopulmonary dysplasia, a major complication of extreme prematurity, has few treatment options. Postnatal steroid use is controversial, but low-dose hydrocortisone might prevent the harmful effects of inflammation on the developing lung. In this study, we aimed to assess whether low-dose hydrocortisone improved survival without bronchopulmonary dysplasia in extremely preterm infants. METHODS: In this double-blind, placebo-controlled, randomised trial done at 21 French tertiary-care neonatal intensive care units (NICUs), we randomly assigned (1:1), via a secure study website, extremely preterm infants inborn (born in a maternity ward at the same site as the NICU) at less than 28 weeks of gestation to receive either intravenous low-dose hydrocortisone or placebo during the first 10 postnatal days. Infants randomly assigned to the hydrocortisone group received 1 mg/kg of hydrocortisone hemisuccinate per day divided into two doses per day for 7 days, followed by one dose of 0·5 mg/kg per day for 3 days. Randomisation was stratified by gestational age and all infants were enrolled by 24 h after birth. Study investigators, parents, and patients were masked to treatment allocation. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. We used a sequential analytical design, based on intention to treat, to avoid prolonging the trial after either efficacy or futility had been established. This trial is registered with ClinicalTrial.gov, number NCT00623740. FINDINGS: 1072 neonates were screened between May 25, 2008, and Jan 31, 2014, of which 523 were randomly assigned (256 hydrocortisone, 267 placebo). 255 infants on hydrocortisone and 266 on placebo were included in analyses after parents withdrew consent for one child in each group. Of the 255 infants assigned to hydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1·48, 95% CI 1·02-2·16, p=0·04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6-200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24-25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1·87, 95% CI 1·09-3·21, p=0·02). Other potential adverse events, including notably gastrointestinal perforation, did not differ significantly between groups. INTERPRETATION: In extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dose hydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates. FUNDING: Assistance Publique-Hôpitaux de Paris.

[Neurological consequences of prematurity]. / Conséquences neurologiques de la prématurité.

Very preterm infants are at risk of neurodevelopmental impairment. Severe disabilities (cerebral palsy, mental retardation) occur in around 10% of cases. The most frequent impairments concern cognitive and neurobehavioral development which usually express at school age. These disorders involve behavior, executive function, attention and speech development. All of these deficiencies can compromise learning functions, social interactions and school integration. Near 40% of very preterm infants need special therapies: psychological therapy, physiotherapy, speech therapy... Environmental, educative and health conditions largely influence the neurodevelopmental outcome. These infants need a special medical and social follow-up.

Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study.

AIM: The aim of this study was to assess the independent role of cerebral lesions on ultrasound scan, and several other neonatal and obstetric factors, as potential predictors of cerebral palsy (CP) in a large population-based cohort of very preterm infants. METHOD: As part of EPIPAGE, a population-based prospective cohort study, perinatal data and outcome at 5 years of age were recorded for 1812 infants born before 33 weeks of gestation in nine regions of France in 1997. RESULTS: The study group comprised 942 males (52%) and 870 females with a mean gestational age of 30 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1367 g (SD 393 g; range 450-2645 g). CP was diagnosed at 5 years of age in 159 infants (prevalence 9%; 95% confidence interval [CI] 7-10%), 97 males and 62 females, with a mean gestational age of 29 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1305 g (SD 386 g; range 500-2480 g). Among this group, 67% walked without aid, 14% walked with aid, and 19% were unable to walk. Spastic, ataxic, and dyskinetic CP accounted for 89%, 7%, and 4% of cases respectively. The prevalence of CP was 61% among infants with cystic periventricular leukomalacia, 50% in infants with intraparenchymal haemorrhage, 8% in infants with grade I intraventricular haemorrhage, and 4% in infants without a detectable cerebral lesion. After controlling for cerebral lesions and obstetric and neonatal factors, only male sex (odds ratio [OR] 1.52; 95% CI 1.03-2.25) and preterm premature rupture of membranes or preterm labour (OR 1.72; 95% CI 0.95-3.14) were predictors of the development of CP in very preterm infants. INTERPRETATION: Cerebral lesions were the most important predictor of CP in very preterm infants. In addition, infant sex and preterm premature rupture of membranes or preterm labour were also independent predictors of CP.

Natural evolution of patent ductus arteriosus in the extremely preterm infant.

OBJECTIVE: The persistence of the patent ductus arteriosus (PDA) is frequently encountered in very preterm infants. Neither preventive nor curative treatments of PDA have been shown to improve the outcome of these infants. Since no consensus on optimal treatment of PDA is established, we evaluated the rate of spontaneous PDA closure in infants born before 28 weeks of gestation. PATIENTS AND METHODS: We studied a retrospective cohort of 103 infants (gestational age 24-27 weeks) admitted to our neonatal intensive care unit from 1 June 2008 to 31 July 2010. Maternal and neonatal characteristics were collected. The PDA was defined by the persistence of ductal patency after 72 h and was followed up by regular echocardiography. RESULTS: Twelve infants died within the first 72 h and were excluded from the analysis. Among 91 infants analysed, 8 (9%) closed their ductus arteriosus before 72 h and the ductus could not be determined patent in 13. Of the 70 infants with a PDA still persistent, one underwent surgical ligation and echocardiography showed spontaneous closure in 51 (73%) of them. In the remaining 18 infants, the date of PDA closure could not be determined either because of their death (n=11) or due to discharge (n=7). Overall, a spontaneous closure of the ductus arteriosus was observed in 59 of the 91 infants. CONCLUSIONS: We have to question whether exposure to the risks of therapeutic interventions targeted for ductal closure is warranted since a PDA closes spontaneously in at least 73% of infants born before 28 weeks.

[Predictive value of magnetic resonance imaging (MRI) in cases of acquired brain injury in neonates].

Magnetic resonance (MRI) is at present the most accurate method of brain imaging in neonates, but it is not always and not everywhere available. This examination is commonly used in neonates born on time but it does not replace transfontanel sonography (US) in routine care in case of preterm babies. In the last years there have been more and more publications dealing with the prognostic value of MRI in both these groups of newborns. In this study the predictive value of MRI was analysed on the basis of own material and literature. The indications for MRI in case of term and preterm neonates were established.

Neuromotor outcome at 2 years of very preterm infants who were treated with high-frequency oscillatory ventilation or conventional ventilation for neonatal respiratory distress syndrome.

OBJECTIVE: In a previous multicenter, randomized trial, elective use of high-frequency oscillatory ventilation was compared with the use of conventional ventilation in the management of respiratory distress syndrome in preterm infants <30 weeks. No difference in terms of respiratory outcome was observed, but concerns were raised about an increased rate of severe intraventricular hemorrhage in the high-frequency ventilation group. To evaluate outcome, a follow-up study was conducted until a corrected age of 2 years. We report the results concerning neuromotor outcome. METHODS: Outcome was able to be evaluated in 192 of the 212 infants who survived until discharge from the neonatal unit: 97 of 105 infants of the high-frequency group and 95 of 104 infants of the conventional ventilation group. RESULTS: In the infants reviewed, mean birth weight and gestational age were similar in the 2 ventilation groups. As in the overall study population, the following differences were observed between the high-frequency ventilation group and the conventional ventilation group: lower 5-minute Apgar score, fewer surfactant instillations, and a higher incidence of severe intraventricular hemorrhage. At a corrected age of 2 years, 93 of the 97 infants of the high-frequency group and 79 of the 95 infants of the conventional ventilation group did not present any neuromotor disability, whereas 4 infants of the high-frequency group and 16 infants of the conventional ventilation group had cerebral palsy. CONCLUSIONS: Contrary to our initial concern about the increased rate of severe intraventricular hemorrhage in the high-frequency ventilation group, these data suggest that early use of high-frequency ventilation, compared with conventional ventilation, may be associated with a better neuromotor outcome. Because of the small number of patients studied and the absence of any explanation for this finding, we can conclude only that high-frequency oscillatory ventilation is not associated with a poorer neuromotor outcome.

Are maternal hypertension and small-for-gestational age risk factors for severe intraventricular hemorrhage and cystic periventricular leukomalacia? Results of the EPIPAGE cohort study.

OBJECTIVE: The purpose of this study was to examine the relationships between different causes of preterm delivery (eg, maternal hypertension, small-for-gestational age [SGA], other) and cerebral damage (eg, cystic periventricular leukomalacia [c-PVL], grade III intraventricular hemorrhage [IVH], and intra-parenchymal hemorrhage [IPH]). STUDY DESIGN: This study included 1902 very preterm singletons who were transferred to neonatal intensive care units in 9 French regions. We used logistic regression models to compare the risk of cerebral injury associated with maternal hypertension, SGA, and all other causes of preterm delivery. RESULTS: We found that the risk of c-PVL and grade III IVH was higher in infants born after preterm premature rupture of membranes (PPROM) with short latency or idiopathic preterm labor than in infants born to hypertensive mothers. We show that SGA and antepartum maternal hemorrhage significantly increase the risk of IPH. CONCLUSION: Our results show that infants born to hypertensive mothers have a lower risk of cerebral injuries than infants born following idiopathic preterm labor and PPROM because they are less exposed to prenatal infection.