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.

Inhaled nitric oxide to prevent bronchopulmonary dysplasia in preterm neonates.

Bronchopulmonary dysplasia is a chronic lung disease that affects premature infants and contributes to their morbidity and mortality. With the advent of prenatal steroids and postnatal exogenous surfactant and less aggressive respiratory support, premature infants can develop chronic oxygen dependency without even acute respiratory distress. This 'new bronchopulmonary dysplasia' could be the result of impaired postnatal growth. Several experimental studies have suggested a possible role of the vascular endothelial growth factor/nitric oxide (VEGF/NO) pathway in restoring pulmonary angiogenesis and enhancing distal lung growth. The results of the clinical studies are, however, inconclusive, and it is currently unclear which subsets of premature infants might benefit from inhaled nitric oxide. Besides, severe intracranial haemorrhage and/or cystic periventricular leucomalacia may affect the most immature babies, many of whom are spared from severe initial respiratory disease. Recently, inhaled nitric oxide was shown to significantly decrease the incidence of these neurological events, and to improve the long-term outcome in a few clinical trials. At times neuroprotective, at times neurotoxic, nitric oxide is capable of divergent effects depending upon the extent of cerebral damage, the redox state of the cell, and the experimental model used. Recently, our group found that inhaled nitric oxide had remote effects including angiogenesis and maturation on the developing brain in rodent pups. Thus, we await the results of the recently completed randomised clinical trial of inhaled nitric oxide to prevent bronchopulmonary dysplasia (the European Nitric Oxide or 'EUNO' trial) where, besides the primary endpoint of chronic oxygen dependency reduction at 36 weeks' postconceptional age, long-term lung and brain will be followed-up until 7 years of age.

Necrotizing enterocolitis (NEC) and the risk of intestinal stricture: the value of C-reactive protein.

Necrotizing enterocolitis (NEC) is a severe complication frequently seen during the neonatal period associated with high mortality rate and severe and prolonged morbidity including Post-NEC intestinal stricture. The aim of this study is to define the incidence and risk factors of these post-NEC strictures, in order to better orient their medicosurgical care. Sixty cases of NEC were retrospectively reviewed from a single tertiary center with identical treatment protocols throughout the period under study, including systematic X-ray contrast study. This study reports a high rate of post-NEC intestinal stricture (n = 27/48; 57% of survivors), either in cases treated surgically (91%) and after the medical treatment of NEC (47%). A colonic localization of the strictures was more frequent in medically-treated patients than in those with NEC treated surgically (87% vs. 50%). The length of the strictures was significantly shorter in case of NEC treated medically. No deaths were attributable to the presence of post-NEC stricture. The mean hospitalization time in NICU and the median age at discontinuation of parenteral nutrition were longer in the group with stricture, but this difference was not significant. The median age at discharge was significantly higher in the group with stricture (p = 0.02). The occurrence of post-NEC stricture was significantly associated with the presence of parietal signs of inflammation and thrombopenia (<100 000 platelets/mm(3)). The mean maximum CRP concentration during acute phase was significantly higher in infants who developed stricture (p<0.001), as was the mean duration of the elevation of CRP levels (p<0.001). The negative predictive value of CRP levels continually <10 mg/dL for the appearance of stricture was 100% in our study. In conclusion, this retrospective and monocentric study demonstrates the correlation between the intensity of the inflammatory syndrome and the risk of secondary intestinal stricture, when systematic contrast study is performed following NEC.

A long-term competent chimeric immune system in a dizygotic dichorionic twin.

We present here a rare case that involved the long-term coexistence of 2 mature, functional, and equilibrated immune systems in a single child after fetofetal transfusion between dizygotic twins. A dichorionic diamniotic pregnancy complicated by twin anemia-polycythemia sequence resulted in the demise of 1 twin. The detection of abnormal vessels on the dichorionic plate strongly suggested the existence of functional vascular anastomoses leading to blood chimerism in the survivor. Genetic, phenotypic, and immunologic analyses at 2 years revealed chimeric lymphoid and myeloid cells in the surviving twin, although no tissue mosaicism was detected, which indicates that early transfusion led to mutual immune tolerance.

Akinesia, arthrogryposis, craniosynostosis: a presentation of neonatal myasthenia with fetal onset.

Major akinesia with arthrogryposis and craniosynostosis at birth mimics irreversible disorders of the nervous system of pejorative outcome. In this context, the early detection of anti-acetylcholine fetal receptor antibodies in the mother may allow rapid diagnosis of transient neonatal myasthenia of favorable prognosis.