H. L. Halliday

Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants.

BACKGROUNDnChronic lung disease (CLD) remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory effects.nnnOBJECTIVESnTo determine if postnatal corticosteroid treatment is of benefit in the prevention of chronic lung disease (CLD) in the preterm infant. This review examines the outcome of trials where preterm infants at risk of CLD were given postnatal steroids within 96 hours after birth.nnnSEARCH STRATEGYnRandomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register, Medline, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists.nnnSELECTION CRITERIAnRandomised controlled trials of postnatal corticosteroid treatment within 96 hours of birth (early) in high risk preterm infants were selected for this review.nnnDATA COLLECTION AND ANALYSISnData regarding clinical outcomes including mortality, failure to extubate, pulmonary air leak, survival without chronic lung disease, CLD defined at 28 days postnatal age and 36 weeks post menstrual age, patent ductus arteriosus (PDA), severe intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL), infection, hyperglycaemia, hypertension, severe retinopathy of prematurity (ROP), necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation and long-term outcomes were abstracted and analysed using RevMan 4.1.nnnMAIN RESULTSnNineteen randomised controlled trials of early postnatal corticosteroid treatment of preterm babies at risk of developing CLD were identified. A meta-analysis of these trials demonstrates benefits as regards earlier extubation, decreased risks of CLD at both 28 days and 36 weeks, death or CLD at 28 days, PDA and pulmonary air leak. There were no differences in the rates of neonatal mortality, infection, severe ROP, severe IVH, PVL, NEC and pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects and the risks of hyperglycaemia and hypertension were also increased. In the two trials which have reported late outcomes, several adverse neurological effects were found at follow-up examinations of survivors treated with early steroids: abnormal neurological examination, cerebral palsy and developmental delay.nnnREVIEWERS CONCLUSIONSnThe benefits of early postnatal corticosteroid treatment (< 96 hours) may not outweigh the known or potential adverse effects of this treatment. Adverse gastrointestinal effects early in the neonatal period and adverse neurological outcomes seen at follow-up mean that current use of early postnatal steroids needs to be reconsidered. There is a compelling need for the long term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. The role of inhaled steroids remains to be elucidated.

Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

BACKGROUNDnChronic lung disease remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat chronic lung disease because of their potent anti-inflammatory effects.nnnOBJECTIVESnTo examine the relative benefits and adverse effects of postnatal corticosteroids commenced within the first seven days of life to preterm infants at risk of developing chronic lung disease.nnnSEARCH METHODSnWe sought randomised controlled trials (RCTs) of postnatal corticosteroid therapy from the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 8), MEDLINE (1966 to August 2013), handsearching paediatric and perinatal journals, and by examining previous review articles and information received from practising neonatologists. We contacted authors of all studies, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.nnnSELECTION CRITERIAnWe selected RCTs of postnatal corticosteroid treatment within the first seven days of life (early) in high-risk preterm infants for this review. Most studies evaluated the use of dexamethasone but we also included studies that assessed hydrocortisone, even if it was used primarily to manage hypotension.nnnDATA COLLECTION AND ANALYSISnWe extracted and analysed data regarding clinical outcomes that included mortality, chronic lung disease, death or chronic lung disease, failure to extubate, complications during the primary hospitalisation, and long-term health outcomes.nnnMAIN RESULTSnTwenty-nine RCTs enrolling a total of 3750 participants were eligible for inclusion in this review. The overall risk for bias was probably low as all were randomised controlled trials, and most trials have used rigorous methods. There were significant benefits for the following outcomes: lower rates of failure to extubate and decreased risks of chronic lung disease at both 28 days and 36 weeks postmenstrual age, death or chronic lung disease at 28 days and 36 weeks postmenstrual age, patent ductus arteriosus and ROP, including severe ROP. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis or pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects. The risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure were also increased. In the 12 trials that reported late outcomes, several adverse neurological effects were found at follow-up examinations, including developmental delay (not defined), cerebral palsy and abnormal neurological examination. However, major neurosensory disability was not significantly increased, either overall in the seven studies where this outcome could be determined, or in the two individual studies where the rates of cerebral palsy or abnormal neurological examination were significantly increased. Moreover, the rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability, were not significantly increased. Dexamethasone was used in most studies (n = 20); only nine studies used hydrocortisone. In subgroup analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone; hydrocortisone had little effect on any outcomes except for an increase in intestinal perforation and a borderline reduction in patent ductus arteriosus.nnnAUTHORS CONCLUSIONSnThe benefits of early postnatal corticosteroid treatment (≤ 7 days), particularly dexamethasone, may not outweigh the adverse effects of this treatment. Although early corticosteroid treatment facilitates extubation and reduces the risk of chronic lung disease and patent ductus arteriosus, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Long-term follow-up studies report an increased risk of abnormal neurological examination and cerebral palsy. However, the methodological quality of the studies determining long-term outcomes is limited in some cases; the surviving children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. Hydrocortisone in the doses and regimens used in the reported RCTs has few beneficial or harmful effects and cannot be recommended for the prevention of chronic lung disease.

Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants

BACKGROUNDnMany preterm babies who survive, having had respiratory distress syndrome (RDS) or not, go on to develop chronic lung disease (CLD). This is probably due to persistence of inflammation in the lung. Corticosteroids have powerful anti-inflammatory effects and have been used to treat established CLD. However it is unclear whether any beneficial effects outweigh the adverse effects of these drugs.nnnOBJECTIVESnTo determine if late (> 3 weeks) postnatal corticosteroid treatment vs control (placebo or nothing) is of benefit in the treatment of chronic lung disease (CLD) in the preterm infant.nnnSEARCH STRATEGYnRandomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Database of Controlled Trials, Medline, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists.nnnSELECTION CRITERIAnRandomised controlled trials of postnatal corticosteroid treatment initiated at > 3 weeks of age in preterm infants with CLD were selected for this review.nnnDATA COLLECTION AND ANALYSISnData regarding clinical outcomes including mortality before discharge, failure to extubate, infection, hyperglycaemia, hypertension, severe retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), gastrointestinal bleeding, bowel perforation, echodensities on ultrasound scan of brain, need for home oxygen, glycosuria, need for late rescue with dexamethasone, cerebral palsy in survivors and blindness in survivors were abstracted and analysed using Revman 4.0.4.nnnMAIN RESULTSnDelayed steroid treatment had no effect on mortality. The only beneficial effects were reductions in failure to extubate by 7 or 28 days, need for late rescue treatment with dexamethasone, chronic lung disease at 36 weeks, and discharge to home on oxygen therapy. There was no increase in risk of infection, necrotising enterocolitis, or gastrointestinal bleeding. Short-term adverse affects included hyperglycaemia, glycosuria and hypertension. There was an increase in severe retinopathy of prematurity, but no effect on blindness. There were increases in long-term neurologic sequelae including abnormal neurologic examination and cerebral palsy, the latter of borderline statistical significance.nnnREVIEWERS CONCLUSIONSnThe benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. There is a worrying increase in adverse neurological outcomes in infants treated with postnatal steroids (see also Review of Early Postnatal corticosteroids). Corticosteroids should be reserved for infants who cannot be weaned from mechanical ventilation. The dose of dexamethasone and the duration of any course of treatment should be minimised.

Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants.

BACKGROUNDnMany preterm infants who survive go on to develop chronic lung disease. This is probably due to persistent inflammation in the lungs. Corticosteroids have powerful anti-inflammatory effects and have been used to treat established chronic lung disease. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs.nnnOBJECTIVESnTo determine the relative benefits and adverse effects associated with late (> 7 days) postnatal systemic corticosteroid treatment compared with control (placebo or nothing) in the preterm infant with evolving or established chronic lung disease.nnnSEARCH METHODSnWe sought randomised controlled trials (RCTs) of postnatal corticosteroid therapy from the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 8), MEDLINE (1966 through August 2013), handsearching paediatric and perinatal journals, and by examining previous review articles and information received from practising neonatologists. When possible, we contacted authors of all studies to confirm details of reported follow-up studies or to obtain any information about long-term follow-up where none had been reported.nnnSELECTION CRITERIAnWe selected RCTs of postnatal corticosteroid treatment initiated after seven days after birth in preterm infants with evolving or established chronic lung disease for this review.nnnDATA COLLECTION AND ANALYSISnWe extracted and analysed data regarding clinical outcomes including mortality, chronic lung disease, death or chronic lung disease, failure to extubate, complications in the primary hospitalisation, and long-term health outcomesnnnMAIN RESULTSnTwenty-one RCTs enrolling a total of 1424 participants were eligible for this review. All were randomised controlled trials, but the methods for random allocation were not always clear. Allocation concealment, blinding of the intervention and blinding of the outcome assessments were mostly satisfactory. Late steroid treatment was associated with a reduction in neonatal mortality (at 28 days), but not mortality at discharge or latest reported age. Benefits of delayed steroid treatment included reductions in failure to extubate by three, seven or 28 days, chronic lung disease at both 28 days and 36 weeks postmenstrual age, need for late rescue treatment with dexamethasone, discharge on home oxygen, and death or chronic lung disease at both 28 days and 36 weeks postmenstrual age. There was a trend towards an increase in risk of infection and gastrointestinal bleeding, but not necrotising enterocolitis. Short-term adverse affects included hyperglycaemia, glycosuria and hypertension. There was an increase in severe retinopathy of prematurity, but no significant increase in blindness. There was a trend towards a reduction in severe intraventricular haemorrhage, but only 247 infants were enrolled in five studies reporting this outcome. The trends to an increase in cerebral palsy or abnormal neurological examination were partly offset by a trend in the opposite direction in death before late follow-up. The combined rate of death or cerebral palsy was not significantly different between steroid and control groups. Major neurosensory disability, and the combined rate of death or major neurosensory disability, were not significantly different between steroid and control groups. There were no substantial differences between groups for other outcomes in later childhood, including respiratory health or function, blood pressure or growth, although there were fewer with a clinically important reduction in the forced expired volume in one second (FEV1) on respiratory function testing.nnnAUTHORS CONCLUSIONSnThe benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. Although there continues to be concern about an increased incidence of adverse neurological outcomes in infants treated with postnatal steroids, this review of postnatal corticosteroid treatment for chronic lung disease initiated after seven days of age suggests that late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes. However, the methodological quality of the studies determining the long-term outcome is limited in some cases; in some studies the surviving children have only been assessed before school age, when some important neurological outcomes cannot be determined with certainty, and no study was sufficiently powered to detect increased rates of important adverse long-term neurosensory outcomes. Given the evidence of both benefits and harms of treatment, and the limitations of the evidence at present, it appears prudent to reserve the use of late corticosteroids for infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of treatment.

Multicentre randomised trial comparing high and low dose surfactant regimens for the treatment of respiratory distress syndrome (the Curosurf 4 trial).

A randomised trial was conducted in 82 centres using the porcine surfactant extract, Curosurf, to compare two regimens of multiple doses to treat infants with respiratory distress syndrome and arterial to alveolar oxygen tension ratio < 0.22. Infants were randomly allocated to a low dosage group (100 mg/kg initially, with two further doses at 12 and 24 hours to a maximum cumulative total of 300 mg/kg; n = 1069) or a high dosage group (200 mg/kg initially with up to four further doses of 100 mg/kg to a maximum cumulative total of 600 mg/kg; n = 1099). There was no difference between those allocated low and high dosage in the rates of death or oxygen dependency at 28 days (51.1% v 50.8%; difference -0.3%, 95% confidence interval (CI) -4.6% to 3.9%), death before discharge (25.0% v 23.5%; difference -1.5%, 95% CI -5.1% to 2.2%), and death or oxygen dependency at the expected date of delivery (32.2% v 31.0%; difference -1.2%, 95% CI -5.2% to 2.7%). For 14 predefined secondary measures of clinical outcome there were no significant differences between the groups but the comparison of duration of supplemental oxygen > 40% did attain significance; 48.4% of babies in the low dose group needed > 40% oxygen after three days compared with 42.6% of those in the high dose group. The total amount of surfactant administered in the low dose regimen (mean 242 mg phospholipid/kg) was probably enough to replace the entire pulmonary surfactant pool. Adopting the low dose regimen would lead to considerable cost savings, with no clinically significant loss in efficacy.

Increased incidence of respiratory distress syndrome in babies of hypertensive mothers

There is controversy over the effect of hypertension in pregnancy on the incidence of neonatal respiratory distress syndrome. We investigated the association between maternal hypertension and the incidence of respiratory distress syndrome in 268 very low birthweight babies of less than 34 weeks gestation. A lower incidence of respiratory distress syndrome was associated with growth retardation and membrane rupture greater than 24 hours. Maternal hypertension was associated with an increased incidence of respiratory distress syndrome. We used the multiple logistic regression model to control for confounding variables, as the maternal and neonatal factors associated with respiratory distress syndrome were not evenly distributed between the two groups. After adjustment for birth weight, gestational age, growth retardation, and membrane rupture greater than 24 hours, the risk of developing respiratory distress syndrome was significantly greater in babies of hypertensive mothers. Significance was lost when labour before delivery and mode of delivery were taken into account. The increased incidence of respiratory distress syndrome in babies of hypertensive mothers may be due to the absence of labour before delivery because of the greater likelihood of caesarean section.

Acute effects of instillation of surfactant in severe respiratory distress syndrome.

Doppler ultrasound measurements of pulmonary blood flow in 20 babies with severe respiratory distress syndrome treated in a randomised controlled trial of surfactant replacement showed that the immediate improvement of oxygenation was not associated with a significant increase in pulmonary blood flow. Reduction in ventilator settings and increases in the extent of chest wall movements measured by a cardiorespiratory monitor suggested that the improvement after surfactant had been given was a result of alveolar stabilisation and increased pulmonary compliance. Further simultaneous studies of pulmonary blood flow and pulmonary compliance are needed to confirm these findings.

Management of bronchopulmonary dysplasia in infants: Guidelines for corticosteroid use

Bronchopulmonary dysplasia (BPD) is a common cause of morbidity and mortality in preterm neonates and at present its management is unclear. Over the past three decades there has been a growing use of corticosteroids in the postnatal period; first for the treatment and then, more recently, for the prevention of BPD. The first published use of corticosteroids to treat neonatal lung disease was in 1956; however, it was only in the 1980s and 1990s that their use in neonates became commonplace. Concerns about their long-term neurodevelopmental consequences arose in the late 1990s when follow-up of randomised controlled trials indicated an increased risk of cerebral palsy after postnatal dexamethasone exposure.Dexamethasone has been the most frequently used corticosteroid in neonatal units, although others, including hydrocortisone, prednisolone and methylprednisolone, have been studied, as have inhaled corticosteroids. Systematic reviews indicate that systemic corticosteroids improve respiratory function in the short term and expedite extubation in preterm neonates. However, there is a high risk of hypertension, hyperglycaemia and gastrointestinal complications in corticosteroid-treated neonates and, if administered in the first 4 days of life, an association with long-term neurodevelopmental delay.There should be emphasis on prevention of BPD by reducing the risk factors associated with its development. There is no role for use of corticosteroids in the first 4 days of life as the high risk of long-term adverse effects outweighs any likely short-term benefits. Corticosteroid use should be limited to exceptional clinical circumstances, such as a ventilator-dependent infant after the second week of life who cannot be weaned from ventilation and whose condition is worsening. If used, they should be prescribed at the lowest effective dose for the shortest possible time. Further randomised trials of low-dose corticosteroids given after the first week of life are warranted and should assess both short- and long-term outcomes.

Perinatal death recording: time for a change?

The new perinatal death certificate proposed by the World Health Organisation was examined in relation to existing measures for recording perinatal death statistics and also with regard to new information gathered. Present procedures appear to underestimate the number of perinatal deaths by roughly 10%, though late registrations may lower this figure slightly. The use of a minimum birth weight as the criterion for inclusion in perinatal statistics removed much of the uncertainty associated with definitions of live birth and stillbirth. The new certificate led to duplication of some information already recorded through birth notification yet failed to provide information on some other factors generally considered relevant to perinatal mortality. The format proposed for recording cause of death provided a more logical presentation of events. Standardizing birth information recorded on all infants, modifying death certificates, and developing efficient record-linkage schemes would be more valuable than introducing the WHO certificate. Useful interpretation of the meaning of the characteristics of infants dying in the perinatal period awaits these timely changes.

Unusual site for oesophageal perforation in an extremely low birth weight infant

Abstract A male infant born at 26 weeks gestation became unwell at 10 days of age with blood-stained pharyngeal aspirates. The chest radiograph revealed a feeding tube in the right pleural cavity, indicating a perforation of the thoracic oesophagus. The infant had had a chest drain inserted on the right side on two previous occasions. These had been allowed to remain across the mediastinum at the site of the subsequent perforation. The infant was successfully managed conservatively with no long-term sequelae The unusual site of the perforation led us to conclude that pressure necrosis from the drains was a contributing factor in the aetiology.nConclusion Oesophageal perforations in the neonate, in contrast to the adult, can be managed conservatively.