Postnatal Corticosteroid Treatment Research Articles

Postnatal corticosteroid treatment as a risk factor for false positivity in severe combined immunodeficiency newborn screening.

From 2011, 37 children were referred to a hospital due to low levels of T cell receptor excision circles (TRECs) from newborn screening. Among them, three children were immunologically characterized and followed up to show that postnatal corticosteroid usage may be among the causes of false positivity in TRECs screening.

Influence of sex on the requirement for and outcomes following late postnatal corticosteroid treatment

There remains a disparity between the outcomes of male and female prematurely born infants. Our aim was to assess the influence of sex on the requirement for late (> 7 days) postnatal corticosteroid (PNS) treatment and the outcomes following treatment. A retrospective whole population study of infants born at less than 28 weeks of gestation in all neonatal units in England between 2014 and 2018. The impact of exposure to at least five consecutive days of dexamethasone or hydrocortisone on bronchopulmonary dysplasia (BPD) at 36 weeks corrected gestation and survival to discharge from neonatal care was determined. Ten thousand, six hundred and fifty-five infants survived to seven days. Male sex was associated with an increased incidence of BPD (OR 1.41, 95%CI 1.287–1.552, p < 0.001) and death (OR 1.227, 95%CI 1.123–1.452, p < 0.001). Two thousand, three hundred and forty-four infants (22%) received at least one course of PNS at a median of 23 (IQR 15–40) days after birth. Males (23.6%) were more likely to receive PNS than females (20.1%), p < 0.001 and receive repeated courses (mean 1.67 compared to a mean of 1.59 in the females), p = 0.027. Multivariate regression analysis identified no significant differences in the incidence of BPD or death between male and females who received PNS. Conclusions: Males and females had similar outcomes after receiving PNS, but a significantly greater proportion of males met the clinical threshold to receive PNS and were more likely to receive repeated courses which may expose them to a greater risk of adverse long-term outcomes.What is Known:• There remains a difference in outcomes of male and female infants born prematurely.• Prematurely born male infants were more likely to receive postnatal corticosteroids and a greater number of courses but had similar outcomes compared to female infants.What is New:• Postnatal corticosteroids have long-term adverse effects. Such outcomes should be considered when weighing up the risk–benefit ratio of prescribing postnatal corticosteroids, particularly in very prematurely born male infants.

Postnatal corticosteroid response in neonates < 32weeks and relation with placental pathology.

Short-term response to postnatal corticosteroids did not significantly differ between premature neonates born after acute chorioamnionitis, maternal vascular malperfusion, or no placenta pathology. However, a trend of better corticosteroid response in maternal vascular malperfusion neonates was found, potentially due to differences in prenatal pulmonary development and postnatal cortisol. •Bronchopulmonary dysplasia is related to chorioamnionitis and maternal vascular malperfusion. •Corticosteroids remain an important treatment in the course of bronchopulmonary dysplasia despite conflicting results and non-responsiveness in some preterm neonates. •Non-responsiveness might be related to differences in pulmonary inflammation and systemic cortisol due to predispositions triggered by chorioamnionitis or maternal vascular malperfusion. •Neonates born after maternal vascular malperfusion seem to respond better to postnatal corticosteroid treatment.

Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Early (&lt; 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Early (&lt; 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

The contribution of postnatal steroid administration to early brain damage in preterm babies with bronchopulmonary dysplasia

Background/aimPostnatal corticosteroids are commonly used to treat bronchopulmonary dysplasia (BPD). We aimed to show whether S100 calcium-binding B (S100B), neuron-specific enolase (NSE), Tau protein or microtubule-associated protein tau (MAPT), and glial fibrillary acid protein (GFAP) levels would provide any evidence of early neurological damage in premature infants receiving postnatal low dose dexamethasone therapy for BPD treatment.Materials and methods In this cohort study, 136 preterm infants diagnosed with BPD at ≤32 weeks of gestation formed the study group, and 64 preterm infants formed the control group. NSE, S100B, GFAP, and MAPT levels were first measured before the postnatal corticosteroid treatment in both the patient and the control group on the 28th day and, for a second time, after treatment termination in the patient group.Results There were significant differences between the measured GFAP, MAPT, and NSE values of the BPD and control groups on the 28th day, whereas there was no significant difference between the measured S100B values of the two groups. There were a statistically significant difference between the NSE values measured on the 28th day and after the treatment within the BPD group, whereas no significant difference existed between the GFAP, MAPT, and S100B values.Conclusion NSE levels, which indicate brain damage in the early period, increased in preterm babies with BPD who had been administered postnatal dexamethasone.

Predictors and outcomes of extubation failure in extremely preterm infants

To determine predictors and outcomes of extubation failure in extremely preterm (EP) infants born <28 weeks' gestational age (GA). Retrospective clinical audit across two tertiary-level neonatal intensive care units in Melbourne, Australia. Two-hundred and four EP infants who survived to their first extubation from mechanical ventilation. Extubation failure (re-intubation) within 7 days after the first extubation. Lower GA (odds ratio [OR] 0.71, 95% confidence interval (CI), 0.61-0.89, P < 0.001) and higher pre-extubation measured mean airway pressure (MAP) on the mechanical ventilator (OR 1.9 [95% CI 1.41-2.51], P < 0.001) predicted extubation failure. The area under a receiver operating characteristic curve for GA and MAP was 0.77 (95% CI 0.70-0.82). After adjustment for GA, infants who experienced extubation failure had higher rates of bronchopulmonary dysplasia (P < 0.001), post-natal systemic corticosteroid treatment (P < 0.001), airway trauma (P < 0.003), longer durations of treatment with mechanical ventilation (P < 0.001), non-invasive respiratory support (P <0.001), supplemental oxygen therapy (P =0.05) and longer hospitalisation (P =0.025). Lower GA and higher pre-extubation measured MAP were predictive of extubation failure within 7 days in extremely preterm infants. Extubation failure was associated with increased morbidity and extended periods of respiratory support and hospitalisation.

Risk factors in early life for developmental coordination disorder: a scoping review.

AimTo perform a scoping literature review of associations between risk factors in early life and developmental coordination disorder (DCD).MethodPubMed, Embase, CINAHL, PsycINFO, and Web of Science (January 1994–March 2019) were searched to identify studies on early risk factors and motor impairment or DCD. The effect of single and multiple risk factors was assessed. Level of evidence was evaluated following the Centre for Evidence‐Based Medicine guidelines. Meta‐analysis on the effect of preterm birth was performed.ResultsThirty‐six studies fulfilled inclusion criteria; 35 had evidence level 3, one had level 4. Highest evidence was available that preterm birth and male sex in term‐born children were associated with DCD. The odds ratio of preterm birth was 2.02 (95% confidence interval: 1.43–2.85). Low to moderate evidence was available that parental subfertility, maternal smoking during pregnancy, postnatal corticosteroid treatment in infants born preterm, extra corporeal membrane oxygenation, retinopathy of prematurity, abnormalities on magnetic resonance imaging scans at term age, and accumulating perinatal or neonatal risk factors were associated with motor impairment.InterpretationLimited information on early risk factors of DCD is available. Only preterm birth and male sex were consistently associated with an increased risk of DCD.What this paper adds Preterm birth is a risk factor for developmental coordination disorder (DCD).In term‐born children, male sex was consistently associated with DCD.Risk factors for DCD are similar to risk factors for cerebral palsy.

Timing of postnatal corticosteroid treatment for bronchopulmonary dysplasia and its effect on outcomes.

To determine the association of timing of steroid therapy for bronchopulmonary dysplasia (BPD) and outcomes. Retrospective cohort study of preterm infants treated with low-dose dexamethasone for BPD. Infants treated with steroids at day of life (DOL) 14-28 (moderately late group) were compared to infants treated at DOL 29-42 (delayed group). Inverse probability of treatment weighting (IPTW) adjusted propensity scores were used to correct for potential confounders. The primary outcome of interest was postmenstrual age (PMA) at discharge. Fifty-five infants (25 with moderately late treatment; 30 with delayed treatment) were identified. The mean age at treatment was 23 days in the moderately late group and 35 days in the delayed group. At time of treatment, infants treated moderately late were more likely to be on high frequency ventilation (96% vs 47%, P < 0.0001) and had higher fraction of inspired oxygen (70.7 ± 17.9% vs 56.2 ± 18.4%, P = 0.005) compared to infants treated later. Despite being the sicker group, moderately late treated infants were discharged at an earlier corrected age compared to infants with delayed treatment (PMA 42.9 ± 4.5 vs 47.5 ± 8.3 weeks, IPTW adjusted P = 0.03). Moderately late treatment was also associated with fewer days on mechanical ventilation (46.0 ± 19.0 days vs 77.4 ± 67.0 days, IPTW adjusted P = 0.02) and fewer days on supplemental oxygen (114.3 ± 40.8 days vs 149.8 ± 57.0 days, IPTW adjusted P = 0.005). Among preterm infants at high risk of BPD, delaying treatment with postnatal steroids is associated with comparatively worse short-term outcomes as compared to earlier treatment.

Late (> 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Many preterm infants who survive go on to develop bronchopulmonary dysplasia, probably as the result of persistent inflammation in the lungs. Corticosteroids have powerful anti-inflammatory effects and have been used to treat individuals with established bronchopulmonary dysplasia. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. To examine the relative benefits and adverse effects of late systemic postnatal corticosteroid treatment (> 7 days) for preterm infants with evolving or established bronchopulmonary dysplasia. For the 2017 update, we used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1); MEDLINE via PubMed (January 2013 to 21 February 2017); Embase (January 2013 to 21 February 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; January 2013 to 21 February 2017). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We selected for inclusion in this review randomised controlled trials (RCTs) comparing systemic postnatal corticosteroid treatment versus placebo or nothing initiated more than seven days after birth for preterm infants with evolving or established bronchopulmonary dysplasia. We used the GRADE approach to assess the quality of evidence.We extracted and analysed data regarding clinical outcomes including mortality, bronchopulmonary dysplasia, death or bronchopulmonary dysplasia, failure to extubate, complications during primary hospitalisation, and long-term health outcomes. Twenty-one RCTs enrolling a total of 1424 participants were eligible for this review. All were RCTs, but methods used for random allocation were not always clear. Allocation concealment, blinding of the intervention, and blinding of outcome assessments most often were satisfactory. Late steroid treatment was associated with a reduction in neonatal mortality (at 28 days) but no reduction in mortality at 36 weeks, at discharge, or at latest reported age. Benefits of delayed steroid treatment included reductions in failure to extubate by 3, 7, or 28 days; bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age; need for late rescue treatment with dexamethasone; discharge on home oxygen; and death or bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age. Data revealed a trend towards increased risk of infection and gastrointestinal bleeding but no increase in risk of necrotising enterocolitis. Short-term adverse affects included hyperglycaemia, glycosuria, and hypertension. Investigators reported an increase in severe retinopathy of prematurity but no significant increase in blindness. Trial results showed a trend towards reduction in severe intraventricular haemorrhage, but only five studies enrolling 247 infants reported this outcome. Trends towards an increase in cerebral palsy or abnormal neurological examination findings were partly offset by a trend in the opposite direction involving 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 participants with a clinically important reduction in forced expired volume in one second (FEV1) on respiratory function testing in the dexamethasone group.GRADE findings were high for all major outcomes considered, but review authors degraded the quality of evidence by one level because we found evidence of publication bias (bronchopulmonary dysplasia at 36 weeks). Benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. This review of postnatal systemic corticosteroid treatment for bronchopulmonary dysplasia 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 studies determining long-term outcomes is limited in some cases (some studies assessed surviving children only before school age, when some important neurological outcomes cannot be determined with certainty), and no studies were sufficiently powered to detect increased rates of important adverse long-term neurosensory outcomes. Evidence showing both benefits and harms of treatment and limitations of available evidence suggests that it may be prudent to reserve the use of late corticosteroids for infants who cannot be weaned from mechanical ventilation, and to minimise both dose and duration for any course of treatment.

Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Postnatal Steroids and Febrile Seizure Susceptibility in Preterm Children.

To investigate risk factors, seizure characteristics, and outcomes of febrile seizure (FS) in children born very preterm. This study used a prospective registry data set of 844 preterm infants (birth weight <1500 g and gestational age <32 weeks) admitted to NICUs from 2001 to 2009 in southern Taiwan. We investigated the prevalence, risks, seizure patterns, and outcomes of FS in children aged 5 years. Among 575 children (follow-up rate, 85.8%) followed up for 5 years, 35 (6.1%) developed FS. The FS and non-FS groups were comparable regarding their mean gestational age, birth weight, 5-minute Apgar score <6, and prenatal and postnatal complications. No difference was observed in the use of prenatal corticosteroids between the 2 groups. The FS group had a significantly higher rate of postnatal corticosteroid treatment than the non-FS group, even after adjusting for confounding factors (odds ratio, 5.4 [95% confidence interval, 1.9-15.8]; P = .006). No differences were observed in IQs or subsequent epilepsy rates between the 2 groups. Although no difference was observed in the age of FS onset or neurodevelopmental outcomes between the 2 groups, children with FS who received postnatal corticosteroid treatment had a significantly lower mean body temperature during the first FS attack compared with those who did not receive postnatal corticosteroid treatment (38.6 ± 0.4°C vs 39.2 ± 0.6°C; P = .034). Children born very preterm have a higher rate of FS, and postnatal corticosteroid treatment was associated with FS susceptibility in these children.

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

Many 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. To 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. We 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. We 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. We 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 outcomes Twenty-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. The 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.

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

Chronic 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. To 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. We 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. We 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. We 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. Twenty-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. The 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.

Inflammatory activity at school age in very low birth weight bronchopulmonary dysplasia survivors

Airway inflammation is involved in the pathogenesis of bronchopulmonary dysplasia (BPD). The aim of the study was to evaluate the inflammatory activity in plasma and exhaled air in very low birth weight (VLBW) BPD survivors at school age. Twenty-one 6-14-year-old former VLBW (birth weight ≤1,500 g) children with severe radiographic BPD (radBPD), 19 without radBPD (nonBPD group) and 19 non-asthmatic term controls underwent measurement of eosinophil cationic protein, IL-6, IL-8, adiponectin, adipsin, leptin, and resistin in plasma, leukotriene B4 and 8-isoprostane in exhaled breath condensate, and NO in exhaled breath. Background data were obtained from patient records, clinical examination and parental questionnaire. Both univariate and multivariate models were applied in the statistical analysis. There were no significant differences between the groups in any of the inflammatory markers measured. Five (25%) radBPD and 2 (11%) nonBPD children reported asthma (P = 0.058). In logistic regression analysis, exposure to chorioamnionitis was associated with low IL-8 (OR 29.0, 95% CI 3.27-258) and postnatal corticosteroid therapy with high adiponectin (OR 32.0, 95% CI 1.29-793). High body mass index standard deviation score (BMI-SDS) was associated with high plasma adipsin (OR 2.47, 95% CI 1.07-5.75) and leptin (OR 5.76, 95%CI 1.83-18.2) levels. The inflammatory activity seems to decrease by school age in VLBW BPD survivors. Chorioamnionitis and postnatal corticosteroid treatment may modulate the inflammatory responsiveness in VLBW subjects even up to school age. The respiratory outcome in VLBW infants might be improved by preventing excessive weight gain.

Drug Utilisation in Very Preterm Infants: Any Changes during the Past Decade?

Improved standards of perinatal care for preterm infants led to decreased hospital mortality rates during the past decade. However, studies investigating changes in drug utilisation in neonatal intensive care units (NICU) during this period are missing. The aim of the present study therefore was to evaluate the most frequently used groups of drugs in preterm infants treated in NICUs and to analyse potential changes in drug utilisation over a period of ten years. Drug utilisation patterns in 164 preterm infants born between 1989 and 1990 (group I; gestational age 27.2+/-1.2 weeks, birth weight 970+/-145 g) were compared to those in 113 preterm infants born between 2001 and 2004 (group II; gestational age 26.9+/-1.65 weeks, birth weight 930+/-253 g, mean and standard deviation each) with need for postnatal mechanical ventilation. Significant changes in drug utilisation patterns were observed for complete courses of antenatal corticosteroids (40 vs. 51.5%), diuretics (78 vs. 36.6%), surfactant (63.3 vs. 75%), methylxanthines (89.9 vs. 56.7%), sedatives/analgesics (82.4 vs. 91.5%) and catecholamines (38.3 vs. 52.4%) (group II vs. group I each). Postnatal corticosteroids were applied more often in group II (17.4 vs. 13.4%). However, duration of postnatal corticosteroid treatment has decreased (6 d vs. 13 d). The use of antibiotics remained unchanged (100 vs. 98.9%). Comparison of clinical outcome variables showed a decreased duration of mechanical ventilation and a significantly increased survival rate. Drug utilisation patterns in preterms have changed considerably during the past decade. Improved standards of care and shorter duration of mechanical ventilation may be operative.

Neurodevelopmental and Respiratory Follow-up Results at 7 Years for Children From the United Kingdom and Ireland Enrolled in a Randomized Trial of Early and Late Postnatal Corticosteroid Treatment, Systemic and Inhaled (the Open Study of Early Corticosteroid Treatment)

The goals were to compare early school-age neurodevelopmental and respiratory outcomes for children who were treated with either early (<3 days) or delayed selective (>15 days) postnatal corticosteroid therapy and to compare systemic dexamethasone treatment with inhaled budesonide treatment. One hundred twenty-seven (84%) of 152 survivors from the United Kingdom and Ireland who were recruited to the Open Study of Early Corticosteroid Treatment, a randomized trial of inhaled and systemic corticosteroid therapy to prevent chronic lung disease, were traced and assessed at a median age of 7 years. Outcome measures were level of disability, presence of cerebral palsy, cognitive ability, behavioral difficulties and competencies, growth, and respiratory symptoms. Results were adjusted for potential confounding variables (gestational age, birth weight, gender, prenatal steroid therapy, method of delivery, Apgar score at 5 minutes, and Clinical Risk Index for Babies score). There were no significant differences among the treatment groups in cognitive ability, behavioral competencies or difficulties, overall disability rates, cerebral palsy, combined outcomes of death or cerebral palsy and death or moderate/severe disability, growth, respiratory morbidity, or diastolic blood pressure. Those assigned to dexamethasone were more likely to have high systolic blood pressure and to have a diagnosis of asthma than were those assigned to budesonide. Although postnatal steroid therapy has been associated with poor long-term outcomes, this study failed to show significant differences in cognitive function between dexamethasone- and budesonide-allocated groups. There may be increased systolic blood pressure and a greater likelihood of developing asthma in childhood after postnatal dexamethasone treatment.

Reopening the Debate on Corticosteroids: In Reply

In Reply.—We thank Drs Fernandes and Johnson for their letter about the DART (Dexamethasone: A Randomized Trial) study. We wholeheartedly agree with them that clinicians should consider both risks and benefits of any therapy, including postnatal corticosteroids. Risks might include outcomes such as death or cerebral palsy; both are possible consequences when clinicians consider postnatal corticosteroid treatment for a chronically ventilator-dependent infant. On the other hand, benefits might include not only extubation but also, perhaps paradoxically, avoidance of death or cerebral palsy. In a systematic review of all randomized trials of postnatal corticosteroids, we have shown that the risk of the combined outcome of death or cerebral palsy varies with risk of chronic lung disease (CLD) in the control group; infants at low risk might experience net harm from corticosteroids, whereas infants at high risk of CLD might experience net benefit.1 The infants in the DART study2 were clearly at very high risk of CLD: the rate of CLD in the control group was 91%, higher than in any of the randomized, controlled trials in the systematic review.1The other issue to consider in the balance of risks versus benefits is the distinction between a prevention trial (such as that by Watterberg et al3) compared with a treatment trial (such as DART). Thus, unless prevention trials are based on highly accurate predictors of CLD, a larger proportion of infants involved will be exposed to the risks with no expectation of benefit; as such, prevention trials perhaps require a different “safety margin” compared with treatment trials such as the DART study, in which the risk of CLD was so much higher.2Fernandes and Johnson suggest a search for subgroups that might be expected to benefit more from postnatal corticosteroids, as well as considering corticosteroids other than dexamethasone. The DART study2 focused on 1 subgroup: infants who are ventilator dependent after the first week of life; most were much older than 1 week when entered into the study, with a median age at entry of 23 days (interquartile range: 17–32 days). Fernandes and Johnson focus on a possible role for early low-dose hydrocortisone in infants exposed to histologic chorioamnionitis. We encourage them to test their hypothesis in a large randomized, controlled trial that encompasses not only short-term morbidity, such as rates of CLD, but also long-term survival and neurologic outcome so that they will be able to establish all the benefits and risks of early hydrocortisone. However, if they intend, as did Watterberg et al,3 to commence hydrocortisone soon after birth, they may have difficulty in establishing who has histologic chorioamnionitis soon enough and with enough certainty.

Strategies for preventing bronchopulmonary dysplasia

Neonatologists and pulmonary biologists have long sought preventive treatments for bronchopulmonary dysplasia (BPD). The purpose of this review is to highlight recent reports of a number of potential treatments intended to prevent BPD and to discuss the controversies surrounding preventive strategies. The evolution of BPD from a disorder of pulmonary injury affecting moderately preterm infants, to one characterized by a developmental pulmonary arrest among survivors of extreme prematurity has important implications for BPD prevention. Recent recognition that the pathogenesis of BPD might have prenatal origins raises new challenges and opportunities for studies of BPD prevention; however, most current preventive strategies for BPD focus on respiratory management. Neither past nor current clinical trials have shown a conclusive benefit of a single preventive treatment strategy. Promising but still largely unproven preventive respiratory treatments include: high frequency oscillatory ventilation, permissive hypercapnea, and inhaled nitric oxide. Observational and recent laboratory data support the need for randomized clinical trials of continuous positive airway pressure versus mechanical ventilation. Additionally, clinical trials are needed to address the deficit in our knowledge of the potential benefits and risks of postnatal low dose corticosteroid treatment. Further study of superoxide dismutase, inositol, and alpha-1 proteinase inhibitor also are warranted on the basis of recent clinical trials or meta-analyses. Only Vitamin A has proven a safe and effective preventive treatment for BPD. Additional studies of respiratory technologies, management strategies, and protective molecules are needed. Directed cytokine and genetic therapies are on the horizon.

Impact of Postnatal Systemic Corticosteroids on Mortality and Cerebral Palsy in Preterm Infants: Effect Modification by Risk for Chronic Lung Disease

In preterm infants, chronic lung disease (CLD) is associated with an increased risk for cerebral palsy (CP). However, systemic postnatal corticosteroid therapy to prevent or treat CLD, although effective in improving lung function, may cause CP. The objective of this study was to determine the effect of systemic postnatal corticosteroid treatment on death and CP and to assess any modification of effect arising from risk for CLD. Randomized, controlled trials of postnatal corticosteroid therapy for prevention or treatment of CLD in preterm infants that reported rates of both mortality and CP were reviewed and their data were synthesized. Twenty studies with data on 1721 randomized infants met eligibility criteria. The relationship between the corticosteroid effect on the combined outcome, death or CP, and the risk for CLD in control groups was analyzed by weighted meta-regression. Among all infants who were randomized, a significantly higher rate of CP after corticosteroid treatment (typical risk difference [RD]: 0.05; 95% confidence interval [CI]: 0.02, 0.08) was partly offset by a nonsignificant reduction in mortality (typical RD: -0.02; 95% CI: -0.06 to 0.02). Consequently, there was no significant effect of corticosteroid treatment on the combined rate of mortality or CP (typical RD: 0.03; 95% CI: -0.01 to 0.08). However, on meta-regression, there was a significant negative relationship between the treatment effect on death or CP and the risk for CLD in control groups. With risks for CLD below 35%, corticosteroid treatment significantly increased the chance of death or CP, whereas with risks for CLD exceeding 65%, it reduced this chance. The effect of postnatal corticosteroids on the combined outcome of death or CP varies with the level of risk for CLD.