Pulmonary hypertension in preterm infants: results of a prospective screening program.

OBJECTIVE: Determine prevalence and associations with pulmonary hypertension (PH) in preterm infants. STUDY DESIGN: Prospective institutional echocardiographic PH screening at 36 to 38 weeks' corrected gestational age (GA) for infants born <32 weeks' GA who had bronchopulmonary dysplasia (BPD; group BPD), and infants without BPD who had a birth weight (BW) <750 g, or clinical suspicion for PH (group NoBPD). RESULTS: Two hundred and four infants were screened (GA 25.9±2 weeks, BW 831±286 g). The PH prevalence in group BPD was higher than in group NoBPD (44/159 (28%) vs 5/45 (11%); P=0.028). In group BPD, BW and GA were lower in infants with PH compared with NoPH. Following correction for BW and GA, necrotizing enterocolitis (NEC), severe intraventricular hemorrhage (IVH), atrial septal defect (ASD), and mortality were independently associated with PH in infants with BPD. In group NoBPD, NEC was the only identified factor associated with PH. Altogether, screening only those infants with NEC and infants with BPD who also had a BW <840 g would have yielded a 84% sensitivity for detecting PH, and reduced the number of screening echocardiograms by 43%. CONCLUSIONS: PH in prematurity is associated with NEC in infants with and without BPD. In infants with BPD, smaller GA and BW, severe IVH, ASD and mortality are also associated with PH. Infants without identified PH-associated factors may not require routine echocardiographic PH screening.

Folic acid supplementation and dietary folate intake, and risk of preeclampsia.

BACKGROUND/OBJECTIVES: Folic acid supplementation has been suggested to reduce the risk of preeclampsia. However, results from few epidemiologic studies have been inconclusive. We investigated the hypothesis that folic acid supplementation and dietary folate intake before conception and during pregnancy reduce the risk of preeclampsia. SUBJECTS/METHODS: A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. A total of 10,041 pregnant women without chronic hypertension or gestational hypertension were enrolled. RESULTS: Compared with nonusers, folic acid supplement users had a reduced risk of preeclampsia (OR=0.61, 95% CI: 0.43-0.87). A significant dose-response of duration of use was observed among women who used folic acid supplemention during pregnancy only (P-trend=0.007). The reduced risk associated with folic acid supplement was similar for mild or severe preeclampsia and for early- or late-onset preeclampsia, although the statistical significant associations were only observed for mild (OR=0.50, 95% CI: 0.30-0.81) and late-onset (OR=0.60, 95% CI: 0.42-0.86) preeclampsia. The reduced risk associated with dietary folate intake during pregnancy was only seen for severe preeclampsia (OR=0.52, 95% CI: 0.31-0.87, for the highest quartile of dietary folate intake compared with the lowest). CONCLUSIONS: Our study results suggest that folic acid supplementation and higher dietary folate intake during pregnancy reduce the risk of preeclampsia. Future studies are needed to confirm the associations.

Temporal quantification of oxygen saturation ranges: an effort to reduce hyperoxia in the neonatal intensive care unit.

OBJECTIVE: To reduce exposure to hyperoxia and its associated morbidities in preterm neonates. STUDY DESIGN: A multidisciplinary group was established to evaluate oxygen exposure in our neonatal intensive care unit. Infants were assigned target saturation ranges and signal extraction technology implemented to temporally quantify achievement of these ranges. The outcomes bronchopulmonary dysplasia/death, retinopathy of prematurity (ROP)/death, severe ROP and ROP requiring surgery were compared in a pre- versus post-intervention evaluation using multivariate analyses. RESULT: A total of 304 very low birth weight pre-initiative infants were compared with 396 post-initiative infants. Multivariate analyses revealed decreased odds of severe ROP (adjusted odds ratio (OR): 0.41; 95% confidence interval (CI): 0.24-0.72) and ROP requiring surgery (adjusted OR 0.31; 95% CI: 0.17-0.59) post-initiative. No differences in death were observed. CONCLUSION: Significant reductions in severe ROP and ROP requiring surgery were observed after staff education and implementation of new technology to quantify success in achieving targeted saturations and reinforce principles and practices.

Randomized trial of enteral protein and energy supplementation in infants less than or equal to 1250 g at birth.

OBJECTIVE: To determine if enteral protein and energy supplementation would significantly improve weight gain as compared with energy supplementation alone in or=14 days, diet of >or=75% enteral nutrition (fortified human milk or formula) and either failure to regain BW or weight gain<15 g kg(-1) per days. Infants were randomized to a multinutrient supplement that provided increased protein and energy (P/E) intake or energy alone (medium chain triglyceride oil, MCT). Growth rates were compared at the end of the 4-week study period. RESULT: Of 30 eligible infants, 23 were enrolled, 12 received MCT (BW=862+/-252 g, mean+/-s.d.) and 11 received P/E (BW=879+/-241 g). Significantly higher protein intake (P/E=3.5+/-0.3 g kg(-1) per day, MCT=3.0+/-0.5 g kg(-1) per day) and better growth (P/E=17.0+/-2.4 g kg(-1) per day, MCT=11.5+/-4.8 g kg(-1) per day) were observed in the P/E group. CONCLUSION: These data are consistent with the importance of providing additional daily protein intake to achieve increased postnatal growth in very low birth weight infants experiencing slow growth.

Clinical parameters do not adequately predict outcome in necrotizing enterocolitis: a multi-institutional study.

OBJECTIVE: Necrotizing enterocolitis (NEC) remains a major cause of neonatal morbidity and mortality. Some infants recover uneventfully with medical therapy whereas others develop severe disease (that is, NEC requiring surgery or resulting in death). Repeated attempts to identify clinical parameters that would reliably identify infants with NEC most likely to progress to severe disease have been unsuccessful. We hypothesized that comprehensive prospective data collection at multiple centers would allow us to develop a model which would identify those babies at risk for progressive NEC. STUDY DESIGN: This prospective, observational study was conducted at six university children's hospitals. Study subjects were neonates with suspected or confirmed NEC. Comprehensive maternal and newborn histories were collected at the time of enrollment, and newborn clinical data were collected prospectively, thereafter. Multivariate logistic regression analysis was used to develop a predictive model of risk factors for progression. RESULT: Of 455 neonates analyzed, 192 (42%) progressed to severe disease, and 263 (58%) advanced to full feedings without operation. The vast majority of the variables studied proved not to be associated with progression to severe disease. A total of 12 independent predictors for progression were identified, including only 3 not previously described: having a teenaged mother (odds ratio, OR, 3.14; 95% confidence interval, CI, 1.45 to 6.96), receiving cardiac compressions and/or resuscitative drugs at birth (OR, 2.51; 95% CI, 1.17 to 5.48), and having never received enteral feeding before diagnosis (OR, 2.41; 95% CI, 1.08 to 5.52). CONCLUSION: Our hypothesis proved false. Rigorous prospective data collection of a sufficient number of patients did not allow us to create a model sufficiently predictive of progressive NEC to be clinically useful. It appears increasingly likely that further analysis of clinical parameters alone will not lead to a significant improvement in our understanding of NEC. We believe that future studies must focus on advanced biologic parameters in conjunction with clinical findings.

Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure.

OBJECTIVES: To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure. STUDY DESIGN: The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O(2) at 36 weeks post-menstrual age). RESULT: Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status, but not the magnitude of response in PaO(2) to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity. CONCLUSIONS: The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender and outborn status, but not the magnitude of initial response to iNO.

Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants.

BACKGROUND: Indomethacin is a prostaglandin inhibitor used for the prevention and the treatment of patent ductus arteriosus (PDA). Although a 3-dose schedule has been commonly used, there is no consensus on optimal dosage and duration of indomethacin therapy for PDA closure. There are potential adverse effects of indomethacin use in premature infants such as a reduction in cerebral, mesenteric and renal blood flow and platelet dysfunction. Administering indomethacin continuously over 36-hours has been suggested as a safer and more effective option to prevent such adverse effects. OBJECTIVES: To compare the efficacy and safety of continuous infusion versus bolus administration of indomethacin in closing a symptomatic PDA in preterm infants. SEARCH STRATEGY: The standard search strategy of Cochrane Neonatal Review was used: MEDLINE and EMBASE (1966 - March 2007), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007), bibliographies of reviews and trials were examined for references to other trials, previous symposia proceedings published in Pediatric Research (Pediatric Academic Societies Annual Meeting Abstract Book, 1972 - 2006). No language restrictions were applied. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing continuous indomethacin infusion to bolus doses for closure of a symptomatic PDA in preterm infants with a symptomatic PDA diagnosed clinically and/or by echocardiography. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed. Authors were contacted regarding missing data as well as to inquire about the outcomes that were not reported. Meta-analysis was performed to calculate relative risk (RR), risk difference (RD) and 95% confidence intervals (CI). MAIN RESULTS: Only two small trials comparing continuous versus bolus indomethacin were eligible. Analysis of these studies showed that, although the primary outcome of PDA closure on days two and five slightly favored bolus administration, there was no statistical difference between the two groups. The estimates for PDA closure were RR 1.57 (95% CI 0.54, 4.60), RD 0.10 (95% CI -0.13, 0.33) for day 2 and RR 2.77 (95% CI 0.33, 23.14), RD 0.15 (95% CI -0.13, 0.42) for day five. There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). These analyses were based on a very small number of events reported by these trials. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), neurodevelopmental outcome and isolated intestinal perforation. The review demonstrated that there was a decrease in cerebral blood flow velocity after bolus injections and that the difference between the bolus and continuous infusion groups remained significant for 12 - 24 hour. In one study (Christmann 2002), the decrease in blood flow was maximum at 10 minutes [MD -46.40 (95% CI -75.41, -17.39)], while the other study (Hammerman 1995) reported a maximum drop at 30 minutes [MD -55.60 (95% CI -62.92, -48.28)]. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). In both of these circulations, the decrease was maximum 30 minutes after the bolus injection [typical estimates for renal and mesenteric circulations, respectively: MD -42.00 (95% CI -76.59, -7.41) and MD -26.50 (95% CI -45.34, -7.66)] and lasted about two hours. None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine. AUTHORS' CONCLUSIONS: Due to a paucity of events and lack of precision, the available data was found to be insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion versus bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration i.e. continuous versus bolus infusions for the treatment of PDA in premature infants cannot be made based on the current findings of this review.

A randomized controlled trial of synchronized nasal intermittent positive pressure ventilation in RDS.

OBJECTIVE: Comparison of outcomes of infants with respiratory distress syndrome (RDS), post-surfactant, extubated to synchronized nasal intermittent positive pressure ventilation (SNIPPV) or continued on conventional ventilation (CV). STUDY DESIGN: Prospective post-surfactant randomized controlled trial of primary mode SNIPPV compared with CV in infants (born from July 2000 to March 2005) with birth weights (BW) of 600 to 1250 g. Primary mode SNIPPV was defined as its use in the acute phase of RDS, following the administration of the first dose of surfactant. RESULT: There were no significant differences in the maternal demographics, antenatal steroid use, mode of delivery, BW, gestational age, gender or Apgar at 5 min between infants continued on CV (n=21) and those extubated to primary mode SNIPPV (n=20). Significantly, more babies in the CV group had the primary outcome of bronchopulmonary dysplasia (BPD)/death, compared to the SNIPPV group (52 versus 20%, P=0.03). There was no difference in the incidence of other common neonatal morbidities. There were no differences in the Mental or Psychomotor Developmental Index scores on follow-up between the two groups. CONCLUSION: Infants of BW 600 to 1250 g with RDS receiving surfactant with early extubation to SNIPPV had a significantly lower incidence of BPD/death. Primary mode SNIPPV is a feasible method of ventilation in small premature infants.

Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure.

OBJECTIVE: Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD). STUDY DESIGN: Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO. RESULTS: Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21). CONCLUSIONS: Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.

BACKGROUND: Corticosteroids have been used late in the neonatal period to treat chronic lung disease (CLD) in preterm babies, and early to try to prevent it. CLD is likely to be the result of persisting inflammation in the lung and the use of powerful anti-inflammatory drugs like dexamethasone has some rationale. Early use tends to be associated with increased adverse effects so that studies of moderately early treatment (7-14 days postnatal) might have the dual benefits of fewer side effects and onset of action before chronic inflammation is established. OBJECTIVES: To determine if moderately early (7-14 days) postnatal corticosteroid treatment vs control (placebo or nothing) is of benefit in the prevention and/or treatment of early chronic lung disease in the preterm infant. SEARCH STRATEGY: Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, Cochrane Database of Controlled Trials, MEDLINE (1966 - October 2002), hand searching paediatric and perinatal journals, examining previous review articles and information received from practicing neonatologists. Authors of all studies were contacted, 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. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment from 7-14 days of birth in high risk preterm infants were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, or need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, hypertrophic cardiomyopathy, pneumothorax, severe intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), gastrointestinal bleeding, and severe retinopathy of prematurity (ROP)), and long term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability), were abstracted and analysed using RevMan 4.1. MAIN RESULTS: Seven studies enrolling a total of 669 participants were eligible for inclusion in this review. Moderately early steroid treatment (vs placebo or nothing) reduced mortality by 28 days, chronic lung disease at 28 days and 36 weeks, and death or chronic lung disease at 28 days or 36 weeks. Earlier extubation was facilitated. There was no significant effect on the rates of pneumothorax, severe ROP, or NEC. Adverse effects included hypertension, hyperglycaemia, gastrointestinal bleeding, hypertrophic cardiomyopathy and infection. Steroid-treated infants were less likely to need late rescue with dexamethasone. There were limited data from four studies of long term follow-up; these did not show evidence of an increase in adverse neurological outcomes. REVIEWER'S CONCLUSIONS: Moderately early corticosteroid therapy (started at 7-14 days) reduces neonatal mortality and CLD, but at the cost of important short term adverse effects. Limited evidence concerning long term effects is provided by the trials included in this review. The methodological quality of the studies determining the long-term outcome is limited in some cases, the children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. Therefore, given the risk:benefit ratio of short-term effects and the limited long-term follow-up data, it seems appropriate to reserve moderately early corticosteroid treatment to infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of therapy. More research is urgently needed, including long term follow-up of survivors included in previous and any future trials, before the benefits and risks of postnatal steroid treatment, including initiation at 7-14 days, can be reliably assessed (See DART study; Doyle 2000a).

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

BACKGROUND: Many 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. OBJECTIVES: To determine if late (usually > 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. SEARCH STRATEGY: Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register, MEDLINE 1966 through October 2002, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. Authors of all studies were contacted, 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. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment initiated at predominantly > 3 weeks of age in preterm infants with CLD were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality, CLD (including need for home oxygen, or need for late rescue with corticosteroids), death or CLD, failure to extubate, complications in the primary hospitalisation (including infection, hyperglycaemia, glycosuria, hypertension, echodensities on ultrasound scan of brain, necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation, and severe retinopathy of prematurity (ROP)), and long term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability), were abstracted and analysed using RevMan 4.1. MAIN RESULTS: Nine trials enrolling a total of 562 participants were eligible for this review. Delayed steroid treatment had no significant effect on mortality. Beneficial effects of delayed steroid treatment included reductions in failure to extubate by 7 or 28 days, chronic lung disease at 36 weeks, need for late rescue treatment with dexamethasone, discharge to home on oxygen therapy, and death or CLD at 36 wk. There was no evidence of increase in risk of infection, necrotising enterocolitis, or gastrointestinal bleeding. Short-term adverse affects included glycosuria and hypertension. There was an increase in severe retinopathy of prematurity, of borderline significance, but no significant increase in blindness. The trend to an increase in cerebral palsy was 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. REVIEWER'S CONCLUSIONS: 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 (see also review of Early postnatal corticosteroids), this review of postnatal corticosteroid treatment for CLD initiated predominantly after three weeks of age suggests that late or delayed therapy may not significantly increase 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, the children have been assessed predominantly before school age, and no study has been sufficiently powered to detect 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 to infants who cannot be weaned from mechanical ventilation, and to minimise the dose and duration of any course of treatment.

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

BACKGROUND: Chronic 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. OBJECTIVES: To 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. SEARCH STRATEGY: Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register, MEDLINE (1966 - October 2002), hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. Authors of all studies were contacted, 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. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment within 96 hours of birth (early) in high risk preterm infants were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, and need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, pulmonary air leak, patent ductus arteriosus (PDA), severe intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL), necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation, severe retinopathy of prematurity (ROP), and long-term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability) were abstracted and analysed using RevMan 4.1. MAIN RESULTS: Twenty-one randomised controlled trials enrolling a total of 3072 participants were eligible for inclusion in this review. A meta-analysis of these trials demonstrated significant benefits as regards earlier extubation and decreased risks of CLD at both 28 days and 36 weeks, death or CLD at 28 days and 36 weeks, PDA and severe ROP. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe IVH, PVL, NEC or pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects and the risks of hyperglycaemia and hypertension were also increased. In the nine trials which have reported late outcomes, several adverse neurological effects were found at follow-up examinations of survivors treated with early steroids: developmental delay (not defined), cerebral palsy and abnormal neurological exam. However, major neurosensory disability was not significantly increased, either overall in the 4 studies where this outcome could be determined, or in the 2 individual studies where the rate of cerebral palsy and abnormal neurological exam were significantly increased. Moreover, the rate of the combined outcome of death or major neurosensory disability was not significantly increased. REVIEWER'S CONCLUSIONS: The benefits of early postnatal corticosteroid treatment (< 96 hours) may not outweigh the known or potential adverse effects of this treatment. Although early steroid treatment facilitates extubation and reduces the risk of chronic lung disease, 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 exam and cerebral palsy. However, the methodological quality of the studies determining the long-term outcome is limited in some cases, the 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. The role of inhaled steroids remains to be elucidated.

Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial.

OBJECTIVES: Infants of

Changes in arterial oxygen tension when weaning neonates from inhaled nitric oxide.

We set out to evaluate changes in arterial oxygen tension (PaO(2)) when weaning neonates from inhaled nitric oxide (INO). We reviewed the records of 505 prospectively collected INO weaning attempts on 84 neonates with hypoxic respiratory failure. PaO(2) values before and 30 min after weaning attempts were recorded. Relationships between change in PaO(2) and decreases in INO concentrations were investigated using regression analysis and ANOVA. PaO(2) decreased (-18.7 +/- 1.8 torr; P < 0.001); when weaning INO. A stepwise decline in PaO(2) was observed weaning INO from 40 ppm. The greatest decline occurred when INO was discontinued (-42.1 +/- 4.1 torr). Forward stepwise multiple regression using variables with significant relationships to the decline in PaO(2) identified the specific dose reduction 7(P < 0.001), the prewean PaO(2) (P < 0.001), and surfactant therapy (P = 0.018) as the variables best describing the change in PaO(2)(P = 0.004, r = 0.51). In conclusion, a graded decline in PaO(2) occurs when reducing INO. INO should be weaned to less than 1 ppm before discontinuing its use. Prior surfactant treatment appears to enhance the oxygenation reserve when weaning INO.

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

BACKGROUND: Many 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. OBJECTIVES: To 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. SEARCH STRATEGY: Randomised 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. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment initiated at > 3 weeks of age in preterm infants with CLD were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality before discharge, failure to extubate, infection, hyperglycaemia, hypertension, severe retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), gastrointestinal bleeding, intestinal 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 including a study reporting 5 year follow-up were abstracted and analysed using Revman 4.1. MAIN RESULTS: Delayed steroid treatment had no effect on mortality. Beneficial effects of delayed steroid treatment included reductions in failure to extubate by 7 or 28 days, need for late rescue treatment with dexamethasone, chronic lung disease at 36 weeks, death or CLD at 36 wk, 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, of borderline significance in survivors, but no significant increase in blindness. Although there were increases in long-term neurologic sequelae, including abnormal neurologic examination and cerebral palsy, those apparent trends were offset by a trend in the opposite direction due to an increased incidence of death before follow-up assessment. REVIEWER'S CONCLUSIONS: 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 (see also review of Early postnatal corticosteroids), this review of postnatal corticosteroid treatment for CLD initiated after three weeks of age suggests that late or delayed therapy may not significantly increase the risk of adverse long-term neurodevelopmental outcomes. Nonetheless, corticosteroids should still be reserved for infants who cannot be weaned from mechanical ventilation. The dose of dexamethasone and the duration of any course of treatment should still be minimized.

Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.

BACKGROUND: Corticosteroids have been used late in the neonatal period to treat chronic lung disease (CLD) in preterm babies and early to try to prevent it. CLD is likely to be the result of persisting inflammation in the lung and the use of powerful anti-inflammatory drugs like dexamethasone has some rationale. Early use tends to be associated with increased adverse effects so that studies of moderately early treatment (7-14 days postnatal) might have the dual benefits of fewer side effects and onset of action before chronic inflammation is established. OBJECTIVES: To determine if moderately early (7-14 days) postnatal corticosteroid treatment vs control (placebo or nothing) is of benefit in the prevention and/or treatment of early chronic lung disease in the preterm infant. SEARCH STRATEGY: Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, Cochrane Database of Controlled Trials, Medline, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment from 7-14 days of birth in high risk preterm infants were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality up to 28 days and before discharge, failure to extubate, mortality or chronic lung disease at 28 days and 36 weeks, CLD at 28 days and 36 weeks, infection, hyperglycaemia, hypertension, severe retinopathy of prematurity (ROP), pneumothorax, necrotizing enterocolitis (NEC), gastrointestinal bleeding, severe intraventricular haemorrhage (IVH), hypertrophic cardiomyopathy, late rescue with dexamethasone and abnormal neurological examination at follow-up were abstracted and analysed using RevMan 4.1. MAIN RESULTS: Moderately early steroid treatment (vs placebo or nothing) reduced mortality by 28 days, chronic lung disease at 28 days and 36 weeks, and death or chronic lung disease at 28 days or 36 weeks. Earlier extubation was facilitated. There was no significant effect on the rates of pneumothorax, severe ROP, and NEC. Adverse effects included hypertension, hyperglycaemia, gastrointestinal bleeding, hypertrophic cardiomyopathy and infection. Steroid-treated infants were less likely to need late rescue with dexamethasone. There was only one small study of longterm follow-up and it did not show any increase in adverse neurological outcome. REVIEWER'S CONCLUSIONS: Moderately early corticosteroid therapy (started at 7-14 days) reduces neonatal mortality and CLD, but at the cost of important short term adverse effects. No reliable evidence concerning long term effects is provided by the trials included in this review. In view of the evidence of an important increase in cerebral palsy and other adverse neurodevelopmental outcomes from trials in which postnatal steroids were begun either earlier or later than 7-14 days, there are reasonable grounds for extending this concern to moderately early initiation of steroid therapy. More research is urgently needed, including long term follow-up of survivors included in previous and any future trials, before the benefits and risks of postnatal steroid treatment, including initiation at 7-14 days, can be reliably assessed (See DART study; ~~ Doyle 2000~~).

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

BACKGROUND: Chronic 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. OBJECTIVES: To 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. SEARCH STRATEGY: Randomised 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. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment within 96 hours of birth (early) in high risk preterm infants were selected for this review. DATA COLLECTION AND ANALYSIS: Data 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. MAIN RESULTS: Nineteen 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. REVIEWER'S CONCLUSIONS: The 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.

Neonatal auditory activation detected by functional magnetic resonance imaging.

The objective of this study was to detect auditory cortical activation in non-sedated neonates employing functional magnetic resonance imaging (fMRI). Using echo-planar functional brain imaging, subjects were presented with a frequency-modulated pure tone; the BOLD signal response was mapped in 5 mm-thick slices running parallel to the superior temporal gyrus. Twenty healthy neonates (13 term, 7 preterm) at term and 4 adult control subjects. Blood oxygen level-dependent (BOLD) signal in response to auditory stimulus was detected in all 4 adults and in 14 of the 20 neonates. FMRI studies of adult subjects demonstrated increased signal in the superior temporal regions during auditory stimulation. In contrast, signal decreases were detected during auditory stimulation in 9 of 14 newborns with BOLD response. fMRI can be used to detect brain activation with auditory stimulation in human infants.

Mediators of fetal inflammation in extremely low gestational age newborns.

To establish levels of mediators of inflammation in cord blood and postnatal serum from extremely low gestational age newborns (ELGANs, < or =28 weeks), we measured sixteen markers of inflammation by recycling immunoaffinity chromatography in 15 ELGANs who had serum sampled at days 2-5. Median levels of IL-1, IL-6, IL-8, IL-11, IL-13, TNF-alpha, G-CSF, M-CSF, GM-CSF, MIP-1alpha, and RANTES were considerably higher than published values of these inflammatory mediators from term newborns. In three of eight ELGANS who had serial measurements taken, levels of IL-1, IL-6, IL-8, IL-11, TNF-alpha, G-CSF, and MIP-1alpha declined from initially very high levels to reach an apparent baseline towards the end of the first postnatal week. In these same three infants, GM-CSF and TGF-beta1 levels increased continuously during the first week. In the other five ELGANs, no consistent changes were observed. We speculate, that in some ELGANs, a fetal systemic inflammatory response is characterized by an antenatal wave of pro-inflammatory cytokines, followed by a second, postnatal wave of anti-inflammatory cytokines. Large epidemiologic studies are needed to clarify relationships among inflammation markers and their expression in the fetal and neonatal circulation over time. Such studies would also add to our understanding of the possible role of inflammatory mediators in the pathophysiology of the major complications of extreme prematurity.

Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network.

OBJECTIVES: To determine the mortality and morbidity for infants weighing 401 to 1500 g (very low birth weight [VLBW]) at birth by gestational age, birth weight, and gender. STUDY DESIGN: Perinatal data were collected prospectively on an inborn cohort from January 1995 through December 1996 by 14 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports. Sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death were evaluated. RESULTS: Eighty four percent of 4438 infants weighing 501 to 1500 g at birth survived until discharge to home or to a long-term care facility (compared with 80% in 1991 and 74% in 1988). Survival to discharge was 54% for infants 501 to 750 g at birth, 86% for those 751 to 1000 g, 94% for those 1001 to 1250 g, and 97% for those 1251 to 1500g. The incidence of chronic lung disease (CLD; defined as receiving supplemental oxygen at 36 weeks' postmenstrual age; 23%), proven necrotizing enterocolitis (NEC; 7%), and severe intracranial hemorrhage (ICH; grade III or IV; 11%) remained unchanged between 1991 and 1996. Furthermore, 97% of all VLBW infants and 99% of infants weighing <1000 g at birth had weights less than the 10th percentile at 36 weeks' postmenstrual age. Mortality for 195 infants weighing 401 to 500 g was 89%, with nearly all survivors developing CLD. Mortality in infants weighing 501 to 600 g was 71%; among survivors, 62% had CLD, 35% had severe ICH, and 15% had proven NEC. CONCLUSIONS: Survival for infants between 501 and 1500 g at birth continued to improve, particularly for infants weighing <1000 g at birth. This improvement in survival was not associated with an increase in major morbidities, because the incidence of CLD, proven NEC, and severe ICH did not change. However, poor postnatal growth remains a major concern, occurring in 99% of infants weighing <1000 g at birth. Mortality and major morbidity (CLD, severe ICH, and NEC) remain high for the smallest infants, particularly those weighing <600 g at birth.