Infants at higher risk of bronchopulmonary dysplasia had increased rates of survival free of cerebral palsy after postnatal corticosteroid treatment in a previous metaregression of data from 14 ...randomized controlled trials. The relationship persists and is stronger in an updated analysis with data from 20 randomized controlled trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To examine how well growth velocity recommendations for preterm infants fit with current growth references: Fenton 2013, Olsen 2010, INTERGROWTH 2015, and the World Health Organization Growth ...Standard 2006.
The Average (2-point), Exponential (2-point), Early (1-point) method weight-gains were calculated for 1,4,8,12, and 16-week time-periods. Growth references' weekly velocities (g/kg/d, gram/day and cm/week) were illustrated graphically with frequently-quoted 15 g/kg/d, 10-30 grams/day and 1 cm/week rates superimposed. The 15 g/kg/d and 1 cm/week growth velocity rates were calculated from 24-50 weeks, superimposed on the Fenton and Olsen preterm growth charts.
The Average and Exponential g/kg/d estimates showed close agreement for all ages (range 5.0-18.9 g/kg/d), while the Early method yielded values as high as 41 g/kg/d. All 3 preterm growth references were similar to 15 g/kg/d rate at 34 weeks, but rates were higher prior and lower at older ages. For gram/day, the growth references changed from 10 to 30 grams/day for 24-33 weeks. Head growth rates generally fit the 1 cm/week velocity for 23-30 weeks, and length growth rates fit for 37-40 weeks. The calculated g/kg/d curves deviated from the growth charts, first downward, then steeply crossed the median curves near term.
Human growth is not constant through gestation and early infancy. The frequently-quoted 15 g/kg/d, 10-30 gram/day and 1 cm/week only fit current growth references for limited time periods. Rates of 15-20 g/kg/d (calculated using average or exponential methods) are a reasonable goal for infants 23-36 weeks, but not beyond.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary The developing brain of the very low birth weight (VLBW) infant is highly sensitive to effects of the nutritional milieu during the neonatal hospitalization and after discharge. Strategies to ...optimize nutritional care play an important role in reducing long-term neurodevelopmental morbidities in this population. Currently available interventions to ensure that the unique nutrient requirements of the VLBW infant are met include various dietary fortification strategies and parenteral nutrition. In this article, we review evidence regarding nutritional strategies and their beneficial effects on neurodevelopment in VLBW infants. We also highlight gaps in current knowledge and areas of current investigation that hold promise for improving nutritional care and long-term outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
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.
Objectives
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.
Search methods
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.
Selection criteria
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.
Data collection and analysis
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.
Main results
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).
Authors' conclusions
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.
Background
Bronchopulmonary dysplasia 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 prevent or treat bronchopulmonary dysplasia because of their potent anti‐inflammatory effects.
Objectives
To examine the relative benefits and adverse effects of systemic postnatal corticosteroids commenced within the first seven days of life for preterm infants at risk of developing bronchopulmonary dysplasia.
Search methods
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 (RCTs) and quasi‐randomised trials.
Selection criteria
For this review, we selected RCTs examining systemic postnatal corticosteroid treatment within the first seven days of life (early) in high‐risk preterm infants. Most studies evaluated the use of dexamethasone, but we also included studies that assessed hydrocortisone, even when used primarily for management of hypotension.
Data collection and analysis
We used the GRADE approach to assess the quality of evidence.
We extracted and analysed data regarding clinical outcomes that included mortality, bronchopulmonary dysplasia, death or bronchopulmonary dysplasia, failure to extubate, complications during primary hospitalisation, and long‐term health outcomes.
Main results
We included 32 RCTs enrolling a total of 4395 participants. The overall risk of bias of included studies was probably low, as all were RCTs, and most trials used rigorous methods. Investigators reported significant benefits for the following outcomes overall: lower rates of failure to extubate, decreased risks of bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age, death or bronchopulmonary dysplasia at 28 days of life and at 36 weeks' postmenstrual age, patent ductus arteriosus, and retinopathy of prematurity (ROP), including severe ROP. Researchers found no significant differences in rates of neonatal or subsequent mortality; they noted that gastrointestinal bleeding and intestinal perforation were important adverse effects, and that risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy, and growth failure were increased. The 13 trials that reported late outcomes described several adverse neurological effects at follow‐up examination, including cerebral palsy. However, study authors indicated that major neurosensory disability was not significantly increased, either overall in the eight studies for which this outcome could be determined, or in the two individual studies in which rates of cerebral palsy or abnormal neurological examination were significantly increased. Moreover, data show that rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability, were not significantly increased. Two‐thirds of studies used dexamethasone (n = 21). Subgroup analyses by type of corticosteroid revealed that most of the beneficial and harmful effects of treatment were attributable to dexamethasone. However, as with dexamethasone, hydrocortisone was associated with reduced rates of patent ductus arteriosus, mortality, and the combined outcome of mortality or chronic lung disease, but with increased occurrence of intestinal perforation. Results showed that hydrocortisone was not associated with obvious longer‐term problems.
Use of the GRADE approach revealed that the quality of evidence was high for the major outcomes considered, but review authors downgraded quality one level for several outcomes (mortality at latest age, bronchopulmonary dysplasia at 36 weeks, and death or bronchopulmonary dysplasia at 36 weeks) because of weak evidence of publication bias or moderate heterogeneity (death or cerebral palsy).
Authors' conclusions
Benefits of early postnatal corticosteroid treatment (≤ 7 days), particularly dexamethasone, may not outweigh adverse effects associated with this treatment. Although early corticosteroid treatment facilitates extubation and reduces risk of bronchopulmonary dysplasia 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 increased risk of abnormal findings on neurological examination and increased risk of cerebral palsy. However, the methodological quality of studies examining long‐term outcomes is limited in some cases: Surviving children have been assessed predominantly before school age; no study has been sufficiently powered to detect important adverse long‐term neurosensory outcomes; and no study has been designed with survival free of adverse long‐term neurodevelopmental disability as the primary outcome. There is a compelling need for 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 reduced rates of patent ductus arteriosus, of mortality, and of the combined outcome of mortality or bronchopulmonary dysplasia, without causing any obvious long‐term harm. However, gastrointestinal perforation was more frequent in the hydrocortisone group. Longer‐term follow‐up into late childhood is vital for assessment of important effects or other effects that cannot be assessed in early childhood, such as effects of early hydrocortisone treatment on higher‐order neurological functions, including cognitive function, academic performance, behaviour, mental health, and motor function. Further randomised controlled trials of early hydrocortisone should include longer‐term survival free of neurodevelopmental disability as the main outcome.
The objectives of this study were to assess whether (1) in-hospital growth velocity is predictive of neurodevelopmental and growth outcomes at 18 to 22 months' corrected age among extremely low birth ...weight (ELBW) infants and (2) in-hospital growth velocity contributes to these outcomes after controlling for confounding demographic and clinical variables.
Infants 501 to 1000 g birth weight from a multicenter cohort study were divided into quartiles of in-hospital growth velocity rates. Variables considered for the logistic-regression models included gender, race, gestational age, small for gestational age, mother's education, severe intraventricular hemorrhage, periventricular leukomalacia, age at regaining birth weight, necrotizing enterocolitis, late-onset infection, bronchopulmonary dysplasia, postnatal steroid therapy for pulmonary disease, and center.
Of the 600 discharged infants, 495 (83%) were evaluated at 18 to 22 months' corrected age. As the rate of weight gain increased between quartile 1 and quartile 4, from 12.0 to 21.2 g/kg per day, the incidence of cerebral palsy, Bayley II Mental Developmental Index (MDI) <70 and Psychomotor Developmental Index (PDI) <70, abnormal neurologic examination, neurodevelopmental impairment, and need for rehospitalization fell significantly. Similar findings were observed as the rate of head circumference growth increased. The in-hospital rate of growth was associated with the likelihood of anthropometric measurements at 18 months' corrected age below the 10th percentile values of the Centers for Disease Control and Prevention 2000 growth curve. Logistic-regression analyses, controlling for potential demographic or clinical cofounders, and adjusted for center, identified a significant relationship between growth velocity and the likelihood of cerebral palsy, MDI and PDI scores of <70, and neurodevelopmental impairment.
These analyses suggest that growth velocity during an ELBW infant's NICU hospitalization exerts a significant, and possibly independent, effect on neurodevelopmental and growth outcomes at 18 to 22 months' corrected age.
Objectives To evaluate data for the period 2004-2013 to identify changes in demographics, pathogens, and outcomes in a single, level IV neonatal intensive care unit. Study design Sepsis episodes were ...identified prospectively and additional information obtained retrospectively from infants with sepsis while in the neonatal intensive care unit from 2004 to 2013. Demographics, hospital course, and outcome data were collected and analyzed. Sepsis was categorized as early (≤3 days of life) or late-onset (>3 days of life). Results Four hundred fifty-two organisms were identified from 410 episodes of sepsis in 340 infants. Ninety percent of cases were late-onset. Rates of early-onset sepsis remained relatively static throughout the study period (0.9 per 1000 live births). For the first time in decades, most (60%) infants with early-onset sepsis were very low birth weight and Escherichia coli (45%) replaced group B streptococcus (36%) as the most common organism associated with early-onset sepsis. Rates of late-onset sepsis, particularly due to coagulase-negative staphylococci, decreased significantly after implementation of several infection-prevention initiatives. Coagulase-negative staphylococci were responsible for 31% of all cases from 2004 to 2009 but accounted for no cases of late-onset sepsis after 2011. Conclusions The epidemiology and microbiology of early- and late-onset sepsis continue to change, impacted by targeted infection prevention efforts. We believe the decrease in sepsis indicates that these interventions have been successful, but additional surveillance and strategies based on evolving trends are necessary.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective To document the mortality and morbidity of infants weighing 501-1500 g at birth according to gestational age, birthweight, and sex. Study design Prospective collection of perinatal events ...and neonatal course to 120 days of life, discharge, or death from January 1990 through December 2002 for infants born at 16 participating centers of the National Institute of Child Health & Human Development Neonatal Research Network. Results Compared with 1995-1996, for 1997-2002 the survival of infants with birthweight of 501-1500 g increased by 1 percentage point (from 84% to 85%). Survival without major neonatal morbidity remained static, at 70%; this includes bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Survival increased for multiple births (26%, up from 22%), antenatal corticosteroid use (79%, up from 71%), and maternal antibiotics (70%, up from 62%) ( P < .05). From 1997 to 2002, birthweight-specific survival was 55% for infants weighing 501-750 g, 88% for 751-1000 g, 94% for 1001-1250 g, and 96% for 1251–1500 g. More females survived. The incidence of NEC (7%), severe IVH (12%), and late-onset septicemia (22%) remained essentially unchanged, but BPD decreased slightly, from 23% to 22%. The use of postnatal corticosteroids declined from 20% in 1997-2000 to 12% in 2001-2002. Growth failure (weight <10th percentile) at 36 weeks’ postmenstrual age decreased from 97% in 1995-1996 to 91% in 1997-2002. Conclusion There have been no significant increases in survival without neonatal and long-term morbidity among VLBW infants between 1997 and 2002. We speculate that to improve survival without morbidity requires determining, disseminating, and applying best practices using therapies currently available, and also identifying new strategies and interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
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NUK, OILJ, UL, UM, UPUK, VSZLJ
Clinicians assess the growth of preterm infants and compare growth velocity using a variety of methods.
We determined the numerical methods used to describe weight, length, and head circumference ...growth velocity in preterm infants; these methods include grams/kilogram/day (g/kg/d), grams/day (g/d), centimeters/week (cm/week), and change in
scores.
A search was conducted in April 2015 of the Medline database by using PubMed for studies that measured growth as a main outcome in preterm neonates between birth and hospital discharge and/or 40 weeks' postmenstrual age. English, French, German, and Spanish articles were included. The systematic review was conducted by using Preferred Reporting Items for Systematic Reviews and Meta-analyses methods.
Of 1543 located studies, 373 (24%) calculated growth velocity.
We conducted detailed extraction of the 151 studies that reported g/kg/d weight gain velocity.
A variety of methods were used. The most frequently used method to calculate weight gain velocity reported in the 1543 studies was g/kg/d (40%), followed by g/d (32%); 29% reported change in
score relative to an intrauterine or growth chart. In the g/kg/d studies, 39% began g/kg/d calculations at birth/admission, 20% at the start of the study, 10% at full feedings, and 7% after birth weight regained. The kilogram denominator was not reported for 62%. Of the studies that did report the denominators, the majority used an average of the start and end weights as the denominator (36%) followed by exponential methods (23%); less frequently used denominators included birth weight (10%) and an early weight that was not birth weight (16%). Nineteen percent (67 of 355 studies) made conclusions regarding extrauterine growth restriction or postnatal growth failure. Temporal trends in head circumference growth and length gain changed from predominantly cm/wk to predominantly
scores.
The lack of standardization of methods used to calculate preterm infant growth velocity makes comparisons between studies difficult and presents an obstacle to using research results to guide clinical practice.
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