Prospective, randomized, double-blind, placebo-controlled evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia.

BACKGROUND: Despite expectant management, preeclampsia remote from term usually results in preterm delivery. Antithrombin, which displays antiinflammatory and anticoagulant properties, may have a therapeutic role in treating preterm preeclampsia, a disorder characterized by endothelial dysfunction, inflammation, and activation of the coagulation system. OBJECTIVE: This randomized, placebo-controlled clinical trial aimed to evaluate whether intravenous recombinant human antithrombin could prolong gestation and therefore improve maternal and fetal outcomes. STUDY DESIGN: We performed a double-blind, placebo-controlled trial at 23 hospitals. Women were eligible if they had a singleton pregnancy, early-onset or superimposed preeclampsia at 23 0/7 to 30 0/7 weeks' gestation, and planned expectant management. In addition to standard therapy, patients were randomized to receive either recombinant human antithrombin 250 mg loading dose followed by a continuous infusion of 2000 mg per 24 hours or an identical saline infusion until delivery. The primary outcome was days gained from randomization until delivery. The secondary outcome was composite neonatal morbidity score. A total of 120 women were randomized. RESULTS: There was no difference in median gestational age at enrollment (27.3 weeks' gestation for the recombinant human antithrombin group [range, 23.1-30.0] and 27.6 weeks' gestation for the placebo group [range, 23.0-30.0]; P=.67). There were no differences in median increase in days gained (5.0 in the recombinant human antithrombin group [range, 0-75] and 6.0 for the placebo group [range, 0-85]; P=.95). There were no differences between groups in composite neonatal morbidity scores or in maternal complications. No safety issues related to recombinant human antithrombin were noted in this study, despite the achievement of supraphysiological antithrombin concentrations. CONCLUSION: The administration of recombinant human antithrombin in preterm preeclampsia neither prolonged pregnancy nor improved neonatal or maternal outcomes.

Accuracy of preterm infant weight gain velocity calculations vary depending on method used and infant age at time of measurement.

BACKGROUND: We examined preterm infants' weight gain velocity (WGV) to determine how much calculation methods influences actual WGV during the first 28 days of life. METHODS: WGV methods (Average 2-point, Exponential 2-point, Early 1-point, and Daily) were calculated weekly and for various start times (birth, nadir, regain, day 3 and day 7) to 28 days of age for 103 preterm < 1500 gram infants, with daily weights. RESULTS: Range of WGV estimates decreased 10-22 g/kg/day to 15.5-15.8 g/kg/day when the Early 1-point method and the postnatal weight loss phase were excluded. WGV were lower when the postnatal weight loss was included and higher using the early method. WGV calculations beginning at day 7 did not differ from calculations beginning at the nadir. CONCLUSIONS: Variations in WGV calculations were large enough to create difficulties for comparing results between studies and translating research to practice. We recommend that the postnatal weight loss phase be excluded from WGV calculations and clinical studies report weight nadir and weights at day 7 and 28 to allow adequate comparison and translation of findings in clinical practice. The Average2pt method may be easier to calculate at bedside, so we recommend it be used in clinical settings and research summaries. The Early1pt method should not be used to summarize WGV for research.

Genetic variants associated with patent ductus arteriosus in extremely preterm infants.

OBJECTIVE: Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants. STUDY DESIGN: Preterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables. RESULTS: SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons. CONCLUSION: We identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants.

An Attempt to Standardize the Calculation of Growth Velocity of Preterm Infants-Evaluation of Practical Bedside Methods.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

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

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.

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

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.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration: clinicaltrials.gov Identifier: NCT00614744.

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

IMPORTANCE: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. OBJECTIVE: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. INTERVENTIONS: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). MAIN OUTCOMES AND MEASURES: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. RESULTS: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. CONCLUSIONS AND RELEVANCE: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

Preterm Infant Growth Velocity Calculations: A Systematic Review.

CONTEXT: Clinicians assess the growth of preterm infants and compare growth velocity using a variety of methods. OBJECTIVE: 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 z scores. DATA SOURCES: 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. STUDY SELECTION: Of 1543 located studies, 373 (24%) calculated growth velocity. DATA EXTRACTION: We conducted detailed extraction of the 151 studies that reported g/kg/d weight gain velocity. RESULTS: 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 z 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 z scores. LIMITATIONS AND CONCLUSIONS: 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.

Neurodevelopmental outcomes and nutritional strategies in very low birth weight infants.

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.

Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants.

Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks' postmenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p < 0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p = 0.12) when controlling for BW and energy intake. Both BW (p = 0.02) and energy intake (p = 0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth.

Growth Outcomes of Preterm Infants Exposed to Different Oxygen Saturation Target Ranges from Birth.

OBJECTIVE: To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO2]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age. STUDY DESIGN: We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 ± 1 weeks, birth weight 839 ± 186 g) or higher (91%-95%, n = 408, PMA 26 ± 1 weeks, birth weight 840 ± 191 g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight <10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression. RESULTS: Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups. CONCLUSION: Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants.

Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants.

BACKGROUND: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. CONCLUSION: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.

Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants.

OBJECTIVE: To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. STUDY DESIGN: We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. RESULTS: The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. CONCLUSIONS: Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.

Biochemical Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia.

BACKGROUND: Pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD) is associated with increased morbidity and mortality. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and decreased levels of amino acid precursors of nitric oxide (NO) have been associated with PH, but have not been studied in infants with PH secondary to BPD. OBJECTIVE: The aim of this study was to identify a biochemical marker for PH in infants with BPD. METHODS: Twenty infants, born at <27 weeks' gestational age (GA) and/or with a birth weight (BW) ≤750 g, who met the criteria for BPD at 36 weeks' corrected GA (CGA) were enrolled in this cross-sectional pilot study. A screening echocardiogram was conducted at 36-38 weeks' CGA and plasma NT-proBNP and amino acid levels were obtained within 1 week of the screening echocardiogram. RESULTS: Five infants (25%) had echocardiographic evidence of PH. GA and BW were not significantly different between the 2 groups (a PH group and a No PH group). NT-proBNP was significantly elevated in the PH group (median 1,650 vs. 520 pg/ml; p = 0.001) but citrulline levels were significantly lower (median 21 vs. 36 µmol/l; p = 0.005). Arginine levels were not significantly different between the groups (median 78 vs. 79 µmol/l; p = 1). CONCLUSION: NT-proBNP and the NO precursor citrulline may be cost-effective biochemical markers for screening for the presence of PH in preterm infants who have BPD. If validated in a larger study, such biochemical markers may, in part, replace PH screening echocardiograms in these patients.

Weight Status in the First 2 Years of Life and Neurodevelopmental Impairment in Extremely Low Gestational Age Newborns.

OBJECTIVE: To examine the extent to which weight gain and weight status in the first 2 years of life relate to the risk of neurodevelopmental impairment in extremely preterm infants. STUDY DESIGN: In a cohort of 1070 infants born between 23 and 27 weeks' gestation, we examined weight gain from 7-28 days of life (in quartiles) and weight z-score at 12 and 24 months corrected age (in 4 categories: <-2; ≥-2, <-1; ≥1, <1; and ≥1) in relation to these adverse neurodevelopmental outcomes: Bayley-II mental development index <55, Bayley-II psychomotor development index <55, cerebral palsy, Gross Motor Function Classification System ≥1 (cannot walk without assistance), microcephaly. We adjusted for confounders in logistic regression, stratified by sex, and performed separate analyses including the entire sample, and excluding children unable to walk without assistance (motor impairment). RESULTS: Weight gain in the lowest quartile from 7-28 days was not associated with higher risk of adverse outcomes. Children with a 12-month weight z-score <-2 were at increased risk for all adverse outcomes in girls, and for microcephaly and Gross Motor Function Classification System ≥1 in boys. However, excluding children with motor impairment attenuated all associations except that of weight z-score <-2 with microcephaly in girls. Similarly, most associations of low weight z-score at 24 months with adverse outcomes were attenuated with exclusion of children with motor impairment. CONCLUSION: Excluding children who have gross motor impairment appears to eliminate the association of low weight status with neurodevelopmental impairments at 2 years in extremely preterm infants.

The Rising Burden of Preeclampsia in the United States Impacts Both Maternal and Child Health.

OBJECTIVE: Preeclampsia is one of the top six causes of maternal mortality in the United States (US) and is associated with considerable perinatal morbidity and mortality. Evidence suggests the US incidence of preeclampsia has increased dramatically over the past two decades. This study aims to compile, summarize, and critique the literature on the health and economic burden of preeclampsia and early-onset preeclampsia. STUDY DESIGN: We reviewed the literature for estimates of burden of preeclampsia and early-onset preeclampsia to both mother and child, summarized the evidence on economic and social burden, and highlighted current gaps in the literature. RESULTS: No recent studies comprehensively assess the costs and health consequences of preeclampsia or early-onset preeclampsia for both mother and child. Where it exists, the literature suggests preeclampsia and early-onset preeclampsia cause numerous adverse health consequences, but these conditions currently lack effective treatment. The need for preterm delivery from early-onset preeclampsia suggests its costs are substantial: very (28-31 weeks) and extremely (<28 weeks) preterm birth cost approximately 40 and 100 times a term pregnancy, respectively. CONCLUSION: Given the severity of outcomes from preeclampsia, further research on its health and economic consequences is essential to inform policy and resource allocation decisions in health care.

Low-Dose Intravenous Soybean Oil Emulsion for Prevention of Cholestasis in Preterm Neonates.

BACKGROUND: Premature infants depend on intravenous fat emulsions to supply essential fatty acids and calories. The dose of soybean-based intravenous fat emulsions (S-IFE) has been associated with parenteral nutrition (PN)-associated liver disease. This study's purpose was to determine if low-dose S-IFE is a safe and effective preventive strategy for cholestasis in preterm neonates. MATERIALS AND METHODS: This is a multicenter randomized controlled trial in infants with a gestational age (GA) ≤29 weeks. Patients <48 hours of life were randomized to receive a low (1 g/kg/d) or control dose (approximately 3 g/kg/d) of S-IFE. The primary outcome was cholestasis, defined as a direct bilirubin ≥15% of the total bilirubin at 28 days of life (DOL) or full enteral feeds, whichever was later, after 14 days of PN. Secondary outcomes included growth, length of hospital stay, death, and major neonatal morbidities. RESULTS: In total, 136 neonates (67 and 69 in the low and control groups, respectively) were enrolled. Baseline characteristics were similar for the 2 groups. When the low group was compared with the control group, there was no difference in the primary outcome (69% vs 63%; 95% confidence interval, -0.1 to 0.22; P = .45). While the low group received less S-IFE and total calories over time compared with the control group (P < .001 and P = .03, respectively), weight, length, and head circumference at 28 DOL, discharge, and over time were not different (P > .2 for all). CONCLUSION: Compared with the control dose, low-dose S-IFE was not associated with a reduction in cholestasis or growth.

Identifying Barriers to Initiating Minimal Enteral Feedings in Very Low-Birth-Weight Infants: A Mixed Methods Approach.

OBJECTIVE: This study aims to elicit physician and nursing perceptions about initiation of minimal enteral feedings (MEF) in very low-birth-weight (VLBW) infants. STUDY DESIGN: A three-phase, mixed methods study including a quantitative chart review of 37 VLBW infants, followed by 26 qualitative observations of morning rounds, 26 interviews of neonatal intensive care unit (NICU) medical team members, tailored interventions based on the identified barriers to MEF, and finally a postintervention chart audit of 50 VLBW infants. RESULTS: The main barriers to initiation of MEF were failure to appreciate the differences between the goals of MEF versus nutritive feedings, inconsistent definition of "sick" infant, indomethacin for intraventricular hemorrhage prophylaxis, awaiting mother's own milk, complicated feeding protocols/algorithms for feeding intolerance, and lack of buy-in from nurses/nurse practitioners. The compliance with early initiation of MEF per the feeding guidelines rose from 25 to 92% after our interventions. CONCLUSION: Understanding the complex interplay of provider, system and patient-based factors that interfere with initiation of MEF may enable NICUs to develop consensus guidelines and targeted interventions and to achieve timely initiation of nonnutritive feedings.

Impaired Activity of Blood Coagulant Factor XIII in Patients with Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) medical/surgical emergency of the newborn and a leading cause of preterm neonate morbidity and mortality. NEC is a challenge to diagnose since it often shares similar clinical features with neonatal sepsis. In the present study, plasma protein profiling was compared among NEC, sepsis and control cohorts using gel electrophoresis, immunoblot and mass spectrometry. We observed significant impairment in the formation of fibrinogen-γ dimers (FGG-dimer) in the plasma of newborns with NEC that could efficiently differentiate NEC and sepsis with a high level of sensitivity and specificity. Interestingly, the impaired FGG-dimer formation could be restored in NEC plasma by the addition of exogenous active factor XIII (FXIII). Enzymatic activity of FXIII was determined to be significantly lower in NEC subject plasma for crosslinking FGG when compared to sepsis. These findings demonstrate a potential novel biomarker and related biologic mechanism for diagnosing NEC, as well as suggest a possible therapeutic strategy.