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Presents a response by Neil N. Finer et al to a letter to the editor about their article "Delivery Room Continuous Positive Airway Pressure/Positive End-Expiratory Pressure in Extremely Low Birthweight Infants: A Feasibility Trial," in a 2004 issue of "Pediatrics" journal.

Background: Early administration of high doses of dexamethasone may reduce the risk of chronic lung disease in premature infants but can cause complications. Whether moderate doses would be as effective but safer is not known. Methods: We randomly assigned 220 infants with a birth weight of 501 to 1000 g who were treated with mechanical ventilation within 12 hours after birth to receive dexamethasone or placebo with either routine ventilatory support or permissive hypercapnia. The dexamethasone was administered within 24 hours after birth at a dose of 0.15 mg per kilogram of body weight per day for three days, followed by a tapering of the dose over a period of seven days. The primary outcome was death or chronic lung disease at 36 weeks' postmenstrual age. Results: The relative risk of death or chronic lung disease in the dexamethasone-treated infants, as compared with those who received placebo, was 0.9 (95 percent confidence interval, 0.8 to 1.1). Since the effect of dexamethasone treatment did not vary according to the ventilatory approach, the two dexamethasone groups and the two placebo groups were combined. The infants in the dexamethasone group were less likely than those in the placebo group to be receiving oxygen supplementation 28 days after birth (P=0.004) or open-label dexamethasone (P=0.01), were more likely to have hypertension (P<0.001), and were more likely to be receiving insulin treatment for hyperglycemia (P=0.02). During the first 14 days, spontaneous gastrointestinal perforation occurred in a larger proportion of infants in the dexamethasone group (13 percent, vs. 4 percent in the placebo group; P=0.02). The dexamethasone-treated infants had a lower weight (P=0.02) and a smaller head circumference (P=0.04) at 36 weeks' postmenstrual age. Conclusions: In preterm infants, early administration of dexamethasone at a moderate dose has no effect on death or chronic lung disease and is associated with gastrointestinal perforation and decreased growth. (N Engl J Med 2001;344:95-101.) [ABSTRACT FROM AUTHOR]

Background: Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials. Methods: We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks. Results: By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome — death or chronic lung disease at 36 weeks' postmenstrual age — occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 μg per deciliter (0.70 μmol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001). Conclusions: Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants. (N Engl J Med 1999;340:1962-8.) [ABSTRACT FROM AUTHOR]

Background: Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown. Methods: We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 g) who had respiratory-index scores (mean airway pressure × the fraction of inspired oxygen) of >2.4 at two weeks of age. One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory-index score of >2.4 on treatment day 14) or additional placebo for two weeks. Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose was then tapered. Results: The median time to ventilator independence was 36 days in the dexamethasone–placebo group and 37 days in the placebo–dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks' postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone–placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo–dexamethasone group, and diminished weight gain and head growth (P<0.001) in both groups. Conclusions: Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of age. (N Engl J Med 1998;338:1112-8.) [ABSTRACT FROM AUTHOR]

Background: The administration of phenobarbital to pregnant women before delivery has been thought to decrease the frequency of intracranial hemorrhage in preterm infants. To evaluate this potential neuroprotective therapy further, we determined the effect of antenatal administration of phenobarbital on the frequency of neonatal intracranial hemorrhage and early death. Methods: We studied 610 women who were 24 to 33 weeks pregnant and who were expected to deliver their infants within 24 hours. The women were randomly assigned to receive either phenobarbital (10 mg per kilogram of body weight) or placebo intravenously, followed by maintenance doses until delivery or 34 weeks of gestation. The infants born to these women underwent cranial ultrasonography to detect the presence of intracranial hemorrhage. Results: There were 309 women in the phenobarbital group and 301 in the placebo group. A total of 247 women (80 percent) in the phenobarbital group and 235 (78 percent) in the placebo group delivered within 24 hours after infusion of the study drug or administration of the last maintenance dose. Intracranial hemorrhage or early death occurred in 83 of the 344 infants born to the women in the phenobarbital group (24 percent) and in 74 of the 324 born to the women in the placebo group (23 percent; risk ratio for the infants in the phenobarbital group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Among infants born before 34 weeks' gestation in whom ultrasonographic studies were performed, intracranial hemorrhage was diagnosed in 70 of 311 infants in the phenobarbital group (23 percent) and 64 of 279 in the placebo group (23 percent; risk ratio, 1.0; 95 percent confidence interval, 0.8 to 1.4). Conclusions: Antenatal administration of phenobarbital does not decrease the risk of intracranial hemorrhage or early death in preterm infants. (N Engl J Med 1997;337:466-71.) [ABSTRACT FROM AUTHOR]

Despite continued advances and developments in neonatal medicine, neonatal sepsis is the third leading cause of neonatal mortality and a major public health problem, especially in developing countries. Sepsis accounts for mortality for almost 50% of global children under 5 years of age.Over the past 50 years, there have been many advances in the diagnosis, prevention, and treatment of neonatal infections. The diagnostic advances include better culture techniques that permit more rapid confirmation of the diagnosis, advent of polymerase chain reaction (PCR) to rapidly diagnose viral infections, use of biologic markers indicating evidence of infection, and a better understanding of immunoglobulin markers of infection. From a therapeutic stand point, there have been a variety of antibiotics, antifungals, and antiviral agents, better approaches to prevent sepsis, specific immunotherapy, for example, respiratory syncytial virus (RSV); bundled approach to prevention of deep-line infection and better antibiotic stewardship, leading to earlier discontinuation of antibiotic therapy.Hand hygiene remains the benchmark and gold standard for late-onset sepsis prevention. The challenge has been that each decade, newer resistant bacteria dominate as the cause of sepsis and newer viruses emerge, for example, human immunodeficiency virus, zika virus, and novel coronavirus disease 2019.Future treatment options might include stem cell therapy, other antimicrobial protein and peptides, and targeting of pattern recognition receptors in an effort to prevent and/or treat sepsis in this vulnerable population. Also, the microbiome of premature infants has a smaller proportion of beneficial bacteria and higher numbers of pathogenic bacteria compared with term infants, likely owing to higher frequencies of cesarean sections, antibiotic use, exposure to the hospital environment, and feeding nonhuman milk products. Modifying the microbiome with more mother's milk and shorter duration of antibiotics in noninfected babies should be a goal. KEY POINTS: · Neonatal sepsis remains a leading cause of mortality.. · Challenges include bacterial resistance and newer viruses.. · Future treatments may include newer antibiotics/antivirals and stem cell therapy.., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Unlabelled: Despite extensive use of the term 'standard of care' (SOC), there is no such medical definition. How are neonatal therapies accepted as SOC with huge centre-to-centre variation? What defines SOC? We will consider paths to acceptance of multiple therapies (antenatal corticosteroids, preventing GBS, others). We conclude single-centre trials drive care, but are not consistently predictive for multicentre trials. Innovation/quality improvement initiatives also alter care, despite strong evidence practice changes take time. Furthermore, there are powerful medico-legal implications if a therapy is designated SOC., Conclusion: Defining SOC is a quandary with more legal implications than medical, but what's most critical is keeping current in a rapidly changing field., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

The tremendous advancement that has occurred in neonatal intensive care over the last 40-50 years can be largely attributed to greater understanding of developmental pathobiology in the newborn lung. Nonetheless, this improved survival from respiratory distress syndrome has been associated with continuing longer-term morbidity in the form of bronchopulmonary dysplasia (BPD). As a result, neonatal lung injury is a renewed focus of scientific interest. The onset of such an injury may begin in the delivery room, and this has generated interest in minimizing oxygen therapy and aggressive ventilatory support during the transition from fetal to neonatal lung. Fortunately, antenatal steroid therapy and selective use of surfactant therapy are now widely practiced, although fine tuning of this therapy for selected populations is ongoing. Newer therapeutic approaches address many aspects of BPD, including the pro-inflammatory component that characterizes this disorder. Finally, there is a greater need to understand the epidemiology and pathogenesis of the longer-term respiratory morbidity, most notably asthma, that persists in the preterm survivors of neonatal intensive care., (Copyright © 2013. Published by Elsevier B.V.)

Context: Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care., Objective: To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation., Design, Setting, and Participants: Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10,541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables., Main Outcome Measures: Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age., Results: Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97])., Conclusion: Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.

Objective: To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia., Design: Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months., Results: There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19)., Conclusions: The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE., (Copyright © 2011 by the American Academy of Pediatrics.)

It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.

Background: It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less)., Methods: We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments., Results: Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g., Conclusions: Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.), (2008 Massachusetts Medical Society)

Although many sick newborns are treated for hypotension and hypertension, the normal physiologic blood pressure range ensuring appropriate organ perfusion is uncertain. Treatment decisions are based on statistically defined gestational and postnatal age-dependent normative blood-pressure values, combined with clinical intuition, because of difficulties evaluating organ perfusion and adequacy of cerebral oxygen delivery. Early-onset hypotension usually results from the combined effects of abnormal peripheral vasoregulation, myocardial dysfunction, and hypovolemia. Volume administration is the primary initial therapy but its use can be associated with significant untoward effects, especially in preterm infants, and should be limited to 10-20 mL/kg of isotonic saline. If the blood pressure cannot be normalized, dopamine should be added, and sometimes followed by adrenaline (epinephrine) and corticosteroids. Hypertension, most often caused by congenital or acquired renovascular disease or volume overload, needs a thorough search for the etiology and cautious treatment, so that blood pressure does not fall too quickly or too low.

Background: Hypotension affects close to half of all ELBW infants, yet an agreement on its definition is still lacking. Despite the fact that neonatal hypotension may be a risk factor for neurologic impairment, there is a paucity of data on the impact of low blood pressure (BP) in extremely low birth weight (ELBW) infants weighing below 1000 g on neuro-developmental outcome., Objectives: Explore the relationship between blood pressure in the first 72 hours of life, perinatal factors, morbidity, and mortality in ELBW infants. Compare neuro-sensory outcome in ELBW infants with and without symptomatic hypotension., Methods: We reviewed the outcome for all 156 infants with a birth weight <1000 g admitted to the neonatal intensive care unit covering the time period 1998 to 1999. Infants who received fluid pushes and/or pressors during the first 72 hours of life in an attempt to increase blood pressure were regarded as "symptomatic" or "treated infants"; the others were designated "non-treated infants." Follow-up at 20 months corrected age included neurologic status, Bayley motor/mental evaluation, plus tests of vision and hearing. Statistical analysis was by SPSS 11.0. Univariate and multivariate analyses were conducted to determine morbidities associated with symptomatic hypotension., Results: A total of 59 infants (mean BW 714 +/- 154 g; GA 24.9 +/- 1.7 weeks) required BP support; 97 infants (mean BW 768 +/- 141 g; GA 26.1 +/- 1.9 weeks) received no BP support. The groups had similar race, gender, delivery mode, and maternal socioeconomic status. Thirty-five (22%) infants died, including 20 who received BP support. There were more infants with severe IVH (grade III/IV), 19% versus 2%, and the mortality was greater, 34% versus 16%, in those infants who received BP support. Of the 121 survivors, 110 (91%) had complete follow-up evaluations. Multivariate analysis controlling for SES and neonatal morbidity revealed that symptomatic hypotension is associated with delayed motor development (-6.0; SE 3.1) and hearing loss (O.R. 8.9; CI 0.92-86.3)., Conclusions: Symptomatic hypotension in ELBW infants in the first 72 hours of life is associated with significant short-term and long-term morbidity. Infants with symptomatic hypotension are more likely to have delayed motor development, hearing loss, and death.

Background: Neonatal hypotension may be a risk factor for neurologic impairment. Few studies have examined the impact of low blood pressure in extremely low birth weight (ELBW) infants weighing 400 to 999 g on neurodevelopmental outcome., Objectives: We set out to explore the relationship between treated hypotension in the first 72 hours of life and perinatal factors, morbidity, and mortality in ELBW infants and then to compare neurosensory outcome in ELBW infants with treated hypotension and those who never received treatment for hypotension., Design/methods: We performed chart review of all 156 ELBW infants admitted to our level III NICU in 1998-1999. Infants had "treated hypotension" if they received fluid pushes, corticosteroids, and/or vasopressors during the first 72 hours of life in an attempt to increase blood pressure. Follow-up included neurologic examination, Bayley Scales of Infant Development, vision and hearing evaluation. Statistical analysis was performed by using SPSS 11.0. Univariate and multivariate analyses were conducted to determine morbidities associated with treated hypotension., Results: Fifty-nine infants received treatment for hypotension. Ninety-seven infants did not. The groups had similar race, gender, delivery mode, chorioamnionitis, and maternal socioeconomic status. Thirty-eight (24%) infants expired, including 20 who received treatment for hypotension. Of the 156 infants in the study group, 110 underwent neurodevelopment testing, and 103 were able to undergo complete neurodevelopment testing and Bayley examination. Multivariate analysis controlling for socioeconomic status and neonatal morbidity revealed that treated hypotension is associated with delayed motor development and hearing loss., Conclusions: Treated hypotension in ELBW infants in the first 72 hours of life is associated with significant short-term and long-term morbidity. Infants with treated hypotension are more likely to have delayed motor development, hearing loss, and death.

Objective: A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks' gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O2) for > or =28 days but not at 36 weeks' postmenstrual age (PMA) or discharge, moderate BPD as O2 for > or =28 days plus treatment with <30% O2 at 36 weeks' PMA, and severe BPD as O2 for > or =28 days plus > or =30% O2 and/or positive pressure at 36 weeks' PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD., Methods: Data from 4866 infants (birth weight < or =1000 g, GA <32 weeks, alive at 36 weeks' PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months' corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks' PMA (36 weeks' definition), and with the consensus definition of BPD., Results: A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months' corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up., Conclusion: The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions.

Objective: To compare multiple logistic regression and neural network models in predicting death for extremely low birth weight neonates at 5 time points with cumulative data sets, as follows: scenario A, limited prenatal data; scenario B, scenario A plus additional prenatal data; scenario C, scenario B plus data from the first 5 minutes after birth; scenario D, scenario C plus data from the first 24 hours after birth; scenario E, scenario D plus data from the first 1 week after birth., Methods: Data for all infants with birth weights of 401 to 1000 g who were born between January 1998 and April 2003 in 19 National Institute of Child Health and Human Development Neonatal Research Network centers were used (n = 8608). Twenty-eight variables were selected for analysis (3 for scenario A, 15 for scenario B, 20 for scenario C, 25 for scenario D, and 28 for scenario E) from those collected routinely. Data sets censored for prior death or missing data were created for each scenario and divided randomly into training (70%) and test (30%) data sets. Logistic regression and neural network models for predicting subsequent death were created with training data sets and evaluated with test data sets. The predictive abilities of the models were evaluated with the area under the curve of the receiver operating characteristic curves., Results: The data sets for scenarios A, B, and C were similar, and prediction was best with scenario C (area under the curve: 0.85 for regression; 0.84 for neural networks), compared with scenarios A and B. The logistic regression and neural network models performed similarly well for scenarios A, B, D, and E, but the regression model was superior for scenario C., Conclusions: Prediction of death is limited even with sophisticated statistical methods such as logistic regression and nonlinear modeling techniques such as neural networks. The difficulty of predicting death should be acknowledged in discussions with families and caregivers about decisions regarding initiation or continuation of care.

Objective: The first objective was to identify factors associated with prolonged hospital stay (PHS: hospitalized >42 weeks postmenstrual age) in extremely premature (EP: born less than or equal to 28 weeks gestation) infants. The second objective was to identify a PHS best-performing benchmark center., Methods: This study was a retrospective cohort analysis of infants born < or =28 weeks gestation and admitted to one of 12 tertiary centers between January 1998 and October 2001. Risk-adjusted odds of PHS, defined as hospitalization beyond 42 weeks postmenstrual age, and the competing outcome, mortality, were assessed using logistic regression models., Results: Among 3892 EP survivors who had complete data for multivariable analysis, 685 (18%) had PHS. Variables contributing to PHS included chronic lung disease (oxygen use at discharge home or 36 week postmenstrual age) (OR 6.75; 95% CI: 5.04 to 9.03), necrotizing enterocolitis requiring surgery (OR 13.83; 95% CI: 8.05 to 23.76), and >two episodes of late-onset sepsis (OR 2.39; 95% CI: 1.66 to 3.44). Centers' risk-adjusted PHS odds differed from the reference center, which had the lowest incidence of PHS and mortality (overall P-value <0.0001). Mortality contributed to PHS, but in an opposite direction compared to other factors. Centers with lowest PHS odds were among those with highest mortality., Conclusions: These findings suggest that reduction of CLD, surgical NEC, and late onset sepsis could reduce PHS in EP infants. Risk adjusted odds of PHS and mortality are both crucial for selecting a PHS best-performing center.

Background: Early onset neonatal sepsis (EOS, occurring in the first 72 hours of life) remains an important cause of illness and death among very low birth weight (VLBW) preterm infants. We previously reported a change in the distribution of pathogens associated with EOS from predominantly gram-positive to primarily gram-negative organisms., Objective: To compare rates of EOS and pathogens associated with infection among VLBW infants born at centers of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network during 3 time periods: 1991-1993; 1998-2000; and 2002-2003., Study Design: Prospectively collected data from the NICHD Neonatal Research Network VLBW registry were retrospectively reviewed. Rates of blood culture confirmed EOS, selected maternal and infant variables and pathogens associated with infection were compared between 2002-2003 and 2 previously published cohorts., Results: During the past 13 years, overall rates of EOS have remained stable (15-19 per 1000 live births of infants 401-1500 g). More than one-half of early infections in the 2002-2003 cohort were caused by gram-negative organisms (53%), with Escherichia coli the most common organism (41%). Rates of group B streptococcal infections remain low (1.8 per 1000 live births). Between 1991-1993 and 1998-2000, there was a significant increase in rates of E. coli infections; but in 2002-2003, there was no significant change (7.0 per 1000 live births). Infants with EOS continue to be at significantly increased risk for death compared with uninfected infants., Conclusion: EOS remains an uncommon but important cause of morbidity and mortality among VLBW infants. Gram-negative organisms continue to be the predominant pathogens associated with EOS.

Objective: To compare duration of ventilation to mortality and adverse neurodevelopmental outcomes among extremely low birth weight (ELBW; 501-1000 g) infants., Study Design: Retrospective analysis of prospectively collected data from 5364 infants with a birthweight of 501 to 1000 g born at National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers from 1995 to 1998. The main outcome measures were: survival, duration of mechanical ventilation, and neurodevelopmental outcome., Results: Overall survival was 71%. The median duration of ventilation for survivors was 23 days; 75% were free of mechanical ventilation by 39 days, and 7% were ventilated for > or = 60 days. Of those ventilated for > or = 60 days, 24% survived without impairment. Of those ventilated for > or = 90 days, only 7% survived without impairment. Of those ventilated > or = 120 days, all survivors were impaired., Conclusions: The prognosis for ELBW with protracted ventilation remains grim. The cohort who remain intubated have diminished survival and high rates of impairment. Parents of these infants should be informed of changes in prognosis as the time of ventilation increases.

Objective: The purpose of this study was to evaluate neurodevelopmental outcome in extremely-low-birth-weight (ELBW) infants, all of whom had 3 characteristics: gestational age (GA) < or =24 weeks, birth weight < or =750 g, and 1-minute Apgar score < or =3., Study Design: Surviving infants were evaluated at 18 to 22 months' corrected age with a neurologic examination and the Bayley II Mental and Psychomotor Developmental Index (MDI and PDI)., Results: Between 1993 and 1999, 1016 infants had GA < or =24 weeks, birth weight < or =750 g, and 1-minute Apgar score < or =3. Of 246 survivors, 30% had cerebral palsy (CP), 5% had hearing impairment, and 2% were blind. MDI was > or =85 in 33% and < 70 in 46% of infants, while PDI was > or =85 in 41% and < 70 in 36% infants. Predictors of MDI < 70 were grade III-IV ICH, cystic periventricular leukomalacia (PVL), male gender, black race, and Medicaid insurance. Two-parent household was associated with an MDI >70. Predictors of PDI < 70 were grade III-IV ICH, PVL, steroids for bronchopulmonary dysplasia (BPD), and Medicaid insurance. CP was associated with grade III-IV ICH and PVL., Conclusion: Perinatologists and neonatologists should be aware of the risk of morbidity and mortality in this high-risk ELBW group.

In July 2003, the National Institute of Child Health and Human Development convened a conference, "Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside." This article will provide a summary of presentations and discussions from this conference. The summary will focus on the identified knowledge gaps in 5 areas related to bilirubin-induced brain injury and kernicterus: 1) neurobiology and neuroimaging; 2) epidemiology and issues of clinical management; 3) methodologies for assessing clinical jaundice and direct and noninvasive measurement of serum bilirubin and hemolysis; 4) therapies for management of neonatal hyperbilirubinemia; and 5) public health surveillance and systems-based approaches to prevention.

To determine the rates of Enterobacter sakazakii (ES) infections among very low birth weight infants, culture data from the National Institute of Child Health and Human Development Neonatal Research Network were reviewed. Only one case of ES sepsis was identified among 10660 neonates. These data suggest that outside of the epidemic situation, ES is very rare in very low birth weight infants.

Context: Neonatal meningitis is associated with significant morbidity and mortality. We speculated that meningitis may be underdiagnosed among very low birth weight (VLBW) infants because of the failure to perform lumbar punctures (LPs) in infants with suspected sepsis., Objective: This study was undertaken to review the epidemiology of late-onset meningitis in VLBW (401-1500 g) infants and to evaluate the concordance of cerebrospinal fluid (CSF) and blood culture (BC) results., Methods: VLBW infants (excluding those with intraventricular shunts) born at centers of the National Institute of Child Health and Human Development Neonatal Research Network from September 1, 1998, through December 31, 2001, were studied. Late-onset meningitis was defined by culture-based criteria and classified as meningitis with or without associated sepsis. Unadjusted comparisons were made using chi2 tests and adjusted comparisons using regression models., Results: Of 9641 VLBW infants who survived >3 days, 2877 (30%) had > or = 1 LPs, and 6056 (63%) had > or = 1 BC performed after day 3. One hundred thirty-four infants had late-onset meningitis (1.4% of all patients; 5% of those with an LP). Pathogens associated with meningitis were similar to those associated with sepsis. One third (45 of 134) of the infants with meningitis had negative BCs. Lower gestational age and prior sepsis increased risk for meningitis. Compared with uninfected infants, those with meningitis had a longer time on mechanical ventilation (28 vs 18 days), had longer hospitalizations (91 vs 79 days), were more likely to have seizures (25% vs 2%), and were more likely to die (23% vs 2%)., Conclusions: Meningitis is a serious complication among VLBW infants, associated with increased severity of illness and risk of death. Of note, one third of the infants with meningitis had meningitis in the absence of sepsis. Because CSF cultures were performed only half as often as BCs, this discordance in blood and CSF culture results suggests that meningitis may be underdiagnosed among VLBW infants.

Objective: To compare the ALGO 3 Newborn Hearing Screener (Natus Medical Inc.) to the ALGO 2e Newborn Hearing Screener (Natus Medical Inc.)., Design: A prospective evaluation., Setting: Three maternity hospitals., Patients/participants: 199 newborns enrolled; 194 completed the study., Interventions: Patients were tested using either the ALGO 3 screener or the ALGO 2e screener first, and then screened with the alternate device. Initial screens resulting in REFER outcomes were repeated using the same device. An ALGO 2e PASS result was accepted as adequate evidence of hearing. Two sequential ALGO 2e REFER results required further diagnostic testing to determine hearing status., Main Outcome Measures: Average screening times and referral rates of both hearing screeners., Results: The ALGO 3 screener averaged 70.8 seconds (95% confidence interval = 34.5-107.1 seconds), or was 23% faster than the ALGO 2e screener (p = .0002). There were 48% fewer REFER results after initial screening with the ALGO 3 screener (5.7%) than with the ALGO 2e screener (10.9%) (p = .06). Faster screen times and fewer referrals were noted at each hospital., Conclusion: The ALGO 3 screener can increase caregiver efficiency by accurately screening hearing in newborns faster and with fewer REFER results than the ALGO 2e screener.

Objective: To assess the association between peak total serum bilirubin (PSB) levels during the first 2 weeks of life and neurodevelopmental outcomes of extremely low birth weight (ELBW) infants at 18 to 22 months' postmenstrual age., Methods: A retrospective analysis was conducted of a cohort of ELBW infants (401-1000 g) who survived to 14 days of age in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1, 1994, and December 31, 1997. Demographic and clinical risk factors and PSB levels during the first 14 days were analyzed with reference to death or adverse neurodevelopmental outcomes at 18 to 22 months' postmenstrual age. The neurodevelopmental variables considered were Psychomotor Developmental Index (PDI) <70, Mental Developmental Index (MDI) <70, moderate or severe cerebral palsy (CP), hearing impairment (needs hearing aids), and a composite category designated as neurodevelopmental impairment (NDI). The NDI is defined as infants with any 1 or more of the following: PDI <70, MDI <70, moderate to severe CP, bilateral blindness, or bilateral hearing impairment requiring amplification., Results: The subjects of this cohort analysis are infants who were admitted to the Network centers during calendar years 1994-1997 and survived beyond 14 days and had PSB recorded during the 14-day period. From this cohort, 3246 infants survived at discharge, 79 died after discharge, and 592 were lost to follow-up. Thus, 2575 of 3167 infants were seen in the follow-up clinics with a compliance rate of 81%. Logistic regression analysis showed that various demographic and clinical variables are associated with poor neurodevelopmental outcomes. After adjustment for these risk factor, significant association were found between PSB (mg/dL) and death or NDI (odds ratio: 1.068; 95% confidence interval [CI]: 1.03-1.11); PDI <70 (R = 1.057; 95% CI: 1.00-1.12), and hearing impairment requiring hearing aids (odds ratio: 1138; 95% CI: 1.00-1.30). There was no significant association between PSB (mg/dL) and CP, MDI <70, and NDI., Conclusions: PSB concentrations during the first 2 weeks of life are directly correlated with death or NDI, hearing impairment, and PDI <70 in ELBW infants. The statistical association based on retrospective analysis of observational data and relatively small effect size should be interpreted with caution. Furthermore, because of the possibility of compounding effects of variables on outcome, the potential benefits of moderate hyperbilirubinemia and the potential adverse effects of phototherapy, a randomized, controlled trial of aggressive and conservative phototherapy is needed to address this controversial issue.

The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network was founded in 1986 to perform trials that, because of their size and complexity, were beyond the scope of a single center and required the expertise and resources of many collaborating centers. This report briefly documents changes in mortality, selected morbidities, and therapies amongst Network centers. The Network registry incorporating perinatal and neonatal data on all infants with a birth weight 501-1500 g cared for at participating centers served as the database. Mortality and selected morbidities were compared for 3 time periods, 1987/1988, (7 centers 1,765 infants, presurfactant); 1993/1994 (12 centers, 4,593 infants, postsurfactant and moderate antenatal corticosteroid utilization); and 1999/2000 (15 centers, 5,848 infants, postsurfactant and widespread corticosteroid use). Detailed outcomes for infants with birth weights between 501 and 800 g, and gestational ages of 23 to 25 weeks are also presented because they dramatically document the changes over time. Mortality for the entire cohort decreased from 23% in 1987/1988 to 17% in 1993/1994 and 14% in 1999/2000. Between 1987/1988 and 1999/2000 mortality prior to discharge, decreased from 66% to 45% for infants weighing 501-750 g; from 34% to 12% for birth weight between 751 to 1000 g, and from 13% to 7% for infants between 1001 and 1500 g. Mortality was higher in boys. Survival free of major morbidity (chronic lung disease/bronchopulmonary dysplasia, necrotizing enterocolitis or grade III/IV intraventricular hemorrhage) did not change significantly over time. Since the inception of the Network, multiple births have increased from 18% to 26%; deliveries by Cesarean section from 47% to 57%, and antenatal corticosteroid use increased from 16% to 79%. Surfactant, which was not used prior to 1990, is now given to 57% of the infants, including 87% with birth weights between 501 and 750 g. There have been significant decreases in the incidence of grade III-IV intraventricular hemorrhage from 18% in 1987/1988 to about 11% since 1993/1994, and periventricular leukomalacia from 8% to 3%. However, other morbidities, including necrotizing enterocolitis, patent ductus arteriosus, and late onset sepsis, have not changed substantially. Advances in perinatal care within NICHD Network centers have resulted in marked improvements in survival. Further advances are required to increase survival free of neonatal morbidity or neurodevelopmental impairment.

Objective: The purpose of this study was to examine the influence of labor on extremely-low-birth-weight infants who were born by cesarean delivery with reference to neonatal and neurodevelopmental outcomes. We hypothesized that infants who are born by cesarean delivery without labor will have better outcomes than those infants who are born by cesarean delivery with labor., Study Design: This was a retrospective cohort study of extremely-low-birth-weight infants (birth weight, 401-1000 g) who were born by cesarean delivery and cared for in the National Institute for Child Health and Human Development Neonatal Network, during calendar years 1995 to 1997. A total of 1606 extremely-low-birth-weight infants were born by cesarean delivery and survived to discharge. Of these, 1273 infants (80.8%) were examined in the network follow-up clinics at 18 to 22 months of corrected age and had a complete data set (667 infants were born without labor, 606 infants were born with labor). Outcome variables that were examined include intraventricular hemorrhage grade 3 to 4, periventricular leukomalacia, and neurodevelopmental impairment., Results: Mothers in the cesarean delivery without labor group were older (P<.001), more likely to be married (P<.05), less likely to be supported by Medicaid (P<.01), more likely to have preeclampsia/hypertension (P<.001), more likely to receive prenatal steroids (P<.005), and less likely to have received antibiotics (P<.001). Infants who were born by cesarean delivery without labor had higher gestational age (P<.001), lower birth weight (P<.01), and were less likely to be outborn (P<.001). By univariate analysis, infants who were born by cesarean delivery with labor had a higher incidence of grade 3 to 4 intraventricular hemorrhage (23.3% vs 12.1%, P<.001), periventricular leukomalacia (8.5% vs 4.7%, P<.02), and neurodevelopmental impairment (41.7% vs 34.6%, P<.02). Logistic regression analysis that controlled for all maternal and neonatal demographic and clinical variables that were statistically associated with labor or no labor revealed that the significant differences in grade 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, and neurodevelopmental impairment were no longer evident., Conclusion: In extremely-low-birth-weight infants who were born by cesarean delivery and after control for other risk factors, labor does not appear to play a significant role in adverse neonatal outcomes and neurodevelopmental impairment at 18 to 22 months of corrected age.

Background: Glutamine is one of the most abundant amino acids in both plasma and human milk and may be conditionally essential in premature infants. However, glutamine is not provided by standard intravenous amino acid solutions., Objective: We assessed the effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants receiving parenteral nutrition (PN)., Design: A total of 141 infants with birth weights of 401-1000 g were randomly assigned to receive a standard intravenous amino acid solution that did not contain glutamine or an isonitrogenous amino acid solution with 20% of the total amino acids as glutamine. Blood samples were obtained just before initiation of study PN and again after the infants had received study PN (mean intake: 2.3 +/- 1.0 g amino acids x kg(-1) x d(-1)) for approximately 10 d., Results: Infants randomly assigned to receive glutamine had mean plasma glutamine concentrations that increased significantly and were approximately 30% higher than those in the control group in response to PN (425 +/- 182 and 332 +/- 148 micromol/L for the glutamine and control groups, respectively). There was no significant difference between the 2 groups in the relative change in plasma glutamate concentration between the baseline and PN samples. In both groups, there were significant decreases in plasma phenylalanine and tyrosine between the baseline and PN samples; the decrease in tyrosine was greater in the group that received glutamine., Conclusions: In extremely low-birth-weight infants, parenteral glutamine supplementation can increase plasma glutamine concentrations without apparent biochemical risk. Currently available amino acid solutions are likely to be suboptimal in their supply of phenylalanine, tyrosine, or both for these infants.

Objective: Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401-1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998-2000)., Methods: The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998., Results: Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%)., Conclusions: Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.

Objective: We previously demonstrated that antenatal phenobarbital does not decrease the risk of intracranial hemorrhage or early death in premature infants. The objective of the present study was to evaluate the impact of antenatal phenobarbital exposure on the neurodevelopmental outcome of premature infants born to women who were participating in the randomized clinical trial of antenatal phenobarbital exposure., Study Design: Infants were evaluated at 18 to 22 months corrected age with a standard neurologic examination and the Bayley scales of infant development measuring the mental developmental index and the psychomotor developmental index., Results: Of the 578 infants <34 weeks of gestational age who were born to women who were enrolled in the primary study, 7 infants died after discharge from the neonatal intensive care unit, and 135 infants were lost to follow-up. Infants who were lost to follow-up had a higher mean birth weight and gestational age and a lower maternal education, but the rates of intracranial hemorrhage were comparable to those infants who were evaluated. Among the infants who were evaluated (n = 436; 76%), the mean birth weight and gestational age, maternal education, and frequency and distribution of intracranial hemorrhage were similar in the antenatal phenobarbital exposed and placebo groups. Eighteen infants (8%) in the antenatal phenobarbital exposed group and 21 infants (11%) in the placebo group had cerebral palsy (P = not significant). There was no difference between the 2 groups in either the median Bayley II mental developmental index (85 in the antenatal phenobarbital and 86 in the placebo group) or the Psychomotor Developmental Index (91 in the antenatal phenobarbital and 91 in the placebo group). Infants with intracranial hemorrhage (23%) had significantly lower mental developmental index and psychomotor developmental index scores than infants with no intracranial hemorrhage, independent of antenatal phenobarbital exposure. In the total cohort of 436 infants, the presence of intracranial hemorrhage or periventricular leukomalacia was associated with lower mental developmental index and psychomotor developmental index scores; the presence of increasing birth weight, maternal education, and a complete course of antenatal steroids was associated with a higher mental developmental index score., Conclusion: Antenatal phenobarbital exposure did not favorably or adversely affect the neurodevelopmental outcome of premature infants at 18 to 22 months of age.

Objective: The purposes of this study were to compare the clinical characteristics of extremely low birth-weight infants (501-1000 g birth weight) who die early (<12 hours of age) with those of infants who die >12 hours after birth and infants who survive to neonatal intensive care unit discharge and to develop a model of risk for early death., Study Design: Perinatal data were prospectively collected on 5986 infants in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from March 1993 through December 1997. Maternal and neonatal characteristics of infants who died early were compared with infants who survived and infants who died beyond 12 hours of age. A model for risk for early death was developed by logistic regression analysis, with results expressed as odds ratio with 95% CI., Results: Mothers of infants who died early were more likely to be delivered in an inborn setting and experience labor and were less likely to have hypertension or preeclampsia, to receive antenatal corticosteroids, or to be delivered by cesarean birth than mothers of infants who died >12 hours after birth or infants who survived. Infants who died early were more likely to have lower Apgar scores and lower gestational age/birth weight and were less likely to be intubated at birth and to receive mechanical ventilation and surfactant therapy than infants who died >12 hours after birth or infants who survived. Greater risk for early death versus survival to neonatal intensive care unit discharge was associated with the lack of surfactant administration (odds ratio, 8.6; 95% CI, 6.3-11.9), lack of delivery room intubation (odds ratio, 5.3; 95% CI, 3.5-8.1), lack of antenatal corticosteroid use (odds ratio, 2.3; 95% CI, 1.6-3.2), lower 1-minute Apgar score (odds ratio, 2.0; 95% CI, 1.8-2.2), male sex (odds ratio, 1.7; 95% CI, 1.3-2.3), multiple gestation (odds ratio, 1.7; 95% CI, 1.2-2.5), no tocolytics (odds ratio, 1.7; 95% CI, 1.2-2.3), lower gestational age per week (odds ratio, 1.4; 95% CI, 1.3-1.6), and lower birth weight per 50 g (95% CI, 1.2-1.4)., Conclusion: Early death (<12 hours of age) among extremely low-birth-weight infants may reflect an assessment of non-viability by obstetricians and neonatologists.