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Objectives: We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group., Study Design: Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness., Results: Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43)., Conclusions: In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

Objective: To demonstrate the association between fluid intake and weight loss during the first 10 days of life and the risk of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants., Study Design: A retrospective analysis of data from a cohort of ELBW infants enrolled in the Neonatal Research; 1,382 infants with birth weight between 401 and 1,000 g were randomized. The daily fluid intake and weight loss during the first 10 days of life were compared between the infants who survived without BPD and those who either died or developed BPD. Demographic and clinical neonatal variables were also compared. Multivariate logistic regression was used to analyze the effect of fluid intake and weight loss on death or BPD, controlling for demographic and clinical factors that are significantly associated with BPD by univariate analysis., Results: 585 infants survived without BPD and 797 infants either died or developed BPD. Univariate analysis showed that the daily fluid intakes were higher (day 2-10) and weight loss less (day 6-9) in the group of infants who either died or developed BPD. In addition, lower birth weight, lower gestational age, male gender, lower 1 and 5-minute Apgar Scores, higher oxygen requirement at 24 hours of age, longer duration of assisted ventilation, use of postnatal steroids for BPD and presence of severe intraventricular hemorrhage, proven necrotizing enterocolitis, patent ductus arteriosus, and late onset sepsis, were associated with higher incidence of death or BPD. The adjusted risk of higher fluid intake and less weight loss during the first 10 days of life remained significantly related to death or BPD., Conclusion: In this cohort of ELBW infants treated during the post surfactant era, higher fluid intake and less weight loss during the first 10 days of life were associated with an increased risk of BPD. The finding suggests that careful attention to fluid balance might be an important means to reduce the incidence of BPD.

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.

Objective: Ballard scores are commonly used to estimate gestational age (GA). The purpose of this study was to determine the accuracy of the New Ballard Score (NBS) for infants <28 weeks GA by accurate menstrual history and to evaluate NBS as an outcome predictor., Methods: Infants weighing 401 to 1500 g in 12 National Institute of Child Health and Human Development Neonatal Research Network centers had NBS performed before age 48 hours. Accuracy of NBS estimates of GA was assessed for infants with GA determined by accurate menstrual history. In a larger cohort of infants, NBS was included in regression models of the association of NBS and death, poor outcome, and duration of hospital stay., Results: At each week from 22 to 28 weeks GA by accurate menstrual history, NBS estimates exceeded GA by dates by 1.3 to 3.3 weeks, and estimates varied widely (range of widths of 95% CIs for the observations, 6.8 to 11.9 weeks). NBS did not contribute significantly to regression models of death, poor outcome, or duration of hospital stay., Conclusions: Inaccuracies in GA determined by the NBS should be considered when treating extremely premature infants, particularly in decisions to forego or administer intensive care. Refinement of GA scoring systems is needed to optimize clinical benefit.

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 7861 VLBW (401 to 1500 gm) neonates admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991 to 1993)., Methods: The NICHD Neonatal Research Network maintains a prospectively collected registry of all VLBW neonates cared for at participating centers. Data from this registry were analyzed retrospectively., Results: Of 6911 infants who survived beyond 3 days, 1696 (25%) had one or more episodes of blood culture-proven sepsis. The vast majority of infection (73%) were caused by gram-positive organisms, with coagulase-negative staphylococci accounting for 55% of all infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of infection included intubation, respiratory distress syndrome, prolonged ventilation, bronchopulmonary dysplasia, patent ductus arteriosus, severe intraventricular hemorrhage, and necrotizing enterocolitis. Among infants with bronchopulmonary dysplasia, those with late-onset sepsis had a significantly longer duration of mechanical ventilation (45 vs 33 days; p <0.01). Late-onset sepsis prolonged hospital stay: the mean number of days in the hospital for VLBW neonates with and without late-onset sepsis was 86 and 61 days, respectively (p <0.001). Even after adjustment for other complications of prematurity, including intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia, infants with late-onset sepsis had a significantly longer hospitalization (p <0.001). Moreover, neonates in whom late-onset sepsis developed were significantly more likely to die than those who were uninfected (17% vs 7%; p <0.000 1), especially if they were infected with gram-negative organisms (40%) or fungi (28%). Deaths attributed to infection increased with increasing chronologic age. Whereas only 4% of deaths in the first 3 days of life were attributed to infection, 45% of deaths after 2 weeks were related to infection., Conclusions: Late-onset sepsis is a frequent and important problem among VLBW preterm infants. Successful strategies to decrease late-onset sepsis should decrease VLBW mortality rates, shorten hospital stay, and reduce costs.

Objective: Early-onset sepsis (occurring within 72 hours of birth) is included in the differential diagnosis of most very low birth weight (VLBW) neonates. To determine the current incidence of early-onset sepsis, risk factors for disease, and the impact of early-onset sepsis on subsequent hospital course, we studied a cohort of 7861 VLBW neonates (401 to 1500 gm) admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991-1993)., Methods: The NICHD Neonatal Research Network maintains a prospectively collected registry on all VLBW neonates born or cared for at participating centers. Data from this registry were analyzed retrospectively., Results: Blood culture-proven early-onset sepsis was uncommon, occurring in only 1.9% of VLBW neonates. Group B streptococcus was the most frequent pathogen associated with early-onset sepsis (31%), followed by Escherichia coli (16%) and Haemophilus influenzae (12%). Decreasing gestational age was associated with increased rates of infection. Antibiotic therapy for suspected sepsis is frequently initiated at birth in VLBW neonates. Almost half of the infants in this cohort were considered to have clinical sepsis and continued to receive antibiotics for 5 or more days, despite a negative blood culture result in 98% of cases. These findings underscore the difficulty of ruling out sepsis in the symptomatic immature neonate and the special concern for culture-negative clinical sepsis in the face of maternal antibiotic use. Neonates with early-onset sepsis were significantly more likely to have subsequent comorbidities, including severe intraventricular hemorrhage, patent ductus arteriosus, and prolonged assisted ventilation. Although 26% of VLBW neonates with early-onset sepsis died, only 4% of the 950 deaths that occurred in the first 72 hours of life were attributed to infection. For those infants discharged alive, early-onset sepsis was associated with a significantly prolonged hospital stay (86 vs 69 days; p <0.02)., Conclusions: Early-onset sepsis remains an important but uncommon problem among VLBW preterm infants. Improved diagnostic strategies are needed to enable the clinician to distinguish between the infected and the uninfected VLBW neonate with symptoms and to target continued antibiotic therapy to those who are truly infected.

Growth outcome for 1 year of corrected age and feeding practices during that first year of life were described for a large population of very low birth weight (VLBW) infants. Growth patterns of weight, length, and occipitofrontal circumference through 12 months of corrected age, and weight/length ratios at 12 months, were determined for 122 VLBW infants less than or equal to 1500 gm and less than or equal to 35 weeks of gestational age at birth; feeding practices were surveyed within a subpopulation of 89 infants. Differences in growth were apparent when infants were grouped according to sex and appropriateness of intrauterine growth. When the mean values of each group were compared, the female infants of appropriate size for gestational age demonstrated growth at higher percentiles (National Center for Health Statistics term-infant norms) for all three measurements (weight, length, and occipitofrontal circumference). Male infants whose size was appropriate for gestational age, and male and female infants who were small for gestational age, all grew similarly, at lower percentiles for weight and length, when compared with the same norms. Growth in occipitofrontal circumference was closest to term infant norms in all subgroups of infants. The majority of the infants, regardless of subgroup, achieved weights and lengths greater than 5th percentile and proportionate growth with a normal weight/length ratio. At 12 months of corrected age, 30% remained at less than 5th percentile in weight, 21% in length, and 14% in occipitofrontal circumference. Eighteen infants (15%) had a marked discrepancy in weight for length, with a weight/length ratio less than 5th percentile. Three prevalent practices that could result in compromised nutrition were identified: (1) cereals were introduced at an early age, (2) 2% and skim cow milk were fed to approximately 50% of the infants within the first year of life, and (3) whole cow milk was introduced to some VLBW infants at an early age. Caretakers apparently viewed their infants in terms of chronologic age rather than age corrected for prematurity when it came to the initiation of solids and cow milk. Whether increased attention to appropriate feeding practices during the first year of life would result in a more favorable growth outcome for VLBW infants is not known.

To investigate the optimal timing for treatment of small premature infants, we performed a double-blind, controlled trial of indomethacin therapy on the first day of life in 104 infants weighing between 700 and 1300 gm. Infants were given indomethacin or placebo at a mean age of 15 hours. Eleven of the 56 infants given placebo developed large left-to-right shunts through a patent ductus arteriosus. In contrast, only two of the 51 infants given indomethacin developed large shunts (P less than 0.025). There were no significant differences in incidence of surgical ligation, duration of oxygen therapy, duration of endotracheal intubation, days required to regain birth weight, or incidence of complications. However, the power of the tests of significance was low because of the small number of patients. Thus, although the incidence of large left-to-right ductus shunts was decreased in the indomethacin group, morbidity was not otherwise altered for the entire group of patients, possibly because of the relatively low incidence (21%) of large shunts in the placebo group. We conclude that although treatment with indomethacin on the first day of life appears to be safe, there is little advantage to its use in centers where the incidence of large shunts through a patent ductus arteriosus is relatively low.