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

OBJECTIVES: Infants of

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

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

Persistent pulmonary hypertension after maternal naproxen ingestion in a term newborn: a case report.

Constricting effect of indomethacin on the ductus arteriosus of the fetus is well known. The fetal effects of other nonsteroid anti-inflammatory drugs (NSAIDs) like naproxen are not well reported. We report here a case of a 3,790-g term neonate who developed persistent pulmonary hypertension after birth with a closed ductus arteriosus. The mother admitted to taking naproxen sodium immediately prior to the birth of the infant. The course of illness was progressively better on conservative management. Like indomethacin, other NSAIDs can also cause premature closure of fetal ductus arteriosus, pulmonary hypertension, and life-threatening problems to the neonate. Patient education regarding over-the-counter pain medication during pregnancy should be emphasized.

Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage.

OBJECTIVE: To determine the differences in short term outcome of very low birthweight infants attributable to sex. METHODS: Boys and girls weighing 501-1500 g admitted to the 12 centres of the National Institute of Child Health and Human Development Neonatal Research Network were compared. Maternal information and perinatal data were collected from hospital records. Infant outcome was recorded at discharge, at 120 days of age if the infant was still in hospital, or at death. Best obstetric estimate based on the last menstrual period, standard obstetric factors, and ultrasound were used to assign gestational age in completed weeks. Data were collected on a cohort that included 3356 boys and 3382 girls, representing all inborn births from 1 May 1991 to 31 December 1993. RESULTS: Mortality for boys was 22% and that for girls 15%. The prenatal and perinatal data indicate few differences between the sex groups, except that boys were less likely to have been exposed to antenatal steroids (odds ratio (OR) = 0.80) and were less stable after birth, as reflected in a higher percentage with lower Apgar scores at one and five minutes and the need for physical and pharmacological assistance. In particular, boys were more likely to have been intubated (OR = 1.16) and to have received resuscitation medication (OR = 1.40). Boys had a higher risk (OR > 1.00) for most adverse neonatal outcomes. Although pulmonary morbidity predominated, intracranial haemorrhage and urinary tract infection were also more common. CONCLUSIONS: Relative differences in short term morbidity and mortality persist between the sexes.

Cerebral blood flow velocity changes after bovine natural surfactant instillation.

OBJECTIVE: To determine the effects of bovine natural surfactant (beractant) instillation on cerebral hemodynamics in preterm infants with respiratory distress syndrome (RDS). STUDY DESIGN: Preterm infants who required surfactant for RDS were enrolled. Cerebral blood flow velocity (CBFV) waveforms from the pericallosal artery were analyzed by pulsed Doppler ultrasonography with the anterior fontanel serving as an acoustic window. CBFV was measured before and at 5, 10, 20, and 30 minutes after the first dose of a bolus instillation of surfactant in four aliquots. Simultaneously with CBFV measurements, mean blood pressure (MBP), heart rate, and ventilator settings were recorded. pH, PACO2, and PAO2 before and at 30 minutes after surfactant administration were also determined. RESULTS: The 30 enrolled preterm infants had a mean birth weight of 973 gm (513 to 1996 gm) and a mean gestational age of 27 weeks (23 to 33 weeks). Mean postnatal age at surfactant administration was 4.7 +/- 2.7 hours. There were no significant changes in pH and PACO2 before and at 30 minutes after surfactant (before surfactant: mean pH of 7.29 +/- 0.07 and mean PACO2 of 44.4 +/- 7.1 torr; after surfactant: mean pH of 7.31 +/- 0.07 and mean PACO2 of 42.7 +/- 8.3 torr). PAO2 increased significantly from a pre-surfactant mean of 83 torr to 130 torr at 30 minutes after surfactant (p < 0.05), with no significant changes in mean airway pressure. There were no significant changes in MBP, heart rate, mean CBFV, peak systolic flow velocity, and diastolic flow velocity before and after surfactant instillation regardless of gestational age. Individual changes in mean CBFV were related to MBP changes (p < 0.001, linear mixed models with random effects). CONCLUSION: In low birth weight infants with RDS, bovine surfactant instillation is not associated with a significant alteration in cerebral hemodynamics. However, the direct relationship between CBFV and MBP is consistent with the reported pressure-passive cerebral circulation in sick preterm infants.

Preservation of cerebrovascular tone and reactivity by sodium channel inhibition in experimental prolonged asphyxia in piglets.

Sodium channels using cAMP as a second messenger play a role in the regulation of cerebral circulation and metabolism. Cerebrospinal fluid (CSF) cAMP levels have been shown to correlate with the degree and duration of hypoxic injury and outcome and to be an indicator of cerebral vascular reactivity. We hypothesize that sodium channel inhibition either before or at termination of experimental asphyxia will attenuate cerebrovascular alterations and maintain CSF cAMP levels. Three groups of piglets with closed cranial windows were studied: asphyxia or group 1 (n = 5) and two treatment groups. Pigs were treated with 50 mg/kg of sodium channel blocker before asphyxia (group 2, n = 6) and after the termination of asphyxia and start of reventilation (group 3, n = 6). Asphyxia was sustained over 60 min by ventilating piglets with 10% O2 gas mixture and decreasing minute ventilation followed by 60 min of reventilation with room air. Every 10 min, pial arterial diameters were measured, and CSF samples were collected for cAMP determination. Vascular reactivity to topically applied isoproterenol (10(-4) M) was evaluated 60 min after recovery. During asphyxia, cAMP levels in group 2 peaked and declined at a later time with mean values remaining significantly higher than those of groups 1 and 3. During reventilation, CSF cAMP concentrations were highest in group 3 and lowest in group 1. Pial arteriolar dilation occurred during asphyxia in all three groups but to a lesser degree in the pretreated group compared with groups 1 and 3. Pial arteriolar reactivity to isoproterenol postasphyxia was preserved in both groups 2 and 3. In summary, in newborn pigs, pretreatment with sodium channel blocker resulted in higher CSF cAMP levels and a lesser degree of pial arteriolar dilation during prolonged asphyxia. Pretreatment or treatment at reventilation restored vascular tone and reactivity.

Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes.

OBJECTIVES: In the era before widespread use of inhaled nitric oxide, to determine the prevalence of persistent pulmonary hypertension (PPHN) in a multicenter cohort, demographic descriptors of the population, treatments used, the outcomes of those treatments, and variation in practice among centers. STUDY DESIGN: A total of 385 neonates who received >/=50% inspired oxygen and/or mechanical ventilation and had documented evidence of PPHN (2D echocardiogram or preductal or postductal oxygen difference) were tracked from admission at 12 Level III neonatal intensive care units. Demographics, treatments, and outcomes were documented. RESULTS: The prevalence of PPHN was 1.9 per 1000 live births (based on 71 558 inborns) with a wide variation observed among centers (.43-6.82 per 1000 live births). Neonates with PPHN were admitted to the Level III neonatal intensive care units at a mean of 12 hours of age (standard deviation: 19 hours). Wide variations in the use of all treatments studied were found at the centers. Hyperventilation was used in 65% overall but centers ranged from 33% to 92%, and continuous infusion of alkali was used in 75% overall, with a range of 27% to 93% of neonates. Other frequently used treatments included sedation (94%; range: 77%-100%), paralysis (73%; range: 33%-98%), and inotrope administration (84%; range: 46%-100%). Vasodilator drugs, primarily tolazoline, were used in 39% (range: 13%-81%) of neonates. Despite the wide variation in practice, there was no significant difference in mortality among centers. Mortality was 11% (range: 4%-33%). No specific therapy was clearly associated with a reduction in mortality. To determine whether the therapies were equivalent, neonates treated with hyperventilation were compared with those treated with alkali infusion. Hyperventilation reduced the risk of extracorporeal membrane oxygenation without increasing the use of oxygen at 28 days of age. In contrast, the use of alkali infusion was associated with increased use of extracorporeal membrane oxygenation (odds ratio: 5.03, compared with those treated with hyperventilation) and an increased use of oxygen at 28 days of age. CONCLUSIONS: Hyperventilation and alkali infusion are not equivalent in their outcomes in neonates with PPHN. Randomized trials are needed to evaluate the role of these common therapies.

Dexamethasone therapy increases infection in very low birth weight infants.

BACKGROUND: Infection is a major complication of preterm infants, resulting in increased morbidity and mortality. We recently reported the results of a multicenter trial of dexamethasone initiated at 14 or 28 days in very low birth weight (VLBW) infants who were at risk for chronic lung disease; the results showed an increase in nosocomial bacteremia in the group receiving dexamethasone. This study is an in-depth analysis of bacteremia/sepsis and meningitis among infants enrolled in the trial. METHODS: Data on cultures performed and antibiotic therapy were collected prospectively. Infections were classified as definite or possible/clinical. RESULTS: A total of 371 infants were enrolled in the trial. There were no baseline differences in risk factors for infection. For the first 14 days of study, infants received either dexamethasone (group I, 182) or placebo (group II, 189). During this period, infants in group I were significantly more likely than those in group II to have a positive blood culture result (48% vs 30%) and definite bacteremia/sepsis/meningitis (22% vs 14%). Over the 6-week study period, 47% of those cultured had at least one positive blood culture result (53% in group I vs 41% in group II) and 25% of the infants had at least one episode of definite bacteremia/sepsis/meningitis (29% in group I vs 21% in group II). Among infants with definite infections, 46.8% were attributable to Gram-positive organisms, 26.6% to Gram-negative organisms and 26.6% to fungi. The factors present at randomization were evaluated for their association with infection. Group I assignment and H(2) blocker therapy (before study entry) were associated with increased risk of definite infection, whereas cesarean section delivery and increasing birth weight were associated with decreased risk. CONCLUSIONS: Infants who received a 14-day course of dexamethasone initiated at 2 weeks of age were more likely to develop a bloodstream or cerebrospinal fluid infection while on dexamethasone therapy than were those who received placebo. Physicians must consider this increased risk of infection when deciding whether to treat VLBW infants with dexamethasone.

Inaccuracy of Ballard scores before 28 weeks' gestation. National Institute of Child Health and Human Development Neonatal Research Network.

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.

Longitudinal growth of hospitalized very low birth weight infants.

BACKGROUND: The interpretation of growth rates for very low birth weight infants is obscured by limited data, recent changes in perinatal care, and the uncertain effects of multiple therapies. OBJECTIVES: To develop contemporary postnatal growth curves for very low birth weight preterm infants and to relate growth velocity to birth weight, nutritional practices, fetal growth status (small- or appropriate-for-gestational-age), and major neonatal morbidities (chronic lung disease, nosocomial infection or late-onset infection, severe intraventricular hemorrhage, and necrotizing enterocolitis). DESIGN: Large, multicenter, prospective cohort study. METHODS: Growth was prospectively assessed for 1660 infants with birth weights between 501 to 1500 g admitted by 24 hours of age to 1 of the 12 National Institute of Child Health and Human Development Neonatal Research Network centers between August 31, 1994 and August 9, 1995. Infants were included if they survived >7 days (168 hours) and were free of major congenital anomalies. Anthropometric measures (body weight, length, head circumference, and midarm circumference) were performed from birth until discharge, transfer, death, age 120 days, or a body weight of 2000 g. To obtain representative data, nutritional practices were not altered by the study protocol. RESULTS: Postnatal growth curves suitable for clinical and research use were constructed for body weight, length, head circumference, and midarm circumference. Once birth weight was regained, weight gain (14.4-16.1 g/kg/d) approximated intrauterine rates. However, at hospital discharge, most infants born between 24 and 29 weeks of gestation had not achieved the median birth weight of the reference fetus at the same postmenstrual age. Gestational age, race, and gender had no effect on growth within 100-g birth weight strata. Appropriate-for-gestational age infants who survived to hospital discharge without developing chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late onset-sepsis gained weight faster than comparable infants with those morbidities. More rapid weight gain was also associated with a shorter duration of parenteral nutrition providing at least 75% of the total daily fluid volume, an earlier age at the initiation of enteral feedings, and an earlier age at achievement of full enteral feedings. CONCLUSIONS: These growth curves may be used to better understand postnatal growth, to help identify infants developing illnesses affecting growth, and to aid in the design of future research. They should not be taken as optimal. Randomized clinical trials should be performed to evaluate whether different nutritional management practices will permit birth weight to be regained earlier and result in more rapid growth, more appropriate body composition, and improved short- and long-term outcomes.

Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.

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 microg per deciliter (0.70 micromol 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.

Cerebrovascular responses to therapeutic dose of indomethacin in newborn pigs.

The aims of this study were 1) to compare the effects of low versus high doses of indomethacin on cerebral blood flow (CBF) responses to hypercapnia and 2) to investigate the effects of low-dose indomethacin on the cerebral vasculature during resting conditions and during vasodilator stimuli. In the first experiment, 27 piglets were randomized into three groups to receive 5 mg/kg indomethacin, 0.2 mg/kg indomethacin, or normal saline. Ninety minutes later, CBF was measured by radioactive microspheres at baseline, during hypercapnia [PaCO2 > or = 70 mm Hg (> or =9.3 kPa)] and normocapnia. Total CBF was comparable among the three groups at baseline. CBF increased during hypercapnia in all groups, but the hyperemic response was significantly attenuated in the high-dose indomethacin group compared with the saline group but not in the group treated with 0.2 mg/kg. CBF returned toward baseline during normocapnia in all piglets. In the second experiment, a closed cranial window was implanted over the parietal cortex of nine piglets. Cerebrovascular responses to hypercapnia and topical application of isoproterenol (10(-7) and 10(-6) M) and histamine (10(-6) and 10(-5) M) were investigated before and after administration of 0.2 mg/kg indomethacin. Within 10 min of indomethacin administration, pial arteriolar diameters decreased from 72 +/- 8 to 58 +/- 6 microm (p < 0.05), and 6-keto-PGF1alpha concentration decreased from 1440 +/- 250 to 570 +/- 30 pg/mL (p < 0.05). Two hours (138 +/- 21 min) later, pial arteriolar diameters had returned toward baseline values (65 +/- 5 microm), whereas 6-keto-PGF1alpha values remained considerably lower than preindomethacin values (530 +/- 30 pg/mL). Cerebrovascular responses to dilator stimuli were preserved after 0.2 mg/kg indomethacin. We conclude that 0.2 mg/kg indomethacin does not markedly affect the cerebral hyperemic responses to hypercapnia in contrast with a very prominent inhibition by 5 mg/kg indomethacin. Also, although indomethacin at a low dose constricts pial arterioles transiently and attenuates cerebral prostanoid production, it does not inhibit the pial arteriolar responsiveness to prostanoid-associated dilator stimuli. This observation may be due to the permissive role that prostacyclin plays in cerebral vasodilatory responses to some vasogenic stimuli such as hypercapnia and histamine.

Prognostic significance of cerebrospinal fluid cyclic adenosine monophosphate in neonatal asphyxia.

OBJECTIVE: In piglets prolonged asphyxia resulted in decreased cerebrospinal fluid (CSF) 3;,5;-cyclic adenosine monophosphate (cAMP) during recovery; this was associated with reduced pial arteriolar responses to stimuli that use cAMP as a second messenger. We hypothesized that asphyxia in human neonates results in decreased CSF cAMP and that low CSF cAMP is associated with abnormal outcome. DESIGN: We studied 27 infants with evidence of hypoxic-ischemic insult; 19 were term (group 1) and 8 were preterm (group 2). The normal values of CSF cAMP were determined from 75 infants with no asphyxia; 44 were term (group 3) and 31 were preterm (group 4). CSF cAMP was measured by using radioimmunoassay procedures. RESULTS: CSF cAMP levels in infants with asphyxia (groups 1 and 2) were 12 +/- 9. 5 and 7.9 +/- 7.1 pmol/mL, respectively, significantly lower than those of groups 3 and 4 (control infants), that is, 21.1 +/- 8.7 and 27.1 +/- 9.2 pmol/mL, respectively (P <.0001). Among infants with asphyxia, 3 died and 10 had abnormal neurologic outcome. Univariate analysis showed that abnormal outcomes were significantly related to CSF cAMP levels, phenobarbital use, and multi-organ failure. However, only CSF cAMP was retained in the model by stepwise logistic regression. CSF cAMP of 10.0 pmol/mL discriminated between those with normal and those with abnormal neurologic outcome. Low CSF cAMP concentration was associated with abnormal long-term outcome, estimated odds ratio of 12.4 (95% CI, 2.1-109.3; P <.006), and sensitivity, specificity, and positive and negative predictive values of 85%, 69%, 73%, and 80%, respectively. CONCLUSION: CSF cAMP concentrations were decreased in infants with asphyxia. Low CSF cAMP levels were associated with poor neurologic outcome.

Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994.

OBJECTIVES: Our purpose was to determine the mortality and morbidity rates for infants weighing 501 to 1500 g according to gestational age, birth weight, and gender. STUDY DESIGN: Perinatal data were collected prospectively on an inborn cohort from January 1993 through December 1994 by 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports. Sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death were evaluated. RESULTS: Eighty-three percent of infants survived until discharge to home or to a long- term care facility (compared with 74% in 1988). Survival to discharge was 49% for infants weighing 501 to 750 g at birth, 85% for those 751 to 1000 g, 93% for those 1001 to 1250 g, and 96% for those 1251 to 1500 g. The majority of deaths occurred within the first 3 days of life. Mortality rates were greater for male than for female infants. Respiratory distress syndrome was the most frequent pulmonary disease (52%). Chronic lung disease (defined as an oxygen requirement at 36 weeks after conception) developed in 19%. Thirty-two percent of infants had evidence of intracranial hemorrhage. Periventricular leukomalacia was noted in 6% of infants who had ultrasonography after 2 weeks. The average duration of hospitalization for survivors was 68 days (122 days for surviving infants weighing 501 to 750 g, compared with an average of 43 days for surviving infants 1251 to 1500 g). Among infants who died, the average length of stay was 19 days. CONCLUSIONS: The mortality rate for infants weighing between 501 and 1500 g at birth continues to decline. This increase in survival is not accompanied by an increase in medical morbidity. There are interactions between birth weight, gestational age, sex, and survival rates.

Outcomes of very low birth weight twins cared for in the National Institute of Child Health and Human Development Neonatal Research Network's intensive care units.

OBJECTIVE: The study's aim was to compare outcomes of very low birth weight twins with those of matched singletons. STUDY DESIGN: With data from the Neonatal Research Network registry (May 1991 to December 1994), univariable and multivariable comparisons of very low birth weight twin pairs and singletons were performed in 2 subgroups: (1) all paired twins and singletons with birth weights between 401 and 1500 g and (2) all paired twins and singletons born at <28 weeks' gestation. RESULTS: Twins constituted 19% of infants admitted with very low birth weight. Mothers of twins were more likely to receive prenatal care, have labor, have cesarean delivery, and receive antenatal glucocorticoids. Twins were more likely to have respiratory disease and to receive surfactant. Second-born twins had more early respiratory disease but similar longer-term outcomes. The risks of death, chronic lung disease, and grade III or IV intracranial hemorrhage were similar in twins and singletons. CONCLUSIONS: Although very low birth weight twins compose a sizable proportion of admissions, in National Institute of Child Health and Human Development Neonatal Research Network intensive care units, twins and singletons have similar outcomes.

Lower incidence of necrotizing enterocolitis in infants fed a preterm formula with egg phospholipids.

Necrotizing enterocolitis (NEC) causes approximately 4000 deaths/y and significant morbidity among U.S.-born preterm infants alone. Various combinations of inadequate tissue oxygenation, bacterial overgrowth, and enteral feeding with immaturity may cause the initial damage to intestinal mucosa that culminates in necrosis. Presently, there is not a way to predict the onset of the disease or to prevent its occurrence. As part of risk-benefit assessment, we compared disease in hospitalized preterm infants fed a commercial (control) preterm formula or an experimental formula with egg phospholipids for a randomized, double-masked, clinical study of diet and infant neurodevelopment. Infants fed the experimental formula developed significantly less stage II and III NEC compared with infants fed the control formula (2.9 versus 17.6%, p < 0.05), but had similar rates of bronchopulmonary dysplasia (23.4 versus 23.5%), septicemia (26 versus 31%), and retinopathy of prematurity (38 versus 40%). Compared with the control formula, the experimental formula provided 7-fold more esterified choline, arachidonic acid (AA, 0.4% of total fatty acids), and docosahexaenoic acid (0.13%). Phospholipids are constituents of mucosal membranes and intestinal surfactant, and their components, AA and choline, are substrates for intestinal vasodilatory and cytoprotective eicosanoids (AA) and the vasodilatory neurotransmitter, acetylcholine (choline), respectively. One or more of these components of egg phospholipids may have enhanced one or more immature intestinal functions to lower the incidence of NEC in this study. Regardless of the potential mechanism, a larger randomized trial designed to test the effect of this egg phospholipid-containing formula on NEC seems warranted.

Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Septicemia is a major antecedent of morbidity and mortality in very low birth weight (501- to 1500-g) infants. Our purpose was to determine prospectively the incidence, clinical presentation, laboratory features, risk factors, morbidity and mortality associated with late onset septicemia in infants 501 to 1500 g. METHODS: Clinical data were prospectively collected for 2416 infants enrolled in a multicenter trial to determine the efficacy of intravenous immunoglobulin in preventing nosocomial infections. Septicemia was confirmed by positive blood culture in 395 symptomatic infants. Multivariate analyses of factors associated with septicemia were performed. RESULTS: Sixteen percent of VLBW infants developed septicemia at a median age of 17 days. Factors associated with septicemia by logistic regression included male gender, lower gestational age and birth weight and decreased baseline serum IgG concentrations. Increasing apnea (55%), feeding intolerance, abdominal distension or guaiac-positive stools (43%), increased respiratory support (29%), lethargy and hypotonia (23%) were the dominant presenting features of septicemia. An abnormal white blood cell count (46%), unexplained metabolic acidosis (11%) and hyperglycemia (10%) were the most common laboratory indicators. Septicemic infants, compared with nonsepticemic infants, had significantly increased mortality (21% vs. 9%), longer hospital stay (98 vs. 58 days) and more serious morbidity, including severe intraventricular hemorrhage, bronchopulmonary dysplasia and increased ventilator days (P < 0.001). CONCLUSIONS: Late onset septicemia is common in very low birth weight infants, and the rate is inversely proportional to gestational age and birth weight. Septicemia is more common in males and those with low initial serum IgG values. A set of clinical signs (apnea, bradycardia, etc.) and laboratory values (leukocytosis, immature white blood cells and neutropenia) increase the probability of late onset sepsis, but they have poor positive predictive value.

A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants.

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 x the fraction of inspired oxygen) of 52.4 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 > or =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 ages.

Interleukin-6, C-reactive protein, and abnormal cardiorespiratory responses to immunization in premature infants.

OBJECTIVE: We report our experience with routine immunization of 89 premature infants in the neonatal intensive care unit because 1) a substantial number of them developed abnormal clinical signs, and 2) all but one of those who received diphtheria, tetanus, and whole-cell pertussis (DTwP) vaccine responded with elevations of interleukin-6 (IL-6) and C-reactive protein (CRP) concentrations that are otherwise characteristic of bacterial disease. METHODOLOGY: We hypothesized that the elevated IL-6 and CRP levels were solely a response to immunization and that treatment with antibiotics was not necessary. We performed this study in two consecutive parts. In part 1, we prospectively evaluated 79 consecutive premature infants who were immunized with DTwP, Haemophilus b conjugate vaccine, hepatitis B vaccine, and inactivated polio vaccine, (Hib, HBV, and IPV). IL-6 and CRP were determined before immunization and every 12 hours on three occasions after immunization. In part 2, we studied an additional 10 infants who received acellular pertussis vaccine (DTaP) and who, 2 days later, received Hib, HBV, and IPV immunization simultaneously. We followed the same schedule of IL-6 and CRP determinations as in part 1. RESULTS: In part 1, 24 infants (30%) developed abnormal cardiorespiratory signs within 24 hours after immunization. CRP and IL-6 values rose to abnormal levels after immunization in all but one infant; that infant was later shown to have a T-cell abnormality. In part 2, 3 infants had abnormal cardiorespiratory signs after simultaneous immunization with Hib, HBV, and IPV, but not after DTaP. IL-6 and CRP levels remained normal in all 10 infants. CONCLUSIONS: Part 1 demonstrates clearly the temporal relationship between IL-6 and CRP increments after DTwP, Hib, HBV, and IPV vaccines. In part 2 (DTaP was substituted for DTwP), there were no elevations of IL-6 or CRP, thus indicating that whole-cell pertussis component of DTwP was responsible for IL-6 and CRP elevations. Abnormal cardiorespiratory signs occurred frequently after immunizations in part 1, but they were unrelated to the magnitude of IL-6 and CRP elevations. The frequency of cardiorespiratory difficulty and its occasional severity suggest a need to monitor premature infants for approximately 48 hours after routine immunization.

The effects of intraventricular/periventricular blood on cerebral 3',5'-cyclic adenosine monophosphate concentration and cerebrovascular reactivity in newborn pigs.

This study investigated the effects of intraventricular/periventricular blood on cerebral cAMP production and cortical cerebrovascular reactivity. Under halothane and N2O anesthesia, 3 mL of either autologous blood or artificial cerebrospinal fluid (CSF) were injected into the left caudate nucleus; volume was adequate to result in extrusion of fluid or blood into the lateral ventricles of 1-2-d-old piglets. Twenty-four hours later, a closed cranial window was implanted over the left parietal cortex. Pial arteriolar responses to vasodilator and vasoconstrictor stimuli were monitored. Before the application of vasoactive agents, cortical periarachioid CSF was collected for cAMP measurement. Pial arteriolar responses to topical application of endothelin-1 (10(-9) and 10(-8) M) and to leukotriene C4 (10(-10) and 10(-9) M) were similar between the two groups. However, pial arteriolar responses to topical application of cAMP-mediated vasodilators, prostaglandin E2 (10(-6) and 10(-5) M), and histamine (10(-6) and 10(-5) M), respectively, were markedly reduced in the blood group when compared with the artificial CSF (control) group. Mean CSF cAMP level in the blood group was significantly lower than the control group (199 +/- 31 versus 1092 +/- 238 fmol/mL, p = 0.0006). We conclude that in newborn pigs intraventricular/periventricular blood results in a marked reduction of CSF cAMP concentration and attenuation of the cerebrovascular responses to cAMP-mediated vasodilators on the cortical surface remote from the site of blood or hematoma.