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Background: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age., Methods: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors., Results: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes., Conclusions: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging., (Copyright © 2015 by the American Academy of Pediatrics.)

Background and Objectives: We recently demonstrated that direct antiglobulin titer (DAT) positive, blood group A or B newborns born to group O mothers had a high incidence of hyperbilirubinemia, attributable to increased hemolysis. We reanalyzed our data asking whether increasing DAT strength plays a modulating role in the pathophysiology of the hemolysis and hyperbilirubinemia., Methods: Data from previously published DAT-positive, ABO-heterospecific neonates were analyzed for hyperbilirubinemia and hemolysis according to strength of DAT. DAT was measured by using a gel agglutination technique and reported as values ranging from DAT ± to DAT ++++. Hemolysis was evaluated by blood carboxyhemoglobin corrected for inspired, ambient CO (COHbc), and expressed as percent total hemoglobin (tHb). Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile on the hour-specific nomogram., Results: Hyperbilirubinemia was more prevalent in those with DAT ++ readings (16 of 20, 80%) than those both DAT ± (37 of 87 [42.5%], relative risk: 1.88, 95% confidence interval: 1.35-2.61) and DAT + (32 of 56 [57.1%], relative risk: 1.40, 95% confidence interval: 1.02-1.92). COHbc values were higher for those with DAT ++ (1.45 ± 0.49% tHb [mean ± SD]) than those DAT ± (1.20 ± 0.37% tHb, P = .01) or DAT + (1.22 ± 0.37% tHb, P = .02)., Conclusions: DAT ++ readings were associated with a higher incidence of hyperbilirubinemia and higher COHbc values than DAT ± or DAT + counterparts. Increasing DAT strength may be a modulator of hemolysis and hyperbilirubinemia in ABO-heterospecific neonates. DAT strength, and not merely DAT presence or absence, should be taken into consideration in the management of ABO-heterospecific newborns., (Copyright © 2014 by the American Academy of Pediatrics.)

Objective: Symptoms of posttraumatic stress disorder are a well-recognized phenomenon in mothers of preterm infants, with implications for maternal health and infant outcomes. This randomized controlled trial evaluated 6-month outcomes from a skills-based intervention developed to reduce symptoms of posttraumatic stress disorder, anxiety, and depression., Methods: One hundred five mothers of preterm infants were randomly assigned to (1) a 6- or 9-session intervention based on principles of trauma-focused cognitive behavior therapy with infant redefinition or (2) a 1-session active comparison intervention based on education about the NICU and parenting of the premature infant. Outcome measures included the Davidson Trauma Scale, the Beck Depression Inventory II, and the Beck Anxiety Inventory. Participants were assessed at baseline, 4 to 5 weeks after birth, and 6 months after the birth of the infant., Results: At the 6-month assessment, the differences between the intervention and comparison condition were all significant and sizable and became more pronounced when compared with the 4- to 5-week outcomes: Davidson Trauma Scale (Cohen's d = -0.74, P < .001), Beck Anxiety Inventory (Cohen's d = -0.627, P = .001), Beck Depression Inventory II (Cohen's d = -0.638, P = .002). However, there were no differences in the effect sizes between the 6- and 9-session interventions., Conclusions: A brief 6-session intervention based on principles of trauma-focused cognitive behavior therapy was effective at reducing symptoms of trauma, anxiety, and depression in mothers of preterm infants. Mothers showed increased benefits at the 6-month follow-up, suggesting that they continue to make use of techniques acquired during the intervention phase., (Copyright © 2014 by the American Academy of Pediatrics.)

Objectives: Evaluate safety and efficacy of filtered-sunlight phototherapy (FS-PT)., Methods: Term/late preterm infants #14 days old with clinically significant jaundice, assessed by total bilirubin (TB) levels, were recruited from a maternity hospital in Lagos, Nigeria. Sunlight was filtered with commercial window-tinting films that remove most UV and significant levels of infrared light and transmit effective levels of therapeutic blue light. After placing infants under an FS-PT canopy, hourly measurements of axillary temperatures, monitoring for sunburn, dehydration, and irradiances of filtered sunlight were performed. Treatment was deemed safe and efficacious if infants were able to stay in FS-PT for $5 hours and rate of rise of TB was ,0.2 mg/dL/h for infants #72 hours of age or TB decreased for infants .72 hours of age., Results: A total of 227 infants received 258 days of FS-PT. No infant developed sunburn or dehydration. On 85 (33%) of 258 treatment days, infants were removed briefly from FS-PT due to minor temperature-related adverse events. No infant met study exit criteria. FS-PT was efficacious in 92% (181/197) of evaluable treatment days. Mean 6 SD TB change was –0.06 6 0.19 mg/dL/h. The mean 6 SD (range) irradiance of FS-PT was 38 6 22 (2–115) mW/cm2/nm, measured by the BiliBlanket Meter II., Conclusions: With appropriate monitoring, filtered sunlight is a novel, practical, and inexpensive method of PT that potentially offers safe and efficacious treatment strategy for management of neonatal jaundice in tropical countries where conventional PT treatment is not available.

Objective: The current study evaluates a treatment intervention developed with the goal of reducing symptoms of posttraumatic stress, depression, and anxiety in parents of premature infants., Methods: A total of 105 mothers of preterm infants (25-34 weeks' gestational age; >600 g) were randomized to receive a 6-session intervention developed to target parental trauma as well as facilitate infant redefinition (n = 62) or to an active comparison group (n = 43). Mothers in the intervention group received a combination of trauma-focused treatments, including psychoeducation, cognitive restructuring, progressive muscle relaxation, and development of their trauma narrative. The intervention also incorporated material targeting infant redefinition, defined as the process of changing the mother's negative perceptions of her infant and the parenting experience., Results: Mothers in the intervention group reported a greater reduction in both trauma symptoms (Cohen's d = 0.41, P = .023) and depression (Cohen's d = 0.59, P < .001) compared with the comparison group. Patients under both conditions improved significantly in terms of anxiety, with no differences between groups. Results of the moderator analysis showed that mothers with higher ratings of baseline NICU stress benefited more from the intervention compared with mothers who had lower ratings (P = .036)., Conclusions: This short, highly manualized intervention for mothers of preterm infants statistically significantly reduced symptoms of trauma and depression. The intervention is feasible, can be delivered with fidelity, and has high ratings of maternal satisfaction. Given that improvements in mothers' distress may lead to improved infant outcomes, this intervention has the potential for a high public health impact.

Objective: Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD., Methods: The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip., Results: Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative., Conclusions: We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

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.)

Objective: Direct antibody titer-positive, blood group A or B neonates who are born to group O mothers may be at risk for hemolysis and hyperbilirubinemia. Immunoglobulin G1 and immunoglobulin G3 subclasses are associated with increased hemolysis relative to immunoglobulin G2 and immunoglobulin G4. We investigated whether identification of immunoglobulin G subclass 1 or 3 may be predictive of hemolysis and hyperbilirubinemia., Methods: Direct antibody titer-positive, blood group A and B neonates born to group O mothers were tested for the presence of immunoglobulin G subclasses 1 and 3 in umbilical cord blood by using a commercially available gel testing technology. By inference, neonates in whom neither immunoglobulin G1 nor immunoglobulin G3 were detected were designated immunoglobulin G2 and/or 4. Mandatory plasma total bilirubin was measured at discharge, and additional measurements performed as clinically indicated. Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile for hour of life. Blood carboxyhemoglobin and total hemoglobin concentrations were also measured on the predischarge sample. Measured carboxyhemoglobin, expressed as percentage of total hemoglobin, was corrected for ambient carbon monoxide to derive "corrected carboxyhemoglobin," a sensitive index of heme catabolism. The corrected carboxyhemoglobin/total hemoglobin ratio was calculated to correct for any differences in total hemoglobin mass between groups., Results: Eighty-two infants were studied, 18 of whom were designated as immunoglobulin G1, 0 as immunoglobulin G3, and 64 as immunoglobulin G2 and/or 4. The incidence of plasma total bilirubin >95th percentile was similar between the subgroupings. Corrected carboxyhemoglobin values and corrected carboxyhemoglobin/total hemoglobin ratio were also similar between the subgroupings., Conclusions: Immunoglobulin G1 was found in 22% of direct antibody titer-positive, group A and B neonates who were born to group O mothers, whereas immunoglobulin G3 was rare. Hemolysis and hyperbilirubinemia could not be predicted by this gel technique that enabled identification of these immunoglobulin G subclasses.

Objectives: The objectives of the study were to measure the effect of 4Z,15E-bilirubin on peroxidase free bilirubin measurements and to review the literature on this topic., Methods: 4Z,15E-Bilirubin was generated in situ in serum or serum albumin solution through controlled irradiation of isomerically pure 4Z,15Z-bilirubin IXalpha, under conditions in which the total amount of bilirubin remained constant. Reactions were monitored by difference spectroscopy, to ensure that solutions were not irradiated beyond the initial photostationary state and that concentrations of other isomers were kept to a minimum. Prepared in this way, 10% to 25% of the total bilirubin in the final solutions was in the form of the 4Z,15E-isomer. Free bilirubin in the solutions was measured with a peroxidase method, before and after irradiation. The use of bovine serum albumin as a surrogate for human albumin in in vitro studies also was investigated., Results: The findings of previous studies are not altogether consistent, with a common flaw in several being the failure to measure photoisomer concentrations. For bilirubin in serum albumin solution, conversion of approximately 25% of the 4Z,15Z-isomer to 4Z,15E-bilirubin led to a much smaller decrease (<20%) in the apparent free bilirubin concentration; for bilirubin in serum, conversion of approximately 15% of the 4Z,15Z-isomer to photoisomers resulted in a much larger increase ( approximately 40%). Irradiation of bilirubin in bovine serum albumin solution generated a very different array of photoisomers than that observed in human albumin solutions., Conclusions: The effect of photoisomers on the accuracy and specificity of free 4Z,15Z-bilirubin measurements remains uncertain. In a clinical setting, free bilirubin measurements need to be interpreted with caution when samples contain photoisomers. Irradiated bovine albumin solutions of isomerically impure bilirubin used in previous studies are poor models for investigating the effects of phototherapy in humans and the albumin binding of photoisomers.

Background: Critically ill, extremely premature infants develop anemia because of intensive laboratory blood testing and undergo multiple red blood cell (RBC) transfusions in the early weeks of life. To date, researchers have had only limited success in finding ways to reduce transfusions significantly in this patient population., Objective: To reduce RBC transfusions for these infants by using a point-of-care bedside monitor that returns analyzed blood to the patient., Design, Setting, and Patients: This was a prospective, 2-center, randomized, open, controlled, clinical trial with a 1:1 assignment of extremely low birth weight infants (weighing 500-1000 g at birth) to control or monitor groups and analysis with the intention-to-treat approach. Predefined RBC transfusion criteria were applied uniformly in the 2 groups., Interventions: Clinical treatment of study subjects with an in-line, ex vivo, bedside monitor that withdraws blood through an umbilical artery catheter, analyzes blood gases and sodium, potassium, and hematocrit levels, and returns the sample to the patient., Main Outcome Measures: The total volume and number of RBC transfusions during the first 2 weeks of life and the total volume of blood removed for laboratory testing., Results: The trial was terminated prematurely when one center's NICU changed its standard method of laboratory testing. In the first 2 weeks of life, there was a nonsignificant 17% lower cumulative RBC transfusion volume in the monitor group (n = 46), compared with the control group (n = 47). However, data from the first week only (the period of greater catheter use) demonstrated a significant 33% lower cumulative RBC transfusion volume in the monitor group. Cumulative phlebotomy loss was approximately 25% less in the monitor group throughout the 2-week study period. There was no difference between groups in neonatal mortality, morbidity, and neurodevelopmental outcome rates at 18 to 24 months. This is the first randomized trial documenting that RBC transfusions administered to neonates can by reduced by decreasing laboratory phlebotomy loss., Conclusions: As long as an umbilical artery catheter is available for blood sampling with an in-line blood gas and chemistry monitor, significant reductions in neonatal RBC transfusions can be achieved. The patients most likely to benefit from monitor use are the smallest, most critically ill newborns.

Objective: The objective of this study was to determine whether transcutaneous bilirubin (TcB) measurements correlate with serum total bilirubin (STB) levels in indigenous, darkly pigmented African newborns with varying degrees of skin pigmentation, some of which had developed kernicterus., Methods: Jaundiced infants who were < or =2 weeks of age and admitted to Baptist Medical Center-Eku (Eku; n = 29) and Jos University Teaching Hospital (Jos; n = 98) in Nigeria were studied. TcB measurements using the BiliChek were made simultaneously with blood sampling for STB measurements by spectrophotometry before phototherapy., Results: Using linear regression analysis, we found that measurements of TcB correlated well with those of STB with r values of.90 and.88 for Eku and Jos, respectively. Mean bias and imprecision of TcB measurements as compared with STB measurements for the total population was 0.5 +/- 7.6 mg/dL using the method of Bland and Altman. At STB > or 12 mg/dL, correlation (r =.84) and bias and imprecision (-1.2 +/- 8.6 mg/dL) of measurements were only slightly poorer. Furthermore, when infants were grouped by degree of skin pigmentation, correlations of TcB and STB measurements remained strong., Conclusions: From these results, we can conclude that TcB measurements are a useful and reliable index for estimating STB levels in pigmented neonates, including those with hyperbilirubinemia and kernicterus. In the absence of reliable STB measurements, the relatively simple and noninvasive TcB measurements can be an important adjunct in directing phototherapy and exchange transfusions, thereby preventing bilirubin-induced morbidity and mortality in low-technology clinical environments.

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: 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: Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth., Methods: In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5 degrees C for 72 hours followed by slow rewarming., Results: In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 +/- 0.2 degrees C (mean +/- standard deviation) around the set point of 33.5 degrees C were reduced to 0.7 +/- 0.2 degrees C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 +/- 0.3 degrees C). In the human investigation, the infants were randomized at 4.1 +/- 1.3 hours (mean +/- standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5 degrees C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 +/- 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups., Conclusions: Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at <6 hours of age to a constant esophageal temperature using servo control and provides no evidence that hypothermia involved greater hazard than benefit.

Objective: The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life., Methods: From 9 multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998, through February 22, 1999. Measurements of both ETCOc and STB were performed at 30 +/- 6 hours of life; STB also was measured at 96 +/- 12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study., Results: A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breastfed infants was 8.92 +/- 4.37 mg/dL at 96 hours versus 7.63 +/- 3.58 mg/dL in those fed formula only. The mean ETCOc at 30 +/- 6 hours for the total population was 1.48 +/- 0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45 +/- 0.47 ppm and 1.81 +/- 0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30 +/- 6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB >/=95th percentile. When infants with STB >95th percentile at <36 hours of age were excluded, the STB at 30 +/- 6 hours yielded a 16.7% PPV and a 98.1% NPV for STB >75th percentile. The combination of these 2 measurements at 30 +/- 6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV. Conclusions. This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30 +/- 6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

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.

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.

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.

Objectives: We assessed the incidence of hyperbilirubinemia, defined as serum total bilirubin >/=15 mg/dL (256 micromol/L), in a cohort of Sephardic Jewish female neonates at risk for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency with especial emphasis on the heterozygotes. We studied the roles of hemolysis by blood carboxyhemoglobin (COHb) determinations and of the variant promoter of the gene for the bilirubin-conjugating enzyme uridine 5'-diphosphate glucuronosyltransferase 1 (UGT1A1) seen in Gilbert's syndrome in the pathogenesis of the hyperbilirubinemia., Methods: Consecutively born, healthy, term, female neonates were screened for G-6-PD deficiency and observed clinically with serum bilirubin evaluations as indicated for hyperbilirubinemia. On day 3, blood was sampled for COHb, total hemoglobin (tHb), and a mandatory serum bilirubin determination. COHb, determined by gas chromatography, was expressed as percentage of tHb and corrected for inspired carbon monoxide (COHbc). DNA was analyzed for the G-6-PD Mediterranean563T mutation and for the variant UGT1A1 gene., Results: The cohort included 54 G-6-PD-deficient heterozygotes, 19 deficient homozygotes, and 112 normal homozygotes. More heterozygotes (12/54, 22%; relative risk: 2.26; 95% CI: 1.07-4.80) and deficient homozygotes (5/19, 26.3%; relative risk: 2.68; 95% CI: 1.05-6.90) developed hyperbilirubinemia, than did normal homozygotes (11/112, 9.8%). Third-day serum bilirubin values that were obtained from 144 neonates were significantly higher in both heterozygotes (11.2 +/- 3. 7 mg/dL [192 +/- 64 micromol/L]) and G-6-PD-deficient homozygotes (12.0 +/- 3.0 mg/dL [206 +/- 52 micromol/L]) than in the G-6-PD normal homozygotes (9.4 +/- 3.4 mg/dL [160 +/- 58 micromol/L). In contrast, COHbc values were higher only in G-6-PD-deficient homozygotes (0.74% +/- 0.14%) and not in heterozygotes (0.69% +/- 0. 19%, not statistically significant), compared with control values (0. 63% +/- 0.19%). High COHbc values were not a prerequisite for the development of hyperbilirubinemia in any of the G-6-PD genotypes. A greater incidence of hyperbilirubinemia was found among the G-6-PD-deficient heterozygotes, who also had the variant UGT1A1 gene, in both heterozygous (6/20, 30%) and homozygous (4/8, 50%) forms, than was found in their counterparts with the normal UGT1A1 gene (2/26, 7.7%). This effect was not seen in the G-6-PD normal homozygote group. A color reduction screening test for G-6-PD deficiency identified only 20.4% (11/54) of the heterozygotes., Conclusions: We showed that G-6-PD-deficient heterozygotes, categorically defined by DNA analysis, are at increased risk for neonatal hyperbilirubinemia. The screening test that was used was unable to detect most heterozygotes. Increased bilirubin production was not crucial to the development of hyperbilirubinemia, but presence of the variant UGT1A1 gene did confer increased risk.

Severe neonatal hyperbilirubinemia can occur without apparent reason in term healthy breast-fed infants and some develop kernicterus. The aim of our study was to assess the incidence of severe hyperbilirubinemia in term healthy newborns discharged from the hospital. From January 1 through December 31, 1994, 6705 infants were delivered at Bikur-Cholim and Misgav-Ladach Community Hospitals. All 1448 newborns discharged with a serum bilirubin level > 10.0 mg/dL were instructed to return to the hospital within 3 days for follow-up, as well as bilirubin determination. Twenty-one newborns with a bilirubin level > 18.0 mg/dL were identified and readmitted at mean +/- standard deviation (SD) 5.5 +/- 1.8 (range, 5 to 10 days of life). This represents 1.7% of the 1220 infants who returned for follow-up examination. Mean +/- SD serum bilirubin levels at readmission were 19.6 +/- 2.5 mg/dL. All but one of the infants were breast-fed. No cases of ABO incompatibility were found and two newborns were glucose-6-phosphate dehydrogenase (G6PD)-deficient. Sepsis work-up and direct Coomb's tests were negative in all cases. None had hemolysis or were found to have any cause for hyperbilirubinemia other than breast-feeding. Phototherapy was provided in all but two cases, and an exchange transfusion was performed in one case. Three additional infants, with bilirubin levels < 10 mg/dL at discharge, were readmitted due to hyperbilirubinemia. One was diagnosed with neonatal hepatitis. We conclude that, based on our study population, 0.36% of term infants may subsequently develop severe neonatal hyperbilirubinemia in the first postnatal week.(ABSTRACT TRUNCATED AT 250 WORDS)

In intensive care nurseries it has become common practice to use microwave thawing of frozen human milk for more rapid accessibility. Twenty-two freshly frozen human milk samples were tested for lysozyme activity, total IgA, and specific secretory IgA to Escherichia coli serotypes 01, 04, and 06. The samples were heated by microwave for 30 seconds at a low- or high-power setting and then reanalyzed. One-mL aliquots of 10 additional human milk samples were microwaved at low (20 degrees C to 25 degrees C), medium (60 degrees C to 70 degrees C), and high (greater than or equal to 98 degrees C) setting before the addition to each of 1 mL of diluted E coli suspension. E coli growth was determined after 3 1/2 hours of incubation at 37 degrees C. Microwaving at high temperatures (72 degrees C to 98 degrees C) caused a marked decrease in activity of all the tested antiinfective factors. E coli growth at greater than or equal to 98 degrees C was 18 times that of control human milk. Microwaving at low temperatures (20 degrees C to 53 degrees C) had no significant effect on total IgA, specific IgA to E coli serotypes 01 and 04, but did significantly decrease lysozyme and specific IgA to E coli serotype 06. Even at 20 degrees C to 25 degrees C, E coli growth was five times that of control human milk. Microwaving appears to be contraindicated at high temperatures, and questions regarding its safety exist even at low temperatures.

To estimate the effect of neonatal hyperbilirubinemia on long-term cognitive ability in full-term newborns with a negative Coombs test, we performed a 17-year historical prospective study of 1948 subjects. Intelligence tests and medical examinations performed at the military draft board were stratified according to serum bilirubin concentration. A logistic regression analysis was used to adjust for the confounding effects of gestational age, birth weight, Apgar score, ethnic origin, socioeconomic class, paternal education, birth order, and the administration of phototherapy and exchange transfusion. No direct linear association was shown between neonatal bilirubin levels and intelligence test scores or school achievement at 17 years of age. However, the risk for low intelligence test scores (IQ score less than 85) was found to be significantly higher (P = .014) among full-term male subjects with serum bilirubin levels above 342 mumol/L (20 mg/dL) (odds ratio, 2.96; 95% confidence interval, 1.29-6.79). This association was not observed among female subjects. We conclude that severe neonatal hyperbilirubinemia, among full-term male newborns with a negative Coombs test, could be associated with lower IQ scores at 17 years of age.

Trimethoprim-sulfamethoxazole was given to a 16-year-old boy as prophylaxis for a urinary tract infection. He developed severe cholestatic hepatitis 41 days after administration of the drug. A liver biopsy specimen showed a mixed inflammatory infiltrate in the portal triads and prominent bile stasis. The clinical course in this patient supports the concept of an indirect hypersensitivity reaction to sulfamethoxazole.

From 1961 to 1976, 229 infants with birth weights ranging from 751 to 1,000 gm were admitted to the Stanford University Hospital Intensive Care Nursery. The overall neonatal mortality for these infants was 63% (144/229), and there were ten late deaths. Before 1967, no infant in this group who required mechanical ventilation survived; thereafter, 30% (34/114) of the ventilated patients survived. Of the 75 long-term survivors 60 participated in a high-risk infant follow-up program; these included 23 infants who had received mechanical ventilation. The mean birth weight of these infants was 928 +/- 67 (SD) gm. Seventeen children (28%) had significant morbidity: seven (12%) with severe handicaps and ten (17%) with moderate handicaps. During this same period, seven infants weighing less than 750 gm at birth were also observed. The three infants who had not required ventilatory support thrived; the other four infants had required respirators and were significantly handicapped. More recently, neonatal mortality for infants with birth weights from 751 to 1,000 gm has improved: for 1977 to 1980, it was 28% (33/118). Furthermore, neonatal mortality for ventilated infants in this weight group was 27% (26/95). These data indicate an improved prognosis for very low-birth-weight infants, even with ventilatory support.

Measurements of the pulmonary excretion rate of carbon monoxide (VEco) as an index of bilirubin production in the first several days of life were taken from 64 breast-fed or bottle-fed infants. Twenty-one infants (greater than or equal to 37 weeks of gestation) were breast-fed; 43 infants (28 to 42 weeks of gestation) were bottle-fed a commercially prepared formula. Information pertaining to their caloric intake during the 24-hour period preceding VEco determination was taken from 38 of the 43 infants who were bottle-fed and they were placed into three groups based on their caloric intake: (1) less than or equal to 60 kcal/kg/day (19 infants); (2) 61 to 100 kcal/kg/day (7 infants); and (3) greater than 100 kcal/kg/day (12 infants). There was no significant difference in bilirubin production between bottle-fed and breast-fed infants. No effect of caloric deprivation on bilirubin production was demonstrated. The mean VEco values were 18.5 +/- 0.9 (SE) for group 1, 17.7 +/- 1.8 (SE) for group 2, and 16.2 +/- 1.1 (SE) microliter/kg/hr for group 3.

Of 40 survivors of necrotizing enterocolitis 19 were completely normal children at the time of follow-up, one to three years later. Among the other 21 children, only six had moderate to severe neurologic impairment, representing 15% of all survivors. Despite the fact that intestinal injury is the main feature of the neonatal disease, only four children were symptomatic from gastrointestinal sequelae, and none of these suffered failure to thrive. Thus, 81% (17) of the children with late morbidity had problems unrelated to the gastrointestinal tract. The nongastrointestinal morbidity was associated with prematurity and the degree of perinatal stress.

Using a single pass, flow-through system, the excretion rate of endogenously produced carbon monoxide (VeCO) was measured as an index of bilirubin production in 41 Caucasian infants of various gestational ages after the first postnatal week. twenty-one were less than or equal to 32 weeks gestation. The mean slope for the 25 premature infants with multiple VeCO determinations was -0.21 +/- 0.11 (SE) microliters/kg/hour per day (P less than .025, one-tailed). Fifteen premature infants with at least three VeCO determinations during the first 30 days of life had an average decrease in total CO excreted of 1.33% per day compared to the extrapolated initial value of total CO excretion of 27.0 +/- 2.0 (SE) microliters/hour, giving a calculated maximum red cell life span of 75 days.