Karen E. Shattuck

Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age

BACKGROUND The last trimester of pregnancy is a period of rapid accretion of long-chain polyunsaturated fatty acids, both in the central nervous system and the body as a whole. Human milk contains these fatty acids, whereas some preterm infant formulas do not. Infants fed formulas without these fatty acids have lower plasma and erythrocyte concentrations than infants fed human milk. Preclinical and clinical studies have demonstrated that single-cell sources (algal and fungal) of long-chain polyunsaturated fatty acids are bioavailable. A balanced addition of fatty acids from these oils to preterm formula results in blood fatty acid concentrations in low birth weight infants comparable to those of infants fed human milk. METHODS In the present study the growth, acceptance (overall incidence of discontinuation, reasons for discontinuation, overall incidence and type of individual adverse events), and plasma fatty acid concentrations were compared in three groups of infants fed a long-chain polyunsaturated fatty acid-supplemented preterm infant formula, an unsupplemented control formula, or human milk. The study was prospective, double-blind (formula groups only), and randomized (formula groups only). Two hundred eighty-eight infants were enrolled (supplemented formula group, n = 77; control formula group, n = 78; human milk group, n = 133). RESULTS Anthropometric measurements at enrollment, at first day of full oral feeding, and at both 40 and 48 weeks postconceptional age did not differ between the formula groups, whereas the human milk-fed group initially grew at a lower rate. The incidence of severe adverse events was rare and not significantly different between formula groups. The groups fed either human milk or supplemented formula had long-chain polyunsaturated fatty acid concentrations higher than those in the control formula group. CONCLUSIONS The results of this study demonstrate the safety and efficacy of a preterm formula supplemented with long-chain polyunsaturated fatty acids from single-cell oils.

Effect of Fluconazole Prophylaxis on Candidiasis and Mortality in Premature Infants: A Randomized Clinical Trial

IMPORTANCE Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00734539.

Hyperbilirubinemia and Transcutaneous Bilirubinometry

BACKGROUND Neonatal jaundice or hyperbilirubinemia is a common occurrence in newborns. Although most cases of neonatal jaundice have a benign course, severe hyperbilirubinemia can lead to kernicterus, which is preventable if the hyperbilirubinemia is identified early and treated appropriately. CONTENT This review discusses neonatal jaundice and the use of transcutaneous bilirubin (TcB) measurements for identification of neonates at risk of severe hyperbilirubinemia. Such a practice requires appropriate serial testing and result interpretation according to risk level from a nomogram that provides bilirubin concentrations specific for the age of the neonate in hours. In this context, we have evaluated the potential impact on clinical outcome and limitations of TcB methods in current use. SUMMARY TcB measurement is a viable option in screening neonates to determine if they are at risk for clinically significant hyperbilirubinemia. Total serum bilirubin should be measured by a clinical laboratory if a newborn is shown to be at higher risk for clinically significant hyperbilirubinemia. In addition, external quality assessment to identify biases and operator training issues should be part of any TcB monitoring program.

Bone Turnover in Preterm Infants

Total parenteral nutrition is associated with osteopenia in preterm infants. Insufficient calcium and phosphate are likely causes; aluminum contamination is another possible contributing factor as this adversely affects bone formation and mineralization. The study was designed to evaluate changes in biochemical markers of bone turnover in 22 preterm infants receiving total parenteral nutrition in comparison with 19 term infants. We collected urine and serum samples from 22 preterm infants, mean gestational age 29 wk, within 48 h and again at 3 wk of life. We also collected urine samples from 19 term infants, mean gestational age 39 wk, during the first day of life. Bone resorption was assessed by the measurement of urinary pyridinium cross-links by HPLC and ELISA and the N-telopeptide of type I collagen by ELISA. Bone formation was assessed in premature infants by the measurement of serum osteocalcin. The N-telopeptide of type I collagen was higher in the preterm infants compared with term at baseline (p < 0.01). There was no difference between the pyridinium cross-links in the preterm and term infants. All the biochemical markers of bone turnover increased significantly in the preterm infants during the first 3 wk of life, e.g. N-telopeptide was a 153% change from baseline (p < 0.001). Aluminum in the total parenteral nutrition solutions did not cause a decrease in bone formation at the level administered (3-6 µg, 0.1-0.2 µmol·kg-1·d-1).

Colonization and infection associated with Malassezia and Candida species in a neonatal unit

The objectives of this study were to determine, in neonates of < 1250 g birthweight (N = 57), the initial time of skin colonization by Malassezia furfur, rate of colonization by Candida spp., and whether skin colonization by these yeasts was predictive of central line colonization or fungaemia. By age two weeks, 51% of neonates were culture-positive for M. furfur on umbilical or groin skin. During hospitalization, positive skin cultures for M. furfur or Candida spp. were obtained in 70% and 37% of neonates, respectively. Risk factors associated with positive skin cultures were mechanical ventilation and three or more episodes of suspected sepsis. Eight of the 52 infants with central venous catheters, had positive blood cultures withdrawn from the lines; five (62%) of these had positive skin surveillance cultures. Although positive skin cultures for M. furfur, Candida spp., or both were commonly observed in this population, they were not predictive of positive central line cultures or systemic illness.

The Changing Spectrum of Neonatal Meningitis Over a Fifteen-Year Period

One hundred seventy-seven cases of neonatal meningitis treated at the University of Texas Medical Branch at Galveston over a 15-year period (1974-1988) were reviewed. Over this period, the incidence of bacterial meningitis decreased, the incidence of aseptic meningitis remained stable, and the diagnosis of enteroviral meningitis increased in frequency. During 1984-1988, enterovirus was the most common cause of meningitis in neonates older than seven days and accounted for one third of all cases of neonatal meningitis. Half of all neonates with bacterial meningitis had negative blood cultures. We recommend that 1) diagnostic lumbar puncture remain part of the routine assessment of the neonate with suspected sepsis, and 2) CSF be cultured for enterovirus as well as for bacteria when a neonate older than seven days presents with suspected sepsis.

High compared with standard gentamicin dosing for chorioamnionitis: a comparison of maternal and fetal serum drug levels.

OBJECTIVE: To compare umbilical cord and maternal serum peak gentamicin concentration, gentamicin elimination, and clinical outcomes between women who received once-daily compared with standard, thrice-daily dosing for clinical chorioamnionitis. METHODS: We randomly assigned 38 laboring women, at least 34 weeks gestation, with clinical chorioamnionitis, into 1 of 2 gentamicin dosing groups: 5.1 mg/kg every 24 hours (once-daily; n = 18), or 120 mg followed by 80 mg every 8 hours (standard; n = 20). We measured maternal serum peak and delivery gentamicin concentrations and cord serum levels at delivery. Polynomial curve fitting was used to summarize gentamicin elimination. We also compared maternal and neonatal outcomes. RESULTS: Demographic characteristics of the 2 groups were similar. Median maternal peak gentamicin levels were higher with once-daily (18.2 μg/mL) compared with standard dosing (7.1 μg/mL) (P < .001). Maternal serum levels decreased below 2 μg/mL by 10 hours in the once-daily group and by 5 hours in the standard dosing group. Extrapolated peak cord serum levels were 6.9 μg/mL in the once-daily and 2.9 μg/mL in the standard dosing arm. Cord levels decreased below 2 μg/mL by 10 hours in the once-daily and by 5 hours in the standard dosing group. We found no differences in maternal or neonatal outcomes. CONCLUSION: Peak maternal serum gentamicin levels ranged from 13 to 25 μg/mL after a dose of 5.1 mg/kg. Single-dose gentamicin resulted in fetal serum peak levels that were closer to optimal neonatal values. Gentamicin clearance in the term fetus was similar to published values for the newborn infant. No adverse effects of high-dose therapy were noted. LEVEL OF EVIDENCE: II-3

Intestinal zygomycosis due to Absidia corymbifera mimicking necrotizing enterocolitis in a preterm neonate.

Zygomycosis is a rare fungal disease that occurs in compromised human hosts, including the preterm infant. The three clinical forms of zygomycosis are cellulitis, disseminated, and gastrointestinal, and the last often mimics necrotizing enterocolitis (NEC), complicating the diagnosis. This report details a case of primary gastrointestinal zygomycosis due to Absidia corymbifera, mimicking NEC, in a preterm infant, and emphasizes features that may lead to earlier diagnosis and treatment of future cases.

Massive Intracranial Immature Teratoma with Extracranial Extension into Oral Cavity, Nose, and Neck

We present a case of congenital massive intracranial teratoma with extracranial extension into oral cavity, nose, and neck diagnosed by antenatal ultrasonography at 25 weeks of gestation. The fetus was delivered by cesarean section because of massive fetal head size and severe maternal pregnancy-induced hypertension. At necropsy the tumor was found to be an immature teratoma, with no recognizable normal brain tissue. An additional finding was hepatomegaly secondary to extensive extramedullary hematopoiesis. Karyotyping of both the fetus and the teratoma revealed a normal female chromosomal composition: 46,XX.

N-Acetylcysteine Protects From Glutathione Depletion in Rats Exposed to Hyperoxia

BACKGROUND N-acetylcysteine (NAC) may protect against oxidative injury by providing cysteine for glutathione (GSH) biosynthesis or by direct reactions with electrophiles. We have recently shown that hyperoxic exposure of rats prior to liver perfusion is associated with significant decreases in hepatic GSH and significant changes in biliary amino acid concentrations. We hypothesized that NAC administration during hyperoxic exposure would prevent depletion of hepatic GSH by providing cysteine for GSH biosynthesis. METHODS NAC was administered during two conditions known to induce GSH depletion: hyperoxic exposure and biochemical inhibition of GSH synthesis using buthionine sulfoximine (BSO). After 48 hours, GSH concentrations in bile, liver and perfusate and biliary amino acid concentrations were determined using isolated perfused liver preparations. RESULTS Administration of NAC to rats maintained in normoxic or hyperoxic conditions, prior to liver perfusion, resulted in dose-dependent increases in GSH concentrations in bile, liver and perfusate, increases in bile flow rates and changes in biliary amino acid concentrations. When BSO was given concurrently with NAC in normal or hyperoxic conditions, these effects were not observed, and oxidant stress was evident. CONCLUSIONS NAC prevents oxidant stress during hyperoxic exposure, most likely by supplying cysteine as a precursor for GSH synthesis.