Perinatal systemic inflammatory response syndrome and retinopathy of prematurity.

Fetal and neonatal inflammation is associated with several morbidities of prematurity. Its relationship to retinopathy of prematurity (ROP) has not been investigated. Our objective was to determine the relationship between cytokine levels and ROP in the first 3 postnatal wks. Data for this study were derived from the NICHD Cytokine Study. Dried blood spots (DBS) were obtained from infants <1000 g on days 0-1, 3 +/- 1, 7 +/- 2, 14 +/- 3, and 21 +/- 3. Infants were classified into three groups-no, mild, and severe ROP. Multiplex Luminex assay was used to quantify 20 cytokines. Temporal profiles of cytokines were evaluated using mixed-effects models after controlling for covariates. Of 1074 infants enrolled, 890 were examined for ROP and 877 included in the analysis. ROP was associated with several clinical characteristics on unadjusted analyses. Eight cytokines remained significantly different across ROP groups in adjusted analyses. IL-6 and IL-17 showed significant effects in early time periods (D0-3); TGF-beta, brain-derived neurotrophic factor (BDNF), and regulated on activation, normal T cell expressed and secreted (RANTES) in later time periods (D7-21) and IL-18, C-reactive protein (CRP), and neurotrophin-4 (NT-4) in both early and later time periods. We conclude that perinatal inflammation may be involved in the pathogenesis of ROP.

Morbidity risk at birth for Asian Indian small for gestational age infants.

Whether the traditional definition of small for gestational age (SGA) is an appropriate marker of risk for populations that have relatively lower birthweight is unclear. We determined proportions of White and Asian Indian SGA infants and those admitted to the special care nursery. Compared with White infants, Asian Indian infants were more likely to be SGA (14.5% versus 2.7%) and more likely to be admitted to the special care nursery (20.7% versus 3.7%), suggesting that traditional definitions of SGA may be applicable as a marker of risk.

Second-trimester serum cytokines in women who develop spontaneous preterm labor at less than 28 weeks' gestation versus term labor.

We sought to determine if there is a relationship between serum concentrations of cytokines and the development of preterm labor. A panel of 28 cytokines was measured using the multiplex assay in serum samples collected between 15 and 18 weeks' gestation from women who developed spontaneous preterm labor and delivered between 24 and 28 weeks' gestation (N = 25) and from women who delivered at term (>or=37 weeks; N = 25). Sixteen of the 28 cytokines measured were detected. Except for vascular endothelial growth factor, which showed a trend toward a significant increase in patients who developed preterm labor, there was no difference in cytokine levels between groups in preterm labor and in term labor. Serum cytokine changes in women who develop spontaneous preterm labor possibly occur in the period between 18 weeks' gestation and the onset of labor.

Plasma biomarkers in a mouse model of preterm labor.

Preterm labor (PTL) is frequently associated with inflammation. We hypothesized that biomarkers during pregnancy can identify pregnancies most at risk for development of PTL. An inflammation-induced mouse model of PTL was used. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry was used to analyze and compare the plasma protein (PP) profile between CD-1 mice injected intrauterine with either lipopolysaccharide (LPS) or PBS on d 14.5 of gestation. The median differences of normalized PP peaks between the two groups were determined using the Mann-Whitney U test and the false discovery rate. In a second series of experiments, both groups of mice were injected with a lower dose of LPS. A total of 1665 peaks were detected. Thirty peaks were highly differentially expressed (p < 0.0001) between the groups. Two 11 kDa protein peaks were identified by MALDI-TOF/TOF-MS and confirmed to be mouse serum amyloid A (SAA) 1 and 2. Plasma SAA2 levels were increased in LPS-treated animals compared with controls and in LPS-treated animals that delivered preterm vs. those that delivered at term. SAA2 has the potential to be a plasma biomarker that can identify pregnancies at risk for development of PTL.

Oropharyngeal atresia in a preterm infant: a case report and review of the literature.

Oropharyngeal atresia is a rare and often fatal condition that presents soon after birth with severe respiratory distress. We present a case of a premature infant who initially was suspected to have tracheo-esophageal atresia due to prenatal ultrasound findings of polyhydramnios and absent stomach bubble, but was found instead to have oropharyngeal atresia and a complete persistent buccopharyngeal membrane. This case is the first described in which the patient was successfully intubated through a small slit in the persistent membrane.

A role for hypoxia-inducible factor-1alpha in desferoxamine neuroprotection.

The newborn brain has increased vulnerability to hypoxia-ischemia from maturational differences in the oxidative stress response. We hypothesized that desferoxamine (DFO), an iron chelator, would provide protection in an in vitro model of ischemia in part through activation of the hypoxia-inducible gene hypoxia-inducible factor-1alpha (HIF-1alpha). Hippocampal neurons from E16 CD1 mice were exposed to 3 h of oxygen and glucose deprivation with and without pretreatment with 10 mmol/L DFO in the presence and absence of 2 micromol/L antisense oligonucleotides specific for HIF-1alpha (antiHIF-1alpha). DFO pretreatment resulted in 45% reduction in cell death (p = 0.006). This protection was diminished with transfection of antiHIF-1alpha (p = 0.049). Blocking HIF-1alpha reduces DFO protection suggesting that DFO protects through iron chelation and HIF-1alpha induction.

Reduction in red blood cell transfusions using a bedside analyzer in extremely low birth weight infants.

BACKGROUND: Preterm infants typically experience heavy phlebotomy losses from frequent laboratory testing in the first few weeks of life. This results in anemia, requiring red blood cell (RBC) transfusions. We recently introduced a bedside point-of-care (POC) blood gas analyzer (iSTAT, Princeton, NJ) that requires a smaller volume of blood to replace conventional Radiometer blood gas and electrolyte analysis used by our neonatal intensive care unit (NICU). The smaller volume of blood required for sampling (100 vs 300-500 microl), provided an opportunity to assess if a decrease in phlebotomy loss occurred and, if so, to determine if this resulted in decreased transfusions administered to extremely low birth weight (ELBW) infants. OBJECTIVE: We hypothesized that the use of the POC iSTAT analyzer that measures pH, PCO(2), PO(2), hemoglobin, hematocrit, serum sodium, serum potassium and ionized calcium would result in a significant decrease in the number and volume of RBC transfusions in the first 2 weeks of life. DESIGN/METHODS: A retrospective chart review was conducted of all inborn premature infants with birth weights less than 1000 g admitted to the NICU that survived for 2 weeks of age during two separate 1-year periods. Blood gas analysis was performed by conventional laboratory methods during the first period (designated Pre-POC testing) and by the iSTAT POC device during the second period (designated post-POC testing). Data collected for individual infants included the number of RBC transfusions, volume of RBCs transfused, and the number and kind of blood testing done. There was no effort to change either the RBC transfusion criteria applied or blood testing practices. RESULTS: The mean (+/-SD) number of RBC transfusions administered in the first 2 weeks after birth was 5.7+/-3.74 (n=46) in the pre-POC testing period to 3.1+/-2.07 (n=34) in the post-POC testing period (p<0.001), a 46% reduction. The mean volume of RBC transfusions decreased by 43% with use of the POC analyzer, that is, from 78.4+/-51.6 ml/kg in the pre-POC testing group to 44.4+/-32.9 ml/kg in the Post-POC testing group (p<0.002). There was no difference between the two periods in the total number of laboratory blood tests done. CONCLUSIONS: Use of a bedside blood gas analyzer is associated with clinically important reductions in RBC transfusions in the ELBW infant during the first two weeks of life.

Animal models of oxygen-induced retinopathy.

Retinopathy of prematurity (ROP) is a neovascularizing disease of the retina affecting premature infants. Much of our current knowledge regarding development of both normal and abnormal blood vessels in the retina has been obtained from animal models of retinopathy. The retina is an excellent organ for studying angiogenesis, since the progress of blood vessel growth can be monitored by angiography or fundoscopy. Also, the entire retinal vasculature can be viewed in flat-mounted retinal preparations. Although these animal models were previously used to study the gross aspects of vasculogenesis and angiogenesis, they are increasingly being used to identify the genes and molecular mechanisms involved in these processes. Knowledge gained from these studies can be applied to non-ocular angiogenic conditions. This paper provides historical perspective on the development and use of animal models of retinal neovascular disease since the 1950's and on the key studies that have led to our current understanding about the pathogenesis these conditions.

Retinopathy of prematurity and pulse oximetry: a national survey of recent practices.

OBJECTIVE: To determine if practices related to the use of pulse oximetry in the first 2 weeks following birth and after 2 weeks of age have a relationship to the rate of retinopathy of prematurity (ROP) and retinal ablation surgery in infants < or =1500 g. STUDY DESIGN: A questionnaire was mailed in July 2001 to 318 neonatal intensive care units (NICUs) in the United States and information was collected regarding SpO2 guidelines and the rate of both severe ROP and retinal ablation surgery. RESULTS: A total of 142 surveys were returned (45%). In all, 87% of the NICUs had SpO2 guidelines, and 60% of these centers maintained a different range of SpO2 for infants < or = or >2 weeks of age. The range of SpO2 was 82 to 100% with an average minimum (min) and maximum (max) of 89 and 95%, respectively. In the NICUs with an SpO2 max of >98% in the first 2 weeks following birth, the rate of retinal ablation surgery was 5.5 vs 3% in those units with a max SpO2 >98% (p<0.05). After 2 weeks of age, the rate of retinal ablation surgery was 3.3% when max SpO2 was >92 vs 1.3% when the max SpO2 was < or =92% (p<0.00001). The rate of > or =stage 3 ROP after 2 weeks of age was 5.5% when max SpO2 was >92 vs 2.4% when max SpO2 was < or =92% (p<0.0005). CONCLUSION: NICUs in the US today have a wide range of SpO2 guidelines. The results of this survey show a "gradient of risk" towards less retinal ablation surgery when the max SpO2 is <98% in the first 2 weeks following birth (p<0.05). There was a statistically significant lower rate of > or =stage 3 ROP and retinal ablation surgery when the max SpO2 was < or =92% after the first 2 weeks of age. A randomized, controlled trial is needed to establish a safe upper limit of SpO2 in the premature infant at risk for developing ROP.

Racial differences in birth weight of term infants in a northern California population.

BACKGROUND: Census data show that an increasing proportion of the population of the United States is of Asian or Hispanic origin. Reference curves used to characterize fetal growth relative to gestational age are predominantly based on data for White infants. The goal of this study was to compare the birth weight distributions for term Asian or Hispanic infants with that for White infants, and to determine whether the prevalence of small (SGA) or large size(LGA) for gestational age differs between Asian or Hispanic and White infants. SETTING: A community hospital in Northern California. STUDY DESIGN: Data was collected prospectively from May 1 to September 13, 2000 on all singleton term infants born at this hospital. Gestational age was assessed by the best obstetrical estimate and ethnicity was determined by parental report. Infants were categorized as White, Hispanic, Chinese, Asian Indian, Other Asian, and Other. Birth weights, length, and head circumferences were compared using ANOVA and the Student-Newman-Keuls test. Differences in rates of diagnosis of SGA or LGA were assessed by chi square. RESULTS: 1539 infants were included in the study sample; 30% were White, 21% Asian Indian, 15% Chinese, 9% Hispanic, 7% other Asian, and 18% Other. Asian (Chinese, Asian Indian, or Other Asian), Hispanic, and Other babies had lower mean birth weights, shorter mean lengths, and smaller mean head circumferences than White babies. Asian, Hispanic, and Other male babies were lighter, shorter, and had smaller heads than white male babies. Asian females, but not Hispanic or Other ones, were lighter and had smaller head circumferences than White females; Asian Indian, Other Asian, and Other females had shorter lengths than White female infants. Indian and Other Asian, but not Chinese, babies were more likely than White babies to be SGA; babies in all three Asian groups were less likely than White babies to be LGA. CONCLUSION: Failure to account for ethnic differences in intrauterine growth may lead to inaccurate diagnosis of fetal growth abnormalities in infants of Asian ancestry.

Frequency and timing of symptoms in infants screened for sepsis: effectiveness of a sepsis-screening pathway.

To determine the frequency and timing of symptoms and to evaluate the effectiveness of a sepsis-screening pathway in term and near-term infants, data were collected prospectively for a period of 1 year from December 1, 2000, to November 30, 2001. Results confirmed that a sepsis-screening pathway using a combination of at least 2 serial complete blood cell count and C-reactive protein measurements in both symptomatic and asymptomatic infants is a safe, simple strategy that prevents unnecessary treatment of infants with risk factors with antibiotics. However, most infants with presumed or suspected early-onset sepsis are symptomatic. Routine treatment of asymptomatic infants with risk factors or prior treatment with intrapartum antibiotics is unnecessary. A combined approach of screening in the presence of risk factors and /or symptoms of sepsis and adequate follow-up for infants discharged at less than 72 hours of age may help reduce unnecessary treatment of infants with antibiotics.

Readmission for newborn jaundice: the value of the Coombs' test in predicting the need for phototherapy.

Current practice at our hospital is to perform a direct antiglobulin test (DAT) on cord blood samples of all infants born to blood type O or Rh-negative mothers. Measurement of serum total bilirubin (STB) level and follow-up after discharge are at the discretion of the individual physician. The purposes of the present study were, first, to determine the clinical utility of performing a routine DAT and, second, to define the clinical characteristics of infants readmitted to the hospital for phototherapy. The study was done over a 1-year period extending from January 1 to December 31, 2000. A retrospective review of the DAT results of all infants born to type O or Rh-negative mothers was conducted. The 2 groups of infants included those who had a positive cord blood DAT and were treated with phototherapy and those who needed readmission to the hospital for phototherapy. We found that routine DAT testing of cord blood from term nonjaundiced infants born to O positive mothers is not necessary. Infants with 2 or more risk factors for jaundice irrespective of the results of the DAT are at an increased risk for needing readmission for phototherapy.

Visuocortical function in infants with a history of neonatal jaundice.

PURPOSE: High concentrations of unconjugated bilirubin are neurotoxic and cause brain damage in newborn infants. However, the exact level of bilirubin that may be neurotoxic in a given infant is unknown. The aim of this study was to use a quantitative measure of neural activity, the swept parameter visual evoked potential (sVEP) to determine the relationship between neonatal bilirubin levels and visual responsivity several months later. METHODS: We compared sVEP response functions over a wide range of contrast, spatial frequency, and Vernier offset sizes in 16 full-term infants with high bilirubin levels (>10 mg/dL) and 18 age-matched infants with no visible neonatal jaundice, all enrolled at 14 to 22 weeks of age. The group means of sVEP thresholds and suprathreshold response amplitudes were compared. The correlation between individual sVEP thresholds and bilirubin levels in jaundiced infants was studied. RESULTS: Infants who had a history of neonatal jaundice showed lower response amplitudes (P < 0.05) and worse or immeasurable sVEP thresholds compared with control infants for all three measures (P < 0.05). Swept parameter visual evoked potential thresholds for Vernier offset were correlated with bilirubin level (P < 0.05), but spatial acuity and contrast sensitivity measures in the infants with neonatal jaundice were not (P > 0.05). CONCLUSIONS: These results indicate that elevated neonatal bilirubin levels affect measures of visual function in infancy up to at least 14 to 22 weeks of postnatal age.

Effect of Grade I and II intraventricular hemorrhage on visuocortical function in very low birth weight infants.

The neurological outcome for infants with Grade I/II intraventricular hemorrhage (IVH) is debated. The aim of this study was to determine whether very low birth weight infants (VLBW, <1500 g) with Grade I/II (IVH) have altered visuocortical activity compared with infants with no IVH. We assessed the quantitative swept parameter visual evoked potential (sVEP) responses evoked by three different visual stimuli. Data from 52 VLBW infants were compared with data from 13 infants with Grade I or II IVH, enrolled at 5-7 months corrected age. Acuity thresholds and suprathreshold response amplitudes were compared. Grating acuity (GA), contrast sensitivity (CS) and vernier acuity (VA) were each worse in the Grade I/II IVH compared with the no IVH groups (8.24 cpd in IVH group vs. 13.07 cpd in no IVH group for GA; 1.44% vs. 1.18% for CS and 1.55 arcmin vs. 0.58 arcmin for VA). The slopes of the response amplitude for CS and VA were significantly lower in IVH infants. The spatial frequency tuning function was shifted downward on the spatial frequency axis, without a change in slope. These results indicate that Grade I/II IVH are associated with deleterious effects on cortical vision development and function.

Visual cortical function in very low birth weight infants without retinal or cerebral pathology.

PURPOSE: Preterm infants are at high risk of visual and neural developmental deficits. However, the development of visual cortical function in preterm infants with no retinal or neurologic morbidity has not been well defined. To determine whether premature birth itself alters visual cortical function, swept parameter visual evoked potential (sVEP) responses of healthy preterm infants were compared with those of term infants. METHODS: Fifty-two term infants and 58 very low birth weight (VLBW) infants without significant retinopathy of prematurity or neurologic morbidities were enrolled. Recruited VLBW infants were between 26 and 33 weeks of gestational age, with birth weights of less than 1500 g. Spatial frequency, contrast, and vernier offset sweep VEP tuning functions were measured at 5 to 7 months' corrected age. Acuity and contrast thresholds were derived by extrapolating the tuning functions to 0 amplitude. These thresholds and suprathreshold response amplitudes were compared between groups. RESULTS: Preterm infants showed increased thresholds (indicating decreased sensitivity to visual stimuli) and reductions in amplitudes for all three measures. These changes in cortical responsiveness were larger in the <30 weeks ' gestational age subgroup than in the ≥30 weeks' gestational age subgroup. CONCLUSIONS: Preterm infants with VLBW had measurable and significant changes in cortical responsiveness that were correlated with gestational age. These results suggest that premature birth in the absence of identifiable retinal or neurologic abnormalities has a significant effect on visual cortical sensitivity at 5 to 7 months' of corrected age and that gestational age is an important factor in visual development.

Multiple cytokine profile in plasma and amniotic fluid in a mouse model of pre-term labor.

PROBLEM: The rate of pre-term birth in the United States continues to rise despite several interventions. Induction of pro-inflammatory cytokines and chemokines has been implicated in the activation of the cascade of events resulting in pre-term labor. To date, no comprehensive panel of the cytokine profile in PTL has been published. METHOD OF STUDY: To address cytokine profiles in pre-term labor, levels of 19 plasma and amniotic fluid cytokines were measured using a multiplex immunoassay in an inflammation-induced murine model of pre-term labor. RESULTS: Pro-inflammatory mediators, RANTES, KC, IL-6, and IL-12p40 were increased by 3 hr and remained high at 15 hr. Concentrations of KC, IL-6, IL-1beta, and MIP-1alpha were increased in the amniotic fluid at 15 hr. Plasma levels of anti-inflammatory mediators IL-10 and IL-13 at 15 hr were unchanged and decreased respectively. CONCLUSION: These results suggest that stimulation of several pro-inflammatory cytokines occurs very early in the cascade of events and remains increased, whereas anti-inflammatory cytokines are either unchanged or decreased until the onset of delivery in an inflammation-induced mouse model of pre-term labor.

Effects of moderate versus deep hypothermic circulatory arrest and selective cerebral perfusion on cerebrospinal fluid proteomic profiles in a piglet model of cardiopulmonary bypass.

OBJECTIVE: Our objective was to compare protein profiles of cerebrospinal fluid between control animals and those subjected to cardiopulmonary bypass after moderate versus deep hypothermic circulatory arrest with selective cerebral perfusion. METHODS: Immature Yorkshire piglets were assigned to one of four study groups: (1) deep hypothermic circulatory arrest at 18 degrees C, (2) deep hypothermic circulatory arrest at 18 degrees C with selective cerebral perfusion, (3) moderate hypothermic circulatory arrest at 25 degrees C with selective cerebral perfusion, or (4) age-matched control animals without surgery. Animals undergoing cardiopulmonary bypass were cooled to their assigned group temperature and exposed to 1 hour of hypothermic circulatory arrest. After arrest, animals were rewarmed, weaned off bypass, and allowed to recover for 4 hours. Cerebrospinal fluid collected from surgical animals after the recovery period was compared with cerebrospinal fluid from controls by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Protein spectra were analyzed for differences between groups by Mann-Whitney U test and false discovery rate analysis. RESULTS: Baseline and postbypass physiologic parameters were similar in all surgical groups. A total of 194 protein peaks were detected. Compared with controls, groups 1, 2, and 3 had 64, 100, and 13 peaks that were significantly different, respectively (P < .05). Three of these peaks were present in all three groups. Cerebrospinal fluid protein profiles in animals undergoing cardiopulmonary bypass with moderate hypothermic circulatory arrest (group 3) were more similar to controls than either of the groups subjected to deep hypothermia. CONCLUSIONS: The mass spectra of cerebrospinal fluid proteins are altered in piglets exposed to cardiopulmonary bypass and hypothermic circulatory arrest. Moderate hypothermic circulatory arrest (25 degrees C) with selective cerebral perfusion compared with deep hypothermic circulatory arrest (18 degrees C) is associated with fewer changes in cerebrospinal fluid proteins, when compared with nonbypass controls.

A potential biomarker in the cord blood of preterm infants who develop retinopathy of prematurity.

Preterm infants are at risk of developing sepsis, necrotizing enterocolitis (NEC), chronic lung disease (CLD), and retinopathy of prematurity (ROP). We used high-throughput mass spectrometry to investigate whether cord blood proteins can be used to predict development of these morbidities. Cord blood plasma from 44 infants with a birth weight of <1500 g was analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF). Six infants developed ROP >or=stage II, 10 CLD, three sepsis, and one NEC. We detected 814 protein signals representing 330 distinct protein species. Nineteen biomarkers were associated with development of >or=stage II ROP [false-discovery rate (FDR) <5%] and none with CLD. Several proteins with molecular weight (Mr) 15-16 kD and pI 4-5 were detected with increased abundance in infants with ROP, while similar Mr proteins with pI 7-9 were less abundant in these patients. Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and sequence analysis identified these proteins as alpha-, beta-, and gamma-globin chains. Partial deamidation of Asn139 in beta-globin chains was observed only in the pI 4-5 proteins. We conclude that there are several promising biomarkers for the risk of ROP. Deamidation of globin chains is especially promising and may indicate underlying prenatal pathologic mechanisms in ROP. Validation studies will be undertaken to determine their clinical utility.