Homocysteine levels in preterm infants: is there an association with intraventricular hemorrhage? A prospective cohort study.

BACKGROUND: The purpose of this study was to characterize total homocysteine (tHcy) levels at birth in preterm and term infants and identify associations with intraventricular hemorrhage (IVH) and other neonatal outcomes such as mortality, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, and thrombocytopenia. METHODS: 123 infants < 32 weeks gestation admitted to our Level III nursery were enrolled. A group of 25 term infants were enrolled for comparison. Two blood spots collected on filter paper with admission blood drawing were analyzed by a high performance liquid chromatography (HPLC) method. Statistical analysis included ANOVA, Spearman's Rank Order Correlation and Mann-Whitney U test. RESULTS: The median tHcy was 2.75 micromol/L with an interquartile range of 1.34 - 4.96 micromol/L. There was no difference between preterm and term tHcy (median 2.76, IQR 1.25 - 4.8 micromol/L vs median 2.54, IQR 1.55 - 7.85 micromol/L, p = 0.07). There was no statistically significant difference in tHcy in 31 preterm infants with IVH compared to infants without IVH (median 1.96, IQR 1.09 - 4.35 micromol/L vs median 2.96, IQR 1.51 - 4.84 micromol/L, p = 0.43). There was also no statistically significant difference in tHcy in 7 infants with periventricular leukomalacia (PVL) compared to infants without PVL (median 1.55, IQR 0.25 - 3.45 micromol/L vs median 2.85, IQR 1.34 - 4.82 micromol/L, p = 0.07). Male infants had lower tHcy compared to female; prenatal steroids were associated with a higher tHcy. CONCLUSION: In our population of preterm infants, there is no association between IVH and tHcy. Male gender, prenatal steroids and preeclampsia were associated with differences in tHcy levels.

Increasing illness severity in very low birth weight infants over a 9-year period.

BACKGROUND: Recent reports have documented a leveling-off of survival rates in preterm infants through the 1990's. The objective of this study was to determine temporal changes in illness severity in very low birth weight (VLBW) infants in relationship to the outcomes of death and/or severe IVH. METHODS: Cohort study of 1414 VLBW infants cared for in a single level III neonatal intensive care unit in Delaware from 1993-2002. Infants were divided into consecutive 3-year cohorts. Illness severity was measured by two objective methods: the Score for Neonatal Acute Physiology (SNAP), based on data from the 1st day of life, and total thyroxine (T4), measured on the 5th day of life. Death before hospital discharge and severe intraventricular hemorrhage (IVH) were investigated in the study sample in relation to illness severity. The fetal death rate was also investigated. Statistical analyses included both univariate and multivariate analysis. RESULTS: Illness severity, as measured by SNAP and T4, increased steadily over the 9-year study period with an associated increase in severe IVH and the combined outcome of death and/or severe IVH. During the final 3 years of the study, the observed increase in illness severity accounted for 86% (95% CI 57-116%) of the variability in the increase in death and/or severe IVH. The fetal death rate dropped from 7.8/1000 (1993-1996) to 5.3/1000 (1999-2002, p = .01) over the course of the study. CONCLUSION: These data demonstrate a progressive increase in illness in VLBW infants over time, associated with an increase in death and/or severe IVH. We speculate that the observed decrease in fetal death, and the increase in neonatal illness, mortality and/or severe IVH over time represent a shift of severely compromised patients that now survive the fetal time period and are presented for care in the neonatal unit.

Maternal antibiotics and decreased periventricular leukomalacia in very low-birth-weight infants.

OBJECTIVE: To investigate the effect of maternal antibiotics, given in the predelivery period, on neonatal outcomes. DESIGN: Retrospective cohort study. SETTING: A single level 3 neonatal intensive care unit. PATIENTS: All infants with birth weights 1500 g or less cared for from July 1994 to July 2000 (n = 834) were included in the study. Mothers were classified as receiving antibiotics if they received any parenteral antibiotics in the predelivery period. Infants whose mothers received antibiotics were compared with infants whose mothers received no antibiotics. MAIN OUTCOME MEASURES: The main outcome variables studied included intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), sepsis, and mortality. RESULTS: Of 834 mothers, 374 (45%) received antibiotics prior to delivery. On univariate analysis, there were no differences in the relative risk (RR) of mortality (1.26; 95% confidence interval [CI], 0.86-1.79) or grades 3 to 4 IVH (RR, 1.39; 95% CI, 0.82-1.90) between the antibiotics and no-antibiotics groups. Infants born to mothers receiving antibiotics had an increased risk of culture-proven sepsis (RR, 1.4; 95% CI, 1.02-1.64) and a decreased risk of cystic PVL (RR, 0.26; 95% CI, 0.09-0.79) compared with infants whose mothers did not receive antibiotics. After controlling for confounding variables, maternal antibiotics were not associated with a decrease in the risk of mortality (adjusted risk [AR], 1.0; 95% CI, 0.5-2.1), grades 3 to 4 IVH (AR, 1.0; 95% CI, 0.5-1.9), or sepsis (AR, 0.9; 95% CI, 0.7-1.4). However, the use of maternal antibiotics was associated with a decreased risk of developing cystic PVL (AR, 0.09; 95% CI, 0.02-0.5). CONCLUSIONS: In our population of very low-birth-weight infants, maternal antibiotics were associated with a decreased risk of cystic PVL. Maternal antibiotics do not change the risk of mortality, sepsis, or severe IVH.

Admission thyroid evaluation in very-low-birth-weight infants: association with death and severe intraventricular hemorrhage.

OBJECTIVES: To determine if thyroxine (T(4)) and thyrotropin (TSH) levels, measured at the time of admission to the neonatal intensive care unit, are associated with the outcomes of death and/or severe intraventricular hemorrhage (IVH). STUDY DESIGN: Blood for total T(4) and TSH was obtained upon admission to the neonatal intensive care unit in infants with birthweights less than 1500 g. Infants were followed until hospital discharge. Statistical analysis included one-way analysis of variance, Pearson correlation, and logistic regression. Data are expressed as mean +/- standard deviation (SD). RESULTS: One hundred twenty-two infants were enrolled. The mean gestational age of the study population was 27 +/- 2.8 weeks. Both T(4) (R = 0.25, p < 0.01) and TSH (R = 0.39, p < 0.01) at the time of admission correlated with gestational age. Infants who died and/or had severe IVH (n = 31) had lower T(4) (5.0 +/- 2.1 vs. 8.4 +/- 4.1 microg/dL, p < 0.01) and lower TSH (5.5 +/- 6.0 vs. 18.1 +/- 18.1 microIU/mL, p = 0.03) at the time of admission compared to infants who survived without severe IVH. After controlling for gestational age, low T(4) remained associated with an increased odds of death and/or severe IVH (odds ratio for every 1 microg/dL decrease in T(4): 1.4, 95% confidence interval 1.1-1.7). CONCLUSIONS: Our data show that both low total T(4) and TSH, measured at the time of nursery admission, are associated with death and severe intraventricular hemorrhage. Our data suggest that it may be feasible to design a study of early T(4) supplementation to determine potential benefit in infants with the lowest T(4) values rather than treating based on associated factors such as gestational age.

Factors influencing levels of 17-hydroxyprogesterone in very low birth weight infants and the relationship to death and IVH.

OBJECTIVES: 17-Hydroxyprogesterone, an intermediary hormone in cortisol synthesis, has been shown to be elevated in premature infants. However, the relationship between levels of 17-hydroxyprogesterone with death and intraventricular hemorrhage has not been extensively explored. The objective of this study was to determine the factors influencing 17-hydroxyprogesterone and determine if there is an association between intraventricular hemorrhage, mortality, and levels of 17-hydroxyprogesterone in a population of very low birth weight infants. STUDY DESIGN: Cohort study of very low birth weight infants cared for at a single level 3 NICU during a 1-year period from July 2001 to July 2002. Infants had a minimum of one screen for 17-hydroxyprogesterone and one cranial sonogram. 17-Hydroxyprogesterone was measured on the fifth day of life and at 2 to 4 weeks of life as part of the State of Delaware Newborn Screening Program. Statistical analysis included chi(2), Pearson correlation, multiple-linear regression, and logistic regression. RESULTS: Levels of 17-hydroxyprogesterone were higher at the time of the first screen compared to the second screen (28.3+/-25.6 vs 17.0+/-18.0 ng/ml, p=0.01), respectively. After controlling for potential confounding variables, gestational age, T(4), and prenatal steroids were all independently associated with 17-hydroxyprogesterone. However, logistic regression analysis showed no association between a 1 log increase in levels of 17-hydroxyprogesterone with the outcomes of death (odds ratio 1.8, 95% CI 0.6 to 5.6), severe IVH (0.7, 0.3 to 1.7), and death and/or severe intraventricular hemorrhage (0.9, 0.4 to 2.1). CONCLUSIONS: In our population of very low birth weight infants, low gestational age, low T(4), and prenatal steroids were all associated with an elevation in levels of 17-hydroxyprogesterone. High levels of 17-hydroxyprogesterone were not associated with death and/or severe IVH. Our data indicate that factors such as gestational age and antenatal steroids must be considered when interpreting 17-hydroxyprogesterone results from newborn screening.

Effect of inhaled corticosteroids on markers of pulmonary inflammation and lung maturation in preterm infants with evolving chronic lung disease.

BACKGROUND: Chronic lung disease (CLD) is one of the most severely disabling conditions of extremely low-birth-weight infants. Systemic corticosteroids are effective but cause many adverse effects. Targeted therapy with inhaled corticosteroids may be an effective and less toxic alternative. STUDY OBJECTIVE: To evaluate the additive effect of inhaled corticosteroids on markers of lung inflammation in infants receiving a 7-day course of systemic steroids. METHODS: Preterm neonates weighing 1 kg or less and aged 12 to 28 days who were prescribed a 7-day course of systemic corticosteroids for evolving CLD were studied prospectively and randomized to receive either a tapering 4-week course of beclomethasone metered-dose inhaler (MDI) (n = 5) or placebo MDI (n = 6). Primary outcome variables were the levels of pro- and anti-inflammatory cytokines, IL-8, TNF-alpha, IL-1alpha, and sIL-2R. RESULTS: This study was terminated early following literature reports of the adverse neurodevelopmental effects of dexamethasone. Measurements of respiratory and serum IL-8, IL-1alpha and TNF-alpha were similar between the study group taking inhaled and systemic corticosteroids and the study group taking systemic steroids alone. No differences were found between the two groups in relation to dynamic compliance or resistance. CONCLUSIONS: The addition of inhaled corticosteroids to a 7-day systemic course of corticosteroids did not alter cytokine response or improve pulmonary function.

Home delivery of palivizumab: outcomes and compliance in regional preterm infants.

Palivizumab, a monoclonal antibody against respiratory syncytial virus (RSV), has been shown to be effective in preventing RSV-related hospitalization in preterm infants; however, ensuring infants receive the desired monthly injections remains a challenge. We studied two cohorts of preterm infants and the rate of documented RSV illness in infants receiving palivizumab at home between 1998 and 2000. Medical records were reviewed for the number of doses received, hospitalization for RSV illness, and other demographic data. Parents in Cohort 1, 1998-1999, were prospectively surveyed to determine satisfaction with delivery of palivizumab. In Cohort 1, the home group (n = 32) received 89 +/- 19 percent of their scheduled course as compared to 66 +/- 32 percent in the office group (n = 41, p < .01), with 67 percent in the home group receiving their entire scheduled course as compared to 36 percent in the office group (p = .02). Of the parents surveyed, 70 percent in the home group indicated that they were satisfied with the way palivizumab was administered as compared to 76 percent in the office group (p = .44). In Cohort 2, 1999-2000, 175 infants received palivizumab at home, and 161 of these (92 percent) completed therapy as ordered. None of the infants had a documented infection with RSV. In our population infants receiving palivizumab at home were more likely to receive their entire scheduled course and less likely to miss doses than infants receiving palivizumab in an office setting. The high rate of compliance with home delivery is associated with a low rate of documented severe RSV illness.

Evidence-based review of oral sucrose administration to decrease the pain response in newborn infants.

Pain assessment and management are important issues for the neonatal nurse today. Clinicians have gradually come to acknowledge that newborn infants (term and preterm) are capable of responding to painful stimuli. This article reviews the evidence regarding the safety and efficacy of oral sucrose administration, to help answer the clinical question of how to manage an infant's pain response to minor invasive procedures that are everyday occurrences in the NICU. This review included information on 1,077 infants enrolled in 16 studies. The evidence presented in the 16 studies reviewed here shows the safety and efficacy of sucrose in decreasing term infants' pain response to a single procedure. In regard to preterm infants, there is insufficient evidence to recommend the use of sucrose as a routine comfort measure. More research is needed to determine the safety and efficacy of repeated doses of oral sucrose given for multiple procedures in preterm infants.

Hypothyroxinemia in mechanically ventilated term infants is associated with increased use of rescue therapies.

OBJECTIVE: Although common in preterm infants, transient hypothyroxinemia (TH) has not been investigated extensively in ill term infants. The objectives of this study were to investigate serum thyroxine (T4) and thyroid-stimulating hormone (TSH) in sick term infants and to determine whether there is any association between measures of thyroid function and short-term outcome in term infants who receive mechanical ventilation. METHODS: The investigation consisted of both a prospective observational study and a retrospective cohort study. In the prospective study, T4 and TSH were measured after birth in a group of sick term infants (n = 38) and compared with a group of well term infants (n = 18). Infants in the sick group received mechanical ventilation or continuous positive airway pressure and/or had neonatal seizures. Illness severity was quantified using the Score for Neonatal Acute Physiology. The retrospective cohort study included term infants who required mechanical ventilation and were born over a 5-year period (n = 347). Routine T4 screening was collected on the fifth day of life. TH was diagnosed in infants with a T4 <10%, with a TSH <25 microIU/mL. Clinical outcomes in infants with TH were compared with infants without TH. RESULTS: In the prospective study, infants in the sick group had lower T4 on the fifth day of life as compared with infants in the well group (11.7 +/- 4.9 vs 18.9 +/- 5.4 microg/dL), and 34% of infants in the sick group had a T4 <10th percentile compared with 6% of infants in the well group. T4 on day of life 5 was inversely correlated with Score for Neonatal Acute Physiology (R = -0.52). In the retrospective study, 21% of mechanically ventilated infants developed TH and were given statistically more inhaled nitric oxide, high-frequency ventilation, vasopressors, and pharmacologic paralysis when compared with infants without TH. Moreover, infants with TH were statistically more likely to die or require transfer to an extracorporeal membrane oxygenation center compared with infants without TH. CONCLUSION: Our data show that, similar to preterm infants, ill term infants develop TH. Term infants with TH required more intensive rescue interventions, including inhaled nitric oxide and transfer to an extracorporeal membrane oxygenation center. However, whether T4 levels are a marker or a mediator of clinical outcome remains to be determined.

Factors that affect satisfaction with neonatal-perinatal fellowship training.

This study was designed to assess neonatal fellows' satisfaction with their training and the role of mentorship. A 31-question survey was sent to all second- and third-year fellows in the United States and Canada (n = 304). Responses were received from 201 fellows (66% response rate). Respondents were evenly distributed between second- and third-year fellows. Overall, 75% were satisfied with their training. Eighty percent had a mentor on the neonatal faculty. Only 2.5% believed that they would not fulfill the sub-board research requirement, but another 24% were unsure of completion. The presence of a mentor correlated with being prepared for academic practice (p = 0.013) and plans to enter academic practice (p = 0.031). Correlation between mentorship and completion of the research requirement showed a trend (p = 0.09). Twenty-five percent of neonatal fellows are not satisfied with their training and believed that they may not complete their research requirement. Fellows who had a mentor were more prepared for academic practice and were more likely to be satisfied with their fellowship training. Mentorship is important in neonatal training programs.

Thrombopoietin in preterm infants: gestational age-dependent response.

PURPOSE: To investigate the factors affecting thrombopoietin (TPO) levels in preterm infants and to determine if TPO levels differ in infants born to mothers with preeclampsia and those infants with culture-proven sepsis. METHODS: Serial serum samples (N = 95) were obtained from 27 infants less than 33 weeks' gestation. Samples were analyzed for TPO using enzyme-linked immunosorbent assay. All samples had an accompanying complete blood count. Analysis of variance with post hoc analysis by least significant difference test, Mann-Whitney test, or chi2 was used to compare groups, as appropriate. Forward, stepwise linear regression was used to account for potential confounding variables. Data are expressed as mean +/- SD. RESULTS: TPO levels were not significantly correlated with the absolute platelet counts (R = -0.04, P = 0.69). TPO levels were significantly correlated with gestational age (R= 0.50, P < 0.001) when the platelet count was less than 150,000/mm3. TPO levels were significantly elevated in infants with platelets less than 150,000/mm3 born to mothers with preeclampsia compared with infants with sepsis (1184 +/- 98 vs. 579 +/- 363 pg/mL, P < 0.01). After adjusting for confounding variables using multivariate analysis (model: r2 = 0.43, P < 0.01), gestational age (r2 = 0.26) and preeclampsia (r2 = 0.03) remained significantly associated with TPO levels, whereas sepsis did not contribute to the variability of TPO. CONCLUSIONS: TPO response of infants with platelets less than 150,000/mm3 is dependent on gestational age. Infants with thrombocytopenia associated with preeclampsia have increased circulating levels of TPO. Infants with thrombocytopenia secondary to sepsis do not show an increase in TPO, but this appears to be an effect of low gestational age.

Caesarean delivery and outcome in very low birthweight infants.

OBJECTIVE: To determine the relationship between mode of delivery, intraventricular haemorrhage (IVH), and mortality in very low birthweight (VLBW) infants. STUDY DESIGN: A historical cohort study of infants admitted to a single level III neonatal intensive care unit during a five-year period. Infants < 1500 g born by caesarean delivery (n = 400) were compared to those born by vaginal delivery (n = 305). RESULTS: After controlling for potential confounding variables including: gestational age, fetal presentation, and multiple birth, caesarean delivery was not associated with a decreased odds of IVH (odds ratio 1.2, 95% CI 0.7-2.0), severe IVH (1.9, 0.9-4.0), or mortality (1.2, 0.6-2.4). CONCLUSIONS: In our population of very low birthweight infants, caesarean delivery is not associated with a decreased risk for mortality or intraventricular haemorrhage.

Transfusion volume in infants with very low birth weight: a randomized trial of 10 versus 20 ml/kg.

BACKGROUND: Although preterm infants often require transfusions of red blood cells for anemia of prematurity, the optimal volume of blood to be transfused has not been established. OBSERVATIONS: Infants with birth weights between 500 and 1,500 g were randomly assigned to receive 10 or 20 mL/kg red blood cells. Infants with transfusions of 20 mL/kg had a greater hemoglobin (14.2 +/- 1.9 vs. 12.0 +/- 1.9 g/dL, P = 0. 003) and hematocrit (41.2 +/- 5.9 vs. 32.3 +/- 7.1%, P = 0.001) levels after transfusion compared with those who received transfusions of 10 mL/kg. There were no measured differences in pulmonary function in either group after transfusion. CONCLUSIONS: Transfusion with 20 mL/kg red blood cells produces a significantly greater increase in hemoglobin and hematocrit levels than does a transfusion with 10 mL/kg, without any detrimental effects on pulmonary function.

Platelet count and sepsis in very low birth weight neonates: is there an organism-specific response?

OBJECTIVE: Thrombocytopenia is commonly observed in very low birth weight (VLBW) neonates with sepsis. Specific platelet responses to different infectious agents have not been extensively characterized. The objectives of this study were to examine platelet counts and platelet indices in preterm neonates with culture-proven sepsis to determine if there are organism-specific platelet responses. STUDY DESIGN: We analyzed a cohort of all VLBW neonates (birthweight <1500 g) born over a 4-year period and admitted to a single level III neonatal intensive care unit (N = 943). Thrombocytopenia was defined as a platelet count <100,000/mm(3). Platelet count, nadir, duration of thrombocytopenia, and mean platelet volume (MPV) were examined during episodes of culture-proven sepsis. Analysis of variance, Kruskal-Wallis, Mann-Whitney U, and chi(2) tests were used to compare groups, and data are expressed as mean +/- standard deviation. RESULTS: Sepsis was diagnosed in 154 (16%) of 943 patients in the study population. Of the sepsis episodes, 54% were associated with thrombocytopenia and 61% with an elevation in MPV. Infections were grouped by organism type: Gram-positive bacteria (117/154, 76%), Gram-negative bacteria (24/154, 16%), and fungi (13/154, 8%). When compared with patients with Gram-positive sepsis, those with Gram-negative or fungal sepsis had a significantly lower initial platelet count, a lower platelet nadir, a higher incidence of thrombocytopenia, and a greater duration of thrombocytopenia. The decrease in platelet count from baseline was also significantly less in the Gram-positive infections than in the fungal infections. Although there was an overall increase in MPV from baseline, there were no differences between groups. CONCLUSIONS: In our population of VLBW infants, sepsis is frequently associated with thrombocytopenia and an elevation in MPV. However, fungal and Gram-negative pathogens are associated with a lower platelet count and more prolonged thrombocytopenia compared with Gram-positive pathogens. We conclude that common pathogens causing sepsis have different effects on platelet kinetics.

Are perinatal risk factors helpful in predicting and optimizing treatment strategies for transient hypothyroxinemia in very-low-birth-weight infants?

Transient hypothyroxinemia is common in premature infants and has been associated with intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), poor neurodevelopmental outcomes, and mortality. Recent trials have failed to show that supplemental thyroid hormone improves overall neurodevelopmental outcome. The objective of this article is too determine perinatal risk factors for transient hypothyroxinemia (TH). We studied a cohort of infants born between July 1993 and July 2000 who were less than 1500 g and who received a newborn screening for thyroid function ( n = 932). Total serum thyroxine (T(4)) was collected routinely on the fifth day of life. T (4) was correlated with gestational age (R = 0.59, p < 0.01). After controlling for potential confounding variables, gestational age, dopamine, and mechanical ventilation were found to be independently associated with low T (4) (overall model: r(2) = 0.41, p < 0.01). Number needed to treat (NNT) analysis showed treating all infants less than 27 weeks would lead to treating 6.3 infants for every one with a subsequent T(4) < 5 microg/dL. By combining gestational age and need for dopamine support, NNT = 2.4 for every one infant with subsequent T(4) < 5 microg/dL. Low gestational age, mechanical ventilation, and need for dopamine were associated with low T(4) levels and may be helpful in optimizing treatment strategies for TH.

Short-term use of umbilical artery catheters may not be associated with increased risk for thrombosis.

OBJECTIVE: Umbilical arterial catheters (UACs) have rare but serious complications related to thrombus formation. Two specific serum markers of thrombogenesis--prothrombin fragment (F1.2) and thrombin-antithrombin (TAT)--can be assayed and correlated with abdominal ultrasound visualization of UAC thrombosis. Levels of these markers of thrombogenesis have not been studied in infants with UACs. The objective of this study was to determine F1.2 and TAT levels longitudinally and compare the levels with platelet counts and ultrasound evidence of thrombi during the first week of life in infants with UACs. METHODS: This study was conducted as a prospective, nonblinded, observational study performed between June 2001 and January 2002 at Christiana Care Hospital, a level III neonatal intensive care unit. Infants with a UAC in place in the first 24 hours of life were studied. All received equal amounts of heparin in the UAC. F1.2, TAT, platelet counts, and abdominal aorta ultrasounds were examined every other day starting within 24 hours of life. Studies were not done when the UAC was removed within the 5-day study period. Enzyme-linked immunosorbent assay for TAT and F1.2 was performed using a commercially available kit from Enzyngost. Data were analyzed with repeated measures analysis of variance evaluating TAT, F1.2, and platelet count over time. RESULTS: Thirty-three patients were investigated (mean +/- standard deviation; gestational age: 27.4 +/- 3.5 weeks; birth weight: 1139 +/- 729 g). A total of 66 measurements of TAT, F1.2, and platelet counts were obtained. Sixty-one abdominal ultrasounds were performed; only 1 study was positive for UAC thrombus. There was no significant difference between F1.2 and TAT over time during the study period. Platelet counts seemed to fall over the 5-day study period, although this decrease did not reach statistical significance. CONCLUSION: Indwelling UACs in sick infants may not carry an increased risk of thrombosis during the first 5 days of use.