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Background: To assess the postnatal rate of rise (ROR) of total serum bilirubin (TSB) in very low birth weight (VLBW) preterm infants, to determine risk factors associated with a rapid rise (>90th percentile), and to compare ROR and hour-specific TSB at postnatal 12-48 h with data of term infants retrieved from the literature., Methods: Retrospective analysis of 2430 routine TSB concentrations obtained between birth and initiation of phototherapy in 483 VLBW infants., Results: TSB increased by a median (interquartile range) ROR of 0.15 (0.11-0.19) mg/dL/h. The 50th percentile of TSB was below the 40th percentile of (near-)term counterparts at 12-48 h. TSB ROR correlated with the age at initiation (R S  = -0.687; p < 0.001) and the duration (R S  = 0.444; p < 0.001) of phototherapy. ROR >90th percentile (>0.25 mg/dL/h) was associated with lower gestational ages [27.2 (25.4-29.3) vs. 28.4 (26.4-30.4) weeks], lower birth weights [978 (665-1120) vs. 1045 (814-1300) g], and lower 5-min Apgar scores [7 (7-8) vs. 8 (7-9)]., Conclusion: ROR of TSB is an indicator for early and prolonged phototherapy. While hour-specific TSB and ROR at 12-48 h are lower than those reported for (near-)term infants, TSB appears to rise more rapidly in infants with low gestational age, low birth weight, and low 5-min Apgar score.

BackgroundThe impact of intrauterine and extrauterine growth on later insulin resistance and fat mass (FM) in very low birth weight (VLBW) infants is not well established. The aim of our study was to evaluate the effects of intrauterine and early/late extrauterine growth on later insulin resistance and body composition in VLBW infants from 6 months' corrected age (CA) to 36 months.MethodsProspective measurements of body composition by dual-energy X-ray absorptiometry and insulin resistance by homeostasis model assessment insulin resistance (HOMA-IR) along with other fasting plasma biochemistries were made in 95 VLBW infants at 6, 12, 18, and 24 months' CA and 36 months' postnatal age. Mixed-effect models were used to evaluate the effects of age, sex, maturation status, and Δweight SD score on percentage FM (PFM), FM index (FMI), fat-free mass index (FFMI), and HOMA-IR.ResultsPFM and FMI were negatively associated with a decrease in weight-SD scores from birth to 36 weeks' postmenstrual age (PMA; P=0.001) and from 36 weeks' PMA to 6 months' CA (P=0.003). PFM and FMI were higher in AGA than in small for gestational age (SGA) infants. HOMA-IR was not associated with the Δweight-SD scores in either period.ConclusionsCatch-down growth in terms of weight is associated with persistently lower adiposity but not insulin resistance up to 36 months of age.

Background: Preterm, very-low-birth-weight (PT-VLBW) neonates are at-risk for metabolic syndrome later in life. At 1-3 y, they exhibit excessive weight-for-length z-scores (Wt-L Z ) and elevated systolic blood pressures (SBP). Serum adipokines are biomarkers of adiposity, but expression in PT-VLBW infants is unclear. We examined the correlation between serum adipokine levels, anthropometric measures and SBP in PT-VLBW neonates at follow-up., Methods: This was a cross-sectional cohort study of PT-VLBW infants at 1, 2, and 3 y of age (40/cohort). We measured SBP, abdominal circumference (AC) and anthropometrics; calculated age/gender-specific z-scores for Wt, L, Wt-L and subscapular skin fold (SS Z ), and measured serum adipokines., Results: Serum leptin was unaffected by chronologic age and gender, but was positively correlated with weight, Wt-L Z , AC, and SS Z at 1 and 3 y (P < 0.01). Female infants at 1 and 3 y had a more significant relationship than males between serum leptin and SS Z (P < 0.001, R = 0.75 and P < 0.001, R = 0.70, respectively). Adiponectin levels were 16-20% lower at 3 vs. 1-2 y (P = 0.02, ANOVA) and negatively correlated with SBP., Conclusion: Although serum leptin was unrelated to advancing age, gender, and SBP in PT-VLBW infants, levels correlated with measures of adiposity at 1 and 3 y, females > males, suggesting leptin resistance may occur in early infancy.

Background: Serum creatinine (s[Cr]) reference ranges for very-low-birth-weight (VLBW) infants must account for physiologic changes in the first months of life., Methods: We retrospectively identified a sample of 218 appropriate-for-gestational age (GA) VLBW infants without risk factors for renal impairment, and classified into one of three GA groups: 25-27, 28-29, and 30-33 wk. We observed three phases of s[Cr] change (initial, decline, and equilibrium), whose characteristics varied by GA group. We used mixed-effects regression models to estimate mean and upper 95th prediction interval of s[Cr] for each GA group from birth to 34-36 wk post menstrual age (PMA)., Results: In phase I, s[Cr] increased after birth, then returned slowly to baseline. The duration of phase I and the magnitude of s[Cr] rise decreased with increasing GA. In phase II, s[Cr] declined abruptly at a rate that increased with GA. A gradual transition to phase III, a steady-state equilibrium with similar s[Cr] among GA groups, began at approximately 34-36 wk PMA. We constructed GA group-specific nomograms depicting s[Cr] behaviour across the three phases., Conclusion: The reference ranges derived from a sample of infants without risk factors for renal impairment provide a context for quantitative interpretation of s[Cr] trends in VLBW infants.

Background: Little is known about the change in circulating red cell volume (RCV) of very-low-birth-weight (VLBW) infants during the first weeks of life., Methods: RCV was measured during the first 5 d in 35 VLBW infants using chromium-51 labeling of the infants' red blood cells (RBCs). RCV was measured again at 6 wk of age in 12 infants, and the volumes of RBCs lost by phlebotomy and those gained by transfusion were recorded between the RCV measurements. In six infants, the volume of waste blood on materials contaminated with blood during phlebotomy, which would usually be discarded, was measured by radioactive counting., Results: The mean RCV in the first several days of life was 39.6 ml (35.7 ml/kg; range: 20.1-58.7 ml/kg). Of the 12 infants whose RCV was measured twice, all but one had a decrease in absolute RCV. The mean RCV initially and at 6 wk were 37.3 and 26.6 ml, respectively. The mean volume of RBCs lost through phlebotomy was 29.2 ml, and the mean volume of RBCs given by transfusion was 34.5 ml., Conclusion: During the first 6 wk of life, when the anemia of prematurity is evolving, the RCV falls despite complete replacement of RBCs lost by diagnostic phlebotomy with transfused RBCs.

Background: Study of the pathophysiology and treatment of anemia of prematurity is facilitated by direct measurement of red cell volume (RCV) utilizing microliter quantities of blood samples. Our objective was to compare concurrent measurements of multiple direct RCV methods in infants., Methods: Eighteen preterm infants receiving clinically indicated transfusions had concurrent flow cytometric determinations of RCV and 24-h red blood cell (RBC) recovery based on donor-recipient differences of biotin-labeled RBCs (BioRBCs), Kidd antigen mismatched RBCs, and fetal hemoglobin-positive (HbF(+)) RBCs. High-performance liquid chromatography (HPLC) was also used for measuring HbF and adult hemoglobin protein concentrations for the determination of RCV., Results: Concurrent RCV measurements using BioRBCs (18 and 54 µg/ml), Kidd antigen, and HbF flow cytometry were not statistically different compared with RCVs measured using the reference BioRBC density (6 µg/ml). By contrast, the HbF-HPLC method overestimated RCV by 45% compared with the reference method. All the methods demonstrated 100% 24-h posttransfusion RBC recovery (PTR24)., Conclusion: Because BioRBC, Kidd antigen, and fetal hemoglobin (HbF) flow cytometry are safe and accurate methods requiring <10 µl of patient blood for determining RCV and PTR24 in preterm infants, they can be useful in clinical and research studies of anemia and other conditions.

Background: As a protective response to an inflammatory stimulus, the antigen-presenting molecules (human leukocyte antigen-DR (HLA-DR)) on monocytes are downregulated. If severe, the response may lead to immunodepression or immunoparalysis, associated with an increased rate of morbidity and mortality in adults. In very low birth weight (VLBW) infants, birth and intensive care present major immunological challenges., Methods: We measured monocyte HLA-DR expression by flow cytometry and determined 13 plasma cytokines in 56 VLBW infants (gestational age (GA): 23.7-31.8 wk) and 25 controls (GA: 34.1-41.4 wk)., Results: HLA-DR expression decreased postnatally both in VLBW and in control infants. In VLBW infants, GA and respiratory distress syndrome (RDS) both showed associations with HLA-DR nadir on day 3, when 45% of them met the criteria of immunodepression. HLA-DR expression was lower in those infants subsequently developing infection (74 vs. 49% (day 3) and 85 vs. 68% (day 7); both P = 0.002). Interleukin (IL)-6 on day 1 was a predictor of the HLA-DR nadir., Conclusion: VLBW infants are in a state of immunodepression postnatally. This immunodepression correlated with GA and was a predisposing factor for late infections. The downregulation of HLA-DR during RDS probably indicates an RDS-induced antigen load on the immune system.

Preterm infants are exposed to conditions that can impair renal function. We evaluated the ability of serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL) to predict renal function in the first weeks of life. From September 2008 to July 2009, infants weighing ≤1500 g at birth with no major congenital anomalies or sepsis were eligible. We measured sNGAL and uNGAL levels at birth. To evaluate renal function, we determined changes in serum creatinine (sCreat) and estimated GFR (eGFR) from birth to d 21. Forty neonates (mean GA, 27 ± 2 wk) completed the study. Renal function improved in 32 of 40 (80%) infants (normal renal function, NRF group) (sCreat, from 0.97 ± 0.2 to 0.53 ± 0.13 mg/dL; eGFR, from 15.3 ± 4.1 to 28.6 ± 7.9 mL/min), whereas renal function worsened in 8 of 40 (20%) infants (impaired renal function, IRF group) (sCreat, from 0.71 ± 0.27 to 0.98 ± 0.43 mg/dL; eGFR from 23 ± 14.7 to 16.4 ± 9.1 mL/min). The uNGAL/urinary creatinine (uCreat) ratio at birth was higher in the IRF group (31.05 ng/mg) than the NRF group (6.0 ng/mg), and uNGAL was significantly higher in IRF group, detecting IRF with a cutoff of 100 ng/mL. uNGAL levels at birth may have a predictive role in very LBW (VLBW) infants.

Acute kidney injury (AKI) independently predicts mortality in children and adults. Our understanding of the epidemiology of AKI in very LBW (VLBW) infants is limited to retrospective studies. After adjustment for demographics, comorbidities, and interventions, infants with AKI have decreased survival compared with those without AKI. The study was conducted in regional quaternary care NICU of the University of Alabama at Birmingham. VLBW infants were followed prospectively and were classified into a serum creatinine (SCr)-based classification for AKI. Forty-one of 229 (18%) VLBW infants developed AKI. Those with AKI were more likely to have umbilical artery catheters, assisted ventilation, blood pressure medications, and lower 1-and 5-min Apgar scores. Of the infants with AKI, 17 of 41 (42%) died compared with 9 of 188 (5%) of those without AKI (p < 0.001). AKI was associated with mortality with a crude hazard ratio (HR) of 9.3 (95% CI, 4.1-21.0). After adjusting for potential confounders, those with AKI had higher chance of death as the adjusted HR was 2.4 (95% CI 0.95-6.04). AKI is associated with mortality in VLBW infants. Efforts to prevent and ameliorate the impact of AKI may improve the outcomes in this vulnerable population.

Lysophosphatidylcholine (LPC) has various stimulatory effects on many types of immune cells. The purpose of our study was to characterize blood LPC levels and to determine the composition of LPC molecular species (LPCs) in the neonatal period. Thirty-six neonates were enrolled in this study and then grouped according to birth-weight as follows: non-very low birth weight (NVLBW); >or=1,500 g (n=17), and very low birth weight (VLBW); <1,500 g (n=19). Sixteen healthy normal adults were used as controls. Levels of total blood LPC and LPCs (16:0-, 18:0-, 18:1-, 18:2-, and 20:4-LPC species) were measured using HPLC coupled with tandem mass spectrometry. Total blood LPC levels at birth in neonates in both groups (NVLBW and VLBW) were significantly lower than those of adult levels. In NVLBW infants, LPC levels reached adult levels at postnatal day 3 compared with VLBW infants, who attained adult levels after postnatal day 57 (around full-term). The composition of the LPCs was different not only between neonates and adults, but between NVLBW and VLBW infants. These findings may be associated with the difference of immunity among adults, NVLBW, and VLBW infants.

Intrauterine infection is associated with chorioamnionitis (CAM), which can lead to preterm delivery. We previously reported that the levels of IgM and the incidence of CAM were elevated in preterm infants with neonatal pulmonary emphysema. The pathogen and target of this IgM remain unclear. By using Western blot and amino acid sequences, we have determined one of the target proteins: annexin A2. Immunohistochemical analysis showed that annexin A2 was expressed at fetal chorion and amnion membranes. Among very low birth weight (VLBW) infants with hyper-IgM (> or = 30 mg/dL), 58.8% showed a high titer against annexin A2 (more than x 16), which accounted for about 20%-40% of the total IgM. Anti-annexin A2 IgM antibody inhibited plasmin generation. Furthermore, the median of anti-annexin A2 IgM titer from preterm infants who were delivered with high-grade (grade III) CAM was significantly higher than those from preterm infants without CAM (p = 0.011) and with low-grade CAM (grade I and II) (p = 0.010). Here, we indicate the fetal autoimmunoreactivity against the fetomaternal interface in preterm infants.

Although circulating red blood cell (RBC) volume is a better measure of total body oxygen delivering capacity than hematocrit (HCT), circulating RBC volume is more difficult to measure. Thus, the HCT is often used in RBC transfusion decisions. However, several previous studies of low birth weight infants have reported that the correlation between HCT and circulating RBC volume is poor. Using a robust nonradioactive method based on in vivo dilution of biotinylated RBC enumerated by flow cytometry, the present study reexamined the correlation between HCT and circulating RBC volume in very low birth weight infants. Venous and capillary HCT levels were compared with circulating RBC volume measured using the biotin method. Twenty-six stable very low birth weight infants with birth weights less than 1300 g were studied on 43 occasions between 7 and 79 d of life. Venous HCT values correlated highly with circulating RBC volume (r = 0.907; p < 0.0001). However, the mean 95% confidence limits for prediction of circulating RBC volume from venous HCT (the average error of prediction) was +/-13.4 mL/kg. The correlation between HCT and circulating RBC volume is strong in older stable very low birth weight infants. However, clinically important uncertainty exists in estimating circulating RBC volume and the associated RBC transfusion needs of an individual infant based on venous HCT. Because direct measurement of circulating RBC volume is not yet practical, the HCT (or the blood Hb concentration) remains the best available indirect indicator.

The purpose of this study was to determine whether protein carbonyls and the lipid peroxidation product malondialdehyde (MDA) are elevated in plasma from very low birth weight (<1500 g) infants, whether they are affected by selenium supplementation, and whether they are associated with poor respiratory outcome or retinopathy. The study group comprised 173 infants enrolled in a randomized controlled trial of selenium supplementation. Plasma samples, collected before randomization, at 7 and 28 d after birth, and at 36 wk postmenstrual age, were analyzed for protein carbonyls and total MDA. Respiratory outcome was assessed as oxygen requirement at 28 d of age or 36 wk postmenstrual age and as number of days on oxygen. Protein carbonyl concentrations in very low birth weight infants were significantly higher than for adults but lower than for cord blood from term infants. Median values decreased significantly by 28 d, and there was no relationship with birth weight. MDA concentrations in very low birth weight infants overlapped the ranges for healthy adults and cord blood from term infants. They correlated positively with birth weight at 28 d but not at other times. Supplementation almost doubled plasma selenium concentrations, but carbonyls and MDA did not differ between the supplemented and unsupplemented groups. There were no significant differences in oxidant marker levels in infants who did or did not develop chronic lung disease or retinopathy. Protein carbonyls and MDA measurements in plasma do not show evidence of systemic oxidative stress in <1500-g infants and are not affected by selenium supplementation. Oxidative injury at sites such as the lung may be important in prematurity, but markers from such sites must be measured to relate to outcome and antioxidant supplementation.

We hypothesized that treatment of very low birth weight premature infants with r-HuEPO would increase erythrocyte incorporation and gastrointestinal absorption of iron. Infants with birth weights < or = 1.25 kg and gestational ages < 31 wk were randomized to receive 6 wk of 500 U of r-HuEPO/kg/wk (epo group, n = 7) or placebo (placebo group, n = 7). All infants received daily enteral supplementation with 6 mg of elemental iron per kg. An enteral test dose of a stable iron isotope, 58Fe, was administered after the 1st ("early dosing") and 4th ("late dosing") wk of treatment. Mean (+/-SD) erythrocyte incorporation of the dose of 58Fe administered determined 2 wk after early dosing was significantly greater in the epo group compared with the placebo group (4.4% +/- 1.6 versus 2.0 +/- 1.4%, p = 0.013). In contrast, after late 58Fe dosing, there was no difference between groups in incorporation (3.8 +/- 1.6% versus 5.5 +/- 2.7%). Within the epo group, percentage erythrocyte incorporation of 58Fe did not differ between early and late dosing, whereas in the placebo group it increased 3-fold (p < 0.01). Percentage absorption of 58Fe was not different between the epo and placebo groups after both early dosing (30 +/- 22% versus 34 +/- 8%) and late dosing (32 +/- 9% versus 31 +/- 6%). Absorption of nonlabeled elemental iron and 58Fe were significantly correlated with one another. The percentage of the absorbed 58Fe dose incorporated into Hb was not different between groups. We conclude that, although erythropoietin treatment stimulates erythrocyte iron incorporation in premature infants, it has no effect on iron absorption at the r-HuEPO dose studied.

The fatty acid composition of plasma phospholipids, triglycerides, sterol esters, and red blood cell phospholipids were determined at birth and again on d 7, 14, and 28 of life in 22 very low birth weight infants (birth weight 1180 +/- 290 g, gestational age 29.8 +/- 2.4 wk) fed exclusively with preterm human milk starting from the first hours postpartum. Milk intake was recorded daily, and intakes of fat and individual fatty acids were measured weekly. The intakes of linoleic acid and linolenic acid rose significantly during the study period, so did their incorporation into plasma and red blood cell lipids. The intakes of arachidonic acid (29.2 +/- 2.4 versus 30.4 +/- 2.1 mg.kg-1.day-1) and docosahexaenoic acid (18.8 +/- 1.7 versus 17.0 +/- 1.2 mg.kg-1.day-1) on d 14 and 28, respectively, were not different; however, their plasma levels declined significantly. The percentages of arachidonic acid declined in all plasma and red blood cell lipids, whereas the fall of docosahexaenoic acid was more notable in triglycerides and sterol esters, intermediate in plasma phospholipids, and less pronounced in red blood cell phospholipids. We conclude that very low birth weight infants fed exclusively with preterm milk, which unlike most preterm formulas contains long chain polyunsaturated fatty acids, exhibit declining levels of arachidonic acid and docosahexaenoic acid from birth up to 28 d of life.

In the present study we assess the effect of recombinant human erythropoietin (r-HuEpo) upon levels of fetal Hb (HbF) and adult Hb (HbA) in preterm infants. Twenty-eight "healthy," appropriate for gestational age infants with birth weights 900-1400 g entered the study at 3 wk of age. Fourteen infants were randomized to receive r-HuEpo, and 14 infants served as controls. Four controls and six r-HuEpo treated infants had been transfused before study start, whereas four control infants were transfused in the course of the study. The untransfused infants showed a high HbF/Hb ratio during the study with only a weak tendency to decline toward the expected time of delivery. The total Hb mass increased (p < 0.05) more in the r-HuEpo-treated infants than in the untreated, whereas the rise in HbF mass was similar in the two groups. After each transfusion, the HbF/Hb ratio reverted gradually to the ratio expected at the infant's postconceptional age. There was no difference in the production rate of HbF between r-HuEpo-treated infants and controls. The present data indicate that the HbF/HbA ratio in preterm infants is subject to the same programmed mechanisms which govern intrauterine erythropoiesis until term and that exogenous r-HuEpo does not influence this pattern significantly.