ObjectiveTo test the ability of the Ages and Stages Questionnaire, Third Edition (ASQ3) to help identify or exclude neurodevelopmental impairment (NDI) in very preterm-born children at the corrected age of two.MethodsWe studied the test results of 224 children, born at <32 postmenstrual weeks, who had scores on ASQ3 and Bayley Scales of Infant and Toddler Development, Third Edition (BSIDIII) and neurological examination at 22-26 months' corrected age. We defined NDI as a score of <70 on the cognitive-or motor composite scale of BSIDIII, or impairment on neurological examination or audiovisual screening. We compared NDI with abnormal ASQ3 scores, i.e., < -2SDs on any domain, and with ASQ3 total scores. To correct for possible overestimation of BSIDIII, we also analyzed the adjusted BSIDIII thresholds for NDI, i.e., scores < 80 and <85.ResultsWe found 61 (27%) children with abnormal ASQ3 scores, and 10 (4.5%) children who had NDI with original BSIDIII thresholds (<70). Twelve children had NDI at BSIDIII thresholds at <80, and 15 had <85. None of the 163 (73%) children who passed ASQ3 had NDI. The sensitivity of ASQ3 to detect NDI was excellent (100%), its specificity was acceptable (76%), and its negative predictive value (NPV) was 100%. Sensitivity and NPV remained high with the adjusted BSIDIII thresholds.ConclusionThe Ages and Stages Questionnaire is a simple, valid and cost-effective screening tool to help identify and exclude NDI in very preterm-born children at the corrected age of two years.

Background and Objective: High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome. Methods: In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks’ gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months’ corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death. Results: Composite motor (100613 vs. 101612) and cognitive (101612 vs. 101611) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for the B/A ratio versus TSB groups were 15.4% versus 15.5% (P = 1.0) and 2.8% versus 1.4% (P = 0.62) for birth weights #1000 g and 1.8% versus 5.8% (P = 0.03) and 4.1% versus 2.0% (P = 0.26) for birth weights of .1000 g. Conclusions: The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome. Trial Registration: : Controlled-Trials.com ISRCTN74465643 Citation: Hulzebos CV, Dijk PH, van Imhoff DE, Bos AF, Lopriore E, et al. (2014) The Bilirubin Albumin Ratio in the Management of Hyperbilirubinemia in Preterm Infants to Improve Neurodevelopmental Outcome: A Randomized Controlled Trial – BARTrial. PLoS ONE 9(6): e99466. doi:10.1371/journal.pone.0099466 Editor: Waldemar A. Carlo, University of Alabama at Birmingham, United States of America Received February 19, 2014; Accepted May 13, 2014; Published June 13, 2014 Copyright: 2014 Hulzebos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study had been funded by the Netherlands Organisation for Health Research and Development (ZonMw), program cost-effectiveness number: 94507407. website: www.zonmw.nl. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interest exist. * Email: p.h.dijk@umcg.nl . These authors contributed equally to this work. " Membership of the BARTrial Study Group is provided in the Acknowledgments. PLOS ONE | www.plosone.org 1 June 2014 | Volume 9 | Issue 6 | e99466

High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome.In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks' gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months' corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death.Composite motor (100 ± 13 vs. 101 ± 12) and cognitive (101 ± 12 vs. 101 ± 11) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for the B/A ratio versus TSB groups were 15.4% versus 15.5% (P = 1.0) and 2.8% versus 1.4% (P = 0.62) for birth weights ≤ 1000 g and 1.8% versus 5.8% (P = 0.03) and 4.1% versus 2.0% (P = 0.26) for birth weights of >1000 g.The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome.Controlled-Trials.com ISRCTN74465643.

BACKGROUND & AIMS:Severe unconjugated hyperbilirubinemia, as occurs in Crigler-Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCB(free)), the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCB(free) fraction, and thus decrease bilirubin accumulation in the brain. METHODS:We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy+HSA. RESULTS:In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCB(free) and brain bilirubin by 88% and 67%, respectively (p<0.001). In the acute model, adjunct HSA also increased the efficacy of phototherapy; it decreased plasma UCB(free) by 76% (p<0.001) and completely prevented the hemolysis-induced deposition of bilirubin in the brain. Phototherapy alone failed to prevent the deposition of bilirubin in the brain during acute hemolytic jaundice. CONCLUSIONS:We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCB(free) in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice.

Objective To evaluate phototherapy practices by measuring the irradiance levels of phototherapy (PT) devices. Design Prospective study. Setting Tertiary neonatal intensive care units. Patients None. Interventions Irradiance levels of PT devices used in the 10 Dutch Neonatal Intensive Care Units (NICUs) were measured according to the local PT practice patterns. The irradiance levels of all overhead and fibre-optic PT devices were measured with a radiometer using an infant silhouette model. Results Eight different PT devices were used in the 10 NICUs; five were overhead devices and three fibre-optic pads. The median (range) irradiance level for overhead PT devices was 9.7 (4.3–32.6) µW/cm2/nm and for fibre-optic pads 6.8 (0.8–15.6) µW/cm2/nm. Approximately 50% of PT devices failed to meet the minimal recommended irradiance level of 10 µW/cm2/nm. Maximal irradiance levels for overhead PT spot lights were inversely related to the distance between device and infant model (R2=0.33). The distances ranged from 37 cm to 65 cm. Conclusions PT devices in the Dutch NICUs show considerable variability with often too low irradiance levels. These results indicate that suboptimal PT is frequently applied and may even be ineffective towards reducing total serum bilirubin levels. These results underline the need for greater awareness among all healthcare workers towards the requirements for effective PT including measurements of irradiance and distance.

Accurate and precise bilirubin and albumin measurements are essential for proper management of jaundiced neonates. Data hereon are lacking for Dutch laboratories. We aimed to determine variability of measurements of bilirubin and albumin concentrations typical for (preterm) neonates. Aqueous, human serum albumin-based samples with different concentrations of bilirubin (100, 200, 300, 400, and 500 μmol/L) and albumin (0, 10, 15, 20, 25, and 30 g/L) were sent to laboratories of all Dutch neonatal intensive care units (n = 10). Bilirubin and albumin recoveries of the specimens were measured using locally available routine analytical methods. The mean, standard deviation, and coefficients of variations (CV) were calculated per sample. Bilirubin concentrations were underestimated in the absence of albumin (maximal CV 26.0%). When the albumin concentration was 10 or 20 g/L, the bilirubin concentrations of the samples were overestimated (maximal CV 14.1% and 9.2%, respectively). Variability increased with higher weighed-in bilirubin concentrations. Measured albumin levels were ~10% lower than albumin levels of manufactured samples. Bilirubin concentration did not influence albumin measurements. The maximal CV was 6.8%. In conclusion, interlaboratory variability of bilirubin and albumin measurements is high. Recalibration and introduction of a specific quality assessment scheme for neonatal samples is recommended to ensure exchangeability of bilirubin and albumin measurements among laboratories and to control the observed large variability.

Background: The relation between total serum bilirubin (TSB) and neurodevelopmental outcome in preterm infants is unclear. Free bilirubin (Bf) and the bilirubin/albumin (B/A) ratio may be more reliable predictors of bilirubin neurotoxicity than TSB, but prospective data regarding neurodevelopmental outcome are lacking. Aim: To determine the relation between TSB, Bf, B/A ratio and neurodevelopmental outcome in preterm infants. Methods: TSB, Bf, and serum albumin levels were measured in preterm infants of 32 or less weeks of gestation during the first 10 postnatal days. The peroxidase method, was used for Bf. Composite cognitive and motor scores were assessed by the Bayley Scales of Infant Development III at 24 months corrected age. Spearman's correlation coefficient (R) was calculated. Results: Demographic data are shown in Table 1. Cognitive scores were significantly correlated to maximal TSB, but not to mean TSB levels (R= -0.32 (p< 0.05). Maximal and mean B/A ratios were not significantly correlated to cognitive scores (R=-0.28 and -0.17, resp.) Maximal and mean Bf measurements did not correlate with cognitive scores (R = -0.14 and -0.1, resp.). Motor scores did not correlate with any of the bilirubin parameters. Table 1 Conclusion: Cognitive, and not motor outcome, is only related to maximal TSB levels in preterm infants of 32 or less weeks of gestation. Neither B/A ratios nor free bilirubin levels are related to outcome.

OBJECTIVE To compare the guidelines of the 10 Dutch neonatal intensive care units (NICUs) for the treatment of preterm infants with hyperbilirubinemia, in order to develop uniform threshold levels for the total serum concentration of bilirubin (TSB) above which treatment with phototherapy or exchange transfusion is indicated. DESIGN Survey. METHODS Guidelines for hyperbilirubinemia in preterm infants (gestational age < 32 weeks) from all 10 Dutch NICUs were obtained and compared with each other and with international guidelines. RESULTS All 10 NICUs used intervention criteria based on TSB. 9 NICUs used TSB thresholds based on birth weight (1 used gestational age) with 2, 3 or 5 categories. 6 NICUs used age-specific TSB thresholds and 4 NICUs used a constant TSB threshold. The maximum range in TSB thresholds was 170 micromol/l for phototherapy and 125 micromol/l for exchange transfusion. Acidosis, sepsis, asphyxia, active haemolysis and intraventricular haemorrhage were the risk factors most frequently used. During a consensus meeting with representatives of the 10 NICUs, a guideline was agreed upon that will now be used for all neonates with a gestational age < 35 weeks. CONCLUSION There was considerable variation in the TSB thresholds used to date by the 10 NICUs. Now in the Netherlands, in addition to guideline 'Hyperbilirubinemia' for children with a gestational age >or= 35 weeks, 'uniform yellow thresholds' shall be used for jaundiced preterm infants with a gestational age < 35 weeks.

Unconjugated hyperbilirubinaemia occurs in almost all premature infants and is potentially neurotoxic. Treatment is based on total serum bilirubin (TSB), but treatment thresholds are not evidence based. Free bilirubin (Bf)—that is, not bound to albumin, seems a better parameter for bilirubin neurotoxicity, but measurements of Bf are not available in clinical practice. The bilirubin/albumin (B/A) ratio is considered a surrogate parameter for Bf and an interesting additional parameter in the management of hyperbilirubinaemia. This paper reviewed the evidence supporting the use of B/A ratios for predicting bilirubin-induced neurological dysfunction (BIND) including neurodevelopmental delay in jaundiced premature infants (gestational age less than 32 weeks). A literature search was performed and six publications reviewed regarding B/A ratios in the management and outcome of jaundiced premature infants. No prospective clinical trials had been undertaken to show whether bilirubin-induced neurotoxicity is reduced or whether unnecessary treatment is avoided by using the B/A ratio in addition to TSB. Recently, a randomised controlled trial evaluating the effect of the additional use of the B/A ratio on neurodevelopmental outcome in jaundiced premature infants has been initiated. Based on the prevailing evidence many authorities suggest that the additional use of the B/A ratio may be valuable when evaluating jaundiced premature infants.

Unconjugated hyperbilirubinaemia occurs in almost all premature infants and is potentially neurotoxic. Treatment is based on total serum bilirubin (TSB), but treatment thresholds are not evidence based. Free bilirubin (Bf) - that is, not bound to albumin, seems a better parameter for bilirubin neurotoxicity, but measurements of Bf are not available in clinical practice. The bilirubin/albumin (B/A) ratio is considered a surrogate parameter for Bf and an interesting additional parameter in the management of hyperbilirubinaemia. This paper reviewed the evidence supporting the use of B/A ratios for predicting bilirubin-induced neurological dysfunction (BIND) including neurodevelopmental delay in jaundiced premature infants (gestational age less than 32 weeks). A literature search was performed and six publications reviewed regarding B/A ratios in the management and outcome of jaundiced premature infants. No prospective clinical trials had been undertaken to show whether bilirubin-induced neurotoxicity is reduced or whether unnecessary treatment is avoided by using the B/A ratio in addition to TSB. Recently, a randomised controlled trial evaluating the effect of the additional use of the B/A ratio on neurodevelopmental outcome in jaundiced premature infants has been initiated. Based on the prevailing evidence many authorities suggest that the additional use of the B/A ratio may be valuable when evaluating jaundiced premature infants.