A Study of General Movement Assessment and Its Association With Neurodevelopmental Outcome at Age 12 to 15 Months Among Term Neonates With Hyperbilirubinemia.

BACKGROUND: To determine the association between optimality score at term age and age three to five months and neurodevelopmental outcome among neonates with hyperbilirubinemia. METHODS: Fifty infants with and without hyperbilirubinemia were enrolled. The motor repertoires of the infants were evaluated through general movement assessment (GMA) at term age and three to five months post-term. The association between the General Movement Optimality Score (GMOS), Motor Optimality Score (MOS), and Development Assessment Scale for Indian Infants (DASII) at age 12 to 15 months was also assessed. RESULTS: During term age, the median GMOS was significantly lower among infants in the study group when compared with the control group (40 [29 to 42] vs 42 [42 to 42], P < 0.001). However, at age three to five months, there was no significant difference between the groups. Significantly higher number of neonates had abnormal motor repertoire at term age and age three to five months in the study group when compared with the control group (18 [36%] vs 2 [4%], P = 0.001, at term age and 6 [12.2%] vs 1 [2%], P =0.04, at age three to five months). Among neonates with hyperbilirubinemia, the median GMOS and MOS were significantly lower at term age and age three to five months in infants with motor and mental developmental quotient scores <85 when compared with ≥85. CONCLUSIONS: GMA including GMOS and MOS performed in neonates with hyperbilirubinemia during the neonatal period and early infancy is associated with neurodevelopmental outcomes in the first year of life. GMA can help initiate early intervention in such neonates.

The cost-effectiveness of home phototherapy for hyperbilirubinemia in neonates: results from a randomized controlled trial.

This study aimed to establish the cost-effectiveness of home phototherapy versus hospital phototherapy treating hyperbilirubinemia in neonates more than 36 weeks. Based on clinical results from a randomised controlled trial showing that home phototherapy for hyperbilirubinemia in term neonates is as effective as hospital phototherapy, we performed a cost-minimisation analysis to identify the most cost-effective alternative. We included costs for health care resource use as well as costs for transportation in connection with re-visits. The cost per patient was €337 for home phototherapy compared with €1156 for the hospital alternative indicating average cost savings of €819 (95% confidence interval €613-1025) or 71% per patient. Transportation and outpatient costs were higher in the home treatment group and hospital care costs were higher in the hospital group. Sensitivity analysis shows that results are robust also when allowing for uncertainty. Home phototherapy for neonates more than 36 weeks costs less than in-hospital phototherapy while being equally effective, meaning that home phototherapy is a cost-effective alternative to hospital treatment for infants with neonatal hyperbilirubinemia.Trial registration NCT03536078 . Date of registration: 24/05/2018.

Role of transcranial Doppler in assessment of cerebral blood flow in full term neonates with extreme unconjugated hyperbilirubinemia.

PURPOSE: To evaluate the difference in cerebral blood flow in neonates with and without extreme unconjugated hyperbilirubinemia. METHODS: Transcranial Doppler parameters of 26 full term newborns with extreme unconjugated hyperbilirubinemia (UCH) were compared to 13 postnatal age and sex matched normal healthy neonates serving as controls. Resistance index (RI), pulsatility index (PI) and peak systolic velocity (PSV) were measured in the middle cerebral, internal carotid and posterior cerebral arteries on both sides by transcranial color Doppler ultrasound. RESULTS: An increase in cerebral blood flow (decreased RI, PI and increased PSV) was observed in the extreme unconjugated hyperbilirubinemia (UCH) group. There was positive correlation between total serum bilirubin level and peak systolic velocity and vice versa with resistivity and pulsatility indices. Eight neonates developed clinical features of acute bilirubin encephalopathy and showed significantly increased peak systolic velocity in the right middle cerebral artery compared to those with normal outcome. Resistivity index and pulsatility index were lower in patients managed by exchange transfusion compared to those managed with phototherapy. CONCLUSION: An increase in cerebral blood flow was observed in neonates with UCH compared to those without hyperbilirubinemia. By assessing the cerebral blood flow velocity, resistivity index (RI), and pulsatility index (PI) of particular intracranial arteries, the transcranial Doppler can identify the at-risk neonates, for development of neurological affliction in extreme unconjugated hyperbilirubinemia.

In Silico Assessment of Tanning Masking Effects on Skin Chromatic Attributes Elicited by Anemia and Hyperbilirubinemia.

Changes in skin appearance are among the most recognizable symptoms of a number of medical conditions. The interpretation of such changes, however, may be inadvertently biased by normal physiological processes affecting skin optical properties. In this paper, we assess the impact of one of the most common of these processes, tanning, on variations in skin chromatic attributes elicited by two ubiquitous and serious medical conditions, anemia and hyperbilirubinemia. We employ a first-principles investigation approach centered on the use of predictive computer simulations of light and skin interactions, and on well-established colorimetry methods. In our in silico experiments, we considered skin chromatic attributes resulting from distinct anemia severity levels and hyperbilirubinemia tox-icity stages. Our findings highlight qualitative and quantitative aspects that need to be considered in the visual screening and monitoring of these conditions, notably when they occur with the concomitant presence of tanning-induced changes in the cutaneous tissues' melanin pigmentation and thickness.

Assessment, management, and incidence of neonatal jaundice in healthy neonates cared for in primary care: a prospective cohort study.

Jaundice caused by hyperbilirubinaemia is a common phenomenon during the neonatal period. Population-based studies evaluating assessment, management, and incidence of jaundice and need for phototherapy among otherwise healthy neonates are scarce. We prospectively explored these aspects in a primary care setting via assessing care as usual during the control phase of a stepped wedge cluster randomised controlled trial.We conducted a prospective cohort study embedded in the Screening and TreAtment to Reduce Severe Hyperbilirubinaemia in Infants in Primary care (STARSHIP) Trial. Healthy neonates were included in seven primary care birth centres (PCBCs) in the Netherlands between July 2018 and March 2020. Neonates were eligible for inclusion if their gestational age was ≥ 35 weeks, they were admitted in a PCBC for at least  2 days during the first week of life, and if they did not previously receive phototherapy. Outcomes were the findings of visual assessment to detect jaundice, jaundice incidence and management, and the need for phototherapy treatment in the primary care setting.860 neonates were included of whom 608 (71.9%) were visibly jaundiced at some point during admission in the PCBC, with 20 being 'very yellow'. Of the latter, four (20%) did not receive total serum bilirubin (TSB) quantification. TSB levels were not associated with the degree of visible jaundice (p = 0.416). Thirty-one neonates (3.6%) received phototherapy and none received an exchange transfusion. Five neonates did not receive phototherapy despite having a TSB level above phototherapy threshold.Jaundice is common in otherwise healthy neonates cared for in primary care. TSB quantification was not always performed in very jaundiced neonates, and not all neonates received phototherapy when indicated. Quality improvement initiatives are required, including alternative approaches to identifying potentially severe hyperbilirubinaemia.Trial registration: NL6997 (Dutch Trial Register; Old NTR ID 7187), registered 3 May 2018.

Incidence, Clinical Characteristics and Outcomes of Early Hyperbilirubinemia in Critically Ill Patients: Insights From the MARS Study.

OBJECTIVE: To investigate the incidence, clinical characteristics and outcomes of early hyperbilirubinemia in critically ill patients. DESIGN AND SETTING: This is a post hoc analysis of a prospective multicenter cohort study. PATIENTS: Patients with measured bilirubin levels within the first 2 days after ICU admission were eligible. Patients with liver cirrhosis were excluded. ENDPOINTS: The primary endpoint was the incidence of early hyperbilirubinemia, defined as bilirubin ≥33 µmol/L within 2 days after ICU admission. Secondary endpoints included clinical characteristics of patients with versus patients without early hyperbilirubinemia, and outcomes up to day 30. RESULTS: Of 4,836 patients, 559 (11.6%) patients had early hyperbilirubinemia. Compared to patients without early hyperbilirubinemia, patients with early hyperbilirubinemia presented with higher severity of illness scores, and higher incidences of sepsis and organ failure. After adjustment for confounding variables, early hyperbilirubinemia remained associated with mortality at day 30 (odds ratio, 1.31 [95%-confidence interval 1.06-1.60]; P = 0.018). Patients with early hyperbilirubinemia and thrombocytopenia (interaction P-value = 0.005) had a higher likelihood of death within 30 days (odds ratio, 2.61 [95%-confidence interval 2.08-3.27]; P < 0.001) than patients with early hyperbilirubinemia and a normal platelet count (odds ratio, 1.09 [95%-confidence interval 0.75-1.55]; P = 0.655). CONCLUSIONS: Early hyperbilirubinemia occurs frequently in the critically ill, and these patients present with higher disease severity and more often with sepsis and organ failures. Early hyperbilirubinemia has an association with mortality, albeit this association was only found in patients with concomitant thrombocytopenia.

Utility of icteric index in clinical laboratories: more than a preanalytical indicator.

INTRODUCTION: Total bilirubin tests are highly demanded in clinical laboratories. Since icteric index (I-index) has zero cost, we aimed to evaluate its clinical utility and cost-effectiveness to determine if total bilirubin is necessary to be tested. We took into account if haemolysis could interfere to icteric index determination. MATERIAL AND METHODS: Retrospectively we reviewed I-index results in two cohorts (43,372 and 8507 non-haemolysed and haemolysed samples, respectively). All determinations were done using Alinity c chemistry analysers (Abbott Diagnostics). Receiver operating characteristic (ROC) curve was used to determine the optimal index cut-off to discriminate between normal and abnormal bilirubin concentration (20.5 µmol/L). RESULTS: The ROC curve analysis suggested 21.4 µmol/L as the optimal I-index cut-off but differences in sensitivity and specificity were detected between patient derivation. For rejecting purpose, 15.4 µmol/L and 17.1 µmol/L I-index thresholds were selected based on patient derivation (inpatients and emergency room; and primary care and outpatients, respectively) with 97% sensitivity and 0.25% false negative results. Sensitivity was much lower in haemolysed samples. We selected 34.2 µmol/L I-index as threshold to detect hyperbilirubinemia with 99.7% specificity and 0.26% false positive results, independent of haemolysis. With the icteric index cut-offs proposed, we would save 66% of total bilirubin requested and analyse total bilirubin in around 2% of samples without total bilirubin requested. CONCLUSIONS: This study supports the use of I-index to avoid bilirubin determination and to identify patients with hyperbilirubinemia. This work considers that the economic and test savings could help to increase the efficiency in clinical laboratories.

Neonatal hyperbilirubinemia management: Clinical assessment of bilirubin production.

The predominant cause of elevated total/plasma bilirubin (TB) levels is from an increase in bilirubin production primarily because of ongoing hemolysis. If undiagnosed or untreated, the risk for developing extreme neonatal hyperbilirubinemia and possibly bilirubin-induced neurological dysfunction (BIND) is increased. Since carbon monoxide (CO) and bilirubin are produced in equimolar amounts during the heme catabolic process, measurements of end-tidal CO levels, corrected for ambient CO (ETCOc) can be used as a direct indicator of ongoing hemolysis. A newly developed point-of-care ETCOc device has been shown to be a useful for identifying hemolysis-associated hyperbilirubinemia in newborns. This review summarizes the biology of bilirubin production, the clinical utility of a novel device to identify neonates undergoing hemolysis, and a brief introduction on the use of ETCOc measurements in a cohort of neonates in China.

Carbon monoxide breath test assessment of mild hemolysis in Gilbert's syndrome.

BACKGROUND: Mild hemolysis is difficult to determinate by traditional methods, and its role in Gilbert's syndrome (GS) is unclear. The main aims were to inspect the erythrocyte (RBC) survival in GS by using Levitt's carbon monoxide (CO) breath test and to assess its contribution to unconjugated hyperbilirubinemia. METHODS: Fifty subjects with GS and 1 with type-II Crigler-Najjar syndrome (CN2) received RBC lifespan measurement with Levitt's CO breath test. Mean RBC lifespan was compared with normal referral value. Correlations of serum total bilirubin (TB) with RBC lifespan, blood panel data, demographic factors, and uridine diphosphate glucuronosyltransferase (UGT1A1) mutation load were calculated by Spearman analysis. Susceptibility factors for mild hemolysis were analyzed by multivariate regression analysis. RESULTS: The mean RBC lifespan of the GS subjects was significantly shorter than the normal reference value (95.4 ±â€Š28.9 days vs 126 days; t = -7.504, P < .01), with 30.0% below the lower limit of the normal reference range (75 days). The RBC lifespan of the participant with CN2 was 82 days. Serum TB correlated positively with UGT1A1 mutation load (γ = 0.281, P = .048), hemoglobin (γ = .359, P = .010) and hematocrit (γ = 0.365, P = .010), but negatively with RBC lifespan (γ = -0.336, P = .017). No significant susceptibility factors for mild hemolysis were found. CONCLUSIONS: The results indicate that mild hemolysis indeed, exists in a portion of patients with GS and might serve as an important contributor to unconjugated hyperbilirubinemia in addition to UGT1A1 polymorphism. Further studies on the mechanism and the potential risks in various medical treatments might be wanted.

Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.

BACKGROUND AND AIM: Crigler-Najjar syndrome (CNS) results from biallelic mutations of UGT1A1 causing partial or total loss of uridine 5'-diphosphate glucuronyltransferase activity leading to unconjugated hyperbilirubinemia and its attendant risk for irreversible neurological injury (kernicterus). CNS is exceedingly rare and has been only partially characterized through relatively small studies, each comprising between two and 57 patients. METHODS: A systematic literature review was conducted to consolidate data on the patient, caregiver, and societal burden of CNS. RESULTS: Twenty-eight articles on clinical aspects of CNS were identified, but no published data on its humanistic or economic burden were found. In patients with complete UGT1A1 deficiency (type 1 CNS [CNS-I]), unconjugated bilirubin levels increase 3-6 mg/dL/day during the newborn period and reach neurologically dangerous levels between 5 and 14 days of age. Phototherapy is the mainstay of treatment but poses significant challenges to patients and their families. Despite consistent phototherapy, patients with CNS-I have worsening hyperbilirubinemia with advancing age. Liver transplantation is the only definitive therapy for CNS-I and is increasingly associated with excellent long-term survival but also incurs high costs, medical and surgical morbidities, and risks of immunosuppression. CONCLUSIONS: Crigler-Najjar syndrome is associated with a substantial burden, even with existing standards of care. The development of novel disease-modifying therapies has the potential to reduce disease burden and improve the lives of CNS patients and their families.

Modelling potential cost savings from use of real-time continuous glucose monitoring in pregnant women with Type 1 diabetes.

AIM: To investigate potential cost savings associated with the use of real-time continuous glucose monitoring (RT-CGM) throughout pregnancy in women with Type 1 diabetes. METHODS: A budget impact model was developed to estimate, from the perspective of National Health Service England, the total costs of managing pregnancy and delivery in women with Type 1 diabetes using self-monitoring of blood glucose (SMBG) with and without RT-CGM. It was assumed that the entire modelled cohort (n = 1441) would use RT-CGM from 10 to 38 weeks' gestation (7 months). Data on pregnancy and neonatal complication rates and related costs were derived from published literature, national tariffs, and device manufacturers. RESULTS: The cost of glucose monitoring was £588 with SMBG alone and £1820 with RT-CGM. The total annual costs of managing pregnancy and delivery in women with Type 1 diabetes were £23 725 648 with SMBG alone, and £14 165 187 with SMBG and RT-CGM; indicating potential cost savings of approximately £9 560 461 from using RT-CGM. The principal drivers of cost savings were the daily cost of neonatal intensive care unit (NICU) admissions (£3743) and the shorter duration of NICU stay (mean 6.6 vs. 9.1 days respectively). Sensitivity analyses showed that RT-CGM remained cost saving, albeit to lesser extents, across a range of NICU costs and durations of hospital stay, and with varying numbers of daily SMBG measurements. CONCLUSIONS: Routine use of RT-CGM by pregnant women with Type 1 diabetes, would result in substantial cost savings, mainly through reductions in NICU admissions and shorter duration of NICU care.

Liver function assessment using indocyanine green plasma disappearance rate in a young male with icteric leptospirosis: a case report.

BACKGROUND: Leptospirosis is one of the leading global zoonotic causes of morbidity and mortality. It is induced by a pathogenic spirochete of the genus Leptospira. The icteric form of leptospirosis is characterized by pronounced hyperbilirubinemia and associated with significantly increased mortality. Conventional static liver function tests insufficiently assess hepatic damage and have limited prognostic value. Dynamic tests, such as indocyanine green plasma (ICG) clearance, more adequately reflect hepatic functional status. In this case report we describe the ICG plasma disappearance rates (ICG-PDR) in a patient with leptospirosis and massive hyperbilirubinemia, expanding our knowledge of liver dysfunction in icteric leptospirosis. CASE PRESENTATION: A 21-year-old Caucasian man presented with acute-onset jaundice, myalgia, fever and headaches. Laboratory tests upon admission revealed, most notably, acute kidney failure and hyperbilirubinemia of 17 mg/dl with mild elevation of aminotransferases. In the course of the following 4 days, total serum bilirubin increased to 54 mg/dl. The clinical outcome was favorable with intravenous ceftriaxone and doxycycline. Presumptive diagnosis of leptospirosis was later confirmed by PCR-based amplification of leptospiral DNA in the blood. ICG-PDR values, bilirubin as well as aminotransferases were recorded throughout hospitalization and a 3-month follow-up period. Initially dramatically reduced ICG-PDR (2.0%/min, normal range: 18-25%/min) rapidly normalized within 10 days, while bilirubin remained elevated up to week 7. Mild elevation of serum alanine aminotransferase was at its peak of 124 U/l by day 12 and reached close to normal levels by week 7 upon admission. CONCLUSIONS: Markedly diminished ICG-PDR values presented in this case report suggest severe liver function impairment in the acute phase of icteric leptospirosis. Prolonged elevation of serum bilirubin may not adequately reflect recovery of liver injury in this disease. ICG clearance appears to be a promising marker for the detection of hepatic dysfunction and recovery in icteric leptospirosis in addition to the static tests.

Usefulness of transcutaneous bilirubin assessment measured in non-photo-exposed skin to guide the length of phototherapy: an observational study.

Background Transcutaneous bilirubinometers are a non-invasive tool to estimate serum bilirubin. However, once on phototherapy (PHT) and after PHT, its usefulness is precluded. The objective of this study was to prove the hypothesis that transcutaneous bilirubin (TcB) assessment in a covered skin area during PHT could be used to guide the duration of PHT in term and moderate-late preterm infants with non-isoimmune hyperbilirubinemia. Methods A small area of parasternal skin was covered before starting on PHT. Total serum and TcB (both in exposed and non-exposed areas) were determined before starting treatment, every 12 h once on PHT and 12 h after its discontinuation. Pearson's correlation coefficient and paired mean differences between TcB and total serum bilirubin (TSB) were calculated. Bland-Altman plots were obtained. The percentage of correct treatment decisions made based on non-exposed TcB values was calculated. Results During PHT, there was a relatively good correlation between TSB and non-exposed TcB (0.74) estimates, in contrast to exposed TcB estimates (0.52). However, even when comparing non-exposed TcB with TSB, there was a wide range of agreement limits (-3.8 to 4.6 mg/dL). Decisions based on non-exposed TcB values would have been incorrect in 26.6% of the cases. Conclusion Although there is a relatively strong correlation between total serum and TcB in non-PHT-exposed regions, the difference is not narrow enough to be utilized in guiding clinical decisions on the duration of PHT.

Learning from claims: hyperbilirubinaemia and kernicterus.

We examined claims made against the National Health Service (NHS) involving neonatal jaundice in order to determine whether there were lessons that could be learnt from common themes.This was a retrospective anonymised study using information from the NHS Resolution database for 2001-2011.Twenty cases (16 males) had sufficient information for analysis. Fifteen had confirmed cerebral palsy and two young children had damage to the globus pallidus without confirmed CP. In three cases, the outcome was uncertain. Two were extremely preterm, five were born at 34-36 weeks' gestation. Jaundice was typically present very early in life; in four cases, it was noted at less than 24hours of age, and in 14 cases, it was first noted on the second to third day. There was a lag between recognition and readmission, with a range of 26-102 hours. The peak serum bilirubin level was over 600 µmol/L in all the babies born at term. An underlying diagnosis was found in all but two; six had glucose-6-phosphatase deficiency (one also had Gilbert's syndrome); five were diagnosed with ABO incompatibility; three with Rh haemolytic disease; one with spherocytosis and three preterm. The total cost of these claims by August 2017 was almost £150.5 million. This figure is likely to rise.These data show that, in the group who litigate, babies who develop kernicterus generally have an underlying diagnosis. We recommend adherence to theNational Institute for Health and Care Excellence guideline that recommends measuring the bilirubin level within 6 hours in all babies who are visibly jaundiced.

Diagnosing Jaundice by Eye-Outpatient Assessment of Conjunctival Icterus in the Newborn.

In pediatric office practices, we compared transcutaneous bilirubin levels in 689 newborns, age 3-10 days, with and without conjunctival icterus. In this age range, and in the absence of other clinical or laboratory indications, the presence of conjunctival icterus does not imply the need to measure the transcutaneous bilirubin or serum bilirubin level, but the absence of conjunctival icterus helps to rule out significant hyperbilirubinemia.

Does maternal asthma contribute to racial/ethnic disparities in obstetrical and neonatal complications?

PURPOSE: To examine whether maternal asthma contributes to racial/ethnic differences in obstetrical and neonatal complications. METHODS: Data on white (n = 110,603), black (n = 50,284), and Hispanic (n = 38,831) singleton deliveries came from the Consortium on Safe Labor. Multilevel logistic regression models, with an interaction term for asthma and race/ethnicity, estimated within-group adjusted odds ratios (aORs) for gestational diabetes, gestational hypertension, pre-eclampsia, placental abruption, premature rupture of membranes, preterm delivery, maternal hemorrhage, neonatal intensive care unit admissions, small for gestational age, apnea, respiratory distress syndrome, transient tachypnea of the newborn, anemia, and hyperbilirubinemia after adjustment for clinical and demographic confounders. Nonasthmatics of the same racial/ethnic group were the reference group. RESULTS: Compared with nonasthmatics, white asthmatics had increased odds of pre-eclampsia (aOR, 1.28; 95% confidence interval [CI], 1.15-1.43) and maternal hemorrhage (aOR, 1.14; 95% CI, 1.04-1.23). White and Hispanic infants were more likely to have neonatal intensive care unit admissions (aOR, 1.19; 95% CI, 1.11-1.28; aOR, 1.16; 95% CI, 1.02-1.32, respectively) and be small for gestational age (aOR, 1.11; 95% CI, 1.02-1.20; aOR, 1.26; 95% CI, 1.10-1.44, respectively), and Hispanic infants were more likely to have apnea (aOR, 1.32; 95% CI, 1.02-1.69). CONCLUSIONS: Maternal asthma did not affect most obstetrical and neonatal complication risks within racial/ethnic groups. Despite their increased risk for both asthma and many complications, our findings for black women were null. Asthma did not contribute to racial/ethnic disparities in complications.