High levels of pathological jaundice in the first 24 hours and neonatal hyperbilirubinaemia in an epidemiological cohort study on the Thailand-Myanmar border.

Population risks for neonatal hyperbilirubinaemia (NH) vary. Knowledge of local risks permits interventions that may reduce the proportion becoming severe. Between January 2015 and May 2016, in a resource-limited setting on the Thailand-Myanmar border, neonates from 28 weeks' gestation were enrolled into a prospective birth cohort. Each neonate had total serum bilirubin measurements: scheduled (24, 48, 72 and 144 hours of life) and clinically indicated; and weekly follow up until 1 month of age. Risk factors for developing NH were evaluated using Cox proportional hazard mixed model. Of 1710 neonates, 22% (376) developed NH (83% preterm, 19% term). All neonates born <35 weeks, four in five born 35-37 weeks, and three in twenty born ≥38 weeks had NH, giving an overall incidence of 249 per 1000 livebirths [95%CI 225, 403]. Mortality from acute bilirubin encephalopathy was 10% (2/20) amongst the 5.3% (20/376) who reached the severe NH threshold. One-quarter (26.3%) of NH occurred within 24 hours. NH onset varied with gestational age: at a median [IQR] 24 hours [24, 30] for neonates born 37 weeks or prematurely vs 59 hours [48, 84] for neonates born ≥38 weeks. Risk factors for NH in the first week of life independent of gestational age were: neonatal G6PD deficiency, birth bruising, Sgaw Karen ethnicity, primigravidae, pre-eclampsia, and prolonged rupture of membranes. The genetic impact of G6PD deficiency on NH was partially interpreted by using the florescent spot test and further genotyping work is in progress. The risk of NH in Sgaw Karen refugees may be overlooked internationally as they are most likely regarded as Burmese in countries of resettlement. Given high levels of pathological jaundice in the first 24 hours and overall high NH burden, guidelines changes were implemented including preventive PT for all neonates <35 weeks and for those 35-37 weeks with risk factors.

Severe neonatal hyperbilirubinemia in the southeast region of Turkey

Background/aim: Severe neonatal hyperbilirubinemia is an important cause of morbidity and mortality in developing countries. The aim was to assess etiologic reasons for development of severe hyperbilirubinemia and define risk factors for exchange transfusion and acute bilirubin encephalopathy (ABE) in Sanliurfa located in the southeast region of Turkey. Materials and methods: An observational cohort study included 115 infants with ≥35 weeks of gestation admitted with diagnosis of severe hyperbilirubinemia in a period of 18 months. Potential risk factors associated with exchange transfusion and development of ABE were analyzed. Results: Among 115 infants, 67 (58.3%) received exchange transfusion and 45 (39.1%) developed ABE. Rh isoimmunization (OR: 24.6, 95% CI = 2.2­271, P = 0.009), glucose-6-phosphate dehydrogenase deficiency (G6PD) (OR: 21.1, 95% CI = 1.8­238.4, P = 0.01), early discharge (OR: 14.4, 95% CI = 4.2­48.9, P ≤ 0.001), and male sex (OR: 4.3, 95% CI = 1.3­14.1, P = 0.02) were independently associated with an increased risk for exchange transfusion. Being a refugee (OR: 6.8, 95% CI = 1.8­25.8, P = 0.005) and G6PD deficiency (OR: 9.9, 95% CI = 1.3­71.9, P = 0.02) were associated with development of ABE. Conclusion: Early discharge, Rh isoimmunization, and G6PD deficiency are significant risk factors for severe hyperbilirubinemia and exchange transfusion. Prevention of early hospital discharges, family education to increase awareness for hazardous effects of hyperbilirubinemia, and early follow-up visits after discharge would reduce the disease burden.

A randomized control trial of phototherapy and 20% albumin versus phototherapy and saline in Kilifi, Kenya.

OBJECTIVE: The study evaluated the efficacy of phototherapy and 20% albumin infusion to reduce total serum bilirubin (TSB) in neonates with severe hyperbilirubinemia. The primary outcome was a reduction of TSB at the end of treatment. The secondary outcomes were the need for exchange transfusion, inpatient mortality, neurological outcomes at discharge, and development outcomes at 12-months follow-up. RESULTS: One hundred and eighteen neonates were randomly assigned to phototherapy and 20% albumin (n = 59) and phototherapy and saline (n = 69). The median age at admission was 5 (interquartile range (IQR) 3-6) days, and the median gestation was 36 (IQR 36-38) weeks. No significant differences were found in the change in TSB (Mann-Whitney U =609, p = 0.98) and rate of change in TSB per hour after treatment (Mann-Whitney U = 540, p = 0.39) between the two groups. There were no significant differences between the two groups in the proportion of participants who required exchange transfusion (χ2 (2) = 0.36, p = 0.546); repeat phototherapy (χ2 (2) = 2.37, p = 0.123); and those who died (χ2 (2) = 0.92, p = 0.337). Trial registration The trial was registered in the International Standardized Randomized Controlled Trial Number (ISRCTN); trial registration number ISRCTN89732754.

Indirect neonatal hyperbilirubinemia in hospitalized neonates on the Thai-Myanmar border: a review of neonatal medical records from 2009 to 2014.

BACKGROUND: Indirect neonatal hyperbilirubinemia (INH) is a common neonatal disorder worldwide which can remain benign if prompt management is available. However there is a higher morbidity and mortality risk in settings with limited access to diagnosis and care. The manuscript describes the characteristics of neonates with INH, the burden of severe INH and identifies factors associated with severity in a resource-constrained setting. METHODS: We conducted a retrospective evaluation of anonymized records of neonates hospitalized on the Thai-Myanmar border. INH was defined according to the National Institute for Health and Care Excellence guidelines as 'moderate' if at least one serum bilirubin (SBR) value exceeded the phototherapy threshold and as 'severe' if above the exchange transfusion threshold. RESULTS: Out of 2980 records reviewed, 1580 (53%) had INH within the first 14 days of life. INH was moderate in 87% (1368/1580) and severe in 13% (212/1580). From 2009 to 2011, the proportion of severe INH decreased from 37 to 15% and the mortality dropped from 10% (8/82) to 2% (7/449) coinciding with the implementation of standardized guidelines and light-emitting diode (LED) phototherapy. Severe INH was associated with: prematurity (< 32 weeks, Adjusted Odds Ratio (AOR) 3.3; 95% CI 1.6-6.6 and 32 to 37 weeks, AOR 2.2; 95% CI 1.6-3.1), Glucose-6-phosphate dehydrogenase deficiency (G6PD) (AOR 2.3; 95% CI 1.6-3.3), potential ABO incompatibility (AOR 1.5; 95% CI 1.0-2.2) and late presentation (AOR 1.8; 95% CI 1.3-2.6). The risk of developing severe INH and INH-related mortality significantly increased with each additional risk factor. CONCLUSION: INH is an important cause of neonatal hospitalization on the Thai-Myanmar border. Risk factors for severity were similar to previous reports from Asia. Implementing standardized guidelines and appropriate treatment was successful in reducing mortality and severity. Accessing to basic neonatal care including SBR testing, LED phototherapy and G6PD screening can contribute to improve neonatal outcomes.

Why is kernicterus still a major cause of death and disability in low-income and middle-income countries?

Neonatal jaundice is predominantly a benign condition that affects 60%-80% of newborns worldwide but progresses to potentially harmful severe hyperbilirubinaemia in some. Despite the proven therapeutic benefits of phototherapy for preventing extreme hyperbilirubinaemia, acute bilirubin encephalopathy or kernicterus, several low-income and middle-income countries (LMIC) continue to report high rates of avoidable exchange transfusions, as well as bilirubin-induced mortality and neurodevelopmental disorders. Considering the critical role of appropriate timing in treatment effectiveness, this review set out to examine the contributory factors to the burden of severe hyperbilirubinaemia and kernicterus based on the 'three delays model' described by Thaddeus and Maine in the 91 most economically disadvantaged LMICs with Gross National Income per capita ≤US$6000 and median human development index of 0.525 (IQR: 0.436-0.632). Strategies for addressing these delays are proposed including the need for clinical and public health leadership to curtail the risk and burden of kernicterus in LMICs.

The use of intensive phototherapy in severe neonatal hyperbilirubinemia.

Phototherapy has been the therapy of choice for the newborn with indirect hyperbilirubinemia. Intensive phototherapy requires a spectral irradiance of 30 microw/ cm2/nm, delivered over as much of the body surface as possible and is nowadays recommended for cases of neonatal hyperbilirubinemia with elevated total serum bilirubin (TSB) levels according to the guidelines. This study was conducted on neonates presenting to the out-born Neonatal Intensive Care Unit (NICU) of Cairo University Hospital with severe and extreme neonatal unconjugated hyperbilirubinemia during a 6 month period from August 2011 to January 2012. A total of 212 neonates presented with TSB > or = 20 mg/dl and were admitted for intensive phototherapy. The mean TSB on admission for all the cases was 26.8 +/- 6.2 mg/dl, ranging from 20 to 44 mg/dl. The mean duration of intensive phototherapy use was 14 hr. The mean rate of TSB declined during stay in the bilisphere was 1.019 mg/dl/hr. Exchange blood transfusion was indicated in 13 cases with extreme hyperbilirubinemia. 31 cases (14.62%) had rebound hyperbilirubinemia after phototherapy removal.

Hyperbilirubinemia in infants with Gram-negative sepsis does not affect mortality.

BACKGROUND: Sepsis is associated with an increased production of oxidant species and a decrease in endogenous antioxidant defenses. Mortality is high, especially when endotoxins are involved, e.g., in infants with Gram-negative sepsis. Yet, chronic as well as acute unconjugated hyperbilirubinemia has been shown to protect against endotoxin-induced shock in vivo in rats and in mice. We hypothesized that hyperbilirubinemia in infants with Gram-negative sepsis improves survival and/or mitigates the inflammatory response. OBJECTIVE: To assess the relationships between serum bilirubin concentrations on the one hand, and leukocyte count, C-reactive protein and survival on the other hand, in infants with Gram-negative sepsis. METHODS: Retrospectively, we retrieved clinical and biochemical data from infants less than 90 days of age with a blood culture-proven Gram-negative sepsis between January 1998 and December 2005. RESULTS: We identified 92 infants with Gram-negative sepsis in the indicated period. Median gestational age was 29 (24-42) weeks. 22 Patients died. Preceding sepsis, median total serum bilirubin concentrations were below 150 µmol/L. Median concentrations of conjugated bilirubin concentrations increased (+63%, p<0.05), and median concentrations of unconjugated bilirubin decreased (-36%, p<0.05) in infants with Gram-negative sepsis. Median total bilirubin concentrations before and during sepsis were not significantly different between survivors and non-survivors. Changes in bilirubin concentrations were not significantly correlated with changes in either white blood cell count or C-reactive protein. CONCLUSION: Present data do not support the concept that bilirubin positively affects survival or the inflammatory response in infants with Gram-negative sepsis.

Risk assessment for adverse outcome in term and late preterm neonates with bilirubin values of 20 mg/dL or more.

The aim of this study is to identify clinical, etiologic, and laboratory factors that potentiate adverse outcome of hyperbilirubinemia among term and late preterm neonates in logistic regression analysis. A retrospective cohort of infants with total serum bilirubin (TSB) ≥ 20 mg/dL from 1995 to 2007 was surveyed. Eighteen infants had adverse outcome. Controls were 270 infants without sequelae. Risks were significantly higher in infants with six etiologies causing hyperbilirubinemia: sepsis (odds ratio [OR] = 161.7, 95% confidence interval [CI] = 11.7 to 2242.8), gastrointestinal obstruction (OR = 39.2, 95% CI = 2.7 to 567.3), Rh incompatibility (OR = 31.0, 95% CI = 5.1 to 188.9), hereditary spherocytosis (OR = 19.6, 95% CI = 1.6 to 235.5), ABO incompatibility (OR = 5.1, 95% CI = 1.3 to 19.7), and glucose-6-phosphate dehydrogenase deficiency (OR = 4.7, 95% CI = 1.3 to 16.7). Infants with acute bilirubin encephalopathy were more likely to have adverse outcome than subjects without acute bilirubin encephalopathy (OR = 281.7, 95% CI = 25.8 to 3076.7). Adverse outcome was more common in infants with a positive direct Coombs test (OR = 4.5, 95% CI = 1.3 to 15.4). Infants with hemoglobin < 10 g/dL tended to have adverse outcome more often than those with hemoglobin ≥ 13 g/dL (OR = 11.8, 95% CI = 3.3 to 42.9). Infants with TSB of 35 mg/dL or more (OR = 472.5, 95% CI = 47.8 to 4668.8) and of 30 to 34.9 mg/dL (OR = 9.5, 95% CI = 1.6 to 57.9) carry greater risks as compared with those with TSB of 20 to 24.9 mg/dL. In conclusion, this study quantitatively verified the potential risks for adverse outcome of neonatal hyperbilirubinemia.

Severe neonatal hyperbilirubinemia and adverse short-term consequences in Baghdad, Iraq.

BACKGROUND: Severe neonatal hyperbilirubinemia, when unmonitored or untreated, can progress to acute bilirubin encephalopathy (ABE). Initiatives to prevent and eliminate post-icteric sequelae (kernicterus) are being implemented to allow for timely interventions for bilirubin reduction. OBJECTIVES: We report an observational study to determine the clinical risk factors and short-term outcomes of infants admitted for severe neonatal jaundice. METHODS: A post-discharge medical chart review was performed for a cohort of infants admitted for management of newborn jaundice to the Children Welfare Teaching Hospital during a 4-month period in 2007 and 2008. Immediate outcomes included severity of hyperbilirubinemia, association of ABE, need and impact of exchange transfusion, and survival. Short-term post-discharge follow-up assessed for post-icteric sequelae. RESULTS: A total of 162 infants were admitted for management of severe jaundice. Incidences of severe sequelae were: advanced ABE (22%), neonatal mortality within 48 h of admission (12%) and post-icteric sequelae (21%). Among the cohort, 85% were <10 days of age (median 6 days, IQR 4-7 days). Readmission total serum bilirubin ranged from 197 to 770 µM; mean 386 ± 108 SD µM (mean 22.6 ± 6.3 SD mg/dl; median 360, IQR 310-445 µM). The major contributory risk factor for the adverse outcome of kernicterus/death was admission with advanced ABE (OR 8.03; 95% CI 3.44-18.7). Other contributory factors to this outcome, usually significant, but not so for this cohort, included home delivery, sepsis, ABO or Rh disease. Absence of any detectable signs of ABE on admission and treatment of severe hyperbilirubinemia was associated with no adverse outcome (OR 0.34; 95% CI 0.16-0.68). CONCLUSIONS: Risks of mortality and irreversible brain injury among healthy infants admitted for newborn jaundice are urgent reminders to promote education of communities, families and primary health care providers, especially in a fractured health system. Known risk factors for severe hyperbilirubinemia were overwhelmed by the effect of advanced ABE.

Morbidity and mortality amongst infants of diabetic mothers admitted into a special care baby unit in Port Harcourt, Nigeria.

BACKGROUND: Infants born to diabetic women have certain distinctive characteristics, including large size and high morbidity risks. The neonatal mortality rate is over five times that of infants of non diabetic mothers and is higher at all gestational ages and birth weight for gestational age (GA) categories.The study aimed to determine morbidity and mortality pattern amongst infants of diabetic mothers (IDMS) admitted into the Special Care Baby Unit of University of Port Harcourt Teaching Hospital. METHODS: This was a study of prevalence of morbidity and mortality among IDMs carried out prospectively over a two year period. All IDMs (pregestational and gestational) admitted into the Unit within the period were recruited into the study.Data on delivery mode, GA, birth weight, other associated morbidities, investigation results, treatment, duration of hospital stay and outcome were collated and compared with those of infants of non diabetic mothers matched for GA and birth weight admitted within the same period. Maternal data were reviewed retrospectively. Data were analyzed using SPSS 16.0. RESULTS: Sixty percent of the IDMs were born to mothers with gestational diabetes, while 40% were born to mothers with pregestational DM. 38 (74.3%) were born by Caesarian section (CS), of which 20 (52.6%) were by emergency CS. There was no significant difference in emergency CS rates, when compared with controls, but non-IDMs were more likely to be delivered vaginally. The mean GA of IDMs was 37.84 weeks ± 1.88. 29 (61.7%) of them were macrosomic. The commonest morbidities were Hypoglycemia (significantly higher in IDMs than non-IDMs) and hyperbilirubinaemia in 30 (63.8%) and 26 (57.4%) respectively.There was no difference in morbidity pattern between infants of pre- gestational and gestational diabetic mothers. Mortality rate was not significantly higher in IDMs CONCLUSIONS: The incidence of macrosomia in IDMs was high but high rates of emergency CS was not peculiar to them. Hypoglycaemia and hyperbilirubinaemia were the commonest morbidities in IDMs.Referring women with unstable metabolic control to specialized centers improves pre- and post- natal outcomes. Maternal-Infant centers for management of diabetes in pregnancy are advocated on a national scale to reduce associated morbidity and mortality.

Incidence of neonatal hyperbilirubinemia: a population-based prospective study in Pakistan.

OBJECTIVE: To estimate the incidence of neonatal jaundice and hyperbilirubinemia in a poor urban community in Karachi, where 70% of births occur at home. METHODS: Home-based pregnancy and newborn surveillance were conducted from September 2004 to July 2006 in a multi-ethnic population by trained community health workers. Newborns were visited several times at scheduled intervals until 59 days of life; any baby with jaundice was referred to the local clinic. Clinical assessments of jaundice were assigned by a physician and recorded using an adapted Kramer scale. Blood for plasma bilirubin was obtained if parents consented. RESULTS: Of a birth cohort of 1690 young infants during the study period, 466 infants (27.6%) were referred to our centre with jaundice. Of these, 64% were 0-6 days old. Bilirubin was measured in 125 of 466 (27%) jaundiced newborns. Overall detected rate of hyperbilirubinemia (bilirubin >5 mg/dl) among 1690 newborns was 39.7/1000 live births (95% CI 29.3-47.6). Rate of plasma bilirubin levels in the range of 15-20 mg/dl was 13/1000 live births (95% CI 7.6-18.4); levels >20 mg/dl were observed in 3.5/1000 live births (95% CI 0.4-5.5). The proportion of newborns with bilirubin > or =15 mg/dl was significantly higher among those assigned a Kramer score of 4-5 compared to those receiving a score of 1-3 (P-value 0.00004). CONCLUSION: A significant burden of untreated severe neonatal jaundice, causing potential neurological sequelae, exists in developing countries such as Pakistan. WHO guidelines are needed for screening and appropriate management of neonatal jaundice in developing countries.

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants.

OBJECTIVES: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants. METHOD: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. RESULTS: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. CONCLUSIONS: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

The use of conjugated hyperbilirubinemia greater than 100 micromol/L as an indicator of irreversible liver disease in infants with short bowel syndrome.

BACKGROUND: The introduction of parenteral nutrition resulted in improved survival of neonates with short bowel syndrome. It is unclear why some may deteriorate to end-stage liver disease (ESLD). Knowledge of when to refer such children for evaluation for transplantation is crucial. A commonly used criterion is conjugated hyperbilirubinemia greater than 100 micromol/L (CB100). OBJECTIVES: The aim of this study is to evaluate if CB100 is a reliable marker for identifying which infants with short bowel syndrome will subsequently develop ESLD. METHODS: All neonates from our short bowel registry (1997-2003) were reviewed. Conjugated hyperbilirubinemia greater than 100 micromol/L was defined as a sustained CB100 for at least 2 weeks with no concurrent sepsis. The sensitivity, specificity, as well as positive and negative predictive values for predicting an outcome of ESLD were calculated. RESULTS: Seventy short gut infants were identified (25 males; mean gestational age of 32.5 +/- 4.9 weeks and weight of 1902 +/- 888 g). Twenty-three patients (33%) developed CB100. Seventeen patients (24%) developed ESLD. Conjugated hyperbilirubinemia greater than 100 micromol/L had a sensitivity of 94% and a specificity of 87% in determining which patients would advance to ESLD. The positive and negative predictive values were 70% and 98%, respectively. The median time from CB100 to ESLD was 60 days (range, 10-365 days). CONCLUSION: A positive predictive value of 70% ensures a safe level of over-triage to the transplant service for assessment; however, the short duration from CB100 to ESLD (60 days) implies a late detection of advanced liver disease, which raises concern about the use of this test in the clinical setting.