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.

Mortality, morbidity and clinical care in a referral neonatal intensive care unit in Haiti.

BACKGROUND: Neonatal mortality rates in Haiti are among the highest in the Western hemisphere. Few mothers deliver with a skilled birth attendant present, and there is a significant lack of pediatricians. The neonatal intensive care unit (NICU) at St. Damien Pediatric Hospital, a national referral center, is one of only five neonatology departments in Haiti. In order to target limited resources toward improving outcomes, this study seeks to describe clinical care in the St. Damien NICU. METHODS: A retrospective medical record review was performed on available medical records on all admissions to the NICU between April 2016 and April 2017. RESULTS: 220 neonates were admitted to the NICU within the study epoch. The mortality rate was 14.5%. Death was associated with a maternal diagnosis of hypertension (p = 0.03) and neonatal diagnoses of lower gestational age (p<0.0001), lower birth weight (p<0.0001), prematurity (p = 0.002), RDS p = 0.01), sepsis (p<0.0001) and kernicterus (p = 0.04). The most common diagnoses were sepsis, chorioamnionitis, respiratory distress syndrome, jaundice, prematurity and perinatal asphyxia. CONCLUSIONS: This study demonstrates that preterm birth, sepsis, RDS and kernicterus are key contributors to neonatal mortality in a Haitian national pediatric referral center NICU and as such are promising interventional targets for reducing the neonatal mortality rate in Haiti.

Early prediction of adverse outcomes in infants with acute bilirubin encephalopathy.

OBJECTIVE: Acute bilirubin encephalopathy (ABE) remains one of the important causes of neonatal mortality and child disability, early identification, and intervention which could improve outcomes. The purpose of this study was to evaluate early predictors of adverse outcomes in infants with ABE. METHODS: Newborns of gestational age ≥ 35 weeks and diagnosed with ABE were included in the study. Bilirubin-induced neurological dysfunction (BIND) score, total serum bilirubin (TSB) peak value, and serum albumin levels were determined. Adverse outcomes were defined as death or survival with auditory dysfunction and/or cerebral palsy. RESULTS: Eighty-two infants were eligible for recruitment in the study. The outcome data from 76 ABE infants (92%) were used for analysis, of which 25 infants got adverse outcomes and 51 live a normal life. Univariate analysis for BIND score, TSB peak value, bilirubin-albumin ratio (B/A), albumin level, abnormal AABR, and neonatal sepsis was performed to elucidate the association with adverse outcomes. Bivariate logistic regression analysis showed B/A (OR 10.48, 95%CI: 1.55-70.81, P = 0.02) and BIND score (OR 3.68, 95%CI: 1.39-9.72, P = 0.01) were correlated with adverse outcomes. ROC curve analysis showed that B/A (≥8.9 mg/g), BIND score (≥6) could predict adverse outcomes of ABE separately; B/A in conjunction with BIND score could increase prediction sensitivity to 100%. INTERPRETATION: Both B/A and BIND score can be used to predict adverse outcomes of ABE, and the combination of the two parameters can increase prediction sensitivity significantly.

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.

Evidence suggests there was not a "resurgence" of kernicterus in the 1990s.

BACKGROUND: Although some have suggested that kernicterus disappeared in the United States in the 1970s to 1980s and dramatically reappeared in the 1990s, population-based data to support such a resurgence are lacking. METHODS: We used diagnosis codes on data collection forms from the California Department of Developmental Services (DDS) to identify kernicterus cases among children born from 1988 to 1997. We examined kernicterus mortality trends in the United States from 1979 to 2006 using death certificate data from the National Center for Health Statistics. RESULTS: We identified 25 cases of physician-diagnosed kernicterus. This figure was augmented to reflect estimates of cases lost to infant mortality, yielding incidence estimates of 1 in 200 000 California live births, 1 in 2500 among children who received services from DDS, and 1 in 400 children with cerebral palsy. There was no significant trend in kernicterus incidence from 1988 to 1997 (P = .77). Incidence before and after the 1994 publication of the AAP practice parameter for hyperbilirubinemia in healthy term infants was not significantly different (P = .92). Nationally, there were 3 reported infant deaths from kernicterus in 1994 and 2 or fewer in the other 28 years from 1979 to 2006 (0.28 deaths per million live births): there was no significant increase in kernicterus mortality over this period. CONCLUSION: Data from California do not support a resurgence of kernicterus in the 1990s. Deaths from kernicterus in the United States have remained rare, with no apparent increase during the last 25 years.

Factors associated with outcome in foals with neonatal isoerythrolysis (72 cases, 1988-2003).

BACKGROUND: Neonatal foals with isoerythrolysis (NI) often die, but the risk factors for death have not been identified. OBJECTIVES: To identify factors associated with outcome in foals with NI and to identify factors associated with death from liver failure or kernicterus in the same population. ANIMALS: Seventy-two foals with NI examined at referral institutions. METHODS: Retrospective case series. Information on signalment, clinical examination findings, laboratory testing, treatment, complications, outcome, and necropsy results were obtained. RESULTS: The overall survival rate was 75% (54 of 72). Liver failure (n=7), kernicterus (n=6), and complications related to bacterial sepsis (n=3) were the 3 most common reasons for death or euthanasia. The number of transfusions with blood products was the factor most strongly associated with nonsurvival in a multivariate logistic regression model. The odds of liver failure developing in foals receiving a total volume of blood products >or= 4.0 L were 19.5 (95% confidence intervals [CI]: 2.13-178) times higher than that of foals receiving a lower volume (P= .009). The odds of kernicterus developing in foals with a total bilirubin >or= 27.0 mg/dL were 17.0 (95% CI: 1.77-165) times higher than that of foals with a lower total bilirubin (P= .014). CONCLUSIONS AND CLINICAL IMPORTANCE: Development of liver failure, kernicterus, and complications related to bacterial sepsis are the most common causes of death in foals with NI. Foals administered a large volume of blood products are at greater risk for developing liver failure.

Kernicterus in late preterm infants cared for as term healthy infants.

OBJECTIVE: To compare the clinical profile and health care experiences related to management of newborn jaundice and hyperbilirubinemia in preterm infants (<37(0/7) weeks gestation) who are cared for as term infants (> or =37(0/7) weeks) and develop acute and/or chronic posticteric sequelae. METHODS: Retrospective study of a convenient sample of term and near term infants voluntarily reported to the Pilot Kernicterus Registry (1992-2003). Study infants were required to meet the clinical definitions for acute bilirubin encephalopathy (moderate or advanced severity) and/or the classical signs of kernicterus. Main outcome measures were the comparison of etiology, severity and duration of extreme hyperbilirubinemia (TSB levels >20 mg/dL), response to interventions of intensive phototherapy and exchange transfusion, and health care delivery experiences in preterm as compared with term infants. RESULTS: No targeted attention was accorded to preterm infants during their neonatal health care experiences as related to predischarge risk assessment, feeding, discharge follow-up instructions, or breastfeeding, regardless of the known vulnerability of preterm infants to safely transition during the first week after birth. The TSB levels, age at re-hospitalization, and birth weight distribution were similar for late preterm and term infants. Large for gestational age and late preterm infants disproportionately developed kernicterus as compared with those who were appropriate for gestational age and term. Clinical management of extreme of hyperbilirubinemia, by the attending clinical providers, was not impacted or influenced by the gestational age, clinical signs, or risk assessment. This resulted in severe posticteric sequelae which was more severe and frequent in late preterm infants. CONCLUSIONS: Late prematurity (34(0/7) to 36(6/7) weeks) of healthy infants was not recognized as a risk factor for hazardous hyperbilirubinemia by clinical practitioners. Unsuccessful lactation experience was the most frequent experience; being large for gestational age as well as the other known biologic risk factors for hyperbilirubinemia and bilirubin neurotoxicity were not identified by the clinical care providers either before discharge or at immediate postdischarge follow up.

Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentrations associated with bilirubin-related morbidity and death in Nigerian infants.

Our objective was to determine whether glucose-6-phosphate dehydrogenase (G6PD) deficiency and elevated carboxyhemoglobin (COHb) levels correlated with bilirubin-related morbidity and mortality rates. For this purpose, we studied 55 clinically jaundiced infants admitted to a rural mission hospital in southern Nigeria. Total serum bilirubin levels (range, 80 to 1016 mumol/L (4.7 to 59.4 mg/dl)) correlated with the percentage COHb concentrations (COHb = 0.45 + 0.08 Total serum bilirubin; r = 0.72). Infants were divided into two groups of equal size around the median COHb concentration (COHb range, 0.43% to 5.93% (median = 1.40%), with ambient carbon monoxide of 0.65 +/- 0.03 microL/L). The COHb levels > or = 1.40% were associated with the need for exchange transfusion (15/28, or 54%, vs 5/27, or 19%; p < 0.01) and with an increased incidence of clinical findings compatible with kernicterus (9/28, or 32%, vs 0/27, or 0%; p < 0.01). Mortality rate was 29% (8/29) among infants with higher COHb levels, and 7% (2/28) in those with lower levels (p = 0.08). Thirty-one percent (14/45) of the clinically jaundiced infants tested had G6PD deficiency. Thirty-six percent of the infants with G6PD deficiency died with presumed kernicterus, compared with only 3% (1/31) of the infants with a normal G6PD screening test result (p < 0.01). These data suggest that G6PD deficiency and increased bilirubin production, as indexed by COHb, are associated with jaundice-related morbidity and death in Nigerian infants.

A neuropathologic analysis of neonatal deaths occurring in a single neonatal unit over a 20-year period.

This study presents an overview of 2515 consecutive autopsies performed on newborn infants who died during the first 28 days of life at The Hospital for Sick Children, Toronto, during the period 1970-89. The infants were grouped into two categories according to their gestational age, then subdivided into groups of early (0-6 days) and late (7-28 days) neonatal death. Trends in the occurrence of neuropathologic observation were documented. For each 5-year period and each gestational group, the following diagnoses were recorded: hypoxic-ischemic neuronal changes, periventricular leukomalacia, infarction, kernicterus, meningitis, and hemorrhage (subependymal, parenchymal, choroidal). Over these 20 years, our results show that death in preterm infants decreased because of a drop in the incidence of subependymal hemorrhage/intraventricular hemorrhage, kernicterus, and meningitis but increased in term infants as a result of a higher frequency of hypoxic-ischemic neuronal necrosis and choroid plexus hemorrhage.

Maternal CW alloimmunization.

The Winnipeg Rh Laboratory has reviewed its experiences with maternal CW alloimmunization. From September 24, 1956, to March 31, 1992, 12 women with significant CW alloimmunization underwent 18 pregnancies. In 3 (4 pregnancies) the antibody, despite its strength, was 'naturally occurring' (i.e. there was no known exposure to CW-positive red cells). The remaining 9 women (14 pregnancies) had CW-positive husbands. Two had CW-negative babies and a third infant, probably CW negative, was stillborn and macerated at 43 weeks gestation. Eleven babies were CW positive and had hemolytic disease of the newborn (HDN), with antiglobulin-positive red cells. Five did not require treatment; 2 needed phototherapy only, and 4 (born between 1956 and 1963) required exchange transfusions. No anti-CW screening was carried out until 1977; thereafter it was sporadic, 11 of 51 screening red cells being CW positive in the 39-month period ending March 31st, 1992. From November 1, 1977, to March 31, 1992, 24 women (30 pregnancies, 31 conceptuses) with insignificant anti-CW alloantibodies were identified. Extrapolating these figures to the entire period from September 24, 1956, to March 31, 1992, we estimate that at least 430 women (at least 573 pregnancies) were CW alloimmunized, most of the antibodies being 'naturally occurring'. Only 2% of the conceptuses were CW positive and affected; none were severely affected. Anti-CW is relatively common, occurring in about 1 pregnant Manitoban woman in 1,100. On very rare occasions (11 times in Manitoba in 36 years and 5 months) anti-CW HDN occurs which, although not severe, may end in kernicterus with brain damage or neonatal death unless it is detected promptly and treated appropriately.

Lack of identifiable risk factors for kernicterus.

In recent years kernicterus at autopsy has been observed in sick premature infants in the absence of markedly elevated levels of serum bilirubin. Potentiating factors have been suggested to explain kernicterus in such a setting. In order to establish which factors are associated with increased risk for kernicterus in these small babies, this retrospective matched control study was undertaken. Thirty-two infants with kernicterus at autopsy were matched for gestational age, birth weight, length of survival, and year of birth to 32 control infants without kernicterus. Multiple historical, clinical, and laboratory factors were compared, including therapy, sepsis, hypothermia, asphyxia as reflected by Apgar score, hematocrit, acidosis, hypercarbia, hypoxia, hypoglycemia, and hyperbilirubinemia. No statistically significant differences between the kernicteric and nonkernicteric infants were demonstrated for any of these factors, including peak total serum bilirubin levels. Multivariant analysis also failed to determine a group of factors associated with increased risk for kernicterus. It was not possible to separate those infants with and without kernicterus at autopsy on the basis of the clinical factors evaluated.

Neonatal death in babies with rhesus isoimmunization.

In the 27 years, 1951--1977, 4315 babies weighing over 1 kg were born alive in Newcastle suffering from haemolytic disease of the newborn due to Rhesus isoimmunization; 197 (4.5 per cent) died within four weeks of delivery. Many babies with severe anaemia (cord Hb less than or equal to 8 g/dl) died of cerebral and/or pulmonary haemorrhage as a result of coagulation failure; others with hydrops had a chance of recovery with intensive care as long as there was no associated pulmonary hypoplasia. Hyaline membrane disease was no more common in babies with haemolytic disease than in other preterm babies of comparable birthweight, but incorrect assessment of gestational age prior to the induction of labour increased the risk of death from hyaline membrane disease. The introduction of closed chest cardiac massage virtually eliminated the risk of sudden unexpected death during exchange transfusion but there was still a 1.5 per cent chance of sudden circulatory collapse during exchange transfusion. Affected babies of less than 36 weeks gestation with respiratory problems face a substantial risk of kernicterus when the indirect serum bilirubin level exceeds 270 mumol/l (15 mg/100 ml). The establishment of a single referral centre for Rhesus isoimmunization reduced neonatal mortality in the area to half the national average in the early 1950's and this superiority was maintained throughout the next decade.