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Naphthalene poisoning due to exposure to mothballs is a common cause of toxicity in children worldwide. Naphthalene toxicity is known to cause hemolytic anemia, methemoglobinemia, and hepatic and renal injury. Neonates are more susceptible to the effects of oxidative stress from naphthalene because of their low glutathione stores and immaturity of hepatic enzymes. However, there are no reported cases of chronic fetal exposure to naphthalene during pregnancy. We report a novel case of chronic fetal exposure to naphthalene-containing mothballs that occurred from the second trimester through the third trimester of pregnancy. Our patient presented with hyperbilirubinemia, requiring exchange transfusion, severe hemolytic anemia, pulmonary hypertension, respiratory failure, and renal failure and progressed to develop “bronze baby” syndrome. Pregnant mothers should be diligently screened for such exposures and if found should receive psychiatric evaluation and counseling to prevent such devastating effects in neonates.

Background: In individuals affected with Hemoglobin SC (HbSC) disease, one β globin gene is affected by thesickle mutation (position 6, a single-base pair change encodes valine instead of glutamine) while the other βglobin gene contains a mutation for hemoglobin C (position 6, lysine is encoded instead of glutamine) In thiscompound heterozygous state individuals typically present with a milder sickle cell disease (SCD) coursecompared to those with homozygous HbS (HbSS) disease Although children with HbSC disease experience asignificant incidence of silent cerebral infarcts, acute stroke presentation is exceptionally rare Herein wedescribe a case of an adolescent male with historically uncomplicated HbSC disease, and otherwiseunremarkable sickle cell surveillance labs on admission presenting with new acute onset stroke CasePresentation: Our patient is a 16 year old male with uncomplicated HbSC disease and no history ofhospitalizations for vasoocclusive crisis He presented with 48 hours of difficulty focusing out of his left eye Physical exam revealed impaired right eye adduction, left eye nystagmus on lateral left gaze, and decreased sensation to touch to the left hemi face and left arm Strength and deep tendon reflexes were normal Normalgait was observed and he had no dysdiadochokinesia STAT MRI orbit and brain with contrast revealedmultiple foci of acute infarct involving the pons and left cerebral peduncle Vessel imaging with MRA wasconcerning for internuclear ophthalmoplegia secondary to stenosis in the posterior cerebral circulation Vitalsigns were normal for age and labs were overall mild and unchanged from his baseline (WBC 8750/mcL,Hemoglobin 13 5g/dL, Platelets 290,000/mcL, Reticulocyte 2 11%, CRP

BACKGROUND AND OBJECTIVES: High bilirubin levels are associated with sensorineural hearing loss (SNHL). However, few large studies of relative and excess risk exist. We sought to quantify the risk of SNHL in newborns who had bilirubin levels at or above American Academy of Pediatrics exchange transfusion thresholds (ETT). METHODS: Infants born at ≥35 weeks gestation in 15 Kaiser Permanente Northern California hospitals from 1995-2011 were eligible (N = 525 409). We used a nested double cohort design. The exposed cohort included subjects with ≥1 bilirubin level at or above ETT. The unexposed cohort was a 3.6% random sample of subjects with all bilirubin levels below ETT (10 unexposed per exposed). An audiologist, blinded to bilirubin levels, reviewed the charts of children in whom SNHL had been diagnosed before age 8 years to confirm the diagnosis. We calculated Cox proportional hazard ratios for time to diagnosis of SNHL. RESULTS: SNHL was confirmed in 11 (0.60%) of the 1834 exposed subjects and in 43 (0.23%) of the 19 004 unexposed. Only bilirubin levels ≥10 mg/dL above ETT were associated with a statistically significant increased risk of SNHL (hazard ratio: 36 [95% confidence interval (CI): 13 to 101]). Likewise, only bilirubin levels ≥35 mg/dL were associated with a statistically significant increased risk of SNHL (hazard ratio: 91 [95% CI: 32 to 255]). For subjects with total serum bilirubin levels 0 to 4.9 mg/dL above ETT, the upper limit of the 95% CI for excess risk was 0.5%. CONCLUSIONS: Only bilirubin levels well above ETT were associated with SNHL. At lower bilirubin levels, the excess risk of SNHL was low.

We cared for a term male infant born to Burmese immigrants. At about 24 hours a total serum bilirubin (TSB) was 9.3 mg/dL, and phototherapy was begun. It was stopped 48 hours later, with a TSB of 10.9 mg/dL, and he was discharged from the hospital with an appointment for a repeat TSB check 48 hours later. A few hours before the appointment he became listless and apneic, and his parents took him to the emergency department of the regional children’s hospital, where sepsis was suspected. The TSB was 41 mg/dL. He died 4 hours later, despite intensive care efforts, with opisthotonus and refractory hypotension. Blood drawn before the exchange transfusion had low glucose-6-phosphate dehydrogenase (G6PD) enzymatic activity, and sequencing of the G6PD gene revealed the G6PD Mahidol mutation (c.487G>A). Cultures and postmortem examination did not demonstrate an infectious process, but kernicterus was present. Acute kernicterus can mimic septic shock.

OBJECTIVES:Adolescents and young adults (A/YA) with sickle cell disease (SCD) are hospitalized in both children’s and general hospitals. We determined the effect of hospital type and provider specialty on outcomes of hospitalized A/YA with SCD and acute chest syndrome (ACS).METHODS:This retrospective cohort study used the 2007–2009 Premier Database, a large multi-institutional database, to identify 1476 patients ages 16 to 25 years with 2299 admissions with SCD and ACS discharged from 256 US hospitals from 2007 to 2009. Multilevel logistic regression and zero-truncated negative binomial regression were performed after adjustment for patient demographic, clinical, and hospital characteristics to test the association of hospital type and provider specialty on death, endotracheal intubation, simple or exchange transfusion, length of stay (LOS), and 30-day readmission.RESULTS:Of all admissions, 14 died and 45% were intubated. General hospitals had 13 deaths and were associated with higher intubation rates (predicted probability [PP], 48% [95% confidence interval (CI), 43%–52%]) and longer LOS (predicted mean LOS, 7.6 days [95% CI, 7.2–7.9]) compared with children’s hospitals (PP of intubation, 24% [95% CI, 5%–42%]; and predicted mean LOS, 6.8 days [95% CI, 5.6–5.8]). There was no difference by hospital type or provider specialty in PP of simple or exchange transfusion, or 30-day readmission.CONCLUSIONS:General hospitals carry higher intubation risks for A/YA with SCD and ACS compared with children’s hospitals. We need to better understand the drivers of these differences, including the role of staff expertise, hospital volume, and quality of ongoing SCD care.

Transfusion-transmitted malaria (TTM) in neonates is rare. TTM can occur in both endemic and nonendemic areas because the current tests used to screen the donor blood for malaria are unreliable when there is low parasitemia. Malaria must be considered as an important differential diagnosis for neonatal sepsis after exchange transfusion. Management strategy in TTM in the neonatal period is not standardized; exchange transfusion is often considered. We used intravenous artesunate in a case of severe malaria caused by Plasmodium vivax in a 30-week preterm neonate after packed red blood cell transfusion on day 19 of life. This is the first clinical report of parenteral artesunate successfully used in the neonatal period. We emphasize the need for further investigation of the safety and efficacy of intravenous artesunate in the treatment of severe neonatal malaria.

BACKGROUND: Acute chest syndrome (ACS) is a leading cause of hospitalization and death of children with sickle cell disease (SCD). An evidence-based ACS/SCD guideline was established to standardize care throughout the institution in February 2008. However, by the summer of 2009 use of the guideline was inconsistent, and did not seem to have an impact on length of stay. As a result, an implementation program was developed. OBJECTIVE: This quality-improvement project evaluated the influence of the development and implementation of a clinical practice guideline for children with SCD with ACS or at risk for ACS on clinical outcomes. METHODS: Clinical outcomes of 139 patients with SCD were evaluated before and after the development of the implementation program. Outcomes included average length of stay, number of exchange transfusions, average cost per SCD admission, and documentation of the clinical respiratory score and pulmonary interventions. RESULTS: Average length of stay decreased from 5.8 days before implementation of the guideline to 4.1 days after implementation (P = .033). No patients required an exchange transfusion. Average cost per SCD admission decreased from $30 359 before guideline implementation to $22 368. Documentation of the clinical respiratory score increased from 31.0% before implementation to 75.5%, which is an improvement of 44.5% (P < .001). Documentation of incentive spirometry and positive expiratory pressure increased from 23.3% before implementation to 50.4%, which is an improvement of 27.1% (P < .001). CONCLUSIONS: Implementation of a guideline for children with SCD with ACS or at risk for ACS improved outcomes for patients with SCD.

OBJECTIVES. Our aims were to estimate the efficacy of hospital phototherapy for neonatal jaundice and the number needed to treat to prevent one infant from reaching the exchange transfusion level.METHODS. From a cohort of 281 898 infants weighing ≥2000 g born at ≥35 weeks' gestation at 12 Northern California Kaiser hospitals from 1995 to 2004, we identified 22 547 who had a “qualifying total serum bilirubin level” within 3 mg/dL of the American Academy of Pediatrics 2004 guideline phototherapy threshold. We used multiple logistic regression to estimate the efficacy of hospital phototherapy within 8 hours at preventing the bilirubin level from exceeding the 2004 guideline's exchange transfusion threshold within 48 hours. We combined this efficacy estimate with other predictors of risk to estimate the numbers needed to treat at different values of covariates.RESULTS. Of the 22 547 eligible newborns, 5251 (23%) received hospital phototherapy within 8 hours of their qualifying bilirubin level. Only 354 (1.6%) ever exceeded the guideline exchange transfusion threshold; 187 (0.8%) did so within 48 hours. Among infants who did not have a positive direct antiglobulin test, hospital phototherapy within 8 hours was highly effective (adjusted odds ratio, 0.16; 95% confidence interval, 0.07–0.34). For infants with bilirubin levels 0–0.9 mg/dL above the phototherapy threshold, the estimated number needed to treat at mean values of covariates was 222 (95% CI: 107–502) for boys and 339 (95% CI: 154–729) for girls, ranging from 10 (95% CI: 6–19) for CONCLUSIONS. While hospital phototherapy is effective, the number needed to treat according to current guidelines varies considerably across different infant subgroups.

OBJECTIVE. Our goal was to identify trends in patient demographics and indications for and complications related to neonatal exchange transfusion over a 21-year period in a single institution using a uniform protocol for performing the procedure.METHODS. A retrospective chart review of 107 patients who underwent 141 single- or double-volume exchange transfusions from 1986–2006 was performed. Patients were stratified into 2 groups, 1986–1995 and 1996–2006, on the basis of changes in clinical practice influenced by American Academy of Pediatrics management guidelines for hyperbilirubinemia.RESULTS. There was a marked decline in the frequency of exchange transfusions per 1000 newborn special care unit admissions over the 21-year study period. Patient demographics and indications for exchange transfusion were similar between groups. A significantly higher proportion of patients in the second time period received intravenous immunoglobulin before exchange transfusion. There was a higher proportion of patients in the 1996–2006 group with a serious underlying condition at the time of exchange transfusion. During that same time period, a lower proportion of patients experienced an adverse event related to the exchange transfusion. Although a similar percentage of patients in both groups experienced hypocalcemia and thrombocytopenia after exchange transfusion, patients treated from 1996–2006 were significantly more likely to receive calcium replacement or platelet transfusion. No deaths were related to exchange transfusion in either time period.CONCLUSIONS. Improvements in prenatal and postnatal care have led to a sharp decline in the number of exchange transfusions performed. This decline has not led to an increase in complications despite relative inexperience with the procedure.

BACKGROUND AND OBJECTIVE: Several studies have shown the benefits of delayed cord clamping (DCC) in preterm and in healthy newborns at short and long term. Our objective was to evaluate the potentials benefits and risks of DCC in red cell alloimmunization. METHODS: This was a comparative before/after study of all living born neonates followed after fetal anemia requiring in utero transfusion. DCC was defined as cord clamping 30 seconds after birth. RESULTS: We included a continuous series of 72 neonates: 36 without DDC (group 1) and 36 with DDC (group 2). Hemoglobin at birth was lower in group 1 (10.2 vs 13.4 g/dL, P = .0003); 7 (25%) neonates in group 1 vs 24 (70.6%) in group 2 had no anemia at birth (P = .004). The rate of transfusion was similar between the 2 groups. Postnatal exchange transfusions were more likely performed in the group without DCC than in the group with DCC (47.2% vs 19.4%, P = .0124). Delay between birth and first transfusion was higher in group 2 (0 [0–13] vs 1 [0–21], P = .0274). The maximum level of bilirubin, the rate of intensive phototherapy, and the total duration of phototherapy were similar in the 2 groups. CONCLUSIONS: This study highlights a significant benefit of DCC in anemia secondary to red blood cell alloimmunization with a resulting decreased postnatal exchange transfusion needs, an improvement in the hemoglobin level at birth and longer delay between birth and first transfusion with no severe hyperbilirubinemia.

This article is adapted from a published evidence report concerning neonatal hyperbilirubinemia with an added section on the risk of blood exchange transfusion (BET). Based on a summary of multiple case reports that spanned more than 30 years, we conclude that kernicterus, although infrequent, has at least 10% mortality and at least 70% long-term morbidity. It is evident that the preponderance of kernicterus cases occurred in infants with a bilirubin level higher than 20 mg/dL. Given the diversity of conclusions on the relationship between peak bilirubin levels and behavioral and neurodevelopmental outcomes, it is apparent that the use of a single total serum bilirubin level to predict long-term outcomes is inadequate and will lead to conflicting results. Evidence for efficacy of treatments for neonatal hyperbilirubinemia was limited. Overall, the 4 qualifying studies showed that phototherapy had an absolute risk-reduction rate of 10% to 17% for prevention of serum bilirubin levels higher than 20 mg/dL in healthy infants with jaundice. There is no evidence to suggest that phototherapy for neonatal hyperbilirubinemia has any long-term adverse neurodevelopmental effects. Transcutaneous measurements of bilirubin have a linear correlation to total serum bilirubin and may be useful as screening devices to detect clinically significant jaundice and decrease the need for serum bilirubin determinations. Based on our review of the risks associated with BETs from 15 studies consisting mainly of infants born before 1970, we conclude that the mortality within 6 hours of BET ranged from 3 per 1000 to 4 per 1000 exchanged infants who were term and without serious hemolytic diseases. Regardless of the definitions and rates of BET-associated morbidity and the various pre-exchange clinical states of the exchanged infants, in many cases the morbidity was minor (eg, postexchange anemia). Based on the results from the most recent study to report BET morbidity, the overall risk of permanent sequelae in 25 sick infants who survived BET was from 5% to 10%.

BACKGROUND AND OBJECTIVES:Total serum bilirubin (TSB) levels ≥30 mg/dL are rare but potentially hazardous. A better understanding of their incidence, causes, and outcomes could help inform preventive efforts.METHODS:We identified infants born ≥35 weeks’ gestational age from 1995–2011 in Kaiser Permanente Northern California (n = 525 409) and examined the medical records of infants with a TSB ≥30 mg/dL to determine etiology and the occurrence of acute bilirubin encephalopathy. We reviewed inpatient and outpatient encounters through 2013 for evidence of sensorineural hearing loss (SNHL) or cerebral palsy (CP).RESULTS:We identified 47 infants with TSB ≥30 mg/dL (8.6 per 100 000 births). In 44 infants (94%), the hyperbilirubinemia occurred after the initial birth hospitalization. The etiology was not identified in 33 (70%). Glucose-6-phosphate dehydrogenase (G6PD) activity was measured in only 25 (53%) of whom 10 (40%) were deficient. Four children had acute bilirubin encephalopathy of whom 2 developed both CP and SNHL, and 1 developed isolated SNHL. These 3 infants all had G6PD deficiency and TSB >40 mg/dL. One additional 35-week infant with TSB 38.2 mg/dL had SNHL.CONCLUSIONS:Hazardous (≥30 mg/dL) hyperbilirubinemia is a rare event. No etiology could be identified from the clinical record in most cases. G6PD deficiency was the leading cause of hazardous hyperbilirubinemia when an etiology was identified, but many were not tested. Chronic, bilirubin-induced neurotoxicity was uncommon and occurred only in the setting of additional risk factors and TSB values well over (>15 mg/dL) the American Academy of Pediatrics exchange transfusion thresholds.

Objective. The religious convictions of parents who are Jehovah’s Witness adherents lead them to reject the use of exchange transfusions as therapy for severe hyperbilirubinemia in newborns in whom intensive phototherapy has failed to control this problem. Consequently, physicians caring for such infants may be obliged to initiate legal action to compel use of the procedure when severe hyperbilirubinemia not sufficiently responsive to phototherapy warrants an exchange transfusion. Our goal was to determine if we could use the potent inhibitor of bilirubin production, Sn-Mesoporphyrin (SnMP), to resolve the troubling medical-legal issues in such situations in 2 infants with hemolytic disease of the newborn who required exchange transfusions for severe hyperbilirubinemia but whose Jehovah’s Witness parents rejected the procedure. SnMP was administered in a single dose, as in previous studies, at the time when exchange transfusion would have been initiated and plasma bilirubin levels were monitored at close intervals thereafter.Methods. SnMP is a potent inhibitor of heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin. We found in earlier studies that in single doses of 6 μmol/kg birth weight, SnMP is extremely effective in moderating the course of hyperbilirubinemia and in eliminating the need for supplemental phototherapy in jaundiced newborns. In the 2 cases described, a single dose of SnMP (6 μmol/kg birth weight) was administered intramuscularly to severely jaundiced infants with immune hemolysis at a time when clinical circumstances dictated the need for exchange transfusion.Case 1. This patient was a preterm male infant (gestational age: 35 5/7 weeks; birth weight: 2790 g) whose plasma bilirubin concentration (PBC) at 1 hour after birth was 5.0 mg/dL. Despite intensive phototherapy with 3 banks of lights and 1 biliblanket, the PBC increased steadily with no diminution in the rate of increase for 75 hours. In view of the problems of immune hemolysis, and prematurity, and the inability of phototherapy to stop progression of hyperbilirubinemia, a decision to carry out an exchange transfusion was made; the decision was, however, rejected by the Jehovah’s Witness parents. Pending legal action to compel use of the procedure, a request to this (Rockefeller) laboratory for SnMP was made; its use was approved by the Food and Drug Administration; and the inhibitor was delivered to the physician-in-charge (D.P.M.) in Sioux Falls, South Dakota. The single dose of SnMP was administered to the infant at 75 hours after birth; the course of hyperbilirubinemia before and after the use of the inhibitor is shown in Fig 1.Case 2. This female term infant (gestational age: 38–39 weeks; birth weight: 4140 g) with immune hemolysis was delivered by cesarean section and because of problems related to meconium aspiration required helicopter transfer to the Special Care Nursery in Abilene, Texas, where 10 hours after birth the first PBC was determined to be 18.0 mg/dL. Double-bank phototherapy plus a biliblanket was initiated; a third bank of lights was later ordered. The PBC fluctuated in the ensuing 2 days between 13.8 to 25.8 mg/dL during which suggestive clinical signs of possible bilirubin encephalopathy became manifest. In view of the clinical circumstances and the continued severe hyperbilirubinemia, permission for a double-exchange transfusion was requested. The parents, who were Jehovah’s Witness adherents, refused the procedure. While preparing legal action to compel use of the exchange, a request was made to this (Rockefeller) laboratory for use of SnMP to attempt control of hyperbilirubinemia. With FDA approval, the SnMP was delivered to the attending neonatologist (J. R. M.) in Abilene and administered in a single dose (6 μmol/kg birth weight) at 56 hours after birth when the PBC was 19.5 mg/dL. The course of bilirubinemia before and after SnMP use is shown in Fig 2.Results and Conclusions. The use of SnMP to moderate or prevent the development of severe hyperbilirubinemia in newborns (preterm, near-term, term with high PBCs [15–18 mg/dL], ABO-incompatibility; glucose-6-phosphate dehydrogenase deficiency) has been extensively studied in carefully conducted clinical trials the results of which have been reported earlier. This inhibitor of bilirubin production has demonstrated marked efficacy in moderating the course of hyperbilirubinemia in all diagnostic groups of unconjugated neonatal jaundice. The 2 cases described in this report confirmed the efficacy of SnMP in terminating progression of hyperbilirubinemia in infants in whom phototherapy had failed to sufficiently control the problem and whose parents, for religious reasons, would not permit exchange transfusions. Interdiction of severe hyperbilirubinemia by inhibiting the production of bilirubin with SnMP can be an effective alternative to the use of exchange transfusion in the management of severe newborn jaundice that has not responded sufficiently to light treatment to ease concern about the development of bilirubin encephalopathy.

Objectives.The early discharge of neonates from hospitals makes transcutaneous measurement of total bilirubin concentration a useful tool to monitor neonatal jaundice. The objectives of this study were to determine whether 1) transcutaneous bilirubin (TcB) measurement, as performed using BiliCheck (BC), correlates with total serum bilirubin (TSB) levels, measured with standard laboratory methods and with high-pressure liquid chromatography (HPLC-B); 2) infant race, gestational age, postnatal age, or body weight interferes with the measurement of TcB levels in newborn infants; 3) the variability of the TcB measurement is comparable to the variability of TSB measurements; and 4) TcB measurements obtained from the forehead (BCF) and sternum (BCS) generate comparable results.Study Design.Newborn infants who were 30 weeks' gestational age and who underwent tests for TSB as part of their normal care in 6 different European hospitals were studied. A total of 210 infants were enrolled in the study, 35 at each site. Near simultaneous (within ± 30 minutes) blood collection for TSB and BCF and BCS measurements were performed. TSB levels were determined by the serum bilirubin method in use at each site, and all HPLC-B determinations were made at the same, independent laboratory.Results.The study group consisted of 140 white, 31 Asian, 14 Hispanic, 9 African, and another 16 newborns of different races. The correlation coefficient (r) between BCF and HPLC-B was 0.890 (95% confidence interval = 0.858–0.915). BCF and BCS generated similar results (r value = 0.890 for BCF and 0.881 for BCS), even if BCS slightly overestimated (mean error = −0.04 mg/dL) and BCF slightly underestimated (mean error = 0.96 mg/dL) in comparison with HPLC-B. Analysis of covariance demonstrated that BC accuracy was independent of race, birth weight, gestational age, and postnatal age of the newborn. Receiver operating characteristic curves were evaluated for BCF and TSB, each compared with HPLC-B. With the use of a cutoff point for HPLC-B of 13 mg/dL (222 μmol/L) and a cutoff of 11 mg/dL on the BCF and TSB, similar sensitivity/specificity (93%/73% for BCF, 95%/76% for TSB) were observed. The use of a cutoff point for HPLC-B of 17 mg/dL (290 μmol/L) and 14 mg/dL (240 μmol/L) for BCF and TSB also produced similar sensitivity/specificity (90%/87% for the BC and 87%/83% for TSB).Conclusions.Because the correlation coefficient for HPLC-B and BCF is very similar to that found for HPLC-B and laboratory TSB, BC could be used not only as a screening device but also as a reliable substitute of TSB determination. At higher levels of TSB, in which phototherapy and/or exchange transfusion might be considered, BC performed slightly better than the laboratory. The accuracy and precision of the TcB measurement in this study was observed to be comparable to the standard of care laboratory test.

Objective.To investigate whether apotransferrin administration and exchange transfusion can improve outcome in patients with the recently described recessive congenital iron overload disease, presenting with intrauterine growth retardation, severe lactic acidosis, aminoaciduria, and hemosiderosis of the liver that so far has been treatment-resistant and lethal.Methodology.Because the patients have hypotransferrinemia, hyperferritinemia, increased transferrin saturation, and bleomycin detectable iron in plasma, we designed a treatment regime aiming at decreasing free iron and iron overload. The serum transferrrin concentration was increased to adult level (2–5 g/L) by intravenous apotransferrin administrations and thereafter exchange transfusion was performed.Results.Two patients were treated. In patient 1, the transferrin saturation decreased from a baseline value of 100% and remained normal after the third exchange transfusion, and in patient 2, a reversible beneficial effect was seen on transferrin saturation and bleomycin-detectable iron. However, both infants died later of the disease, at 10 and 8 weeks of age, respectively.Conclusions.Exogenous apotransferrin administration proved to be safe and might deserve evaluation in other neonatal diseases with presence of free iron in plasma. hemosiderosis, metabolic acidosis, newborn infant, transferrin.

Objective. To determine practice patterns of office-based pediatricians and neonatologists in the treatment of neonatal hyperbilirubinemia in healthy, term newborns during 1992, before the publication of the practice guideline for treatment of neonatal jaundice by the American Academy of Pediatrics (AAP).1 The survey was undertaken to inform the AAP's Subcommittee on Hyperbilirubinemia on current practices and to aid it in its preparation of the guidelines. It was also anticipated that this survey would serve as a basis for comparison for a second survey to be performed several years after the publication of the practice guidelines.Methods. A self-administered questionnaire describing a single case of a jaundiced, breastfed 36-hour-old healthy, full-term infant with a total serum bilirubin concentration of 11.0 mg/dL (188 μM/L) was sent to a random sample of 600 office-based pediatricians and 606 neonatologists who were members of the AAP. The final response rate was 74%. Respondents were asked to answer questions regarding treatment of the case based on their actual practices. Ranges of total serum bilirubin concentration were provided as possible answers to questions on initiation of phototherapy and exchange transfusion, and interruption of breastfeeding. Respondents were also queried about frequency of serum bilirubin testing, locations of phototherapy administration, and factors influencing their therapeutic decisions.Results. Four hundred forty-two office-based pediatricians and 444 neonatologists completed the survey. There was a tendency for neonatologists to initiate both phototherapy and exchange transfusions at lower serum bilirubin concentrations than office-based general pediatricians. At a serum bilirubin of 13 to 19 mg/dL (222 to 325 μM/L), 54% of office-based pediatricians stated they would initiate phototherapy whereas 76% of neonatologists would do so. Forty percent of office-based practitioners said they would perform exchange transfusions at serum bilirubin levels of 20 to 25 mg/dL (342 to 428 μM/L), whereas 60% of neonatologists said they would. Only a small percentage of both office-based practitioners (13%) and neonatologists (16%) indicated they would interrupt breastfeeding at 8 to 13 mg/dL (137 to 222 μM/L); but with each incremental level of serum bilirubin, an increasing proportion of neonatologists would interrupt breastfeeding. Little correlation was found between treatment practices and demographic characteristics except for years in practice; physicians with the fewest years in practice (5 years or less) differed significantly from all other groups of physicians in initiating exchange transfusions at higher serum bilirubin concentrations.Conclusions. The results of this survey indicated a wide range of variation of opinion among both groups of physicians, most likely a reflection of the uncertainty and controversy surrounding these issues. The data may also reflect a possible wide range of “acceptable practice” as opposed to a narrow treatment standard. Office-based practitioners more closely approximated the new 1994 recommendations than neonatologists.1

Objective. Blue light phototherapy is commonly administered to neonates as treatment of indirect hyperbilirubinemia, often in conjunction with blood transfusions to treat hemolytic anemia. We observed a distinctive cutaneous complication of phototherapy in six neonates with hyperbilirubinemia. Methodology. We studied the clinical and histologic characteristics of the eruption, as well as the porphyrin levels in affected neonates. Five of the patients had erythroblastosis fetalis; the other had profound anemia from twin–twin transfusion. All of the neonates developed purpuric patches at sites of maximal exposure to the phototherapy lights, with dramatic sparing at shielded sites within 24 hours after initiation of the phototherapy. On discontinuation of phototherapy, all eruptions cleared within 1 week. Examination of skin biopsy sections showed purpura without significant inflammation or keratinocyte necrosis. Plasma porphyrins (copro- and proto-) were elevated in the two patients in which they were assessed. Conclusions. The distribution of the eruption in areas exposed to light and presence of circulating porphyrins suggest that porphyrinemia may underlie the light-induced purpuric eruption. Additional studies will be required to determine definitively the mechanisms of both the purpuric phototherapy-induced eruption and the development of increased blood porphyrin levels in these transfused neonates.

* Abbreviations: Rh — : Rhesus factor TSB — : total serum bilirubin Phototherapy was developed in the late 1950s and is today considered the mainstay of managing neonatal jaundice. Yet prominent academic leaders continued to promote the older approach of exchange transfusion well into the 1970s, despite the considerable risks involved. This article explores why phototherapy took so long to be embraced, and how pediatric residents were caught in the middle of the controversy.—Jeffrey P. Baker, MD, PhDSection Editor, Historical Perspectives The chief rationale of treating newborn jaundice is the prevention of kernicterus, a devastating and often fatal outcome attributed to bilirubin’s effects on the basal ganglia. Infants so affected commonly develop a characteristic choreoathetoid form of cerebral palsy accompanied by severe intellectual disability.1 In the mid-20th century, pediatric researchers scored a breakthrough by demonstrating the efficacy of exchange transfusion in preventing this devastating syndrome. The majority of infants thus treated were Rhesus factor positive (Rh+) children born to Rh– mothers exposed to the Rh factor during a previous pregnancy. Maternal antibodies to neonatal red blood cells caused extensive hemolysis, causing the total bilirubin level to rise rapidly and overwhelm the liver’s ability to process and excrete it. Exchange transfusion, rarely performed today, was a challenging procedure that might keep physicians up all night, patiently withdrawing the infant’s blood through an umbilical venous catheter in small increments by syringe and replacing them with an equal volume of donor blood. The procedure was technically difficult and fraught with the possibility of a fatal electrolyte or fluid imbalance.2 In the late 1950s, phototherapy emerged as another potential treatment of jaundice. In 1956 at Rochford General Hospital in Essex, England, Sister J. Ward noted that sunshine decreased neonatal jaundice. Meanwhile, hospital biochemists noted erroneously low bilirubin levels in samples sitting in sunlight before processing.3 Soon afterward came the first evidence … Address correspondence to Elliott Mark Weiss, MD, 550 First Ave #NBV 8S4-11, Department of Pediatrics, NYU School of Medicine, New York NY 10016. E-mail: elliottmweiss{at}gmail.com

Background. Sn-mesoporphyrin (SnMP) is a potent inhibitor of bilirubin production. In our previous studies a single dose (6 µmol/kg birth weight) significantly moderated hyperbilirubinemia and reduced phototherapy (PT) time by >75% when administered within 24 hours of birth to preterm infants. Objective. To directly compare the efficacy of SnMP and PT for controlling hyperbilirubinemia in term and near-term infants. Methods. Two randomized, sequentially analyzed trials (Study I: male term infants; Study II: infants of both sexes and gestational age [GA] 245-265 days) were conducted. SnMP (6 µmol/kg birth weight) or PT (Phillips F20T12/BB lamps) was administered to paired infants according to strict criteria of plasma bilirubin levels and age. Time of enrollment and closure of cases and crossover, if necessary, of SnMP infants to PT or all infants to exchange transfusion were precisely defined in each pair. SnMP or PT was considered superior if the time between enrollment and closure of the case was reduced by >24 hours over the alternative treatment or if crossover had occurred. Results. None of the 44 SnMP-treated infants required supplemental PT. Of the 22 pairs of term infants enrolled in Study I, SnMP proved superior to PT in 20 and equal in two. Of the 20 pairs of near-term infants enrolled in Study II, SnMP was superior in 12 and PT in two; six were tied. Two SnMP-treated infants were unpaired. The PT-treated infants in Study I required an average of 33 hours of treatment; those in Study II, 48 hours. None of the enrolled infants required exchange transfusion or interruption of breast-feeding. In both studies, times between case enrollment and closure were reduced by >30 hours in SnMP compared with PT infants; requirements for additional days of medical observation and bilirubin measurements were also significantly less in SnMP infants. Conclusion. A single dose of SnMP entirely supplanted the need for PT in jaundiced term and near-term newborns and significantly reduced medical resource use to monitor hyperbilirubinemia.

A neonatal bilirubin workshop took place at The Rockefeller University on June 20 through 22, 1993 to consider controversial issues in the field of neonatal jaundice and bilirubin neurotoxicity, particularly as they relate to management. The conference was sponsored by the National Institute of Child Health and Human Development (Pregnancy and Perinatology Branch, Center for Mothers and Children), The Rockefeller University, and the Consiglio Nazionale delle Richerche (Italy). tk;4Presentations and discussion emphasized diagnosis, biochemistry, and mechanisms of bilirubin toxicity, the definition and consequences of kernicterus, and the appropriateness and safety of the various therapies currently in use. Identification of future research needs was an important agenda item. The conferees agreed that conventional management of jaundice in the newborn with phototherapy and exchange transfusion, as well as with phenobarbital in certain situations, had significantly reduced the occurrence of "traditional" kernicterus. However, the conferees acknowledged that the classical definition of kernicterus was in need of re-examination in view of the potential of bilirubin as a CNS toxin. Early discharge of newborns from the hospital has significantly altered diagnostic and therapeutic management of neonatal jaundice, transforming it into an outpatient problem. This transformation raises new questions regarding the best time to ascertain the cause(s) of jaundice and to identify risk factors to insure optimal management of the infant. Review of the current state of knowledge of bilirubin metabolism focused on new methods for measurement of unconjugated and conjugated bilirubin, measurement of bilirubin synthesis rates, the molecular biology of bilirubin conjugation and the developmental role of the family of enzymes known as glucuronyl transferase(s), and the role of genetic and other host factors in determining the safety or toxicity of bilirubin in the newborn.

Objective. A widely published set of exchange transfusion criteria lowers critical bilirubin concentrations when the serum albumin falls to Design and participants. The bilirubin/albumin ratio was defined as a reliable indicator of bilirubin-albumin binding if the frequency curves of specific unbound bilirubin concentrations are normally distributed functions of the ratio. Therefore the bilirubin/albumin ratios at which the unbound bilirubin reached 10, 15, and 20 nmol/L were determined by the peroxidase method in 35 well full-term, 10 ill full-term, and 19 ill preterm neonates. The frequency curves for each unbound bilirubin concentration plotted against the bilirubin/albumin ratio were tested for normality. Results. The frequency of each unbound bilirubin concentration was a normally distributed function of the bilirubin/albumin ratio. Furthermore, the mean ratio at which each unbound bilirubin occurred did not differ significantly among the groups of neonates. Conclusion. The bilirubin/albumin ratio is a simple, nonambiguous way of incorporating the serum albumin concentration into exchange transfusion criteria.

OBJECTIVES: Bordetella pertussis is a common, underrecognized, and vaccine-preventable cause of critical illness with a high mortality in infants worldwide. Patients with severe cases present with extreme leukocytosis and develop refractory hypoxemia and pulmonary hypertension that is unresponsive to maximal intensive care. This may reflect a hyperviscosity syndrome from the raised white blood cell (WBC) count. Case reports suggest improved outcomes with exchange transfusion to reduce the WBC count. Our objective was to quantify possible benefits of aggressive leukodepletion. METHODS: We, as a regional PICU and extracorporeal membrane oxygenation referral center, adopted a strategy of aggressive leukodepletion in January 2005. The impact of this strategy on crude and case mix–adjusted survival of all infants who were critically ill with B pertussis were compared with control subjects from January 2001 to December 2004 and Extracorporeal Life Support Organisation registry data. RESULTS: Nineteen infants (7 [37%] boys) received intensive care for B pertussis from 2001 to 2009. Admission WBC counts were equivalent in 2 time periods: 2001–2004 (mean: 52 000/μL) and 2005–2009 (mean: 75 000/μL). In 2001–2004, 5 (55%) of 9 patients survived the ICU. Between 2005 and 2009, 9 (90%) of 10 patients survived. When case-mix adjustment for age, WBC count, and extracorporeal membrane oxygenation referral were considered, the 2001–2004 predicted survival (4.4 [49%] of 9.0) was equivalent to the observed mortality (4.0 [44%] of 9.0). Between 2005 and 2009, observed mortality (1.0 [10%] of 10.0) was significantly better than predicted (4.7 [47%] of 10.0). CONCLUSIONS: Leukodepletion should be considered in critically ill infants with B pertussis and leukocytosis.

The effect of an exchange transfusion on antioxidants in the plasma of newborns with rhesus hemolytic disease was studied. The antioxidant concentrations in donor blood were similar to normal adult values except for the lower vitamin C concentrations. Exchange transfusion decreased the newborns' iron and ferritin levels and increased their ceruloplasmin and transferrin (primary antioxidants) concentrations and latent iron-binding capacity. The changes in secondary antioxidant concentrations were variable; uric acid and thiols were stable, vitamin C and bilirubin fell, and vitamin E rose. The total peroxyl-radical trapping capacity of the secondary antioxidants did not change significantly. The fall in levels of thiobarbituric acid reactive substances, an index of lipid peroxidation, was related to the lower levels present in the donor blood. Exchange transfusion rapidly produced variable changes in the concentrations of prooxidant and antioxidant substances in plasma and may thus influence free radical metabolism in the newborn.

Standard recommendations for evaluating and treating jaundice in term babies include following all babies closely for jaundice, obtaining several laboratory tests in those with early jaundice or bilirubin levels more than 12 to 13 mg/dL (205 to 222 µmol/L), using phototherapy to try to keep bilirubin levels below 20 mg/dL (342 µmol/L), and doing exchange transfusions if phototherapy fails, regardless of the cause of the jaundice. These recommendations are likely to lead to unnecessary testing and treatment of many jaundiced term infants. Because most jaundiced infants have no underlying illness, and the generally recommended laboratory tests lack sensitivity and specificity, they are seldom useful. In most babies, the only blood tests needed to evaluate jaundice are the blood type and group (of baby and mother) and a direct Coombs' test. A determination of direct bilirubin level should be added if jaundice is prolonged (>2 to 4 weeks) or the baby has other signs of illness. Bilirubin toxicity is rare in term babies without hemolysis. In this low-risk group, the risks and cost of identifying and treating high bilirubin levels may exceed the benefits. Such infants need not be closely followed for jaundice. If significant jaundice is nonetheless found, treatment should be deferred to relatively high levels of serum bilirubin, with a goal of keeping bilirubin levels below 400 to 500 µmol/L (23.4 to 29.2 mg/dL). Babies with hemolytic disease should be followed more closely, and their bilirubin levels kept below 300 to 400 µmol/L (17.5 to 23.4 mg/dL). These recommendations should be reevaluated as new data become available. In the meantime, currently available data justify an approach to the jaundiced term infant that is less aggressive than previously recommended.

Scrub typhus called tsutsugamushi disease, is a mite-born acute febrile disease caused by Rickettsia tsutsugamushi. To our knowledge, neonatal scrub typhus has not been reported in the literature. We report on a 26-day-old newborn with aseptic meningitis. The newborn showed an increased specific 1gM antibody to R.tsutsugamushi conjointly with his mother's 1gM titer to the organism. This is the first case in the literature documenting neonatal scrub typhus and may be related to infection in the mother. CASE REPORT A 26-day-old male newborn was well until 4 days prior to this admission. He suffered from intermittent high fever, abdominal distention, and skin pallor.

OBJECTIVE: The objective of this study was to assess whether the use of high-dose intravenous immunoglobulin (IVIG) in late-preterm and term newborns with severe isoimmune hemolytic jaundice caused by Rh and ABO incompatibility was a risk factor for necrotizing enterocolitis (NEC). METHODS: An observational, retrospective study that encompassed 16 years was conducted. A total of 492 liveborn infants who were of ≥34 weeks' gestation and had severe isoimmune hemolytic jaundice caused by Rh (n = 91) and ABO (n = 401) incompatibility and were treated with phototherapy were included in the study. IVIG (500 mg/kg over 2–4 hours) was indicated when total serum bilirubin level plus 2 points reached 85% of the cutoff value for performing exchange transfusion. RESULTS: A total of 167 (34%) infants received IVIG. NEC was diagnosed in 11 (2.2%) patients: 10 (6%) in the IVIG-treated group and 1 (0.3%) in the non–IVIG-treated group. Five patients required urgent operation, and 1 of them died as a result of massive intestinal necrosis. Another patient died 2 years later as a result of short bowel syndrome. In the multivariate analysis, cesarean delivery (odds ratio [OR]: 3.76 [95% confidence interval (CI): 1.10–12.90), Apgar test at 5 minutes (OR: 0.50 [95% CI: 0.40–0.64), and IVIG (OR: 31.66 [95% CI: 3.25–308.57]) were independent factors significantly associated with NEC. CONCLUSIONS: The use of high-dose IVIG for severe isoimmune hemolytic jaundice in late-preterm and term infants was associated with a higher incidence of NEC.

Results of the National Institute of Child Health and Human Development Randomized Controlled Trial of Phototherapy were examined for the relationship of neonatal bilirubin level to neurological and developmental outcome at 6-year follow-up. This analysis focused on 224 control children with birth weight of less than 2000 g. Bilirubin levels were maintained below previously specified levels by the use of exchange transfusion only (24%). Rates of cerebral palsy were not significantly higher for children with elevated maximum bilirubin level than for those whose level remained low. No association was evident between maximum bilirubin level and IQ (Full Scale, Verbal, or Performance) by simple correlation analysis (r = -.087, P = .2 for Full Scale) or by multiple linear regression adjusting for factors that covary with IQ (β = -.15, P = .58). IQ was not associated with mean bilirubin level, time and duration of exposure to bilirubin, or measures of bilirubin-albumin binding. Thus, over the range of bilirubin levels permitted in this clinical trial, there was no evidence of bilirubin toxicity to the central nervous system. Measures used to control the level of bilirubin in low birth weight neonates appear to prevent effectively the risk of bilirubin-induced neurotoxicity.

OBJECTIVES. Acute intravascular hemolysis after exchange transfusion with glucose 6-phosphate dehydrogenase–deficient blood has been reported; however, it is not routine to screen donor blood for glucose 6-phosphate dehydrogenase deficiency while performing exchange transfusion. We hypothesized that exchange transfusion with glucose 6-phosphate dehydrogenase–deficient blood would lead to a less-than-expected decrease in total serum bilirubin. The objective of this study was to evaluate the effect of exchange transfusion with glucose 6-phosphate dehydrogenase–deficient blood in neonates with idiopathic hyperbilirubinemia on postexchange total serum bilirubin levels, duration of phototherapy, and need for repeat exchange transfusions. METHODS. All neonates who were undergoing exchange transfusion for idiopathic hyperbilirubinemia were enrolled. A sample of donor blood was collected at the time of exchange transfusion for a glucose 6-phosphate dehydrogenase assay. The standard criteria for starting and stopping phototherapy and exchange transfusion were applied. RESULTS. During the 1-year study period, 21 infants underwent exchange with glucose 6-phosphate dehydrogenase–deficient blood, and 114 neonates with similar baseline characteristics underwent exchange transfusion with glucose 6-phosphate dehydrogenase–normal blood. From 6 to 60 hours after exchange transfusion, there was a significantly lesser drop in total serum bilirubin in the recipients of glucose 6-phosphate dehydrogenase–deficient donor blood compared with recipients of glucose 6-phosphate dehydrogenase–normal blood. The mean duration of phototherapy in the postexchange period and number of infants who underwent repeat exchange transfusions were significantly higher in recipients of glucose 6-phosphate dehydrogenase–deficient donor blood in comparison with control subjects. Concurrently, there was a significantly higher drop in hematocrit and rise in plasma hemoglobin in the glucose 6-phosphate dehydrogenase–deficient donor group. CONCLUSIONS. Exchange transfusion with glucose 6-phosphate dehydrogenase–deficient donor blood leads to a lesser drop in postexchange total serum bilirubin. It prolongs the duration of phototherapy and increases the need for repeat exchange transfusions.

OBJECTIVES. The purpose of this study was to compare the efficiency and safety of exchange transfusion by using peripheral arteries and veins with that of conventional exchange transfusion via the umbilical vein in treating neonatal pathologic hyperbilirubinemia.PATIENTS AND METHODS. We retrospectively reviewed the medical charts of all neonates who had undergone exchange transfusion at our institution from January 1995 to December 2006. Causes of jaundice, efficiency of exchange transfusion in lowering serum bilirubin concentrations, adverse events, and outcomes were recorded. Data were compared between neonates who had undergone exchange transfusion via the peripheral arteries and veins method and those who had undergone exchange transfusion via the umbilical vein method. Data were also compared between stable neonates (body weight > 1500 g without medical problems other than jaundice) and unstable neonates.RESULTS. A total of 123 exchange-transfusion procedures were performed in 102 neonates in the 12-year study period: 24 were performed via the umbilical vein method and 99 via the peripheral vessels method. A total of 87 procedures were performed in 75 stable neonates and 36 in 27 unstable neonates. There was no significant difference in reduction of serum bilirubin level from circulation or the duration of procedures between the 2 methods. Eight neonates died before discharge, but none of the deaths seem to have been attributable to the exchange-transfusion procedure. Severe adverse events occurred more commonly in the umbilical vein group than the peripheral arteries and veins group in the stable neonates. All of the severe and minor events resolved completely without noticeable sequelae before discharge.CONCLUSIONS. Exchange transfusion using peripheral arteries and veins is efficient and effective in reducing serum bilirubin from circulation and is associated with few adverse events. This method should be considered for all neonates requiring exchange transfusion for treatment of neonatal hyperbilirubinemia.

We report a case series of acute arsenic poisoning of 2 siblings, a 4-month-old male infant and his 2-year-old sister. Each child ingested solubilized inorganic arsenic from an outdated pesticide that was misidentified as spring water. The 4-month-old child ingested a dose of arsenic that was lethal despite extraordinary attempts at arsenic removal, including chelation therapy, extracorporeal membrane oxygenation, exchange transfusion, and hemodialysis. The 2-year-old fared well with conventional therapy.

A 3-month-old infant of 33 weeks' gestation was hospitalized with pneumonia caused by Bordetella pertussis. Respiratory insufficiency worsened, and on hospital day 3, there was severe pulmonary dysfunction (arterial oxygen pressure/fraction of inspired oxygen ratio: 120), extreme leukocytosis (white blood cell count 104 000/mm3), and severe pulmonary hypertension as assessed by 2-dimensional echocardiogram. A double volume exchange transfusion was performed to reduce the leukocyte mass. Oxygenation began to improve during the exchange and continued to improve over the ensuing 31 hours (arterial oxygen pressure/fraction of inspired oxygen ratio: 280). The white blood cell count fell dramatically after the exchange, and the rate of rise was slower after exchange therapy compared with preexchange.

Jaundice occurs in most newborn infants. Most jaundice is benign, but because of the potential toxicity of bilirubin, newborn infants must be monitored to identify those who might develop severe hyperbilirubinemia and, in rare cases, acute bilirubin encephalopathy or kernicterus. The focus of this guideline is to reduce the incidence of severe hyperbilirubinemia and bilirubin encephalopathy while minimizing the risks of unintended harm such as maternal anxiety, decreased breastfeeding, and unnecessary costs or treatment. Although kernicterus should almost always be preventable, cases continue to occur. These guidelines provide a framework for the prevention and management of hyperbilirubinemia in newborn infants of 35 or more weeks of gestation. In every infant, we recommend that clinicians 1) promote and support successful breastfeeding; 2) perform a systematic assessment before discharge for the risk of severe hyperbilirubinemia; 3) provide early and focused follow-up based on the risk assessment; and 4) when indicated, treat newborns with phototherapy or exchange transfusion to prevent the development of severe hyperbilirubinemia and, possibly, bilirubin encephalopathy (kernicterus).

Objective. The objective of this study was to evaluate the Minolta/Hill-Rom Air-Shields Transcutaneous Jaundice Meter model JM-103. Methods. We studied a convenience sample of 849 newborns ≥35 weeks of gestation in 3 hospitals. These infants had total serum bilirubin (TSB) levels measured on clinical indication, and transcutaneous bilirubin (TcB) levels were obtained within 1 hour of the TSB levels. The population was 59.2% white, 29.8% black, 4.5% East Asian, 3.8% Middle Eastern, 1.6% Indian/Pakistani, and 1.1% Hispanic. Results. There was a close correlation between TSB and TcB values in all of the population groups: white (n = 503, r = .949); black (n = 253, r = .822); and East Asian, Indian/Pakistani, and Hispanic (n = 93, r = .926). In the black population, the correlation was less close than in the other groups, and differences between the TcB and TSB measurements tended to increase with rising TSB values. JM-103 values differed from TSB values by 3 mg/dL or more in 2% of white, 3.2% of other, and 17.4% of black infants. In these black infants, the JM-103 value was always greater than the TSB value. Conclusions. We conclude that TcB measurements using the JM-103 jaundice meter correlate very closely with TSB levels over the range of TSB encountered in this study. Because only 3.3% of our infants had TSB values >15 mg/dL (257 μmol/L), more data are needed in this range of TSB concentration. The correlation in black infants is not as close as in other groups, but because the tendency in blacks is for the JM-103 to overestimate serum bilirubin levels, dangerous clinical errors are unlikely to occur. The measurement technique is rapid and simple, and it is easy to perform repeated measurements over time, thus reducing the likelihood of error. TcB measurements with the JM-103 jaundice meter should obviate the need for most serum bilirubin levels in newborn infants ≥35 weeks of gestation, although serum bilirubin measurements are still required when treatment with phototherapy or exchange transfusion is being considered.

Severe neonatal hyperbilirubinemia can occur without apparent reason in term healthy breast-fed infants and some develop kernicterus. The aim of our study was to assess the incidence of severe hyperbilirubinemia in term healthy newborns discharged from the hospital. From January 1 through December 31, 1994, 6705 infants were delivered at Bikur-Cholim and Misgav-Ladach Community Hospitals. All 1448 newborns discharged with a serum bilirubin level >10.0 mg/dL were instructed to return to the hospital within 3 days for follow-up, as well as bilirubin determination. Twenty-one newborns with a bilirubin level >18.0 mg/dL were identified and readmitted at mean ± standard deviation (SD) 5.5 ± 1.8 (range, 5 to 10 days of life). This represents 1.7% of the 1220 infants who returned for follow-up examination. Mean ± SD serum bilirubin levels at readmission were 19.6 ± 2.5 mg/dL. All but one of the infants were breast-fed. No cases of ABO incompatibility were found and two newborns were glucose-6-phosphate dehydrogenase (G6PD)-deficient. Sepsis work-up and direct Coomb's tests were negative in all cases. None had hemolysis or were found to have any cause for hyperbilirubinemia other than breast-feeding. Phototherapy was provided in all but two cases, and an exchange transfusion was performed in one case. Three additional infants, with bilirubin levels

In premature newborns, bilirubin-induced changes in the auditory brainstem response (ABR) begin at unbound (nonalbumin-bound or “free”) bilirubin levels above .5 μg/dL,1 and kernicterus becomes likely at levels between ∼1 and 1.5 μg/dL (.017-.026 μmol/L).2,3 In term newborns, however, unbound bilirubin levels between .9 and 2 μg/dL, which would be associated kernicterus in premature newborns, produce only subtle, reversible changes in ABR wave latency and amplitude.4 Although the unbound bilirubin levels associated with kernicterus in term newborns are unknown, they clearly are greater than the levels associated with kernicterus in premature infants. This indicates that, as with the total bilirubin and total bilirubin/albumin ratio, the unbound bilirubin levels associated with kernicterus increase as birth weight and gestation increase.1,5 We have been using a Food & Drug Administration-approved method6 for measuring unbound bilirubin in jaundiced newborns as an adjunct to their clinical care since 1998. We use a weight-based unbound bilirubin reference value of 1.3 μg/dL/kg (the level of unbound bilirubin at which exchange transfusion should be considered) up to a maximum of 4 μg/dL to accommodate the need to increase the reference unbound bilirubin as birth weight increases and to incorporate the solubility limits of unbound bilirubin at ph 7.4 (∼4 μg/dL) into the reference criteria.1–5,7–9 We recently encountered a term, jaundiced newborn that developed acute shock and died, apparently from kernicterus. This report describes the infant’s clinical course and bilirubin-albumin binding data. This case provides insight into the levels of unbound bilirubin associated with kernicterus in term infants as well as the acute changes in distribution of the bilirubin load (miscible bilirubin pool) between the tissues and the vascular space following the onset of kernicterus. A 110-hour-old (4.5-day-old) Nigerian male newborn presented to … Reprint requests to (C.E.A.) Division of Neonatology, Department of Pediatrics, California Pacific Medical Center, 3850 California St, San Francisco, CA 94118. E-mail: ligand{at}centurytel.net

Objective. In the era of early discharge of newborns from the hospital, newborns with ABO incompatibility are at especially greater risk for developing a subsequent significant hyperbilirubinemia because some of these infants also may present with some degree of ABO isoimmune disease. In this study, we aimed to determine prospectively the critical serum total bilirubin level to predict significant hyperbilirubinemia and severe hemolytic disease in healthy term newborns with ABO incompatibility based on a serum bilirubin measurement made at a postnatal age at which all newborns are at the hospital before discharge and at which any therapeutic intervention, if necessary, could be started as early as possible.Methods. A total of 136 healthy term newborns with ABO (O-A or O-B) blood group incompatibility were followed prospectively with daily serum total bilirubin measurements for the first 5 days of life. Newborns with serum total bilirubin levels of ≥5 mg/dL and an increase in serum total bilirubin concentration of >0.5 mg/dL/h in the first 24 hours, ≥12 mg/dL on day 2, ≥15 mg/dL on day 3, and ≥17 mg/dL on days 4 and 5 were defined to have significant hyperbilirubinemia and were started on phototherapy treatment. Additional treatment modalities, including intense phototherapy, intravenous immunoglobulin treatment, and exchange transfusion, were used when serum bilirubin concentrations exceeded 20 mg/dL or increased by >1 mg/dL/h despite a phototherapy treatment of at least 4 hours. The additional assessment of the predictive ability of the sixth-hour serum total bilirubin value in determining the development of significant hyperbilirubinemia was made on the basis of the placement of any of the first 5 days’ serum bilirubin measurements in the ≥90th percentile of the study population. On the basis of the percentile tracks constructed from the 10th, 35th, 50th, 60th, and 90th percentiles of serum total bilirubin values, a nomogram demonstrating the 3 percentile tracks as risk zone demarcators with divided risk zones was produced.Results. Twenty-nine newborns (21.3%) had significant hyperbilirubinemia. There were significant differences between the newborns who did and the newborns who did not develop significant hyperbilirubinemia with respect to the reticulocyte count (4.39 ± 3.46% vs 2.95 ± 1.63) and the presence of a direct antiglobulin test positivity (6 of 23 vs 0 of 107) and a sibling with neonatal jaundice (6 of 23 vs 5 of 102). A mean serum bilirubin level of ≥4 mg/dL at the sixth hour of life was determined to have the highest sensitivity (86.2%) and negative predictive value (94.5%) and a positive predictive value of 39.7% to predict the newborns who would develop significant hyperbilirubinemia. At the mean serum bilirubin level of 6 mg/dL, the sensitivity, specificity, and negative and positive predictive values were 100%, 91.5%, 100%, and 35.3%, respectively, in diagnosing 6 cases of severe ABO hemolytic disease. On the hour (age)-specific percentile-based nomogram, the zone above the 90th percentile was determined as high risk and that below the 35th percentile as low risk.Conclusions. The reticulocyte count, a positive direct antiglobulin test, and the presence of a sibling with neonatal jaundice were determined to be the good predictors for the development of significant hyperbilirubinemia and severe hemolytic disease of the newborn. A serum bilirubin measurement and the use of the critical bilirubin levels of 4 mg/dL and 6 mg/dL at the sixth hour of life will predict nearly all newborns who will have significant hyperbilirubinemia and those who will develop severe hemolytic disease of the newborn, respectively. An hour (age)-specific percentile-based nomogram can be used to predict which newborn is at high risk (≥90th percentile), intermediate risk (35th–90th percentiles), and low risk (

* Abbreviations: AAP = : American Academy of Pediatrics • G-6-PD = : glucose-6-phosphate dehydrogenase The American Academy of Pediatrics (AAP) Subcommittee on Hyperbilirubinemia is currently revising the practice parameter (guidelines) on neonatal hyperbilirubinemia published in October 1994.1 Although this revision is in progress, the Subcommittee wishes to bring the issue of kernicterus to the attention of the pediatric community and provide additional information pending a more formal assessment of the literature and an analysis of the risks and benefits of new approaches to the jaundiced infant. The Joint Commission on Accreditation of Healthcare Organizations has already issued an alert on this subject.2 Kernicterus, or bilirubin encephalopathy, is a condition caused by bilirubin toxicity to the basal ganglia and various brainstem nuclei. In the acute phase, severely jaundiced infants become lethargic, hypotonic and suck poorly. If the hyperbilirubinemia is not treated, the infant becomes hypertonic and may develop a fever and a high-pitched cry. The hypertonia is manifested by backward arching of the neck (retrocollis) and trunk (opisthotonus). Surviving infants usually develop a severe form of athetoid cerebral palsy, hearing loss, dental dysplasia, paralysis of upward gaze and, less often, intellectual and other handicaps. Kernicterus is a condition that is unfamiliar to most pediatricians practicing today. In the 1940s and 1950s, kernicterus was a common complication of hyperbilirubinemia associated with Rh erythroblastosis fetalis and, occasionally, ABO hemolytic disease. With the introduction of exchange transfusion, kernicterus became much less common. The use of Rh immunoglobulin all but eliminated erythroblastosis fetalis and phototherapy drastically reduced the need for exchange transfusion. In the last several years, however, there have been reports of kernicterus associated with extremely high serum bilirubin levels.3–9Most of these infants did not have obvious hemolytic disease or another recognized cause of neonatal jaundice. Many appeared to be otherwise healthy, breastfeeding newborns although frequently they were not receiving adequate nutrition and hydration. …

We performed a questionnaire survey about 42 patients with Crigler–Najjar syndrome type 1 who were currently alive. Information was obtained on their age, sex, birth weight, gestation, parental consanguinity, other family members affected, age of onset of jaundice, neonatal and postneonatal bilirubin values, neonatal and postneonatal therapy, problems faced with phototherapy, liver transplantation, current growth status, current neurologic status, and the status of hearing. Patients were between 2 months and 21 years of age. There were 18 males and 24 females. Thirty-nine patients had been born at full term gestation and 3 had been preterm. Jaundice was noted on postnatal day 1 in 34%, between days 2 and 4 in 55%, and after day 11 of life in 11% of patients. In the neonatal period bilirubin values (mean ± SD) were typically 19.8 ± 4.5 mg/dL. Eighty-six percent of patients had neonatal peak bilirubin values of >20 mg/dL. Parental consanguinity was present in 44% and a history of Gilbert's disease in one parent was present in 10% of patients. Causes of exacerbations of jaundice reported were respiratory infections, febrile illnesses, vaccinations, fasting, surgery, emotional stress, and noncompliance with treatment. Neonatal therapy consisted of exchange transfusion in 28%, phototherapy in 79%, phenobarbitone in 20%, and cholestyramine, albumin, infusions, and plasmapheresis in one case each. The mainstay of postneonatal therapy was home phototherapy for 10 to 16 hours, primarily at night during sleep, using blue lights or a combination of blue and fluorescent lights. Some patients used innovatively designed phototherapy units. Problems reported with phototherapy were decreased effectiveness with age, poor compliance, restriction of activity and play, inability to travel or take vacations, irritation from eye shades, difficulty keeping eye protection on, difficulties in temperature maintenance, tanning of the skin, embarrassment from the need to be nearly nude during phototherapy, and difficulty in procuring phototherapy lamps. Other therapies that had been tried included oral agar, albumin infusions, antioxidants, acupuncture, bilirubin oxidase, calcium infusions, clofibrate, cruciferous vegetables, cholestyramine, chlorpromazine, flumecinol, plasmapheresis, tin mesoporphyrin, ursodeoxycholic acid, and urinary alkalinization. Fifteen children had undergone liver transplantation (5 auxiliary and 10 orthotopic). All 42 patients are reportedly of normal height and weight. Neurodevelopmental status is said to be normal in 77% of patients. Two patients have kernicterus, 4 have cerebellar symptoms, and 1 each has developmental delay, mild intention tremor, and mild speech delay. Hearing was reported to be normal in 94% of patients. The 2 children with hearing loss have conductive loss from otitis media. With home phototherapy prolonged, survival free of neurologic deficits is possible in Crigler–Najjar syndrome type 1, but there are many problems associated with phototherapy. Avoiding exacerbations of jaundice is an important aspect of management. Liver transplantation offers the prospect of cure but its risk versus benefit ratio is undetermined. Hearing loss was absent in the patients surveyed despite prolonged exposure to high bilirubin levels, which suggests that bilirubin may not be as ototoxic as is commonly believed.

To the Editor.— In October 2004, the Subcommittee on Hyperbilirubinemia of the American Academy of Pediatrics (AAP) issued a clinical practice guideline on the management of hyperbilirubinemia in the newborn infant of ≥35 weeks' gestation.1 On the basis of the best available scientific evidence and expert opinion, these guidelines incorporated specific figures for suggesting follow-up procedures according to hour-specific nomograms,2 indications to initiate phototherapy in hospitalized infants, and bilirubin concentrations that are indicative of the need for a double-volume exchange transfusion. The application of these …

We present two near term sick infants with unanticipated kernicterus noted at autopsy, which developed in the absence of hemolysis and at serum bilirubin levels that would not have been considered neurotoxic. The kernicterus evolved in the context of known experimental conditions that would have favored the passage of unbound bilirubin across a disrupted blood brain barrier with injury of specific neurons. The relationship between serum bilirubin concentrations and the development of kernicterus in the term infant is complex. While a distinct link between the maximum recorded level of serum bilirubin and the occurrence of kernicterus is apparent with hemolytic disease of the newborn (most often due to Rh isoimmunization), the risk is less clear in markedly jaundiced babies without hemolytic disease.1-6Moreover, in some instances, clinical and pathologic kernicterus has been observed in premature infants without hemolytic disease and with low bilirubin levels.7,8 The management of jaundice in sick term newborns is a challenge to clinicians vis a vis the risks of undertreatment and overtreatment. To underscore the complexity of this important clinical relationship, we present two patients of unanticipated kernicterus noted at autopsy which evolved in two sick infants, one near term and the other term, in the absence of overt hemolysis and at serum bilirubin concentrations that usually would have not been considered neurotoxic. ### Patient 1 BM was a 2210-g, 37-week-old, Latin-American female, born to a 20-year gravida 4, para 3 mother, whose pregnancy was uncomplicated. The infant was delivered vaginally and was meconium stained. The Apgar scores were 9 at 1 and 5 minutes, respectively. Upon delivery the infant was noted to be wasted, with a distended abdomen. No masses could be palpated. An initial hematocrit was 70% and a partial exchange transfusion was performed. The post transfusion hematocrit was 64%. On the second …

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is frequently associated with neonatal hyperbilirubinemia, and sometimes kernicterus, often in the absence of any identifiable trigger or hematological evidence of hemolysis. The aim of this study was to compare the incidence and severity of, and the effect of phototherapy on, jaundice in G-6-PD-deficient vs G-6-PD-normal neonates in the Sephardic-Jewish community. Healthy term newborns, born to mothers of families stemming from geographic areas known to be "at risk" for G-6-PD deficiency, were screened for the condition and surveyed for hyperbilirubinemia. Seventy-five G-6-PD-deficient neonates formed the study group, while 266 neonates with normal levels of the enzyme formed the control group. Neonates with any other identifiable cause for jaundice were excluded. Phototherapy was commenced when the serum bilirubin levels reached 16 mg/dL (274 µmol/L) or more, and it was discontinued at 12 mg/dL (205 µmol/L) or less. Hyperbilirubinemia developed in 27 (36%) of the deficient neonates (serum total bilirubin >13.9 mg/dL [238 µmol/L]), compared with 50 (18.8%) of control neonates (P = .002), while 20 (26.7%) of the study group required phototherapy, compared with 31 (11.7%) of control neonates (P = .002). Two neonates in the study group required exchange transfusion (serum bilirubin >20 mg/dL [342 µmol/L]), vs 0 in the control group (not significant). Further analysis was performed on male neonates only: despite a tendency for the hyperbilirubinemia to behave differently with regard to peak bilirubin levels, age at the time of the peak, duration of phototherapy, and rate of bilirubin decrease during phototherapy, these differences failed to attain statistical significance. Values for hematocrit and reticulocyte count did not show evidence of overt hemolysis. Routine daily clinical evaluation and use of phototherapy according to the above criteria made it possible to keep the need for exchange transfusion to a minimum and to prevent kernicterus in this population.

Every now and then, in a pharmaceutical world dominated by agents that are “me-toos” or “variations on a theme,” there appears a truly new molecular entity that offers an entirely new approach to treating a disorder that previously had only partially effective therapies or, sometimes, no effective therapy at all. The article by Attallah Kappas1 in this issue describes such a potential advance: tin-mesoporphyrin. This truly new entity was developed specifically by Kappas and his colleagues to block the action of heme oxygenase in converting hemoglobin to bilirubin. By shutting off the production of bilirubin at its source rather than removing it by exchange transfusion or phototherapy after it is formed, this agent has the potential to revolutionize management of jaundice from any cause just as Rh immune globulin did for preventing Rh hemolytic disease of the newborn when introduced in the 1960s. What is remarkable (and lamentable) is that … Address correspondence to Duane Alexander, MD, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, 31 Center Dr, Room 2A03, MSC 2425, Bethesda, MD 20892-2425. E-mail: da43w{at}nih.gov

Objective. To determine the incidence of adverse events attributable to exchange transfusion during the past 15 years and compare the incidence of severe complications between healthy and ill infants.Design. Medical records for the past 15 years from two teaching hospitals with neonatal intensive care units were reviewed. Those newborns who underwent exchange transfusions were classified as healthy or ill. Adverse events were analyzed to determine whether they were attributable to the procedure.Results. Of the 106 patients who underwent exchange transfusion, 81 were healthy and had no medical problems other than jaundice. The remaining 25 patients were classified as ill and had medical problems ranging from mild to severe. At least 2 (2%) of the 106 patients died of complications probably attributable to exchange transfusion. None of the 81 healthy infants died, but 1 had severe necrotizing enterocolitis requiring surgery. Of the 25 ill infants, at least 3 (12%) experienced severe complications (including 2 deaths) probably attributable to exchange transfusion. Serious complications from the most common adverse events, hypocalcemia and thrombocytopenia, were limited to the group of infants already ill with other medical problems.Conclusions. Because of the significantly greater rate of severe complications in ill infants, exchange transfusion should be delayed until the risk of bilirubin encephalopathy is as high as the risks of severe complications from the procedure itself (12%). These results do not support recommendations to use lower exchange levels in ill infants compared with healthy infants. exchange transfusion, whole-blood; adverse events, jaundice, neonatal; kernicterus, infant, newborn.