Hyperbilirubinemia and Early Discharge - Nature

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combined administration of SnMP and phototherapy. Zinc protoporphyrin (ZnPP), a naturally occurring metallopor- phyrin, has been extensively studied in vitro ...
Hyperbilirubinemia and Early Discharge Rena Gale, MD Daniel S. Seidman, MD David K. Stevenson, MD Hyperbilirubinemia is back on the agenda due to the reappearance of recorded cases of kernicterus, which until few years ago was virtually unreported in the United States.1 Recently more than 40 cases of kernicterus occurring among apparently healthy term infants have been described.2 ± 7 However, it is yet to be determined whether the current accumulation of reports reflects a true increase in the incidence of the disease or merely a growing recognition of this grave complication of neonatal jaundice. It is recognized widely that a surge in the number of litigation cases concerning kernicterus has occurred in recent years. This happens at a time when hyperbilirubinemia due to Rh incompatibility has been nearly eliminated, and kernicterus among preterm infants has become apparently uncommon.8 There is a growing concern that early discharge of healthy full-term breast-feeding infants, complicated by unrecognized pathologic propensities for jaundice, may be associated with the morbidities of severe hyperbilirubinemia. Therefore, the policies of discharge and follow-up are the focus of scrutiny and reconsideration. BILIRUBIN NEUROTOXICITY A concern also exists that only those infants with extreme forms of bilirubin toxicity come to our attention, whereas much more frequent, though less severe, morbidities remain undetected. More subtle brain dysfunction may be of great disadvantage to individuals who fail to achieve their full cognitive potential, and may have a substantial negative impact on the overall health of a population. Although neurotoxicity of bilirubin has been demonstrated in many ways, such as its effect on auditory functions,4,8,9 visual evoked potentials,10 or characteristics of the infant's cry,11 it is not clear how these toxic effects translate into functional impairments later in life. There is little doubt that changing clinical conditions, such as duration of exposure, sepsis, hypoxia, acidosis, hypernatremic dehydration, concentration of free bilirubin, and prematurity, influence the phenomena of bilirubin toxicity. Reanalyzing the data from the Collaborative Perinatal Project, Department of Neonatology ( R.G. ) , Bikur - Cholim Hospital, Jerusalem, Israel; Department of Obstetrics and Gynecology ( D.S.S. ) , Sheba Medical Center, Tel - Hashomer, Israel; Division of Neonatal and Developmental Medicine ( D.K.S. ) , Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. Address correspondence and reprint requests to Daniel S. Seidman, MD, Department of Pediatrics, S - 226, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA 94305 - 5208.

Newman and Klebanoff 12 found no adverse effect of hyperbilirubinemia on intelligence quotient (IQ) scores at age 7 years. However, abnormal neurologic findings, consisting mainly of mild nonspecific motor abnormalities were more frequent in infants with higher bilirubin levels. In our 17-year follow-up study, subjects with bilirubin levels over 20 mg/dl had a three-fold higher risk of having an IQ test score lower than 85.13 In a later analysis of a similar study in a different population (unpublished) we found a positive relationship between rising bilirubin levels in male infants and intelligence at age 17 years. However, IQ testing may not necessarily be the most sensitive tool to detect the entire spectrum of bilirubin neurotoxicity. Furthermore, the question of whether a linear relationship or a threshold level exists for bilirubin neurotoxicity has not yet been answered. Revised guidelines for the management of jaundice in well newborns were introduced by the American Academy of Pediatrics in 1994.14 They were based, to a large extent, on a data analysis published by Newman and Maisels.15 This retrospective analysis argued that there are few data supporting the present practice of applying uniformly phototherapy under 17 mg/dl, or exchange transfusion under 25 to 27 mg/dl of serum bilirubin in healthy infants without hemolytic disease. However, no evidence was referenced to set unequivocally the maximal level of bilirubin that may be considered safe for the newborn. Most importantly, poor compliance and the inability to exclude definitely hemolysis or some other complicating factors has plagued the implementation of the Practice Guidelines.

EARLY DISCHARGE Neonatal hyperbilirubinemia commonly develops between 24 and 96 hours after delivery.16 As more newborns are discharged within 24 hours of birth, it is not surprising that hyperbilirubinemia requiring phototherapy is currently the most commonly reported readmission diagnosis, accounting in some studies for approximately threefourths of all cases.17,18 A study from Ontario, Canada, showed that the number of infants readmitted every year with serum bilirubin values of 510 mol/l (30 mg/dl) or greater, increased significantly from 0 to 2 in the years 1987 to 1992, to 4 to 5 in 1993 and 1994, respectively,18 in spite of a decline in the annual number of births. The initial drive for early discharge may have been motivated by good intentions, directed at allowing earlier return of the parents and child to the home environment. However, the current trend toward early discharge of all mothers, regardless of their individual background and the home support available, seems largely driven by cost considerations. The dangers of early postpartum discharge in the Journal of Perinatology 2001; 21:40 ± 43

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Jaundice and Early Discharge

absence of adequate follow-up care have been highlighted by several reports of kernicterus.3 The problem of offering satisfactory follow-up is compounded by failure to return for follow-up visits, especially among low-income mothers.19 The ideal length of hospital stay after delivery has not been assessed by adequately controlled trials. Moreover, even among term newborns discharged from the hospital on the third day of life, 0.3% to 0.4% will subsequently develop moderate to severe hyperbilirubinemia.20 In addition, it remains to be determined whether the provision of home-based follow-up is superior to clinic-based services.17,18 As severe hyperbilirubinemia is not common among healthy term newborns, economic considerations dictate that the limited health care resources be used effectively. This requires targeting follow-up programs toward selective high-risk groups. The ability to identify infants who are most likely to develop clinically significant hyperbilirubinemia is also of great importance for possible implementation of preventive pharmacological interventions. Therefore, an urgent need exists for improved methods of early prediction and prevention. RISK FACTORS FOR HYPERBILIRUBINEMIA Several factors associated with a higher risk of developing hyperbilirubinemia in the newborn have been identified.21,22 These include male sex, Asian ethnicity, instrumental delivery, family history of neonatal jaundice, short gestation, and breast-feeding. The significant differences in bilirubin levels in infants of different ethnic origins and on different feeding protocols have also been demonstrated recently in a large international study.23 A recessive mutation in the bilirubin UDP glucuronosyltransferase gene may compound increased bilirubin production in these populations.23 However, the wide prevalence of these factors renders them of limited value for defining high-risk groups, qualifying for intensive followup. For instance, breast-feeding, although associated with an increased risk of hyperbilirubinemia,24,25 but rarely bilirubin encephalopathy,4 is so common that the knowledge of feeding practices alone helps little in defining a group at risk. However, factors like prematurity ( 5 mg/dl on day 1 had a high specificity (91.9%) but a low sensitivity (45.5%) for detecting severe jaundice. The positive predictive value was very low (8.9%), whereas the negative predictive value was very high (99.0%).28 Therefore, measurement of serum bilirubin on day 1 could not accurately identify all those for whom treatment would be needed, but was a relatively successful measure for identifying those infants who are unlikely to need further intervention for hyperbilirubinemia. This observation was confirmed and extensively discussed in a recent study,29 which included 2840 healthy term or near-term newborns. By hourly measuring the predischarge bilirubin levels up to 72 hours of age, 62% of the population carrying no risk of clinically significant jaundice could be determined with a 100% sensitivity and a 65% specificity. Six percent of the study population was in the high-risk zone, and nearly 40% of this population remained in that zone. However, 32% of the population had total serum bilirubin levels in the intermediate risk zone and 6% of this population eventually moved into the high-risk zone. This study suggests a universal screening protocol for predischarge serum bilirubin levels to predict subsequent hyperbilirubinemia. However, not all infants in this study were included in the testing, leading to a falsely low negative estimation. More importantly, the 95% value for total serum bilirubin may be different for different populations.30 An estimation of bilirubin production would complement further the identification of neonates likely to develop significant jaundice. A combination of a timed bilirubin determination and an estimate of bilirubin production would identify directly infants with hemolysis, but also indirectly those with bilirubin conjugating or other elimination defects. However, it has not been established that predictability of ``high-risk zone'' jaundice would be improved by a combination of measures, whereas diagnostic refinement seems likely. A rapid and convenient estimation of the bilirubin production rate can be derived from measurements of carbon monoxide (CO) in the breath, because one molecule of CO is produced for each molecule of bilirubin. Noninvasive methods for measuring end-tidal breath CO (ETCO) have been used to index total bilirubin formation in human neonates.31 ± 33 Furthermore, the association of increased CO 41

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production with kernicterus and death related to hyperbilirubinemia has been demonstrated in jaundiced Nigerian infants.34 A portable automated instrument is now available for bedside ETCO determinations of infant breath.35,36 In a recent collaborative, multicenter study carried out on 564 neonates,37 an ETCO determination greater than 75th percentile, was found to have a 58% positive and a 95% negative predictive value for hyperbilirubinemia. In a study carried out on 154 Chinese infants, the combination of bilirubin determination at 30 hours of age with ETCO estimation at 48 hours of age predicted hyperbilirubinemia with a 100% sensitivity, a 64% specificity, a 25% positive predictive value, and a 100% negative predictive value.38 PREVENTION Educating mothers, and especially the inexperienced, to maintain more successful and frequent breast-feeding can be helpful in ameliorating jaundice and preventing hypernatremic dehydration. For some high-risk populations, such as G6PD deficient infants, there are reports on the prevention of jaundice by way of decreasing the exposure to environmental oxidant factors such as infection, use of dyes applied on umbilicus or skin,34 and ingestion of herbal medications.39 Another innovative approach to medical prevention of jaundice has been suggested over recent years. Metalloporphyrins, heme analogues, are given to the newborn, soon after birth.40 ± 42 They act as competitive inhibitors of heme oxygenase (HO), and thus arrest the first step of the metabolic degradation of heme and prevent bilirubin production. Tin mesoporphyrin (SnMP) is the preparation most studied in human infants.43,44 A single 6-mol/kg dose of SnMP, injected soon after birth, was found to be as effective as intensive phototherapy in controlling nonhemolytic jaundice in term and near-term newborns.44 In a recent study carried out on breast-fed, full-term, nonhemolytic infants, with plasma bilirubin concentrations of 15 and 18 mg/dl, a single dose of SnMP entirely eliminated the need for phototherapy, and shortened the time until hyperbilirubinemia subsided, decreasing the number of bilirubin determinations necessary.45 The only reported side effect of SnMP has been a mild, self-limited, light-induced erythema, found after the combined administration of SnMP and phototherapy. Zinc protoporphyrin (ZnPP), a naturally occurring metalloporphyrin, has been extensively studied in vitro and in animal models and found to be minimally photoreactive and nonphototoxic in vivo.46 However, further investigations are required to determine its efficacy and safety in humans.42,47 Other metalloporphyrins are also being investigated, including zinc bis glycol porphyrin, which might be used as an oral preparation.

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dl serum bilirubin level.50 However, the algorithm developed by the Academy for the management of hyperbilirubinemia refers only to term healthy hospitalized newborns. Prematurity, hemolytic disease of the newborn, or infection have to be carefully considered before and after discharge from the hospital. Information on family history of severe neonatal jaundice, ethnic background, and cultural circumstances has to be taken into account when timing the discharge from hospital. The tendency toward early discharge is unlikely to be reversed, despite recent legislative action dictating a minimal postpartum hospital stay. Therefore, clinical strategies are needed to ensure that the rare, 1 in 10,000 infants who develops hyperbilirubinemia of 30 mg/dl is not missed.51 Proper medical supervision in a safe and costeffective way remains an ultimate goal. To achieve that, a significant number of infants discharged within 48 hours will have to be examined again, 48 to 96 hours later outside the hospital. This offers an opportunity not only to diagnose hyperbilirubinemia, but also to attenuate jaundice by reinforcing breast-feeding practices, and to prevent dehydration weight loss. Such strategies have already been attempted with success.52 The management of neonatal jaundice continues to present a clinical challenge. Although the degree of risk associated with severe hyperbilirubinemia remains to be determined, the danger of permanent long-term neurologic damage is a real concern. Neonatal observation can be safely undertaken outside the hospital. However, ways to ensure that early discharge is followed by proper medical supervision remain to be established. Further, what accounts for ``adequate'' home follow-up is not yet clearly defined. At present it seems that efforts must be invested in individualizing infant care. Improved methods for determination of bilirubin levels, and estimates of bilirubin production using the ETCO method and the forthcoming possibility of utilizing heme oxygenase inhibition for prevention of extreme hyperbilirubinemia, may further reduce, or more accurately identify the infants requiring close follow-up after early discharge. References 1. 2.

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DISCHARGE AND FOLLOW-UP STRATEGIES The recommendations of the Academy of Pediatrics14 and studies hinting at a protective role of bilirubin as an antioxidant 48,49 contributed to alleviating vigintiphobia Ð the fear of the 20-mg/ 42

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