Objective. There is concern about an increasing incidence of kernicterus in healthy term neonates in the United States. Although the incidence of kernicterus is unknown, several potential strategies that are intended to prevent kernicterus have been proposed by experts. It is necessary to assess the costs, benefits, and risks of such strategies before widespread policy changes are made. The objective of this study was to determine the direct costs to prevent a case of kernicterus with the following 3 strategies: (1) universal follow-up in the office or at home within 1 to 2 days of early newborn discharge, (2) routine predischarge serum bilirubin with selective follow-up and laboratory testing, and (3) routine predischarge transcutaneous bilirubin with selective follow-up and laboratory testing.
Methods. We performed an incremental cost-effectiveness analysis of the 3 strategies compared with current practice. We used a decision analytic model and a spreadsheet to estimate the direct costs and outcomes, including the savings resulting from prevented kernicterus, for an annual cohort of 2 800 000 healthy term newborns who are eligible for early discharge. We used a modified societal perspective and 2002 US dollars. With each strategy, the test and treatment thresholds for hyperbilirubinemia are lowered compared with current practice.
Results. With the base-case assumptions (current incidence of kernicterus 1:100 000 and a relative risk reduction [RRR] of 0.7 with each strategy), the cost to prevent 1 case of kernicterus was $10 321 463, $5 743 905, and $9 191 352 respectively for strategies 1, 2, and 3 listed above. The total annual incremental costs for the cohort were, respectively, $202 300 671, $112 580 535, and $180 150 494. Sensitivity analyses showed that the cost per case is highly dependent on the population incidence of kernicterus and the RRR with each strategy, both of which are currently unknown. In our model, annual cost savings of $46 179 465 for the cohort would result with strategy 2, if the incidence of kernicterus is high (1:10 000 births or higher) and the RRR is high (≥0.7). If the incidence is lower or the RRR is lower, then the cost per case prevented ranged from $4 145 676 to as high as $77 650 240.
Conclusions. Widespread implementation of these strategies is likely to increase health care costs significantly with uncertain benefits. It is premature to implement routine predischarge serum or transcutaneous bilirubin screening on a large scale. However, universal follow-up may have benefits beyond kernicterus prevention, which we did not include in our model. Research is required to determine the epidemiology, risk factors, and causes of kernicterus; to evaluate the effectiveness of strategies intended to prevent kernicterus; and to determine the cost per quality-adjusted life year with any proposed preventive strategy.
Comments
Kernicterus and subcortical sites affected
Kernicterus is a neurological disorder associated with bilirubin staining of subcortical brain nuclei. But bilirubin levels have long been known to be high in newborn infants, and bilirubin is not directly toxic to the brain. Only when bilirubin crosses the blood-brain barrier does it cause damage. Factors that compromise the blood-brain barrier and allow leakage of bilirubin into neurons must be sought in any effort at prevention.
The earliest reports of the neuropathology of kernicterus emphasized that yellow staining was not uniform throughout the brain, but only affected brainstem nuclei susceptible to damage by anoxia [1, 2, 3]. As Zimmerman and Yannet pointed out, "This differs in no way from the well known fact that any intravital dye will localize in zones of injury, and will leave unstained tissues which are not damaged"
A body of evidence that seems now largely forgotten should be taken into account: the studies of William Windle and Ronald Myers on the neuropathology found in monkeys subjected to asphyxia and hypoxia at birth [4, 5]. Catastrophic total asphyxia produced ischemic damage of what Myers referred to as a "monotonous rank order of brainstem nuclei;" Myers produced cerebral palsy and damage of cortical motor areas by inflicting partial hypoxic compromise of umbilical blood flow late in gestation. Windle suggested that the brainstem damage caused by catastrophic asphyxia might be associated with what was then known as "minimal cerebral dysfunction" (or MCD, now better designated as pervasive developmental disorder, PDD). Can any cerebral dysfunction be considered minimal?
Lucey and co-workers investigated the effects of bilirubin in neonatal monkeys and observed a pattern of damage that also reflected the rank order of brainstem nuclei found by Windle and Myers to be affected by asphyxia at birth [6]. However, in neonatal monkeys bilirubin produced brain damage only if preceded by asphyxia.
The finding that bilirubin is damaging only when accompanied by asphyxia at birth is an example of dual mechanisms each compounding the effect of the other. Unfortunately in real life complications of this type happen, and may partly explain why a brief period of anoxia around the time of birth appears harmless to most infants, but in combination with any toxic factor can affect brain function and lead to disability.
Fears of "circulatory overload" and jaundice appear to be the rationale for adoption of a fairly recent obstetric protocol, immediate clamping of the umbilical cord at birth [7]. But if the umbilical cord is clamped before the infant's first breath, a brief period of catastrophic asphyxia can occur, with low Apgar scores until pulmonary respiration can be established. Myers pointed out that it is the infant heart, not the brain, that is resistant to anoxia. Until about 20 years ago teaching was explicit that the newborn infant must be clearly breathing on its own before clamping the cord. Could the increased incidence of kernicterus be more the result of early cord clamping than high levels of bilirubin?
References:
[1] Orth J (1875) Ueber das Vorkommen von Bilirubinkrystallen bei neugebornen Kindern. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin 63:447-462
[2] Schmörl G (1904) Zur Kenntnis des Ikterus neonatorum, insbesondere der dabie auftretenden Gehirn veränderungen. Verhandlung der deutschen pathologischen Gesellschaft 6:109-115.
[3] Zimmerman HM and Yannet H (1933). Kernicterus: jaundice of the nuclear masses of the brain. American Journal of Diseases of Children, 45, 740-759.
[4] Windle WF (1969a) Brain damage by asphyxia at birth. Scientific American 221(#4):76-84.
[5] Myers RE (1972) Two patterns of perinatal brain damage and their conditions of occurrence. American Journal of Obstetrics and Gynecology 112:246-276.
[6] Lucey JF, Hibbard E, Behrman RE, Esquival FO, Windle WF (1964) Kernicterus in asphyxiated newborn monkeys. Experimental Neurology 9:43- 58.
[7] Turrentine JE (2003) Clinical Protocols in Obstetrics and Gynecology, Second Edition. The Parthenon Publishing Group, Boca Raton, London, New York, Washington DC.