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.
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