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Available at : http://emedicine.medscape.com/article/975276-overview
Backgrond
!he term kernicters literall" means #"ellow kern$# with kern indicating the most commonl"
a%%licted region o% the brain &ie$ the nclear region'. (istoricall"$ the term re%ers to an anatomic
diagnosis made at atops" based on a characteristic pattern o% staining %ond in babies who had
marked h"perbilirbinemia be%ore the" died.
(ervie) %irst described the condition in *+,7$ and -chmorl %irst sed the term kernicters as
earl" as *9./. 0egions most commonl" a%%ected inclde the basal ganglia1 hippocamps1
geniclate bodies1 and cranial nerve nclei$ sch as the oclomotor$ vestiblar$ and cochlear. !he
cerebellm can also be a%%ected. Bilirbin-indced nerologic d"s%nction &B234' re%ers to the
clinical signs associated with bilirbin to)icit" &ie$ h"potonia %ollowed b" h"pertonia and/or
opisthotons or retrocollis' and is t"picall" divided into acte and chronic phases. !he 2 terms
are commonl" sed interchangeabl"$ bt this se is not technicall" accrate becase one re%ers to
clinical mani%estations and the other to an anatomic diagnosis.
5onventional wisdom characteri6es kernicters as prevalent in the *95.s and *96.s$ virtall"
eradicated in the *97.s and *9+.s$ onl" to reappear dring the *99.s. 2t was speclated that earl"
discharge o% term in%ants &be%ore their serm bilirbin concentration peaks' cold be a %actor in
the reemergence o% this devastating nerologic a%%liction$ and medical research %ocsed on
developing srveillance and treatment paradigms to eliminate the condition. 7hereas it is
ndeniable that kernicters remains a case o% ma8or nerologic morbidit" in the in%ant
poplation$ poplation stdies o% children born in 5ali%ornia between *9++ and *997 sggest the
prevalence o% kernicters has remained virtall" nchanged since *9+..
9*:
;ch o% the traditional teaching regarding h"perbilirbinemia is now being <estioned as more
is learned abot bilirbin metabolism and nerologic in8r". =ernicters is now recogni6ed in the
prematre in%ant and$ ver" rarel"$ in the term in%ant in the absence o% pro%ond
h"perbilirbinemia
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1 however$ other problems &eg$ acidosis or in%ection' are present in term
in%ants withot pro%ond h"perbilirbinemia. 5onversel"$ ph"siologic 8andice &sometimes to
levels previosl" thoght to be niversall" dangeros' has been recogni6ed to be within the
re%erence range in the %irst week o% li%e in health" term babies$ particlarl" those who are
breast%ed. >andice o% this t"pe sall" spontaneosl" resolves withot se<elae.
4espite the lack o% a clear-ct case-and-e%%ect relationship between kernicters and the degree
o% h"perbilirbinemia$ laborator" investigations have demonstrated that bilirbin is neroto)ic at
a celllar level. ?ther in vitro stdies have shown bilirbin to have more antio)idant capabilit"
than vitamin @$ which is commonl" assmed to be the most potent antio)idant in the hman
s"stem.
9/:
!his possible role o% bilirbin in earl" protection against o)idative in8r"$ copled with
identi%ication o% mltiple neonatal mechanisms to preserve and potentiate bilirbin prodction$
has led to speclation abot an as-"et-nrecogni6ed bene%icial role %or bilirbin in the hman
neonate.
Aathoph"siolog"
Bilirbin staining can be noted on atops" o% %resh specimens in the regions o% the basal ganglia$
hippocamps$ sbstantia nigra$ and brainstem nclei. -ch staining can occr in the absence o%
severe h"perbilirbinemia1 in this sitation$ %actors in%lencing permeabilit" o% the blood-brain
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barrier &eg$ acidosis$ in%ection' and the amont o% nbond &verss albmin-bond' bilirbin
ma" pla" a role.
5haracteristic patterns o% neronal necrosis leading to the clinical %indings consistent with
chronic bilirbin encephalopath" are also essential in the pathoph"siolog" o% this entit".
Bilirbin staining o% the brain withot accompan"ing neronal necrosis can be observed in
babies who did not demonstrate clinical signs o% bilirbin encephalopath" bt who sccmbed
%rom other cases. !his staining is thoght to be a secondar" phenomenon$ dissimilar %rom the
staining associated with kernicters.
2mproved brain imaging modalities$ sch as ;02 and ltrasonograph"$ ma" be emerging as
instrmental tools to help clari%" the comple) pictre o% kernicters in contrast with
as"mptomatic bilirbin staining o% brain tisses. Bilirbin staining has been sggested to be
visali6ed on ;02 as an increased signal in the posteromedial aspect o% the globs pallids.
4espite its theoretical vale$ however$ e%%orts to se cranial imaging in the clinical setting have
remained nsatis%"ing. A 2..+ case series b" Bkoltsio et al reported the ine)plicable conclsion
that$ while all children with severe cerebral pals" and a histor" o% h"perbilirbinemia had
abnormal central gre" matter on later scans$ the characteristic central gre" matter ;02 %eatres
o% kernicters were not seen in earl" scans.
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@pidemiolog"
Frequency
United States
!he e)act incidence o% kernicters is nknown. A pilot kernicters registr" monitoring the cases
o% babies with kernicters in the Cnited -tates who have been volntaril" reported shows *25
babies with chronic kernicters enrolled in the registr" %rom *9+,-2..2.
95$ 6:
All bt , babies
reported in the registr" had been discharged %rom the hospital %ewer than 72 hors a%ter birth
&97D'. Eive babies were born at home &,D'. 3o se<elae were identi%ied in 9 o% **5 in%ants$ and
* was lost to %ollow-p.
International
2n 4enmark$ + cases o% kernicters were reported %rom *99,-2..2
97:
$ whereas no cases had been
reported %or the preceding 2. "ears
9+:
. Eollowing this report$ %rom 2..2-2..5$ a more vigilant
approach was taken to the management o% newborn 8andice$ and no more cases have been
reported in 4enmark.
99:
!hese combined data reslt in an overall incidence o% kernicters in
4enmark o% *.* in *..$... live births %rom *99,-2..5.
2n >ne 2../$ !he Farterl" Blletin o% the 0o"al 5ollege o% Aaediatrics and 5hild (ealth
annonced the commencement o% a srveillance program o% cases o% severe neonatal
h"perbilirbinemia %ollowing anecdotal reports throghot Britain and 2reland o% increasing
observation o% kernicters.
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A 2.., C= srveillance std" has reported kernicters occrring at
a rate o% * in *..$... live births.
A 5anadian srve" pblished in 2.., assessed the %re<enc" o% e)treme h"perbilirbinemia
&serm bilirbin G,27 Hmol/I or G25 mg/dI' as *:2$+,. live births$ o% which */ &2 in *..$...'
had abnormal nerological otcomes at the time o% discharge.
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Csing these data$ the risk o% developing kernicters in in%ants mani%esting e)treme
h"perbilirbinemia &G25 mg/dI' can be estimated across poplations. 2n 5anada$ this risk
calclates to * in *7.6 in%ants$ whereas in 4enmark$ the poplation risk is estimated as * in *6.2.
9*2:
7hen the threshold o% e)treme h"perbilirbinemia is increased to G/. mg/dI &G5*/ Hmol/I'$
the risk o% developing kernicters increases to * in 5.5-7 live births$ depending on the reports. 2t
shold be noted that kernicters also occrs in in%ants in whom bilirbin levels remained J 25
mg/dI$ and the poplation risk o% this occrrence remains nknown.
(ispanic and Asian poplations appear to have a greater propensit" to develop
h"perbilirbinemia$ althogh the nderl"ing e)planation %or this observation remains elsive.
Benetic variants$ sch as Bilbert disease or B6A4 de%icienc" that occr in se<estered
poplations$ reslt in geographic and/or ethnic di%%erences in the risk and %re<enc" o%
kernicters.
Mortality/Morbidity
5lassic kernicters has been de%ined in the term in%ant. 2ncreasing e)perience with prematre
babies indicates that the clinical presentation in prematre in%ants ma" be somewhat di%%erent.
2denti%"ing kernicters as the speci%ic case o% death in either the term or preterm in%ant ma" be
di%%iclt becase o% concomitant ongoing pathologic conditions. 3erologic se<elae de to
bilirbin encephalopath" var"$ and correctl" attribting some o% the long-term nerologic de%icits
%re<entl" associated with prematrit" alone to kernicters ma" be problematic.
0eview o% the *25 cases reported to the Ailot 0egistr" b" Agst 2.., revealed 26 patients with
nderl"ing B-6-A4 de%icienc"$ 25 with hemol"tic disorders$ *+ with birth trama contribting to
their h"perbilirbinemia$ and 5/ with idiopathic h"perbilirbinemia. ?% these patients$ /. were
born at /5 to less than /7 weeks estimated gestational age &@BA'$ 2, at /7 weeks @BA$ and 7*
at greater than /7 weeks @BA.
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&-ee theBestational Age %rom @stimated 4ate o%
4eliver" calclator.' Bamaleldin et al$ in an attempt to better predict the development o%
bilirbin encephalopath" based serm total bilirbin levels$ reviewed 2,9 newborns admitted to
5airo Cniversit" 5hildrenKs (ospital in a *2-month period with total serm bilirbin levels
greater than or e<al to 25 mg/dI. Althogh the correlation between total serm bilirbin and
encephalopath" was poor$ patients with h"perbilirbinemia reslting %rom 0h
incompatibilit"developed B234 at an odds ratio o% ,+.6 and those with sepsis an odds ratio o%
2..6 as compared with other etiologies.
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2n the kernicters registr" mentioned above$ 6 o% *25 patients &,.+D' died.
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Additional risk
%actors %or mortalit" inclded late prematrit"$ B6A4 de%icienc"$ and sepsis. !he nmber o%
patients who died %rom kernicters withot being reported to the registr" is nknown$ as is the
e)perience in contries other than the Cnited -tates$ especiall" those with a high prevalence o%
hereditar" hemol"tic disorders. ?% patients reported to the kernicters registr"$ *** o% **9
srvivors &9/D' had severe se<elae de to B2341 + o% **9 babies &6.7D' had no discernible
se<elae a%ter age * "ear1 one bab" was lost to %ollow-p prior to / months o% age.
Race
Among in%ants reported in the C- kernicters registr"$ 5+D were white.
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Asian and (ispanic
babies born either in their native contries or in the Cnited -tates and 3ative American and
@skimo in%ants have higher prodction levels o% bilirbin than white in%ants. Black in%ants have
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lower prodction levels &see image below'. !he reasons %or these racial di%%erences have not been
%ll" elcidated.
!"pical patterns o% total serm
bilirbin levels in neonates o% di%%erent racial origins. Csed with the permission o% the Academ"
o% Aediatrics.
Sex
;ale in%ants have consistentl" higher levels o% serm bilirbin than do %emale in%ants. Among
in%ants reported in the C- kernicters registr"$ 67D o% the patients were male.
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Age
Acte bilirbin to)icit" appears to occr in the %irst %ew da"s o% li%e o% the term in%ant. Areterm
in%ants ma" be at risk o% to)icit" %or slightl" longer than a %ew da"s. 2% in8r" has occrred$ the
%irst phase o% acte bilirbin encephalopath" appears within the %irst week o% li%e.
!he pilot kernicters registr" data show that$ o% *22 in%ants &all G/5 weeksK gestational age at
birth'$ s"mptoms became apparent in */ babies &*..6D' aged /.5 da"s or "onger and in 66
babies &5,D' aged ,-7 da"s.
9*/:
2n /6 babies &29.5D'$ s"mptoms did not appear ntil a%ter the %irst
week o% li%e. ;ost o% these babies &76D' were term in%ants &at least /7 completed weeksK
gestation'$ and no in%ant was "onger than /5 weeksK estimated gestational age.
(istor"
7hen assessing possible kernicters$ remember that a histor" o% risk %or hemol"tic disease can
be an important cle to a neonateKs increased risk o% pathologic h"perbilirbinemia$ particlarl"
0h antigen incompatibilit" between mother and bab"
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. AB? incompatibilit" and a %amil"
histor" o% 0B5 abnormalities &ie$ glcose-6-phosphate deh"drogenase de%icienc"$ hereditar"
spheroc"tosis' are also concerning. A review o% neonatal readmissions in 5anada showed that$ o%
25+ in%ants readmitted %or severe h"perbilirbinemia %rom 2..2-2..,$ +7 &/,D' demonstrated
one o% these hematologic abnormalities.
9*5:
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5ertain cltral postnatal practices ma" also contribte to signi%icant h"perbilirbinemia and
shold be in<ired abot i% cltrall" relevant. 2n the ;iddle @ast$ Aeker et al reported in 2.*. a
case series o% *. severel" h"pernatremic babies who also presented with kernicters$ 2 o% whom
died.
9*6:
?% **2 postpartm women srve"ed in >ordan (ospital$ Amman$ >ordan$ almost 5.D o%
them admitted to #salting# their newborns as is the common cstom. 7omen doing this practice
broadl" represented all socioeconomic and edcational strata.
9*7:
5onversel"$ i% the bab" is breast%eeding well and appears health" and vigoros$ this can be
reassring. !he mother ma" have breast%ed previos babies who also developed signi%icant
8andice. 2% so$ she ma" be one o% the appro)imatel" 2.-,.D o% women who have above-average
levels o% beta-glcronidase in their breast milk$ which potentiates and prolongs
h"perbilirbinemia in their breast%ed babies.
Ah"sical
Bilirbin-indced nerologic d"s%nction &B234' is the term applied to the spectrm o%
nerologic abnormalities associated with h"perbilirbinemia. 2t can be %rther divided into
characteristic signs and s"mptoms that appear in the earl" stages &acte' and those that evolve
over a prolonged period &chronic'.
Acute bilirubin encephalopathy
!he clinical %eatres o% this diagnosis have been well described and can be divided into / stages.
?% babies with B234$ appro)imatel" 55-65D present with these %eatres$ 2.-/.D ma" displa"
some nerologic abnormalities$ and appro)imatel" *5D have no nerologic signs.

Ahase * &%irst %ew da"s o% li%e': 4ecreased alertness$ h"potonia$ and poor %eeding are the
t"pical signs. ?bviosl"$ these are <ite nonspeci%ic and cold easil" be indicative o% a
mltitde o% neonatal abnormalities. A high inde) o% sspicion o% possible B234 at this stage
that leads to prompt intervention can halt the progression o% the illness$ signi%icantl"
minimi6ing long-term se<elae. ?% note$ sei6re is not t"picall" associated with acte bilirbin
encephalopath". Among in%ants reported in the C- kernicters registr"$ the mean birth weight
was /2+* g.
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Ahase 2 &variable onset and dration': ("pertonia o% the e)tensor mscles is a t"pical
sign. Aatients present clinicall" with retrocollis &backward arching o% the neck'$ opisthotons
&backward arching o% the back'$ or both. 2n%ants who progress to this phase develop long-term
nerologic de%icits.

Ahase / &in%ants aged G* wk': ("potonia is a t"pical sign.

Chronic bilirubin encephalopathy
!he clinical %eatres o% chronic bilirbin encephalopath" evolve slowl" over the %irst several
"ears o% li%e in the a%%ected in%ant. !he clinical %eatres can be divided into phases1 the %irst phase
occrs in the %irst "ear o% li%e and consists o% h"potonia$ h"perre%le)ia$ and dela"ed ac<isition o%
motor milestones. !he tonic neck re%le) can also be observed. 2n children older than * "ear$ the
more %amiliar clinical %eatres develop$ which inclde abnormalities in the e)trap"ramidal$
visal$ and aditor" s"stems. ;inor intellectal de%icits can also occr.
@)trap"ramidal abnormalities: Athetosis is the most common movement disorder
associated with chronic bilirbin encephalopath"$ althogh chorea can also occr. !he pper
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e)tremities are sall" more a%%ected than the lower ones1 blbar %nctions can also be
impacted. !he abnormalities reslt %rom damage to the basal ganglia$ the characteristic %eatre
o% chronic bilirbin encephalopath".
Lisal abnormalities: ?clar movements are a%%ected$ most commonl" reslting in
pward ga6e$ althogh hori6ontal ga6e abnormalities and ga6e palsies can also be observed.
!hese de%icits reslt %rom damage to the corresponding cranial nerve nclei in the brain stem.
Aditor" abnormalities: (earing abnormalities are the most consistent %eatre o% chronic
bilirbin encephalopath" and can develop in patients who show none o% the other characteristic
%eatres. !he most common abnormalit" is high-%re<enc"hearing loss$ which can range %rom
mild to severe. !hese de%icits can reslt %rom damage both to the cochlear nclei in the brain
stem and to the aditor" nerve$ which appear to be e)<isitel" sensitive to the to)ic e%%ects o%
bilirbin$ even at relativel" low levels. 5linicall"$ this de%icit can mani%est as dela"ed langage
ac<isition. (ence$ aditor" %nction mst be assessed earl" in an" bab" at risk %or chronic
bilirbin encephalopath".
5ognitive de%icits: 5ognitive %nction is relativel" spared in chronic bilirbin
encephalopath". (owever$ individals with chronic bilirbin encephalopath" are o%ten
mistakenl" considered to have mental retardation becase o% their choreoathetoid movement
disorders and hearing de%icits. !he clinician mst emphasi6e that intellectal %nctioning is not
t"picall" severel" a%%ected.
Abnormalities o% dentition: -ome degree o% dental enamel h"poplasia can be observed in
abot three <arters o% patients with chronic bilirbin encephalopath". A smaller nmber o%
individals develop green-stained teeth.
5ases
Eamiliarit" with bilirbin metabolism leads to an nderstanding o% the %actors leading to an
increased risk o% kernicters &see image below'. Bilirbin is prodced dring the catabolism o%
the heme component o% 0B5s. 0ed cell destrction is sall" increased in the immediate
neonatal period1 it can be pathologicall" elevated in the presence o% immne-mediated or
nonimmne-mediated hemol"tic disease. !he %irst en6"me in the catabolic cascade leading to
bilirbin is heme o)"genase. A constittive %orm and an indcible %orm are recogni6ed and are
indced b" ph"siologic stressors. !he creation o% bilirbin$ a potentiall" to)ic water-insolble
compond$ %rom biliverdin$ a nonto)ic water-solble sbstance$ consmes energ".
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?verview o% bilirbin metabolism.
Becase o% its lipophilic natre$ bilirbin mst be bond to albmin to travel throgh the blood
stream. 2n this state$ it is not %ree to cross the blood-brain barrier and case kernicters. !he
albmin-bilirbin comple) is carried to the liver$ where bilirbin enters the hepatoc"te %or %rther
metabolism. ?nce in the liver$ bilirbin is con8gated via the action o% ridine diphosphate
glcron"l trans%erase &C4AB!'$ an en6"me not %ll" %nctional ntil /-, months o% li%e.
5on8gated bilirbin is e)creted into the intestinal tract via the biliar" s"stem. Beta-
glcronidase$ present in the intestinal lmen o% hman neonates$ decon8gates the con8gated
bilirbin$ allowing it to be reabsorbed across the intestinal lipid cell membranes back into the
blood stream where it mst be re-bond to albmin to repeat the c"cle. !his process$ called
enterohepatic recirclation$ is a ni<e neonatal phenomenon and contribtes signi%icantl" to
ph"siologic 8andice. Eeeding and e)cretion o% meconim and stool interrpt the enterohepatic
recirclation.
Among in%ants reported in the C- kernicters registr"$ 56D had abnormalities known to increase
the bilirbin concentration in the blood.
9*/:
-evere hemol"tic processes were identi%ied in 25 o%
*22 babies &2..5D'1 glcose-6-phosphate deh"drogenase de%icienc" was diagnosed in 26 babies
&2*./D'$ birth trama identi%ied in *+ patients &*5D'$ and other cases sch as galactosemia$
5rigler-3a88ar s"ndrome$ and sepsis were diagnosed in + babies &7D'. 2n 5/ o% *22 in%ants
&,/.,D'$ no etiolog" %or the severe h"perbilirbinemia was discovered.
2ncreased Bilirbin Arodction
;ost o% the circlating bilirbin in the neonate arises %rom destrction o% circlating 0B5s.
3eonates prodce bilirbin at more than doble the dail" rate o% the average adlt$ primaril"
becase o% the larger circlating volme o% 0B5s and their shorter li%e span. An" event reslting
in increased serm bilirbin load pts the in%ant at risk %or h"perbilirbinemia.
Polycythemia
Arenatal %actors$ sch as maternal smoking$ maternal illness$ placental ins%%icienc"$ and
gestation at high altitde$ can reslt in neonatal pol"c"themia. ?bstetric %actors$ sch as dela"ed
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clamping o% the cord$ stripping the cord$ or holding the bab" below the level o% the introits %or a
prolonged period$ can reslt in increased 0B5 mass in the bab". !his is particlarl" tre %or
babies born in the absence o% a trained birth attendant.
Hemolysis
2mmne hemol"tic disease$ most o%ten 0h isoimmni6ation &er"throblastosis %etalis'$ is the
protot"pe etiolog" %or kernicters.
AB? isoimmni6ation$ as well as minor blood grop antigens$ can also case hemol"tic disease
in the newborn$ sall" o% moderate severit". 2n%ants born to mothers o% blood t"pe ? negative
are at greatest risk$ with one series o% 2,9 in%ants with severe h"perbilirbinemia reporting an
odds ratio o% ,+.6 %or in%ants with 0h incompatibilit".
9*,:
Abnormalities o% the red cell itsel% can also predispose to hemol"sis. !hese can be groped into
membrane de%ects$ sch as hereditar" spheroc"tosis and elliptoc"tosis1 en6"me de%ects$ sch as
glcose-6-phosphate deh"drogenase de%icienc" andp"rvate kinase de%icienc"1 and
hemoglobinopathies$ sch as alpha and betathalassemias.
-ickle cell disease does not t"picall" case hemol"tic disease in the neonatal period.
Extraasated blood
-igni%icant areas o% brising$ sch as severe cephalohematoma$ sbgaleal hemorrhage or
peripheral ecch"moses %rom birth trama$ can reslt in an increased bilirbin load in the serm
as the blood collection resolves. 2nternal areas o% hemorrhage$ sch as plmonar" or
intraventriclar bleeds$ can also be a signi%icant occlt sorce o% serm bilirbin.
En!yme induction
As mentioned above$ heme-o)"genase-one &(?-*' is the indcible %orm o% the %irst en6"me
involved in the creation o% bilirbin. !his en6"me is activated b" ph"siologic stressors$ sch as
h"pothermia$ acidosis$ h"po)ia$ and in%ection &odds ratio 2..6 in sepsis'.
9*,:
Epidemiologic "actors
@ast Asian and 3ative American babies prodce bilirbin at higher rates than do white in%ants1
black in%ants have lower prodction rates than do in%ants o% other racial grops. ;ale in%ants
have higher serm bilirbin levels than %emales. ("perbilirbinemia also rns in %amilies1 the
etiolog" is nclear bt ma" relate to geneticall" increased levels o% beta-glcronidase in the
in%ant$ in the motherKs breast milk$ or both &i% the in%ant is breast%ed'.
4ecreased @limination
@ven with normal bilirbin prodction$ abnormalities in transport$ e)cretion$ or both can reslt in
an increased level o% %ree bilirbin in the serm.
Albumin binding
Becase o% its lipophilic natre$ bilirbin mst be bond to carrier protein to be transported in the
a<eos environment o% the serm. Albmin has one primar" high-a%%init" binding site %or
bilirbin and two lower-a%%init" sites. At ph"siologic p($ the amont o% %ree bilirbin &eg$
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bilirbin not bond to albmin' is ver" low. !his is important becase onl" %ree bilirbin is
available to cross the blood-brain barrier and case neroto)icit". 4ecreased albmin binding
capacit"$ decreased albmin binding a%%init"$ or both can serve to increase the amont o% %ree
serm bilirbin. Binding a%%init" is lower in neonates than in older in%ants and is lower still in
prematre and sick in%ants than in health" term ones.
-ome athors advocate inclding measres o% nbond &ie$ %ree' bilirbin when assessing the
risk o% bilirbin neroto)icit"$
9*+:
in part becase some stdies have shown a closer association
between the nbond bilirbin concentration and aditor" abnormalities than those seen with
total serm bilirbin$ althogh identi%"ing the neroto)ic nbond bilirbin concentration
threshold remains elsive.
9*9:
4ecreased binding capacit" can occr in h"poalbminemia or i% the binding sites are %illed with
other anions. 7hether parenterall" administered lipid can displace bilirbin %rom its albmin-
binding site is controversial. 2% %aced with dangerosl" high levels o% serm bilirbin$ restricting
lipid administration to less than ma)imal levels ma" be prdent. 4rgs$ sch as sl%iso)a6ole and
ce%tria)one$ can also compete %or bilirbin-binding sites on the albmin molecle and mst be
sed with cation or avoided in the neonatal period.
Hepatic upta#e and con$ugation
Albmin carries bilirbin to the liver$ where it is incorporated into the hepatoc"te b" an acceptor
protein called ligandin. (epatic levels o% ligandin do not reach adlt vales ntil arond age 5
da"s$ bt the" can be indced b" administration o% phenobarbital.
?nce inside the hepatoc"te$ bilirbin is con8gated to a sgar moiet"$ glcronic acid$ via the
en6"me C4AB!. 2nherent neonatal de%icienc" o% this en6"me is the principal etiolog" o%
ph"siologic 8andice. Eor the %irst *. da"s o% li%e$ C4AB! is present at levels abot ..*D o%
adlt vales$ and h"perbilirbinemia appears to be the primar" stimls to en6"me prodction.
Be"ond ph"siologic 8andice$ congenital inherited de%ects in C4AB! case pathologic
h"perbilirbinemia o% var"ing severit". 5rigler-3a88ar s"ndrome t"pe 2 is the virtal absence o%
C4AB! and is characteri6ed b" pro%ond re%ractor" h"perbilirbinemia with the ongoing risk o%
kernicters at an" point dring an individalKs li%espan. 5rrentl"$ liver transplantation is the onl"
de%initive therap"$ althogh e)perimental therapies are nder investigation. Aatients with 5rigler-
3a88ar s"ndrome t"pe 22 &ie$ Arias s"ndrome' have a similar clinical presentation as patients with
t"pe 2. (owever$ patients with t"pe 22 dramaticall" respond to therap" with phenobarbital$ which
is how the diagnosis is made.
Bilbert s"ndrome is characteri6ed b" a benign chronic indirect h"perbilirbinemia withot
evidence o% liver disease or abnormalit". !he genetic basis %or this s"ndrome has recentl" been
identi%ied as an ampli%ied triplet repeat in the coding gene %or C4AB!$ and investigations are
contining to clari%" the possible role o% Bilbert s"ndrome in in%ants with neonatal
h"perbilirbinemia.
Excretion
?nce con8gated$ water-solble bilirbin is e)creted in an energ"-dependent manner into the bile
canalicli %or ltimate deliver" into the small intestine. 4isrption in this s"stem or obstrction
[Type text]
in the biliar" s"stem reslts in accmlation o% con8gated bilirbin in the serm$ identi%ied b"
an elevation in the direct %raction o% total bilirbin. 4irect h"perbilirbinemia in the neonate
&de%ined as a direct %raction greater than one third o% total bilirbin' is alwa"s pathologic$ and an
etiolog" mst be prsed.
2n the small intestine$ con8gated bilirbin cannot be reabsorbed. 2ntestinal %lorae convert it into
robilinogen$ which is e)creted. 2n the neonate$ the pacit" o% colonic bacteria impedes this
conversion. Erthermore$ the neonatal gt &bt not that o% the adlt' prodces beta-
glcronidase$ an en6"me that acts pon con8gated bilirbin$ releasing %ree bilirbin %or
potential absorption across the intestinal cell lipid membrane into the blood stream. Breast milk
also contains beta-glcronidase$ and breast milk %eedings increase the level o% this en6"me in
the neonatal intestine. 5ombined with slow intestinal motilit" in the %irst %ew da"s o% li%e$ the
above %actors reslt in what is called enterohepatic recirclation o% bilirbin back into the blood
stream.
-"stemic Eactors
Larios s"stemic conditions increase the risk o% h"perbilirbinemia and the risk o% kernicters
withot severe h"perbilirbinemia.
%alactosemia
Aatients with this rare inborn error o% metabolism ma" primaril" present with
h"perbilirbinemia$ althogh the direct %raction t"picall" increases dring the second week o%
li%e. !he bab" ma" mani%est other characteristic signs$ sch as hepatomegal"$ poor %eeding$ or
letharg". Crine %or redcing sbstances$ bt not glcose$ is diagnostic. ;an" state newborn
metabolic screens inclde a test %or this disorder.
Hypothyroidism
Althogh the etiolog" is nclear$ prolonged indirect h"perbilirbinemia is one o% the t"pical
%eatres o% congenital h"poth"roidism$ and this diagnosis mst be rled ot in an" bab" with
h"perbilirbinemia persisting a%ter age 2-/ weeks. ;ost state metabolic screens inclde an assa"
o% th"roid %nction$ althogh %alse-negative reslts and dela"ed receipt o% reslts ma" necessitate
individal testing in s"mptomatic in%ants.
&rugs
;aternal administration o% o)"tocin$ dia6epam$ or prometha6ine ma" reslt in increased serm
bilirbin in the in%ant. -imilarl"$ neonatal administration o% pancronim and chloral h"drate
increases bilirbin levels. Additionall"$ some drgs$ sch as sl%onamides and some penicillins$
can displace bilirbin %rom its albmin-binding site$ e%%ectivel" increasing the serm
concentration o% %ree bilirbin available to cross the blood-brain barrier.
Acidosis
-"stemic acidosis decreases the binding a%%init" o% albmin %or bilirbin$ reslting in increased
levels o% %ree bilirbin in the blood stream. 0ead" availabilit" o% protons promotes the %ormation
o% bilirbin acid &%ree bilirbin anion pls 2 h"drogen ions'1 that moiet" demonstrates increased
binding and transport into neral cell membranes.
[Type text]
&isrupted blood'brain barrier
!he neonatal blood-brain barrier is more permeable to sbstances than is the adltKs.
Administration o% h"perosmolar sbstances$ h"percarbia$ asph")ia$ in%ection &particlarl"
meningitis'$ and impaired atoreglation with variations in blood pressre all ma" weaken
capillar" tight 8nctions$ increasing capillar" permeabilit". !his$ in trn$ might lower the
concentration at which bilirbin is to)ic to the 53-.
(reast mil# "eedings
!he well-described ph"siologic 8andice observed in the %irst %ew da"s o% li%e$ particlarl" in the
breast%ed in%ant$ is called breast%eeding 8andice. Breast%eeding 8andice is thoght to reslt %rom
mltiple mechanisms$ described above$ which promote prodction and inhibit e)cretion o%
bilirbin$ as well as %rom ins%%icient milk intake becase o% redced mammar" gland milk
prodction in the %irst %ew da"s postpartm. Breast%eeding 8andice shold be distingished
%rom breast milk 8andice.
-ome breast%ed in%ants$ althogh clinicall" thriving$ contine to mani%est an indirect
h"perbilirbinemia o% nidenti%iable etiolog" %or several months. 2% this is witnessed in a
breast%ed in%ant$ the e)clsion diagnosis o% breast milk 8andice ma" be made. -ch
h"perbilirbinemia is thoght to be cased b" persistentl" high levels o% as-"et-nidenti%ied
components in some womenKs breast milk$ which reslt in persistence o% the in%antKs
h"perbilirbinemia. ?ne cle ma" be a histor" o% similar h"perbilirbinemia in other breast%ed
siblings. !his entit" is benign.
Iaborator" -tdies
Hematologic studies
(ematologic laborator" evalation is the cornerstone o% evalation o% the bab" with
h"perbilirbinemia. Althogh 8andice can be appreciated clinicall"$ observation alone is not a
reliable method to assess the severit" or estimate risk %actors %or the in%ant.
)otal and direct bilirubin
Fantitative measrement o% total and direct bilirbin levels shold be ndertaken in ever" bab"
at risk %or signi%icant h"perbilirbinemia or kernicters.
!otal bilirbin measres the aggregate o% all %orms o% bilirbin in the serm. !he direct %raction
measres the amont o% con8gated bilirbin. -btraction o% the direct %raction %rom the total
"ields the calclated indirect bilirbin$ or the ncon8gated %orm. 0emember that the indirect
%raction is composed o% bond bilirbin$ %ree bilirbin$ and lmirbin$ as well as man" other
clinicall" nidenti%iable isomers i% the bab" is receiving phototherap".
92.:
?nl" the %ree bilirbin
is available to cross the blood-brain barrier and has the potential to case neroto)icit"1 i% and
how the presence o% other isomers modlates this process is nclear.
Attempts to measre the amont o% bond albmin or to estimate the bond %raction %rom
measres o% serm albmin have not proven to be clinicall" se%l$ althogh there has been some
renewed interest in the clinical se o% this tool.
92*$ 22$ *+:
[Type text]
-erial measrements ma" be necessar" to track the evoltion o% h"perbilirbinemia1 %re<enc" o%
measrements depends on the bab"Ks gestational age$ chronologic age$ risk %actors$ and other
clinical characteristics.
2n in%ants who were reported to the C- kernicters registr"$ total serm bilirbin levels ranged
%rom 2..7-59.9 mg/dI at the time o% presentation with the classic ph"sical signs o% kernicters.
96:
A similar series o% 2,9 in%ants in 5airo reported b" Bamaleldin et al presented with total serm
bilirbin levels ranging %rom 25-76., mg/dI1 at presentation$ ,, in%ants &*+D' had moderate or
severe acte bilirbin encephalopath".
9*,:
@ver" bab" with h"perbilirbinemia shold have a direct %raction measred at least once to rle
ot direct h"perbilirbinemia. 4irect h"perbilirbinemia in the neonate is de%ined as a direct
%raction o% more than 2 mg/dI or more than one third o% the total bilirbin concentration and is
alwa"s pathologic. -bse<entl"$ i% the h"perbilirbinemia is established as the indirect t"pe$
obtaining a direct %raction with ever" measrement is nnecessar" nless the h"perbilirbinemia
develops a%ter the e)pected time %rame %or t"pical neonatal h"perbilirbinemia.
7ith the advent o% earl" discharge &be%ore the ph"siologic peak o% serm bilirbin' some
clinicians are advocating niversal bilirbin measrements in all babies prior to discharge.
3omograms have been pblished that estimate a bab"Ks risk o% disease based on measred levels
o% bilirbin. ?ne nomogram that assessed the risk o% critical h"perbilirbinemia in babies leaving
the hospital within 2,-,+ hors o% birth ad8sted %or gestational age and postnatal age in hors
&see %ollowing image'.
92/:
2n 2.**$ M et al pblished a similar nomogram sing transctaneos
measrements in health" term and late-preterm 5hinese in%ants.
92,:
(owever$ a%ter reviewing
available e)perimental and observational stdies that inclded comparison grops$ the C-
Areventive -ervices !ask Eorce conclded there was ins%%icient evidence to assess the balance
o% bene%its and harms o% niversal screening %or h"perbilirbinemia to prevent bilirbin
encephalopath".
925:
(or-speci%ic nomogram %or total serm
bilirbin and attendant risk o% sbse<ent severe disease in term and preterm in%ants. Csed with
the permission o% the Academ" o% Aediatrics.
(lood type
!he bab"Ks blood t"pe shold be determined and compared with that o% the mother. ;others with
t"pe ? blood ma" have circlating antibodies to other red cell antigens that can cross the
[Type text]
placenta and case hemol"tic disease in a bab" with a di%%erent blood t"pe$ sch as blood t"pe A
or B. -imilarl"$ mothers who are 0h negative ma" have antibod" to the 0h antigen i% the" have
not been treated with 0hoBA;. Antibod" to the 0h antigen cases the most %lminant t"pe o%
hemol"tic h"perbilirbinemia$ termed er"throblastosis %etalis in its most severe %orm. AB?
incompatibilit" can case signi%icant hemol"sis as well. ;inor antigens on the bab"Ks 0B5 are
also ssceptible to immne-mediated hemol"sis %rom maternall" ac<ired antibod" bt sall"
to a lesser e)tent than the ma8or antigens. 4ocmentation o% maternal antibod" stats dring the
pregnanc" shold alert the caretaker abot potential risk %or hemol"tic disease and
h"perbilirbinemia.
Reticulocyte count
Babies t"picall" have reticloc"te conts higher than older in%ants and adlts. (owever$
signi%icant elevation in the neonateKs reticloc"te cont &G7 mg/dI' can indicate the presence o%
an ongoing hemol"tic process.
&irect Coombs test
!his test assa"s %or antibod" on the 0B5 membrane. A positive reslt indicates that antibodies
are attached to the 0B5$ placing it at risk %or immne-mediated destrction. !his is a <alitative
test$ so a positive reslt does not sggest the amont o% antibod" or the degree o% hemol"sis.
(owever$ pairing these reslts with the reticloc"te cont can provide some idea o% the severit"
o% the process. !his test$ althogh reliable$ does not have *..D sensitivit". Becase %alse-
negative reslts do occr$ repeating a test with an initial negative reslt is not nreasonable i% the
clinical corse spports an ongoing hemol"tic process. 2n a man" cases o% AB? incompatibilit"$
direct 5oombs test %indings ma" be negative. !here%ore$ an eltion test shold be per%ormed to
demonstrate anti-A or anti-B antibodies in the serm.
C(C count
A 5B5 with manal di%%erential shold alwa"s be inclded in the evalation o% a newborn with
8andice. ;easrement o% the hemoglobin and hematocrit can be help%l to determine i% ongoing
hemol"sis severe enogh to case anemia is present. !he peripheral smear inspection is
particlarl" valable becase it ma" reveal large amonts o% ncleated 0B5s$ sggesting active
reticloc"tosis1 it ma" reveal abnormall" shaped 0B5s in the case o% hereditar" membrane
de%ects sch as spheroc"tosis and elliptoc"tosis or marked ovaloc"tosis in the case o% hemol"tic
disease o% the newborn. Babies with sepsis can develop h"perbilirbinemia$ and$ althogh not
conclsive$ normal total 7B5 cont and manal di%%erential can be reassring in a health"-
appearing bab" with h"perbilirbinemia.
Serum electrolytes
Breast%ed babies are known to normall" develop higher levels o% serm bilirbin than their
%ormla-%ed conterparts. (owever$ with the trend toward earlier discharge$ most breast%ed
babies are being discharged home be%ore breast%eeding is well established$ and a concomitant
increase in the nmber o% in%ants readmitted to the hospital in the %irst week o% li%e with
h"pernatremic deh"dration has occrred. ;an" o% these babies are also signi%icantl"
h"perbilirbinemic. !here%ore$ assessing serm sodim$ potassim$ chloride$ bicarbonate$ BC3$
and creatinine levels is essential1 initiate treatment as appropriate. 2n regions where the cltral
[Type text]
practice o% newborn salting e)ists$ assessing serm electrol"tes is especiall" important as reports
o% severe h"perbilirbinemia$ kernicters$ and death have been reported with serm sodim
levels as high as *9, m@</dI.
9*6:
*umbar puncture
2n the initial evalation o% h"perbilirbinemia$ sepsis shold be inclded in the di%%erential
diagnosis &odds ratio 2..6
9*,:
'. 2% so$ collection o% spinal %lid %or cltre and cell cont shold be
considered to rle ot meningitis. 2% the bab" is having nerologic s"mptoms$ cerebral spinal
%lid &5-E' evalation is imperative1 depending on the bab"Ks s"mptoms$ e)panding the
evalation be"ond the normal aerobic bacterial cltre ma" be prdent. 2%$ on the other hand$ the
bab" is vigoros and well-appearing with isolated h"perbilirbinemia as the onl" s"mptom &ie$
sepsis is not likel" to be the case o% the h"perbilirbinemia'$ a spinal tap ma" not be necessar".
)ranscutaneous bilirubin measurement
3meros devices that transctaneosl" measre total serm bilirbin levels have become
commerciall" available. !hese devices have been tested in babies o% var"ing ethnicities$ skin
pigmentations$ and gestational ages 5orrelation with serm bilirbin measrements is generall"
good. Althogh this approach is not recommended to replace the criterion standard o% serm
measrement$ it ma" be a se%l ad8nct to the clinical management o% h"perbilirbinemia in the
term and/or preterm in%ant.
2n 2..9$ Bental et al reported on the correlation o% transctaneos measrements obtained with
the >andice ;eter ;inolta/4raeger >;-*./ and serm measrements in *.9* paired
measrements obtained on 62+ in%ants. Iinear regression anal"sis o% the reslts "ielded a
correlation coe%%icient &0
2
' o% ..+,61 the grop sed these data to create a local Bhtani-t"pe !cB
nomogram %or niversal predischarge screening in C- poplations.
926:
M et al per%ormed /6$92*
measrements in 6$./5 health" term and late-preterm 5hinese in%ants to develop a
comprehensive nomogram %or this poplation.
92,:
2maging -tdies
2n the acte phase o% bilirbin encephalopath"$ neroimaging has no ma8or diagnostic bene%it.
(owever$ it can help rle ot other diagnoses$ particlarl" in the absence o% pro%ond
h"perbilirbinemia.
Head ultrasonography +H,S-
!his modalit" is particlarl" well sited to the neonate becase it is painless$ portable$ and
noninvasive1 also$ the neonatal brain is easil" imaged throgh the %ontanelles. Cltrasonograph" is
not help%l in diagnosing acte bacterial encephalopath"1 however$ other entities$ sch as
intraventriclar hemorrhage or parench"mal abnormalities$ can be rled ot.
C) scanning
5! scanning has little place in the evalation o% the neonatal brain. !he sbtle abnormalities
o%ten present in the neonatal period are not well visali6ed b" 5! scanning$ and %alse-negative
%indings are not ncommon.
[Type text]
MR.
Areviosl"$ the neronal damage characteristic o% kernicters was thoght to onl" be identi%iable
on histologic e)amination postmortem. (owever$ e)perience has revealed that ;02 can be sed
to depict characteristic bilateral s"mmetric high-intensit" signals in the globs pallids on both
!*-weighted and !2-weighted images in patients srviving with chronic bilirbin
encephalopath" &see image below'. !he se%lness and cost-e%%ectiveness o% this modalit" in the
diagnosis o% more sbtle %orms o% bilirbin-indced nerologic d"s%nction &B234' remains to
be %ll" elcidated.
;agnetic resonance image o% 2*-month-old with kernicters. Area o%
abnormalit" is the s"mmetric high-intensit" signal in the area o% the globs pallids &arrows'.
5ortes" o% ;.>. ;aisels.
?ther !ests
Brainstem aditor" evoked response &BA@0': (earing impediment is the most common se<ela
o% bilirbin to)icit". 2mpairment ma" be sbtle and ma" not be clinicall" apparent ntil the bab"
mani%ests dela"ed langage ac<isition. !o ma)imi6e the bab"Ks long-term nerologic
%nctioning$ earl" identi%ication o% an" degree o% hearing loss is important so that earl"
developmental assessment and intervention can be initiated in a timel" %ashion. -erial
assessments o% hearing %nction ma" be necessar". 7ith the advent o% mandated niversal
newborn hearing screening$ man" newborn hearing screening programs contain speci%ic
protocols %or in%ants with signi%icant h"perbilirbinemia designed to identi%" earl" hearing loss.
(istologic Eindings
?n macroscopic e)aminations$ characteristic "ellow staining can be readil" observed in %resh or
%ro6en sections o% the brain obtained within 7-*. da"s a%ter the initial bilirbin inslt. !he
regions most commonl" involved inclde the basal ganglia$ particlarl" the globs pallids and
sbthalamic ncles1 the hippocamps1 the sbstantia nigra1 cranial nerve nclei$ inclding the
oclomotor$ cochlear$ and %acial nerve nclei1 other brainstem nclei$ inclding the reticlar
%ormation and the in%erior olivar" nclei1 cerebellar nclei$ particlarl" the dentate1 and the
anterior horn cells o% the spinal cord.
3eronal necrosis occrs later and reslts in the clinical %indings consistent with chronic
bilirbin encephalopath". (istologicall"$ this appears as c"toplasmic vacolation$ loss o% 3issl
sbstance$ increased nclear densit" with ha6iness to the nclear membrane$ and p"knotic nclei
&see image below'.
[Type text]
;edical 5are
!he cornerstone o% management o% h"perbilirbinemia is prevention o% neroto)icit". !he
de%initive method o% removing bilirbin %rom the blood is via e)change trans%sion. !his is
crrentl" the indicated approach in the presence o% clinical bilirbin-indced nerologic
d"s%nction &B234' when the bilirbin level has reached dangeros levels despite preventive
e%%orts. Ahototherap" is the most common method aimed at prevention o% bilirbin to)icit".
5linical research e%%orts evalating the se o% metalloporph"rins to block bilirbin %ormation b"
competing with the en6"me heme o)"genase have not "ielded a clinicall" se%l intervention to
date.
Exchange trans"usion
!his de%initive therap" is sed to mechanicall" remove alread"-%ormed bilirbin %rom the blood.
2t is indicated whenever clinical signs o% acte bilirbin encephalopath" are present in patients
who present with criticall" high serm bilirbin levels that contine to rise despite attempts to
redce it.
!his procedre is not withot risk. 7hereas e)change trans%sion remains the de%initive therap"$
as recommended in the AAAKs 5linical Aractice Bideline N;anagement o% h"perbilirbinemia
in the newborn in%ant /5 or more weeks o% gestationO pblished in 2..,$ all babies shold
ndergo a trial o% phototherap"$ i% onl" while the blood is being prepared$ prior to initiating
e)change trans%sion.
92/:
2n the presence o% 0h isoimmni6ation$ a cord bilirbin level o% more
than 5 mg/dI or a rate o% rise in serm bilirbin o% more than ..5-* mg/dI/h is predictive o% the
ltimate need %or e)change trans%sion. !his relationship has not been demonstrated in
h"perbilirbinemia o% other etiologies. A report o% spplemental intravenos %lid administration
in 7, term babies with nonhemol"tic severe h"perbilirbinemia &total serm bilirbin level$ *+-
25 mg/dI' demonstrated a decreased rate o% e)change trans%sion in babies receiving the e)tra
%lid &*6D' compared with controls &5,D'.
927:
!he procedre involves removing the bab"Ks native blood and replacing it with citrate phosphate
de)trose &5A4' banked blood that does not contain bilirbin. ?bviosl"$ this mst be per%ormed
gradall". Csing an estimate o% +.-9. mI/kg total blood volme$ doble this amont is sall"
removed and replaced se<entiall" in ali<ots &*.-*5 mI in term babies1 5-*. mI in smaller
preterm babies' over several hors. !his approach$ called a doble volme e)change trans%sion$
harvests the most e%%icient amont o% bilirbin %rom the blood %or the amont o% intervention and
reslts in a decrease in total serm bilirbin levels b" abot ,.D.
Becase o% ongoing patholog" and e<ilibrim between the intravasclar and e)travasclar
spaces$ having to repeat the procedre at least once is not ncommon.
[Type text]
Csing ? negative blood rather than the bab"Ks blood t"pe is important becase not all circlating
antibodies ma" be removed. Aacked 0B5s resspended in %resh %ro6en plasma mst be sed %or
this procedre. 2rradiated 0B5s are sed to decrease the risk o% gra%t-verss-host reaction.
!his procedre carries both inherent risks and iatrogenic ones and shold be care%ll" per%ormed.
!he reported overall mortalit" rate is abot /:*...1 the risk o% signi%icant morbidit" has been
reported at abot 5:*... 2n babies who were ver" ill$ the risks are higher. ?ne series o% 25 in%ants
who were ill reported a mortalit" rate o% 2.D. As e)change trans%sion is becoming an
increasingl" rare intervention$ iatrogenic complications can be e)pected to increase.
A review o% *+/ e)change trans%sions per%ormed in *65 neonates in Bangkok$ !hailand$ %rom
*99,-2../ reported an overall morbidit" o% *5./D$ o% which 67D was attribted to in%ection
associated with the procedre.
92+:
2n%ants who were sick at the time o% the procedre &/*./D' were
more likel" to develop complications than were in%ants who were basicall" health" bt
h"perbilirbinemic &6.+D'. Areterm in%ants who re<ired e)change trans%sion also developed
procedre-related complications o% anemia$ apnea$ and cardiac arrest1 overall$ basicall" health"
preterm in%ants were more likel" to develop some morbidit" than were similarl" treated %ll-term
in%ants. ;orbidities were identi%ied in in%ants at the same rate regardless o% gestational age
&preterm vs term'. 3o mortalities were reported. 2n 2ran$ e)change trans%sions per%ormed %rom
2..*-2.., in 6+ in%ants %or h"perbilirbinemia reslted in one death directl" related to
complications %rom the procedre.
929:
!rans%sing with banked blood prodcts carries a risk o% in%ection. 5rrentl"$ the risk o% in%ection
with known pathogens is e)ceedingl" small. (owever$ a risk o% in%ection with pathogens that
have not "et been discovered &ie$ most recentl" hepatitis 5' contines.
4ring the procedre$ continall" monitor %or attendant ph"siologic aberrations$ sch as
h"pogl"cemia$ thromboc"topenia &reported in 6D o% patients in the 2ranian series
929:
'$
h"perkalemia &particlarl" i% the banked blood is G5 d'$ and h"pocalcemia &i% eth"lenediamine
tetra-acetic acid 9@4!A: preservative is sed in the banked blood'.
;echanical isses can contribte to the overall mortalit" and morbidit" o% the procedre. !he
need %or central access$ catheter-related and in%sion-related problems$ and hman error dring
in%sion are all areas that can pose potentiall" signi%icant risk. -ince the advent o% phototherap"
and obstetric treatment o% 0h disease$ the need %or e)change trans%sion has diminished. As
%ewer contemporar" clinicians are %amiliar with e)change trans%sion$ the risk o% iatrogenic
complications increases.
As mentioned above$ no clear-ct level o% bilirbin above which encephalopath" is assred and
below which nerologic sa%et" is assred has been determined. Birthweight$ gestational age$ and
chronologic age are all important$ as are a bab"Ks s"stemic condition$ %lid and ntritional stats$
acid-base stats$ and the presence or absence o% known patholog".
2n 2..,$ the AAA pblished revised practice parameters %or the management o%
h"perbilirbinemia in health" in%ants aged /5 weeksK gestation or older.
92/:
2n this docment$ the
AAA presented recommendations %or e)change trans%sion %or serm bilirbin levels greater than
2.-25 mg/dI$ depending on the postconceptional age o% the in%ant and the bilirbin-to-albmin
ratio$ a tool that is not widel" incorporated into the decision algorithm. !he series b" Bamaleldin
et al o% 2,9 in%ants with severe h"perbilirbinemia &P25 mg/dI' sggested that when
[Type text]
neroto)icit" risk isses sch as 0h incompatibilit" or sepsis were present$ 9.D o% in%ants who
developed B234 mani%ested total serm bilirbin levels o% greater than 25., mg/dI. (owever$ in
the *** in%ants withot risk %actors$ neroto)icit" was %irst observed with total serm bilirbin
levels greater than /*.5 mg/dI.
9*,:
-tdies have reported nerologicall" normal otcomes in health" term in%ants with histories o%
serm bilirbin levels as high as ,6 mg/dI. (owever$ kernicters has been reported to occr in
near-term in%ants with serm bilirbin levels as low as 2..7 mg/dI and$ more recentl"$ in preterm
in%ants with peak total serm bilirbin as low as */.* mg/dI.
9*9:
!he level at which to intervene is
a clinical <estion that remains to be answered. A srve" answered b" *6/ hospitals in the
Cnited =ingdom in 2..9 "ielded a range o% 2.-/. mg/dI as thresholds %or e)change trans%sion
in otherwise health" term in%ants.
9/.:
!he procedre shold be strongl" considered in babies with
signi%icant risk %actors predisposing %or kernicters &eg$ sepsis$ acidosis$ hemol"tic disease' i% the
bilirbin level has approached the range o% 2.-25 mg/dI.
Enteral interentions
Administration o% agar has been tried in an attempt to decrease the enterohepatic recirclation o%
con8gated bilirbin. 2t has not proved to be clinicall" se%l and ma" case intestinal
obstrction.
Aarenteral administration o% immnogloblin B &2gB' has been shown in controlled clinical trials
to redce the need %or e)change trans%sion in both 0h and AB? immne-mediated hemol"tic
disease. 2ts mechanism o% action is not entirel" clear.
Administration in h"perbilirbinemia reslting %rom isoimmne hemol"tic disease that is
nresponsive to phototherap" and/or is approaching e)change level has been recommended b"
the AAA in its 2.., revised clinical practice gideline.
Accelerated meconium eacuation
Administration o% gl"cerin sppositories to %acilitate stooling has been evalated as a potential
method o% ameliorating h"perbilirbinemia. Althogh a controlled trial demonstrated earlier
passage o% meconim$ no e%%ect was demonstrated on total serm bilirbin levels$ e)cept %or a
small statisticall" signi%icant e%%ect identi%ied in males with blood t"pe A positive. 7hether this
was a statistical aberration or a tre treatment e%%ect is nclear.
Enteral prebiotics
@nterohepatic recirclation and dela"ed stooling contribte to perpetation o%
h"perbilirbinemia. 0ecent investigation has %ocsed on the role o% oligosaccharides &galactose
and %rctose' natrall" occrring in breastmilk as a modlator o% intestinal %lora and %nction. As
a reslt$ ma8or in%ant %ormla man%actrers are now adding these so-called prebiotics to their
%ormlations. A randomi6ed$ doble-blind trial o% %ormla and prebiotics verss %ormla and
maltode)trine placebo was e)amined the e%%ect o% the investigational %ormla on stooling
%re<enc". Eor the %irst 2+ da"s o% li%e$ 76 newborns were randoml" assigned to receive one o%
the %ormlations. !ransctaneos bilirbin measrements and nmber o% stools per da" were
recorded. 2n%ants in the prebiotic grop showed signi%icantl" more stools per da" %or the dration
o% the trial period$ as well as lower transctaneos bilirbin levels &pJ ...5'.
9/*:
[Type text]
(eta'glucuronidase inhibition
I-aspartic acid and en6"maticall" h"drol"6ed casein &@(5' are known inhibitors o% beta
glcronidase$ the en6"me that promotes enterohepatic recirclation o% con8gated bilirbin in
the neonatal intestine. A randomi6ed controlled trial o% enteral administration o% these sbstances
&2 treatment grops' compared with babies who received nothing &grop /' or enteral
whe"/casein &no known en6"matic activit"$ grop ,' showed signi%icantl" lower transctaneos
bilirbin measrements in breast%ed babies aged /-7 da"s who received the en6"me inhibitors
when compared with the controls.
9/2:
(owever$ a similar treatment e%%ect observed in grop ,
raises some <estions regarding the vale o% these therapies.
Sn'mesoporphyrin
@)perimental therap" with -n-mesoporph"rin inhibits bilirbin prodction b" inter%ering with
heme-o)"genase$ an essential en6"me in the catabolic pathwa" o% hemoglobin. !his therap" is in
clinical trials bt has not been approved %or se b" the Eood and 4rg Administration &E4A'. A
report o% a single case o% compassionate se in the Cnited -tates in a ver" low birth weight in%ant
with severe growth restriction who was not a candidate %or e)change trans%sion showed a more
than 25D redction in total serm bilirbin levels a%ter administration o% a single dose at ,6
hors o% li%e.
9//:
Althogh more e)tensivel" stdied in other contries$ the sa%et" and possible
long-term se<elae o% this therapetic modalit" remain to be elcidated.
-rgical 5are
-table central venos access is re<ired to sccess%ll" per%orm an e)change trans%sion.
-rgical placement o% appropriate lines ma" be re<ired to %acilitate this procedre i% a catheter
cannot be placed into the mbilical vein.
5onsltations
?btaining inpt %rom a pediatric nerologist dring the acte presentation o% B234 ma" be
se%l. (owever$ the histor" and clinical presentation ma" make the diagnosis apparent.
2n the chronic phase$ involving nerodevelopmental specialists in the care and evalation o% the
in%ant is important. 4evelopmental potential can be ma)imi6ed b" earl" identi%ication o% and
intervention %or nerologic de%icits.
2% the patient develops h"drocephals$ consltation with a nerosrgeon is recommended.
4iet
4epending on the degree o% nerologic impairment$ in%ants or children ma" have limitations in
their abilit" to eat normall". 4iet and ntrition mst be individali6ed with the help o% the
nerodevelopmental team caring %or the patient.
Activit"
-ome nerologic de%icits t"picall" appear dring the phase o% motor skill ac<isition b" the
in%ant. ;otor de%icits shold be identi%ied earl"$ and appropriate intervention shold be initiated
to ma)imi6e the in%antKs abilit" in this critical area.
;edication -mmar"
[Type text]
3o medications are available to treat the s"mptoms o% acte or chronic bilirbin encephalopath".
Aharmacologic intervention is aimed at prevention. 5rrent therapies are indicated as ad8ncts to
phototherap" when total bilirbin is approaching e)change level1 e)perimental therap" contines
with the se o% bilirbin prodction inhibitors.
Blood Arodct 4erivatives
Class Summary
!hese methods decrease the amont o% %ree bilirbin in the intravasclar space$ ths theoreticall"
redcing the risk o% neroto)icit". Bilirbin is prodced via indction o% its en6"matic pathwa"
and b" 0B5 degradation. 2nhibition o% either o% those 2 mechanisms can decrease the amont o%
bilirbin in the blood.
Liew %ll drg in%ormation
Albumin +Albuminar/ Albutein/ Plasbumin-

Becase bilirbin bond to albmin is not available to cross the blood-brain barrier$ increasing
the amont o% serm albmin theoreticall" increases the amont o% available binding sites and
decreases %ree bilirbin. @%%orts to <anti%" albmin-binding capabilit" or serm levels o% bond
bilirbin have not proved to be clinicall" se%l$ althogh assessment o% the bilirbin-to-albmin
ratio has recentl" been incorporated into the decision-making algorithm %or e)change
trans%sion. (owever$ administration o% albmin %or the prpose o% increasing bilirbin-binding
capacit" is not a recommended standard o% care. 2t ma" be considered in cases o% signi%icant
h"poalbminemia. ;easred albmin levels J / g/dI ma" be considered an additional risk %actor
%or B234 when considering therapetic interventions.
Liew %ll drg in%ormation
.mmune globulin intraenous +%amimune/ %ammagard S/&/ %ammar'P/ Polygam S/&-

Aarenteral administration has been shown in controlled clinical trials to redce the need %or
e)change trans%sion in both 0h and AB? immne-mediated hemol"tic disease. 2ts mechanism
o% action is not entirel" clear.
Administration in h"perbilirbinemia reslting %rom isoimmne hemol"tic disease that is
nresponsive to phototherap" and/or is approaching e)change level has been recommended b"
the AAA in its 2.., revised clinical practice gideline.
Anticonvlsant Agents
Class Summary
Ahenobarbital ma" increase hepatic con8gation and e)cretion. 4ecreased hepatic con8gation
cased b" normal dela" in en6"me indction increases the amont o% ncon8gated bilirbin in
the blood stream. 5on8gated bilirbin does not pose a threat o% neroto)icit". ?nce con8gated$
this nonto)ic %orm o% bilirbin proceeds toward intestinal e)cretion.
[Type text]
Liew %ll drg in%ormation
Phenobarbital +*uminal/ Sol"oton-

2ndces the hepatic en6"mes involved in bilirbin con8gation and increases biliar" e)cretion.
4o not administer intra-arteriall". 4osing can be enteral or parenteral.
Erther ?tpatient 5are
!o help ensre that in%ants ma" reach their ma)imm nerodevelopmental potential$ re%erring
babies with bilirbin-indced nerologic d"s%nction &B234' to a nerodevelopmental
pediatrician skilled in caring %or these patients is important. @arl" identi%ication o% and
intervention %or nerodevelopmental de%icits has been shown to positivel" impact an in%antKs
long-term nerodevelopmental prognosis.
!he nmeros areas o% ncertaint" srronding the diagnosis and treatment o%
h"perbilirbinemia in the in%ant$ copled with the in%re<enc" o% se<elae$ make it eas" to
become cavalier abot the evalation o% an in%ant with 8andice. (owever$ remember that
ph"siologic h"perbilirbinemia is a diagnosis o% e)clsion$ and kernicters$ when it occrs$ is a
devastating and legall" inde%ensible se<ela.
-epsis mst alwa"s be e)clded in the in%ant with 8andice. Cncommon$ bt treatable$ metabolic
cases o% 8andice inclde h"poth"roidism and galactosemia. !he %irst sign o% occlt immne or
nonimmne hemol"tic disease ma" be h"perbilirbinemia.
2n its 2.., clinical practice gideline$ the AAA inclded recommendations regarding interval
between hospital discharge and otpatient %ollow-p evalation b" a <ali%ied health care
pro%essional.
92/:
0ecommendations are based on the in%antKs age &in hors o% li%e' at discharge$
presence or absence o% risk %actors %or e)aggerated h"perbilirbinemia$ and the presence o% other
neonatal problems. 0ecommendations %or %ollow-p range %rom as earl" as prior to 72 hors o%
li%e &i% discharged be%ore 2, h' to no later than *2. hors &5 d' i% discharged be%ore 72 hors.
!rans%er
!he recentl" reported cases o% kernicters have occrred in near-term or term in%ants who were
discharged %rom the hospital %ewer than ,+ hors a%ter birth.
;ost in%ants discharged at %ewer than 72 hors a%ter birth have clearl" not reached their
ph"siologic peak bilirbin level prior to discharge.
An" in%ant at risk %or signi%icant h"perbilirbinemia and possible neroto)icit" shold be cared
%or in a nrser" capable o% rendering appropriate care %or the h"perbilirbinemia and an"
contribting diagnoses.
A recentl" pblished nomogram predicts which babies ma" be at risk %or signi%icant disease$
based on hor-o%-li%eQspeci%ic bilirbin levels &see image below'.
92/:
2n%ants whose levels %all in
the high-intermediate and high-risk 6ones shold be closel" monitored in a nrser" capable o%
[Type text]
caring %or sick newborns1 the" ma" re<ire trans%er %rom the birth hospital to a regional perinatal
center.
(or-speci%ic nomogram %or total serm bilirbin and attendant
risk o% sbse<ent severe disease in term and preterm in%ants. Csed with the permission o% the
Academ" o% Aediatrics.
4eterrence/Arevention
Preention
Arevention o% h"perbilirbinemia is the best wa" to minimi6e the incidence o% kernicters.
(owever$ becase some babies develop kernicters with relativel" modest bilirbin levels$ no
known absolte level o% bilirbin below which the in%ant is completel" sa%e is recogni6ed.
Additionall"$ becase other %actors contribte to the abilit" o% bilirbin to cross the blood-brain
barrier$ management o% these components mst be appropriatel" considered.
2n 2..9$ 3ewman et al reported the nmbers needed to treat with phototherap" to prevent
kernicters$ based on the AAA 2.., gideline phototherap" threshold. Assessment o% 22$5,7
in%ants %rom a cohort o% 2+*$+9+ in%ants born in a 5ali%ornia hospital s"stem %rom *995-2..,
reslted in varios 33!s %or di%%erent sbpoplations o% in%ants. Averaging 222 %or bo"s and //9
%or girls$ the sbgrop 33!s ranged %rom *. %or less than 2,-hor-old$ /6Qweek-gestation bo"s
to /$.,* %or older than or /-da"-old$ ,*-week-gestation girls.
9/5:
Serum bilirubin
!otal serm bilirbin comprises a con8gated %raction &loosel" called direct bilirbin' and an
ncon8gated %raction &indirect bilirbin'. !he" are additive. (owever$ the indirect %raction is
composed o% bond bilirbin &bond to albmin'$ lmirbin and other isomers i% the bab" is
nder phototherap" &nbond bt water-solble and nlikel" to cross the blood-brain barrier'$
and %ree bilirbin. !he %ree component is potentiall" to)ic$ bt its e)act serm level cannot be
readil" measred.
Ris# o" reduction o" serum bilirubin
!he crrent level o% knowledge does not recogni6e the ph"siologic bene%its o% bilirbin$ despite
the mltiple mechanisms operant in the neonate to promote and preserve h"perbilirbinemia. 2n
vitro e)periments have demonstrated a potent antio)idant capabilit" o% bilirbin$ more so than
the crrentl" identi%ied mechanisms.
An emerging %ield o% research in hman medicine is the role o% o)idative in8r" in the
development o% varios pathologic processes$ which ma" be contribtor" to man" neonatal
diseases$ sch as retinopath" o% prematrit"$ periventriclar lekomalacia$ bronchoplmonar"
[Type text]
d"splasia$ and necroti6ing enterocolitis. 0ecent observational stdies in the neonate have
demonstrated an inverse correlation between peak serm bilirbin levels and the development o%
these varios pathologies. 2nvestigation into this line o% research contines.
Phototherapy
2rradiance with light in the ble-green spectrm &,,.-,+. nm' indces a photochemical reaction
that changes the bilirbin molecle into other photoisomers that are water-solble$ readil"
e)cretable$ and nlikel" to cross the blood-brain barrier into the lipid-rich neronal tisse. -ch
conversion begins immediatel" pon e)posre o% the skin sr%ace to the light.
!he most important photoreaction is an irreversible strctral isomeri6ation o% bilirbin into a
water-solble sbstance called lmirbin$ which is then e)creted in the bile. 0eversible
con%igrational isomeri6ation and photo-o)idation also contribte somewhat to the e%%ectiveness
o% phototherap" to redce %ree bilirbin in the bab".
!o be e%%ective$ ade<ate skin sr%ace mst be e)posed to the appropriate wavelength$ with
enogh intensit" &l)' to indce the desired reaction. !he AAA has recentl" inclded
recommendations %or wavelength &,/.-,9. nm' and irradiance &G/. R7/cm
2
' in their clinical
practice gideline.
92/:
-erm bilirbin levels shold be closel" monitored dring phototherap". A *-mg/dI to 2-mg/dI
decrease o% measred bilirbin levels over a period o% ,-6 hors is an appropriate response to
phototherap". 2% an inade<ate response has been observed$ lining the bab"Ks bedding with
alminm %oil or white material can increase the sr%ace area o% e)posre and ma" increase the
e%%ectiveness o% phototherap".
Larios devices are commerciall" available to %acilitate provision o% phototherap". ;odels
inclde overhead lights$ blankets$ and swaddling devices1 selection is based on abilities to cover
a broad sr%ace area$ ease o% administration$ and personal pre%erence. !he assortment o%
commerciall" available phototherap" devices contines to e)pand$ and each new market entr" is
advertised as sperior to the previos entr". (ead-to-head clinical trials repeatedl" show that
time$ irradiance$ and skin sr%ace area are the most signi%icant %actors in e%%icac" o%
phototherap".
9/6$ /7$ /+:
2n 2..,$ the AAA revised its clinical practice gideline %or the management o%
h"perbilirbinemia in the health" in%ant older than /5 weeksK estimated gestational age.
92/:
!he
gideline incorporates a nomogram that delineates serm bilirbin levels b" hor o% li%e with
sbse<ent risk %or signi%icant disease &see %ollowing image'.
[Type text]
(or-speci%ic nomogram %or total serm bilirbin and attendant
risk o% sbse<ent severe disease in term and preterm in%ants. Csed with the permission o% the
Academ" o% Aediatrics.
An 2nternet-based tool$ Bili!ool$ is now available to help clinicians assess and treat
h"perbilirbinemia based on the hor-speci%ic nomogram and pblished gidelines.
!his re%erence shold be sed when deciding how closel" to monitor babies being discharged
home be%ore their bilirbin levels have peaked. -ince its development$ some e)perts have
recommended niversal bilirbin screening &per%ormed with the state metabolic screen to
minimi6e blood draws' be%ore discharge.
Althogh %alling short o% recommending niversal bilirbin measrement$ the AAA gideline
does recommend assessment o% risk o% severe h"perbilirbinemia in ever" bab" prior to hospital
discharge. !his assessment can inclde either a bilirbin measrement &serm or transctaneos'$
a clinical assessment o% risk %actors$ or a combination o% these 2 approaches. Erther prospective
anal"sis o% these strategies %ond that the hor-speci%ic nomogram was a better predictor than a
clinical risk %actor approach and that predischarge bilirbin level combined with gestational age
most accratel" predicted an in%antKs risk o% developing severe h"perbilirbinemia.
9/9$ ,.:
5rrent <anti6ation o% bilirbin has been limited to direct serm measrement. !ransctaneos
measrement devices have recentl" become commerciall" available and are slowl" being
integrated into clinical se. !he man%actrers claim e)cellent reliabilit" and validit" in babies o%
all skin t"pes and colors.
Ris#s o" phototherapy
Ahototherap" b" itsel% is generall" considered sa%e in babies$ e)cept in some rare genetic skin
disorders and congenital porph"ria. (owever$ some risks are associated with its se.
@)posre to phototherap" can increase insensible %lid loss and lead to deh"dration$ especiall" in
babies in open warmers i% %lid intake and otpt are not closel" monitored. !his$ in trn$
potentiates h"perbilirbinemia.
-ome e)tremel" prematre in%ants have reportedl" e)perienced skin brns %rom %iberoptic
blankets on which the" were l"ing. -ch devices shold be sed catiosl" in in%ants with
vlnerable skin.
?% potentiall" greater concern with respect to e)tremel" prematre in%ants is the report o%
increased mortalit" associated with phototherap". A std" condcted b" the 325(4 3eonatal
3etwork as reported b" 7atchko evalated the otcomes o% aggressive verss conservative
phototherap" in e)tremel" low birth weight in%ants. Althogh aggressive phototherap" seemed to
[Type text]
improve nerodevelopmental otcomes in the 75*- to *...-g cohort$ aggressive phototherap"
sed in the grop with birth weights o% 5.*-75. g showed a 5D higher mortalit" rate$ with a
post-hoc Ba"esian anal"sis estimating an +9D probabilit" that aggressive phototherap" increased
the rate o% death in this cohort. !he athors speclate that greater light penetration deeper into
sbctaneos tisses and possible o)idative in8r" to cell membranes ma" be responsible.
9*9:
5oncern e)ists abot the risk o% retinal damage in in%ants e)posed to the e)tremel" bright light o%
phototherap". Accordingl"$ all in%ants shold wear protective e"e coverings while being treated.
An observed increase in the prevalence o% patent dcts arterioss &A4A' has been shown to
occr in prematre in%ants receiving phototherap"$ and %oil shields to the chest have been shown
to ameliorate this increase. !he operant mechanism has not been %ll" elcidated.
Bilirbin photosensiti6es the skin$ and skin damage is a theoretical risk. Bllos erptions have
been described in several in%ants with porph"rin abnormalities1 congenital porph"ria is a
contraindication to the se o% phototherap". 2n 2.**$ 5soma et al %rom (ngar" reported on 59
sets o% twins$ one o% which received ble-light phototherap" and the other o% which did not.
3eonatal phototherap" was associated with a signi%icantl" higher prevalence o% both ctaneos
and veal melanoc"tic lesions$ a%ter controlling %or sn e)posre and other con%onders.
9,*:
Bron6e bab" s"ndrome occrs in in%ants with direct h"perbilirbinemia who are e)posed to
phototherap". !his seems likel" to be the reslt o% dermal accmlation o% coproporph"rins.
;easrement o% the direct %raction o% total bilirbin shold be per%ormed in ever" bab" be%ore
starting phototherap".
Ahototherap" can inter%ere with maternal-child bonding at a critical time in the d"adKs
development. 2% a mother is breast%eeding$ initiation o% phototherap" introdces mechanical
barriers to the breast%eeding process$ which can be overwhelming at this critical time. An"
comments abot the role o% breast milk in the development o% h"perbilirbinemia ma" %rther
sabotage this process. Altered parental perceptions o% their in%ant %rom health" to ill ma" %rther
in%lence their short-term and long-term interactions with their in%ant. !he pediatrician shold
address these isses with the %amil".
Ahototherap" ma" be associated with iles and/or %eeding intolerance in prematre in%ants
treated with overhead &bt not %iberoptic' devices. 4oppler %low stdies o% splanchnic blood %low
per%ormed on babies receiving overhead phototherap" showed increased resistance to %low in the
sperior mesenteric arter" &-;A' compared with prephototherap" measrements1 no sch e%%ect
was observed in babies being treated with %iberoptic devices. A retrospective review o% 52
consective e)tremel" low birth weight in%ants showed a higher incidence o% iles &abdominal
distention$ bilios aspirates' in babies receiving phototherap" &6/.,D' compared with those who
did not &9D'.
9,2:
?tcomes between the 2 grops were comparable.
(reast"eeding
!he link between h"perbilirbinemia and breast%eeding has long been recogni6ed$ and$ ntil
recentl"$ breast%eeding was t"picall" interrpted in in%ants with 8andice. 0andomi6ed controlled
trials have shown that o%%ering %ormla or de)trose water to the breast%ed in%ants with 8andice
actall" increases total serm bilirbin levels and$ ths$ shold not be advocated. !he AAA
recommends against this practice$ with evidence <alit" B and 5 in its 2.., clinical practice
[Type text]
gideline.
92/:
Erthermore$ this practice has also been shown to reslt in a decrease in breast milk
intake a%ter breast%eeding is reestablished. -td" o% the e%%ect o% contining breast%eeding verss
its interrption has not shown an" ntoward e%%ect o% contined breast%eeding. Becase o% the
clear short-term and long-term advantages to the in%ant o% breast milk %eeds$ the evidence wold
indicate that breast%eeding shold be contined in the in%ant who is well enogh to have enteral
%eedings.
.n"ant massage
2n 2.**$ 5hen et al reported %rom 3iigata$ >apan the reslts o% a randomi6ed controlled trial o%
the bene%its o% in%ant massage on h"perbilirbinemia. Eort"-two health" term breast%ed in%ants
ranging in weight %rom 2+..-/6.. g were randomi6ed to massage or no massage &control'.
2n%ants receiving massage had a signi%icantl" higher %re<enc" o% stooling on da"s * and 2 &P J .
.5' and a lower total serm bilirbin on da" , compared with the control grop.
9,/:
Clinical algorithms
A recent >ornal o% Aediatrics spplement devoted e)clsivel" to h"perbilirbinemia and
prevention o% kernicters advocated 2 models %or pblic health polic" aimed at eliminating
kernicters %rom the poplation.
9,,$ ,5:
!o date$ notwithstanding the e%%orts o% some hospital
s"stems and the American Academ" o% Aediatrics to standardi6e this aspect o% newborn care$
approaches to the srveillance and management o% h"perbilirbinemia remain individali6ed$
both throghot the Cnited -tates and elsewhere.
9/.:
5omplications
!he complications o% acte bilirbin encephalopath" encompass the classic scope o% chronic
bilirbin encephalopath" described above. Abnormalities can be e)pected in the e)trap"ramidal
s"stem and in aditor" and ga6e %nction1 dental d"splasia can be e)pected.
Arognosis
!he spectrm o% nerologic disabilit" %rom kernicters can range %rom mild to severe. Attempts
to correlate %eatres o% h"perbilirbinemia with prognosis %or disabilit" have %ailed. 4espite
mltiple attempts$ no de%initive association has been identi%ied between the degree o% de%icit and
parameters sch as total serm bilirbin level$ dration o% h"perbilirbinemia$ presence o%
hemol"tic disease$ gestational age$ birthweight$ or concomitant s"stemic illness.
Aatient @dcation
!o %acilitate the provision o% appropriate evalation and %ollow-p %or babies withot recogni6ed
risk %actors$ the AAA has pblished an hor-o%-age-speci%ic gideline that correlates total serm
bilirbin levels with degree o% risk and recommendations %or %ollow-p.
92/:
!he AAA recommends pro%essional medical evalation in 2-/ da"s %or babies who are discharged
%rom the hospital %ewer than ,+ hors a%ter birth.
92/:
Babies discharged %ewer than 72 hors a%ter
birth ma" also be at risk$ and the" shold be closel" monitored as well. ?ther risk %actors
warranting additional vigilance ma" inclde ne)plained %amil" histor" o% neonatal
h"perbilirbinemia$ near-term gestation$ low birth weight$ e)cessive brising or hematomata$
and ethnicit" at risk %or e)aggerated h"perbilirbinemia.
[Type text]
Aarents shold be in%ormed o% the importance o% keeping these appointments$ as well as be
%amiliari6ed with the s"mptoms o% poor %eeding in breast%ed babies and how to seek help.
[Type text]
Available at : http://www.cdc.gov/ncbddd/8andice/hcp.html
Bidelines and !ools %or (ealth Aro%essionals
=ernicters in Ell !erm 2n%ants
Erom the 5enters %or 4isease 5ontrol and Arevention$ 2..*
@arl" h"perbilirbinemia detection is critical to the prevention o% the irreversible e%%ects o%
kernicters. (ealth care providers$ parents$ and other caretakers shold be aware o% risk %actors
%or h"perbilirbinemia$ and treatment shold begin immediatel" a%ter h"perbilirbinemia is
diagnosed. Lerbal and written in%ormation received be%ore the in%ant is discharged ma" be se%l
in gaining an nderstanding o% risk %actors %or and signs and treatment o% 8andice and
h"perbilirbinemia. Bilirbin levels be%ore discharge ma" provide <antitative measrement that
cold aid management. 2n%ants discharged Slt1,+ hors a%ter birth shold be e)amined b" a
health care provider within 2 to / da"s to receive rotine %ollow-p visits and a 8andice
assessment.
;a8or 0isk Eactors %or ("perbilirbinemia in Ell-!erm 3ewborns
0andice within %irst 2, hors a%ter birth.
A sibling who was 8andiced as a neonate.
,nrecogni6ed hemol"sis sch as AB? blood t"pe incompatibilit" or 0h incompatibilit".
1onoptimal scking/nrsing.
&e%icienc" in glcose-6-phosphate deh"drogenase$ a genetic disorder.
.n%ection.
Cephalohematomas/brising.
East Asian or ;editerranean descent.
0ead more abot this recommendation T
;anagement o% ("perbilirbinemia in the 3ewborn 2n%ant /5 or ;ore 7eeks o% Bestation
Erom the American Academ" o% Aediatrics Aractice Bidelines$ 2..,
!hese gidelines provide a %ramework %or the prevention and management o% h"perbilirbinemia
in newborn in%ants o% /5 or more weeks o% gestation. 2n ever" in%ant$ we recommend that
clinicians *' promote and spport sccess%l breast%eeding1 2' per%orm a s"stematic assessment
be%ore discharge %or the risk o% severe h"perbilirbinemia1 /' provide earl" and %ocsed %ollow-
[Type text]
p based on the risk assessment1 and ,' when indicated$ treat newborns with phototherap" or
e)change trans%sion to prevent the development o% severe h"perbilirbinemia and$ possibl"$
bilirbin encephalopath" &kernicters'.
0ead more abot this gideline T
-evere 3eonatal >andice: 5ases$ 5are$ ?tcome$ Arevention
Erom 5hildrenUs (ospital o% Aittsbrgh
*. Aromote and spport sccess%l breast%eeding.
2. @stablish nrser" protocolsVinclde circmstances in which nrses can order a bilirbin.
/. ;easre !-B or !cB i% 8andice occrs in the %irst 2, hors.
,. 4o not rel" on visal estimation o% 8andice. !his can lead to errors$ particlarl" in darkl"
pigmented in%ants.
5. 2nterpret bilirbin levels according to the in%antUs age in hors.
6. 3ote that in%ants Slt1/+ weeks$ particlarl" i% breast%ed$ are high risk.
7. Aer%orm risk assessment be%ore discharge.
+. Bive parents written and oral in%ormation abot 8andice.
9. Arovide appropriate %ollow-p based on time o% discharge and risk assessment.
*.. !reat newborns$ when indicated$ with phototherap" or e)change trans%sion.
[Type text]
Available at : http://www.dkemedicine.org/blog/newborn-8andice
>andice -- a "ellow coloring o% the skin and e"es -- occrs in appro)imatel" 6. percent o% %ll-
term newborns.
2t is generall" a temporar" condition that does not case babies harm and does not re<ire an"
treatment. (owever$ a %ew babies do re<ire treatment -- both when the" are in the newborn
nrser" and %or a short period a%ter the" retrn home.
>andice is cased b" a pigment that we all have in or blood called bilirbin. Bilirbin is
released into the blood b" the normal breakdown and trnover o% red blood cells$ which natrall"
occrs all the time. 2t is then processed b" the liver into a %orm that can be removed in the
digestive tract.
3ewborns t"picall" develop higher bilirbin levels than adlts over the %irst %ew da"s o% li%e
becase the" have higher levels and %aster trnover o% red blood cells -- and prodce more
bilirbin. !heir livers are also immatre and less able to remove the bilirbin %rom their bodies.
!hese %actors lead to physiologic $aundice.
!he "ellow coloring o% a bab" with ph"siologic 8andice will o%ten be noticeable arond two
da"s o% li%e$ will peak at three to %ive da"s$ and will then resolve within two weeks. Ah"siologic
8andice poses no danger to the newborn.
Ris# "actors "or pathologic $aundice
Pathologic $aundice/ however$ involves a higher level o% bilirbin and re<ires treatment to
hasten the removal o% bilirbin. !his can occr in an" newborn who has an e)aggerated %orm o%
ph"siologic &normal' 8andice. !here are also risk %actors that can help gide clinicians as to
which babies mst be %ollowed more care%ll".
?ne risk %actor is prematrit" -- babies born more than two weeks be%ore their de date are more
likel" to develop higher levels o% bilirbin. !he more prematre a child is$ the less matre their
liver is at the time o% birth$ and the harder it is %or them to start eliminating the bilirbin.
A blood t"pe incompatibilit" between the mother and bab" is also a reason to track the
newbornUs 8andice more closel". !his e)ists when a mother has the blood t"pe ? &and there%ore
[Type text]
has antibodies against A and B cells' and her newborn is o% blood t"pe A or B. !hismay case the
newbornUs red blood cells to break down more <ickl" de to maternal antibodies that have
leaked into the bab"Us bloodstream.
A blood t"pe incompatibilit" also e)ists i% the mother has a 0h &0hess' %actor negative blood
t"pe and the newborn is 0h %actor positive. !his had been a common case o% severe neonatal
8andice$ bt is now ver" ncommon becase 0h immne globlin &0hogham' is given to
mothers at risk be%ore deliver".
Althogh breast%eeding is also considered a risk %actor$ it is actall" lack of effective
breastfeeding that is the risk %actor. !he likelihood o% problems with nrsing are minimi6ed b"
nrsing the newborn as soon a%ter birth as possible and to contine nrsing eight to *2 times per
da" %or the %irst several da"s. Breast milk is an ideal %ood %or babies$ and 8andice is sall" not a
reason to add %ormla to the diet.
?ther risk %actors %or pathologic 8andice inclde e)cessive brising o% the newborn$ having a
sibling that re<ired treatment %or 8andice$ and being o% @ast Asian race.
>andice in the %irst 2, hors o% li%e is never ph"siologic and alwa"s merits an evalation.
&etection
A ph"sical e)am is alwa"s important in assessing the level o% 8andice. >andice %irst appears on
the %ace$ and$ as the bilirbin level rises$ spreads down the bod". !he "ellow color is best
appreciated in natral light$ so doing the e)am b" a window is help%l.
@stimation o% the level o% 8andice b" e)am alone$ however$ is di%%iclt and prone to errors. B"
obtaining blood thogh a prick o% a newbornUs heel$ an e)act bilirbin level can be obtained.
!he American Academ" o% Aediatrics has provided gidelines as to which newborns shold be
treated %or 8andice &N;anagement o% ("perbilirbinemia in the 3ewborn 2n%ant /5 or ;ore
7eeks o% Bestation$O Pediatrics$ >l" 2..,'.
!he necessit" o% treatment depends pon the bilirbin level$ the newbornUs age in hors and the
babies gestation. 2n general$ the older the newborn$ the higher the bilirbin level can be and not
re<ire treatment. Eor newborns with particlar risk %actors$ sch as prematrit"$ treatment is
started at lower bilirbin levels %or a given age in hors.
[Type text]
Complications o" extreme $aundice
@)tremel" high levels o% bilirbin can lead to the rare bt serios condition o% #ernicterus/ a
%orm o% brain damage. !his is now a ver" rare condition with most cases occrring in prematre
or ver" ill babies. !reatment %or 8andice starts at levels that are %ar lower that those that cold
case kernicters.
)reatment
Iight therap" &phototherap"' is the most common treatment %or 8andice. !he bab" ma" be
placed nder ble light &visible light in the ble region o% the spectrm' or on top o% a %iber-optic
blanket &Nbili-blanketO' -- or both.
!he ble light converts the bilirbin into a %orm that can be removed %rom the bod" in the rine.
-ince bili-blankets are available %or home se$ man" newborns can be treated %or 8andice at
home. 7hether a bab" is a candidate %or home phototherap" depends on the level o% the bilirbin
and the reasons %or the 8andice. !reatment generall" takes several da"s.
0arel"$ an e)change blood trans%sion ma" be per%ormed to treat e)tremel" high levels o%
bilirbin. !his is done in a neonatal intensive care nit and involves removing small amonts o%
the bab"Us blood at a time and replacing it with %resh blood repeatedl" over several hors.
Preention
As discssed above$ ph"siologic 8andice is not a process that can or shold be prevented. !he
likelihood o% developing pathologic 8andice$ or 8andice that re<ires treatment$ can be
minimi6ed b" %re<ent %eedings. A newborn shold %eed at least eight to *2 times per 2, hors.
2t is essential that a newbornUs 8andice be monitored closel" b" a health care pro%essional. As
most health" newborns re<ire onl" a brie% hospital sta"$ prompt %ollow p in the primar" care
ph"sicianUs o%%ice is recommended.
A doctor or nrse shold see "or newborn between three to %ive da"s o% age as this is when the
bilirbin level sall" peaks. Mo shold certainl" call "or childUs ph"sician i% "or newborn
appears more 8andiced or i% he or she is especiall" sleep"$ %ss"$ or %eeding poorl".
[Type text]
Available at : http://emedicine.medscape.com/article/97,/,9-overviewWshowall
Backgrond
A Erench midwi%e was the %irst to report hemol"tic disease o% the newborn &(43' in a set o%
twins in *6.9. 2n *9/2$ 4iamond and colleages described the relationship among%etal h"drops$
8andice$ anemia$ and er"throblasts in the circlation$ a condition later called er"throblastosis
%etalis. Ievine later determined the case a%ter Iandsteiner and 7einer discovered the 0h blood
grop s"stem in *9,.. 2n *95/$ 5hown sbse<entl" con%irmed the pathogenesis o% 0h
alloimmni6ation to be the reslt o% passage o% 0h-positive %etal 0B5s a%ter transplacental
hemorrhage into maternal circlation that lacked this antigen.
2n *966$ 2 grops %rom the Cnited =ingdom and the Cnited -tates demonstrated$ in a combined
std"$ that anti-4 immnogloblin B &2gB' proph"la)is soon a%ter deliver" prevented
sensiti6ation in 0h-negative women. !he 7orld (ealth ?rgani6ation &7(?' technical report in
*97* recommended that a dose o% 25 mcg &*25 2C' o% anti-4 immnogloblin B &2gB' shold be
given intramsclarl" %or ever" * mI o% %etomaternal hemorrhage o% 0h-positive packed 0B5s
or 2 mI o% whole blood.
9*:
2n *99+$ this recommendation was rein%orced b" the American Association o% Blood Banks and
the American 5ollege o% ?bstetrics and B"necologists with inclsion o% proph"la)is at 2+ weeksK
gestation.
92:
0otine se o% 0h 2gB proph"la)is reslted in a signi%icant decline in the incidence
o% 0h4 alloimmni6ation$ and er"throblastosis %etalis has become rare. !he perinatal e%%ects o%
maternal 0h alloimmni6ation are now re%erred to as hemol"tic disease o% the %ets and
newborn$ and %etal mani%estations o% the disease are more appreciated with newer technologies
sch as cordocentesis and %etal ltrasonograph".
Aathoph"siolog"
%enetics
Althogh the 0h antibod" was and still is the most common case o% severe hemol"tic disease o%
the newborn$ other alloimmne antibodies belonging to =ell &= and k'$ 4%%" &E"a'$ =idd &>ka
and >kb'$ and ;3-s &;$ 3$ -$ and s' s"stems do case severe hemol"tic disease o% the newborn.
9/:
!he 0h blood grop s"stem ses Eisher-0ace nomenclatre$ and the 0h gene comple) consists
o% / genetic loci each with 2 ma8or alleles. !he" code %or 5 ma8or antigens denoted b" letters$ 5$
c$ @$ e$ and 4. 0h blood grop antigens are inherited as determined b" at least 2 homologos bt
distinct membrane-associated proteins. !wo separate genes &0h5@ and 0h4'$ located on the
short arm o% chromosome *$ encode 0h proteins. @ach gene is *. e)ons in length$ and a 96D
homolog" between these genes is observed.
Arodction o% 2 distinct proteins %rom the RHCE gene is de to alternative splicing o% messenger
03A. 0h gene comple) is described b" / loci$ and$ there%ore$ + gene comple)es are possible.
!hese comple)es are as %ollows &listed in decreasing order o% %re<enc" among whites': 54e$
cde$ 54@$ c4e$ 5de$ cd@$ 54@$ and 5d@. @)pression is limited to 0B5s$ with an increasing
densit" dring their matration$ nlike the AB( s"stem$ which e)ists in a wide variet" o% tisses.
0h antigen is not e)pressed on 0B5 progenitors.
?% individals who are 0h positive$ ,5D are homo6"gos &54e/54e'$ and 55D are
hetero6"gos &54e/cde' %or the RhD gene. !he 0h-negative phenot"pe represents absence o% 4
protein on 0B5s and most commonl" reslts %rom deletion o% the RHDgene on both
[Type text]
chromosomes. (owever$ the RHD gene has signi%icant heterogeneit"$ and several inherited
mtations and rearrangements in its strctre can reslt in a lack o% e)pressions o% the 0h4
phenot"pe as well.
2mportant e)amples o% sch mtations inclde the RHD psedogene and RHD-CE-Dh"brid gene.
!he %ormer leads to a stop codon in RHD gene and reslts in a lack o% transcription prodct
despite all intact e)ons. 2t is %ond in 7.D o% -oth A%rican blacks and in 25D o% A%rican
Americans. !he RHD-CE-D &Ccde' gene is also %ond in 22D o% 4-negative A%rican Americans.
2t also reslts in an 0h positive genot"pe bt a negative phenot"pe. ;ost 5acasians who are
0h4 negative have a complete deletion o% RHDgene whereas onl" *+D o% A%rican blacks and
5,D o% A%rican Americans who are 0h4 negative have complete deletion o% the gene1 the rest
have above non%nctional variants o% the RHD gene.
9,:
Be"ond the 5 ma8or antigens$ more than *.. antigenic variants o% 0h grop s"stem have been
identi%ied. 2ndividals with these weak-4 phenot"pes comprise o% 2 poplations: %irst grop
&9.D' that e)presses normal bt redced <antities o% 4 antigen on the 0B5 sr%ace$ and most
cannot be sensiti6ed to prodce anti-4. (owever$ the second grop &remaining *.D' known as
partial-4 &eg$ 5w$ 4' that e)press partial 4 epitopes on 0B5 sr%ace and can make anti-4 and
rarel" e)perience %atal hemol"tic disease o% the newborn. !he partial 4 phenot"pe reslts %rom
amino acid snstittion in the active 0h4 epitope.
95:
;ost women with partial-4 phenot"pe are
classi%ied as 0h negative on rotine testing and are candidates %or 0h immne globlin &0h2B'.
5rrentl"$ testing o% all 0h-negative women %or weak e)pression o% 4 is not recommended.
(owever$ 0h-negative in%ants born to 0h-negative women shold ndergo testing to detect the
partial-4 phenot"pe so that 0h2B can be administeredin theevent o%weak e)pression.
Ere<enc" o% 0h negativit" is higher in whites &*5D' than in blacks &5D' and (ispanics &+D'
and is rare in @skimos$ 3ative Americans$ >apanese$ and Asians$ especiall" in 5hinese
individals. !he paternal hetero6"gosit" determines the likelihood o% an 0h-positive child being
born to an 0h-negative mother.
Pathophysiology
!he e)posre o% the 0h-negative mother to 0h-positive red cells occrs as a reslt o%
as"mptomatic %etomaternal hemorrhage dring pregnanc". !he =leihaer-Betke acid eltion
techni<e that determines the proportion o% %etal 0B5s in maternal circlation has shown the
incidence o% %etomaternal hemorrhage to be 75D o% all pregnancies. 2ncidence and degree o%
sch hemorrhage appears to increase with gestation. Eetomaternal hemorrhage has been
docmented in 7D$ *6D$ and 29D o% mothers dring their %irst$ second and third trimesters$
respectivel". 0isk is also increased in pregnancies complicated b" placental abrption$
spontaneos or therapetic abortion$ and to)emia$ as well as a%ter cesarean deliver" and ectopic
pregnanc".
Arocedres sch as amniocentesis$ chorionic vills sampling$ and cordocentesis also increase the
risk o% alloimmni6ation. Becase the transplacental hemorrhage is less than ..* mI in most
pregnancies$ most women are sensiti6ed as a reslt o% small$ ndetectable %etomaternal
hemorrhage.
A%ter the initial e)posre to a %oreign antigen$ B-l"mphoc"te clones that recogni6e the 0B5
antigen are established. !he maternal immne s"stem initiall" prodces antibodies o% the
[Type text]
immnogloblin ; &2g;' isot"pe that do not cross the placenta and later prodces antibodies o%
the 2gB isot"pe that traverse the placental barrier. Aredominant antibod" sbclass appears to be
2gB* in one third o% individals whereas a combination o% 2gB* and 2gB/ sbclasses are %ond
in the remaining individals.
2gB/ is more e%%icient in binding to reticloendothelial cells and casing hemol"sis becase o%
its longer hinge region. !his is termed the primar" response and is dose dependent &docmented
in *5D o% pregnancies with * mI o% 0h-positive cells in an 0h-negative individal compared
with 7.D o% pregnancies a%ter 25. mI'. A repeat e)posre to the same antigen rapidl" indces
the prodction o% 2gB. !his secondar" immne response can be indced with as little as .../ mI
o% 0h-positive 0B5s.
!he risk o% 0h immni6ation a%ter the deliver" o% the %irst child to a nlliparos 0h-negative
mother is *6D i% the 0h-positive %ets is AB? compatible with its mother$ 2D i% the %ets is
AB? incompatible$ and 2-5D a%ter an abortion. !he AB?-incompatible 0B5s are rapidl"
destro"ed in the maternal circlation$ redcing the likelihood o% e)posre to the immne s"stem.
!he degree o% 0h sensiti6ation o% the mother is directl" related to the amont o% %etomaternal
hemorrhage &ie$ /D with J ..* mI compared with 22D with G..* mI'.
A%ter sensiti6ation$ maternal anti-4 antibodies cross the placenta into %etal circlation and attach
to 0h antigen on %etal 0B5s$ which %orm rosettes on macrophages in the reticloendothelial
s"stem$ especiall" in the spleen. !hese antibod"-coated 0B5s are l"sed b" l"sosomal en6"mes
released b" macrophages and natral killer l"mphoc"tes and are independent o% the activation o%
the complement s"stem.
0eticloc"tosis is noted when %etal (b de%icit e)ceeds 2 gm/dl compared with gestational age
norms. !isse h"po)ia develops as %etal anemia becomes severe. 7hen the hemoglobin &(b'
level drops below + g/dI$ a rise in mbilical arterial lactate occrs. 7hen the (b level drops
below ,g/dI$ increased venos lactate is noted. ("drops %etalis occrs when %etal (b de%icit
e)ceeds 7 g/dI and starts as %etal ascites and evolves into pleral e%%sions and generali6ed
edema. !he varios mechanisms responsible %or h"drops are h"poalbminemia secondar" to
depressed liver %nction$ increased capillar" permeabilit"$ iron overload secondar" to hemol"sis$
and increased venos pressres de to poor cardiac %nction.
96:
Arolonged hemol"sis leads to severe anemia$ which stimlates %etal er"thropoiesis in the liver$
spleen$ bone marrow$ and e)tramedllar" sites$ sch as the skin and placenta. 2n severe cases$
this can lead to displacement and destrction o% hepatic parench"ma b" er"throid cells$ reslting
in d"s%nction and h"poproteinemia. 4estrction o% 0B5s releases heme that is converted to
ncon8gated bilirbin. ("perbilirbinemia becomes apparent onl" in the delivered newborn
becase the placenta e%%ectivel" metaboli6es bilirbin. (emol"tic disease o% the newborn de to
=ell sensiti6ation reslts in hemol"sis and sppression o% er"thropoiesis becase the =ell antigen
is e)pressed on the sr%ace o% er"throid progenitors. !his leads to severe %etal disease at a lower
maternal antibod" titer than in 0hess disease.
(emol"sis associated with AB? incompatibilit" e)clsivel" occrs in t"pe-? mothers with
%etses who have t"pe A or t"pe B blood$ althogh it has rarel" been docmented in t"pe-A
mothers with t"pe-B in%ants with a high titer o% anti-B 2gB. 2n mothers with t"pe A or t"pe B$
natrall" occrring antibodies are o% the 2g; class and do not cross the placenta$ whereas *D o%
[Type text]
t"pe-? mothers have a high titer o% the antibodies o% 2gB class against both A and B. !he" cross
the placenta and case hemol"sis in %ets.
(emol"sis de to anti-A is more common than hemol"sis de to anti-B$ and a%%ected neonates
sall" have positive direct 5oombs test reslts. (owever$ hemol"sis de to anti-B 2gB can be
severe and can lead to e)change trans%sion. Becase A and B antigens are widel" e)pressed in
varios tisses besides 0B5s$ onl" a small portion o% antibodies crossing the placenta are
available to bind to %etal 0B5s. 0ecent anal"sis o% 2gB sbclass in AB? incompatible direct
coombs positive neonates showed 2gB2 was predominent antibod" which is poorl" trans%erred
across placenta and less e%%icient in casing hemol"sis while 2gB* was noted in 22D o% neonates
and as a grop had similar rate o% hemol"sis and severit" o% h"perbilirbinemia.
97:
2n addition$ %etal 0B5s appear to have less sr%ace e)pression o% A or B antigen$ reslting in %ew
reactive sites1 hence the low incidence o% signi%icant hemol"sis in a%%ected neonates. !his reslts
in h"perbilirbinemia as a predominant mani%estation o% incompatibilit" &rather than anemia'$
and peripheral blood %ilm %re<entl" reveals a large nmber o% spheroc"tes and %ew
er"throblasts$ nlike what is seen in 0h incompatibilit" &er"throblastosis %etalis'$ in which blood
%ilm reveals a large nmber o% ncleated 0B5s and %ew spheroc"tes.
9+:
@pidemiolog"
Frequency
United States
Be%ore the establishment o% modern therap"$ *D o% all pregnant women developed 0h
alloimmni6ation. -ince the advent o% rotine proph"la)is o% at-risk women$ incidence o% 0h
sensiti6ation has declined %rom ,5 cases per *.$... births to *..2 cases per *.$... total births$
with less than *.D re<iring intraterine trans%sion
99:
. Alloimmni6ation de to =ell antigen
acconts %or *.D o% severel" a%%ected %etses. !he most recent data %rom review o% 2..* birth
certi%icates in the Cnited -tates b" the 5enters %or 4isease 5ontrol and Arevention &545'
indicates that 0h sensiti6ation a%%ects 6.7 newborns per *... live births.
9*.:
5rrentl"$ anti-4 is still one o% the most common antibodies %ond in pregnant women$ %ollowed
b" anti-=$ anti-c$ and anti-@. ?% those %etses who re<ire intraterine trans%sions$ +5D$ *.D$
and /.5D were de to anti-4$ anti-=$ and anti-c$ respectivel".
9**:
AB? incompatibilit" %re<entl"
occrs dring the %irst pregnanc" and is present in appro)imatel" *2D o% pregnancies$ with
evidence o% %etal sensiti6ation in /D o% live births. Iess than *D o% births are associated with
signi%icant hemol"sis.
Mortality/Morbidity
Almost 5. di%%erent red cell sr%ace antigens have been %ond to be responsible %or hemol"tic
disease o% %ets and newborn. ?nl" / antibodies are associated with severe %etal disease: anti-
0h4$ anti-0hc$ and anti-=ell&=*'. 3earl" 5.D o% the a%%ected newborns do not re<ire
treatment$ have mild anemia and h"perbilirbinemia at birth$ and srvive and develop normall".
Appro)imatel" 25D are born near term bt become e)tremel" 8andiced withot treatment and
either die &9.D' or become severel" a%%ected b" kernicters &*.D'. !he remaining 25D o%
a%%ected newborns are severel" a%%ected in tero and become h"dropic1 abot hal% o% newborns
[Type text]
are a%%ected be%ore /, weeksK gestation$ and the other hal% are a%%ected between /, weeksK
gestation and term.
9*:
Be%ore an" interventions were available$ the perinatal mortalit" rate was 5.D. 7allerstein
introdced e)change trans%sion in *9,5 and redced the perinatal mortalit" rate to 25D. Iater$
5hown sggested the earl" deliver" o% those severel" a%%ected nonh"dropic %etses b" /, weeksK
gestation %ollowed b" prompt e)change trans%sion helped improve srvival. !he introdction o%
intraperitoneal trans%sion b" 7illiam Iile" in *96/ and intravasclar trans%sion &2L!' b"
0odeck in *9+* redced the perinatal morbidit" and the mortalit" rate was %rther redced to the
crrent rate o% *6D.
;ortalit" rises to /.D with an" degree o% %etal h"drops. ;ost %etses who are able to reverse
%etal h"drops a%ter 2L! srvive$ compared with 25D o% those in whom %etal h"drops was severe
and persisted despite treatment. !he overall rate o% nerodevelopmental impairment is *.D$
which is comparable to that %ond in the general poplation$ bt hearing loss is increased 5-*.
%old over the general poplation in those in%ants who re<ire in tero therap" %or hemol"tic
disease o% the newborn. 0ecentl"$ the I?!C- std" in a 4tch poplation reported
nerodevelopmental otcomes in 2+* children with hemol"tic disease o% the %ets treated with
2L! at + "ears$ showing normal otcome in 9,D$ cerebral pals" in 2.*D$ severe developmental
dela" in /.*D$ and bilateral dea%ness in *D.
9*2:
-evere h"drops %etalis was the onl" independent
risk %actor identi%ied %or poor otcome.
3o relationship was noted between global developmental scores and the severit" o% hemol"tic
disease o% the newborn &as evidenced b" sch %actors as the nmber o% intraterine trans%sions
92C!s:$ the lowest hematocrit 9(ct: level$ or the presence o% h"drops'. 3ormal nerological
otcome is noted in more than 9.D o% in%ants even i% %etal h"drops noted at the time o% the %irst
2C!.
9*/:
Race
2ncompatibilit" involving 0h antigens &anti-4 or anti-c' occrs in abot *.D o% all pregnancies
among whites and blacks1 in contrast$ it is ver" rare in Asian women.
Sex
Eetal se) pla"s a signi%icant role in the degree o% response to maternal antibodies. An apparent
*/-%old increase is observed in %etal h"drops in 0h4-positive male %etses compared with %emale
%etses in similarl" sensiti6ed pregnancies.
96:
(istor"
!wo sal patterns o% 0h isoimmni6ation severit" are noted. !he disease ma" remain at the
same degree o% severit" or ma" become progressivel" worst with each pregnanc". A histor" o%
h"dropic birth increases the risk o% %etal h"drops in the ne)t pregnanc" to 9.D1 the %etal h"drops
occrs at abot the same time or earlier in gestation in the sbse<ent pregnanc". 7omen at risk
%or alloimmni6ation shold ndergo an indirect 5oombs test and antibod" titers at their %irst
prenatal visit. 2% reslts are positive$ obtain a paternal blood t"pe and genot"pe with serologic
testing %or other 0h antigens &5$ c$ @$ e'.
[Type text]
!he paternal 6"gosit" %or the 4 allele is determined %rom race-speci%ic gene %re<enc" tables that
take into accont the serolog" reslts o% 0h antigen e)pression$ ethnicit"$ and nmber o%
previos 0h-positive children.
9*,:
2n the event o% nclear ethnicit"$ <antitative pol"merase chain
reaction &A50' o% the RHD gene has been sed to detect the hetero6"gos state.
9*5:
!wo sch
assa"s$ one based on direct ampli%ication o% deletion and the other sing RHD gene cop" nmber
with a re%erence gene$ are available. 0ecent research revealed <antitative A50 to be highl"
accrate %or detecting a paternal hetero6"gos state and now is pre%erred over serologic testing
owing to the high %re<enc" o% interracial marriages.
9*6:
?btaining serial maternal titers is sggested i% the %ather is homo6"gos. 2% the %ather is
hetero6"gos$ determine %etal 0h genot"pe sing A50 %or the RHD gene on %etal cells obtained
at amniocentesis
9*7:
or on cell-%ree 43A in maternal circlation.
9*+:
!he sensitivit" and speci%icit"
o% A50 t"ping on amniotic %lid is 9+.7D and *..D$ respectivel". (owever$ obtaining maternal
blood to rle ot a maternal RHD psedogene &in a 0h-positive %ets' and obtaining paternal
blood to rle ot RHD gene locs rearrangement &in a 0h-negative %ets' is important to improve
the accrac".
9*9:
4etermining %etal 0h genot"pe is also possible b" per%orming cordocentesis$
which is also called %etal blood sampling &EB-'. EB- is associated with a more than ,-%old
increase in perinatal loss compared with amniocentesis.
2ndicators %or severe hemol"tic disease o% the newborn &(43' inclde mothers who have had
previos children with hemol"tic disease$ rising maternal antibod" titers$ rising amniotic %lid
bilirbin concentration$ and ltrasonographic evidence o% %etal h"drops &eg$ascites$ edema$
pleral and pericardial e%%sions$ worsening bioph"sical pro%ile$ decreasing hemoglobin 9(b:
levels'. !he ma8or advance in predicting the severit" o% hemol"tic disease was the delta-?4 ,5.
reported b" Iile" in *96*.
92.:
!he serial vales o% deviation %rom baseline at ,5. nm$ the
wavelength at which bilirbin absorbs light$ are plotted on a Iile" crve &see the image below'
against the gestational weeks. !he vales above 65D on 6one 2 indicate direct %etal monitoring
b" cordocentesis. (ematocrit &(ct' levels below /.D or a single vale in 6one / are indications
%or intraterine trans%sion.
Iile" crve. !his graph illstrates an e)ample o% amniotic %lid
spectrophotometric reading o% ..2.6$ which when plotted at /5 weeksK gestation %alls into 6one /$
indicating severe hemol"tic disease.
!he modi%ication o% Iile" chart was developed b" e)trapolating the Iile" crve
92*:
and is sed to
correct %or gestations o% less than 27 weeks becase bilirbin levels normall" peak at 2/-25
weeksK gestation in na%%ected %etses &see the image below'.
922:
[Type text]
;odi%ied Iile" crve %or gestation o% less than 2, weeks showing
that bilirbin levels in amniotic %lid peak at 2/-2, weeksK gestation.
Another crve was developed b" Feenan %or management o% pregnancies be%ore 27 weeksK
gestation &see the image below'.
92/:
Feenan 5rve: ;odi%ied Iile" crve that shows delta-?4 ,5.
vales at *,-,. weeksK gestation.
2n a recent prospective evalation$ the Feenan crve predicted moderate anemia with a
sensitivit" o% +/D and a speci%icit" o% 9,D$ whereas the sensitivit" and speci%icit" %or severe
anemia were *..D and 79D$ respectivel".
92,:
!he delta-?4 ,5. vale that plots ot in the
intraterine death risk 6one o% Feenan crve indicates the need %or EB-. A recent comparison o%
the crves %ond the Feenan crve to be sperior to the Iile" crve in overall sensitivit"$
speci%icit"$ and accrac"1 when limited to less than 27 weeksK gestation$ its sensitivit" was higher
b" *.D$ with both having a speci%icit" o% ,.D.
925:
Ah"sical
An in%ant born to an alloimmni6ed mother shows clinical signs based on the severit" o% the
disease. !he t"pical diagnostic %indings are 8andice$ pallor$ hepatosplenomegal"$ and %etal
h"drops in severe cases. !he 8andice t"picall" mani%ests at birth or in the %irst 2, hors a%ter
birth with rapidl" rising ncon8gated bilirbin level. ?ccasionall"$ con8gated
h"perbilirbinemia is present becase o% placental or hepatic d"s%nction in those in%ants with
severe hemol"tic disease. Anemia is most o%ten de to destrction o% antibod"-coated 0B5s b"
the reticloendothelial s"stem$ and$ in some in%ants$ anemia is de to intravasclar destrction.
!he sppression o% er"thropoiesis b" intravasclar trans%sion &2L!' o% adlt (b to an anemic
%ets can also case anemia. @)tramedllar" hematopoiesis can lead to hepatosplenomegal"$
portal h"pertension$ and ascites.
Anemia is not the onl" case o% h"drops. @)cessive hepatic e)tramedllar" hematopoiesis cases
portal and mbilical venos obstrction and diminished placental per%sion becase o% edema.
2ncreased placental weight and edema o% chorionic villi inter%ere with placental transport. Eetal
[Type text]
h"drops reslts %rom %etal h"po)ia$ anemia$ congestive cardiac %ailre$ and h"poproteinemia
secondar" to hepatic d"s%nction. 5ommonl"$ h"drops is not observed ntil the (b level drops
below appro)imatel" , g/dI &(ct J *5D'
96:
. 5linicall" signi%icant 8andice occrs in as man" as
2.D o% AB?-incompatible in%ants.
5ases
2n the absence o% a positive direct 5oombs test reslt$ other cases o% pathologic 8andice shold
be considered$
926:
inclding intraterine congenital in%ections1 er"throc"te membrane de%ects &eg$
hereditar" spheroc"tosis$ hereditar" elliptoc"tosis$ hereditar" p"ropoikiloc"tosis'1 0B5 en6"me
de%iciencies &eg$ glcose-6-phosphate deh"drogenase 9B6A4: de%icienc"$ p"rvate kinase
de%icienc"$ triosephosphate isomerase de%icienc"'1 and nonhemol"tic cases &eg$ enclosed
hemorrhages$h"poth"roidism$ B2 obstrction$ and metabolic diseases'.
-imilarl"$ h"drops can occr %rom nonimmne hematologic disorders that case anemia$ sch as
hemoglobinopathies &eg$ X-thalassemia ma8or'$ cardiac %ailre de to d"srh"thmia$ congenital
heart de%ects$ and in%ections &eg$ s"philis$ c"tomegalovirs 95;L:$ parvovirs'.
5ommon cases o% hemol"tic disease o% the newborn
o 0h s"stem antibodies
o AB? s"stem antibodies
Cncommon cases - =ell s"stem antibodies
0are cases
o 4%%" s"stem antibodies
o ;3- and s s"stem antibodies
3o occrrence in hemol"tic disease o% the newborn
o Iewis s"stem antibodies
o A s"stem antibodies
Iaborator" -tdies
!he %ollowing %indings ma" be noted in hemol"tic disease o% the newborn &(43':
(emol"tic disease o% the newborn is characteri6ed b" one or more o% the %ollowing clinical
presentations:
927:
0apidl" progressive severe h"perbilirbinemia or prolonged h"perbilirbinemia
Aositive maternal antenatal antibod" %indings and/or diagnosis o% anemia or %etal h"drops
Aositive neonatal direct 5oombs test &direct antigloblin test'
(emol"sis on blood %ilm %indings
!he severit" o% hematologic abnormalities is directl" proportional to the severit" o% hemol"sis
and the e)tent o% hematopoiesis. !he %ollowing abnormalities are observed on 5B5 cont
%indings:
Anemia: ;easrements are more accrate sing central venos or arterial samples rather
than capillar" blood.
2ncreased ncleated 0B5s$ reticloc"tosis$ pol"chromasia$ anisoc"tosis$ spheroc"tes$ and
cell %ragmentation
[Type text]
o
!he reticloc"te cont can be as high as ,.D in patients withot intraterine
intervention.
o
!he ncleated 0B5 cont is elevated and %alsel" elevates the lekoc"te cont$
re%lecting a state o% er"thropoiesis.
o
-pheroc"tes &J ,.D' are more commonl" observed in cases o% AB?
incompatibilit". Blcose does not correct the atohemol"sis in AB? incompatibilit" nlike
hereditar" spheroc"tosis.
o
2n severe hemol"tic disease$ schistoc"tes and brr cells ma" be observed$
re%lecting ongoing disseminated intravasclar coaglation.
o
A low reticloc"te cont is observed in %etses provided with intravasclar
trans%sion in tero and with =ell alloimmni6ation.
o
Abnormall" elevated mean cell hemoglobin concentration &;5(5' and red cell
distribtion width &047' vales shold prompt a diagnosis o% hereditar" spheroc"tosis.
92+:
3etropenia: !his condition seems to be secondar" to stimlation o% er"thropoiesis in
%avor o% m"elopoiesis. (owever$ netrophilia can be observed a%ter intraterine trans%sion
becase o% an increase in circlating c"tokines &granloc"te-macrophage colon"-stimlating
%actor'.
!hromboc"topenia: !his condition is common$ especiall" a%ter intraterine or e)change
trans%sions becase o% platelet-poor blood prodct and sppression o% platelet prodction in
%avor o% er"thropoiesis.
("pogl"cemia is common and is de to islet cell h"perplasia and h"perinslinism
929:
. !he
abnormalit" is thoght to be secondar" to release o% metabolic b"prodcts sch as gltathione
%rom l"sed 0B5s. ("pokalemia$ h"perkalemia$ and h"pocalcemia are commonl" observed
dring and a%ter e)change trans%sion.
-erologic test %indings inclde the %ollowing:

2ndirect 5oombs test and direct antibod" test reslts are positive in the mother and
a%%ected newborn. Cnlike 0h alloimmni6ation$ direct antibod" test reslts are positive in onl"
2.-,.D o% in%ants with AB? incompatibilit".
9/.:
2n a recent std"$
9/*:
positive direct antibod" test
%indings have a positive predictive vale o% onl" 2/D and a sensitivit" o% onl" +6D in
predicting signi%icant hemol"sis and need %or phototherap"$ nless the %indings are strongl"
positive &,Y'. !his is becase %etal 0B5s have less sr%ace e)pression o% t"pe-speci%ic antigen
compared with adlt cells. A prospective std" has shown that the titers o% maternal
immnogloblin B &2gB' anti-A or anti-B ma" be more help%l in predicting severe hemol"sis
and h"perbilirbinemia. !he sensitivit" and speci%icit" o% 2gB titers o% 5*2 or higher in
predicting need %or invasive intervention was 9.D and 7/D$ respectivel".
9/2:

Althogh the indirect 5oombs test reslt &neonateKs serm with adlt A or B 0B5s' is
more commonl" positive in neonates with AB? incompatibilit"$ it also has poor predictive
vale %or hemol"sis. !his is becase o% the di%%erences in binding o% 2gB sbt"pes to the Ec
receptor o% phagoc"tic cells and$ in trn$ in their abilit" to case hemol"sis.

2gB2 is more commonl" %ond in maternal serm bt has weak l"tic activit"$ which leads
to the observation o% little or no hemol"sis with a positive direct antibod" test reslt. ?n the
other hand$ signi%icant hemol"sis is associated with a negative direct antibod" test reslt when
2gB* and 2gB/ are predominant antibodies$ which are in low concentration bt have strong
l"tic activit"$ crossing to neonatal circlation.
[Type text]

2n newborns with hemol"tic disease de to anti-c or anti-5 antibodies$ direct antibod" test
reslts ma" be negative$ and the diagnosis is established a%ter indirect 5oombs testing.
!able. 5omparison o% 0h and AB? 2ncompatibilit" &?pen !able in a new window'
Characteristics Rh A(2
5linical aspects Eirst born 5D 5.D
Iater pregnancies ;ore severe 3o increased severit"
-tillborn/h"drops Ere<ent 0are
-evere anemia Ere<ent 0are
>andice ;oderate to severe$ %re<ent ;ild
Iate anemia Ere<ent 0are
Iaborator" %indings 4irect antibod" test Aositive 7eakl" positive
2ndirect 5oombs test Aositive Csall" positive
-pheroc"tosis 0are Ere<ent
2maging -tdies
(igh-resoltion ltrasonograph" has been a ma8or advance in detection o% earl" h"drops and has
also redced the %etal trama and morbidit" rate to less than 2D dring perctaneos mbilical
blood sampling &ACB-' and placental trama dring amniocentesis. (igh-resoltion
ltrasonograph" has been e)tremel" help%l in directing the needle with intraperitoneal
trans%sion &2A!' and intravasclar trans%sion &2L!' in %etal location.
;edical 5are
Management o" maternal alloimmuni!ation
As a rle$ serial maternal antibod" titers are monitored ntil a critical titer o% *:/2$ which
indicates that a high risk o% %etal h"drops has been reached. At this point$ the %ets re<ires ver"
intense monitoring %or signs o% anemia and %etal h"drops. 2n =ell alloimmni6ation$ h"drops can
occr at low maternal titers becase o% sppressed er"thropoiesis$ and$ ths$ a titer o% *:+ has
been sggested as critical. (ence$ delta-?4 ,5. vales are also nreliable in predicting disease
severit" in =ell alloimmni6ation.
9//:
;aternal titers are not se%l in predicting the onset o% %etal anemia a%ter the %irst a%%ected
gestation. Iarge di%%erences in titer can be seen in the same patient between di%%erent
laboratories$ and a newer gel techni<e prodces higher titer reslts than the older tbe method.
!here%ore$ standard tbe methodolog" shold be sed to determine critical titer$ and a change o%
more than * diltion represents a tre increase in maternal antibod" titer. Eor all the antibodies
[Type text]
responsible %or hemol"tic disease o% the newborn &(43'$ a ,-%old increase in an" antibod" titer
is t"picall" considered a signi%icant change that re<ires %etal evalation.
9/,:
7hen indicated$ amniocentesis can be per%ormed as earl" as *5 weeksK gestation &rarel" needed
in %irst a%%ected pregnanc" be%ore 2, weeksK gestation' to determine %etal genot"pe and to assess
the severit". ;aternal and paternal blood samples shold be sent to the re%erence laborator" with
amniotic %lid sample to eliminate %alse-positive reslts &%rom maternal psedogene
or Ccde gene' and %alse-negative reslts &%rom a rearrangement at the RHD gene locs in the
%ather'.
Eetal 0h-genot"pe determination in maternal plasma has become rotine in man" @ropean
contries and is being o%%ered in the Cnited -tates.
9/5:
Eetal cell-%ree 43A acconts %or /D o%
total circlating maternal plasma 43A$ is %ond as earl" as /+ da"s o% gestation$ and is derived
%rom apoptosis o% the placental c"totrophoblast la"er. 2t is sb8ected to real-time A50 %or the
presence o% RHD geneQspeci%ic se<ences and has been %ond to be accrate in 99.5D o% cases.
!he SRY gene &in the male %ets' and 43A pol"morphisms in the general poplation &in the
%emale %ets' are sed as internal controls to con%irm the %etal origin o% the cell-%ree 43A.
9*,:
A
panel o% 92 -3As is compared between maternal sample %rom b%%" coat and plasma. A
di%%erence o% more than 6 single ncleotide pol"morphisms con%irms presence o% %etal 43A and
the validit" o% the test in a %emale %ets.
9/5:
Cn%ortnatel"$ cell-%ree %etal 43A testing %or determining the genot"pe %or other red blood cell
antigens sch as @ and =ell is not "et available in Cnited -tates.
-erial amniocentesis is begn at *.-*, da" intervals to monitor the severit" o% the disease in the
%ets. All attempts shold be made to avoid transplacental passage o% needle which can lead to
%etomaternal hemorrhage &E;(' and a %rther rise in antibod" titer. -erial delta-?4 ,5. vales
are plotted on the Feenan chart or the e)tended Iile" chart to evalate the risk o% %etal h"drops.
@arl" ltrasonograph" is per%ormed to establish correct gestational age. Ere<ent
ltrasonographic monitoring is also per%ormed to assess %etal well-being and to detect moderate
anemia and earl" signs o% h"drops.
!he peak s"stolic middle cerebral arter" &;5A' 4oppler velocit" has proved to be a reliable
screening tool to detect %etal anemia and has replaced amniocentesis. !he ;5A is easil"
visali6ed with color-%low 4oppler1 plsed 4oppler is then sed to measre the peak s"stolic
velocit" 8st distal to its bi%rcation %rom the internal carotid arter". Becase the ;5A velocit"
increases with advancing gestational age$ the reslt is reported in mltiples o% median &;?;s'.
2n recent stdies$ the sensitivit" %or detection o% moderate and severe %etal anemia has been
proven to be *..D$ with a %alse-positive rate o% *.D at *.5 ;?;.
9/6:
2t has been shown to redce
the need %or invasive diagnostic procedres sch as amniocentesis and cordocentesis b" more
than 7.D.
9/6:
;5A 4oppler stdies can be started as earl" as *+ weeksK gestation bt are not reliable a%ter /5
weeksK gestation
9/7:
. 2t has also been sed to time the sbse<ent %etal trans%sion and to diagnose
anemia %rom mltiple cases$ sch as in twin-twin trans%sion. !he ;5A slope %rom /-weekl"
readings is now sed to predict %etal risk %or severe anemia &see the image below'.
9/+:
[Type text]
-lopes %or peak s"stolic velocit" in middle cerebral arter" &;5A'
%or normal %etses &dotted line'$ mildl" anemic %etses &thin line'$ and severel" anemia %etses
&thick line'.
7ith ac<isition o% e)perience in per%orming ;5A 4oppler std"$ serial amniocentesis %or
detecting %etal anemia has been sed to lesser e)tent.
9/9:
4ring the period when intraterine peritoneal trans%sion was the onl" means o% treatment$
newborns were rotinel" delivered at /2 weeksK gestation. !his approach reslted in a high
incidence o% h"aline membrane disease and e)change trans%sions. 7ith the advent o%
intravasclar trans%sion &2L!' in tero$ the general approach to the severel" a%%ected %ets is to
per%orm 2L! as re<ired ntil /5 weeksK gestation$ with deliver" planned at term. @stablishment
o% lng matrit" is di%%iclt in these %etses becase o% contamination o% amniotic %lid with
residal blood dring trans%sion1 however$ i% deliver" is planned prior to /, weeksK gestation$
maternal steroid administration to enhance %etal lng matrit" is indicated.
2n addition$ e)cess amniotic %lid bilirbin levels case %alse elevation on the %lorescence
depolari6ation !4) %etal lng matrit" test$ version 22 &!4Z-EI;22'1 there%ore$ other tests to
determine %etal lng matrit" shold be sed$ sch as in%rared spectroscop"$ lamellar bod" cont$
phosphatid"lgl"cerol <antitation or lecithin/sphingom"elin &I/-' ratio.
Iile" %irst described intraperitoneal trans%sion &2A!' in *96/. A !oh" needle is introdced into
the %etal peritoneal cavit" nder ltrasonographic gidance. An epidral catheter is threaded
throgh the needle. A radiopa<e medim is in8ected into the %etal peritonem. !he proper
placement is con%irmed b" delineation otside o% bowel or nder the diaphragm or b" di%%sion
in %etal ascites. Aacked 0B5s at (ct o% 75-+.D that are 5;L-negative$ less than ,-da"s-old$
grop ?$ 0h-negative$ =ell-negative$ lekoredced$ irradiated with 25 B" to prevent gra%t verss
host disease$ and cross-matched with maternal serm are in8ected in *.-mI ali<ots to a volme
calclated b" the %ollowing %ormla:
9*:
2A! volme [ &gestation in wk - 2.' Z *. mI
0esidal (b in the %ets is estimated to allow %or proper spacing o% 2A! and selection o% gestation
o% deliver" b" the %ollowing %ormla:
(b g/dI [ ..+5/*25 Z a/b Z *2. - c/*2.
2n the %ormla$ a is the amont o% donor 0B5 (b trans%sed$ b is the estimated %etal bod"
weight$ and c is the interval in da"s %rom the time o% trans%sion to the time o% donor (b
estimation.
2A! is repeated when the %etal (b is estimated to have dropped to *. g/dI. Csall"$ a second 2A!
is per%ormed *. da"s a%ter the %irst trans%sion in order to raise the (b above *. g/dI. !hen
[Type text]
another trans%sion is per%ormed ever" , weeks ntil the time o% planned deliver" at /,-/5
weeksK gestation. Eetal diaphragmatic movements are necessar" in order %or absorption o% 0B5
to occr. !his approach is o% no vale %or a moribnd nonbreathing %ets. ;aternal complications
inclde in%ection and transplacental hemorrhage$ whereas %etal complications are
overtrans%sion$ e)sangination$ cardiac tamponade$ in%ection$ preterm labor$ and gra%t verss
host disease. -rvival rates a%ter 2A! approached appro)imatel" 75D with the help o%
ltrasonograph".
4irect 2L! has become a pre%erred rote o% %etal intervention becase o% the higher rate o%
complications and limited e%%ectiveness o% 2A! in a h"dropic %ets. 0odeck %irst sccess%ll"
per%ormed 2L! in *9+*. 7ith ltrasonographic gidance$ a needle is introdced into an mbilical
vein at the cord insertion into the placenta or into its intrahepatic portion$ and a %etal blood
sample is obtained. !he blood sample is con%irmed to be o% %etal origin b" rapid alkaline
denatration test. All the relevant %etal tests &eg$ blood t"pe$ direct antibod" test$ reticloc"te
cont$ platelet cont$ (b level$ (ct level$ serm albmin level$ er"thropoietin level' are
per%ormed. 2% the (b level is less than ** g/dI or i% the (ct level is less than /.D$ an 2L! is
started. !he position o% the needle is con%irmed b" noting the trblence in the %etal vessel on
in8ection o% saline. !he %ets is %re<entl" paral"6ed with pancronim in order to prevent the
displacement o% the needle b" %etal movements.
!he trans%sion is per%ormed in *.-mI ali<ots to a volme o% appro)imatel" 5. mI/kg
estimated bod" weight sing ltrasonograph" or ntil an (ct level o% ,.D is reached. !he
procedre is promptl" discontined i% cardiac decompensation is noted on ltrasonograph"
%indings. -everel" anemic %etses do not tolerate acte correction o% their (ct to normal vales$
and the initial (ct shold not be increased b" more than ,-%old at the time o% %irst 2L!. !he"
shold then be monitored ever" 2-7 da"s. !he 2L! is repeated when it reaches a vale that
re%lects critical anemia in the %ets. A loss o% *D o% trans%sed cells per da" can be anticipated.
9*,:
-ome centers per%orm repeat trans%sion at intervals o% *. da"s$ 2 weeks$ and ever" / weeks.
?thers trans%se based on an anticipated decline in %etal hemoglobin o% .., g/dI/da"$ ../
g/dI/da"$ and ..2 g/dI/da" %or %irst$ second$ and third trans%sion intervals$ respectivel".
9,.:
!he
peak s"stolic ;5A velocit" has been sed to time the second trans%sion$ with a threshold o%
*./2 ;?;.
9,*:
A%ter the %irst intraterine trans%sion$ the presence o% red blood cells with adlt
hemoglobin sppress er"thropoiesis and improve o)"gen deliver"$ which is responsible %or the
poor correlation between peak ;5A velocit" and severit" o% %etal anemia.
2n addition to the complications o% 2A!$ transient %etal brad"cardia$ cord hematoma$ mbilical
vein compression$ and %etal death have been reported dring 2L!. (owever$ 2L! has man"
advantages$ inclding immediate correction o% anemia and resoltion o% %etal h"drops$ redced
rate o% hemol"sis and sbse<ent h"perinslinemia$ and acceleration o% %etal growth %or
nonh"dropic %etses who are o%ten growth retarded. 2L! is the onl" intervention available %or
moribnd h"dropic %etses and those with anterior placenta. !he risk o% %etal loss is abot ..+D
with 2L! verss /.5D per procedre %or 2A!$ and the overall srvival rate is ++D.
0ecentl" washed maternal 0B5s have been sccess%ll" sed as a sorce o% antigen-negative
0B5s in the event o% rare incompatibilit" bt also have been rotinel" sed becase o% bene%its
sch as decreased risk %or sensiti6ation to new red cell antigens$ a longer circlating hal%-li%e
[Type text]
being %resh$ and decreased risk o% transmission o% viral agents.
9,2:
;other can donate a nit o% red
cells a%ter the %irst trimester.
2n the event o% plmonar" immatrit" and delta-?4 ,5. in the a%%ected 6one o% the Feenan
crve$ oral administration o% /. mg o% phenobarbital to the mother / times per da"$ %ollowed b"
indction in one week$ redces the need %or e)change trans%sion in the a%%ected neonate.
9,/:
@)cellent algorithms %or management o% the %irst a%%ected pregnanc" and the pregnanc" in a
mother with previosl" a%%ected %ets are otlined in a review b" ;oise &see the images below'.
9,,:
;anagement o% %irst a%%ected pregnanc".
;anagement o% pregnant women with previosl" a%%ected %ets.
2nitial attempts to sppress 0h antibod" prodction with 0h hapten$ 0h-positive 0B5 stroma$
and administration o% prometha6ine were nsccess%l. @)tensive plasmapheresis with partial
replacement sing 5D albmin and intravenos immnogloblin &2L2B' or the administration o%
2L2B at * g/kg bod" weight weekl" has been shown to be moderatel" e%%ective. !he mechanism
o% action appears to be blockage o% Ec receptors in the placenta$ redcing antibod" transport
across to the %ets$ Ec receptors on the phagoc"tes in the %etal reticloendothelial s"stem$ and
%eedback inhibition o% maternal antibod" s"nthesis.
(owever$ these techni<es onl" postpone the need %or perctaneos mbilical blood sampling
&ACB-' and 2L! ntil 2.-22 weeksK gestation$ when these procedres can be per%ormed at a
more acceptable risk. A review o% 2L2B se shows its se%lness in preventing the onset o% %etal
h"drops and in dela"ing the need %or intraterine trans%sion &2C!'.
9,5:
!hs$ a combined
approach o% plasmapheresis that starts at *2 weeksK gestation / times in that week$ %ollowed b"
2L2B at a loading dose o% 2 g/kg a%ter the third plasmapheresis$ and then contined 2L2B *
g/kg/wk ntil 2. weeksK gestation has been sggested %or at-risk %etses prior to 2. weeksK
gestation and can also be sed later in gestation i% 2L! cannot be per%ormed or i% h"drops is
nresponsive to 2L!.
?ne report indicated that treatment o% %etses with severe alloimmni6ation sing 2L! combined
with %etal 2L2B therap" at * g/kg/dose starting %rom the third 2L! helped in redcing the
%re<enc" o% 2L! and improving signs o% h"drops.
9,6:
A case report shows sccess%l treatment o%
severe anemia and h"drops in a %ets with alloimmni6ation de to anti-; antibod" with %etal
intraperitoneal 2L2B in8ections 2 g/kg given weekl" starting /. weeks.
9,7:
(owever$ this was a
case report$ and a randomi6ed controlled trial is needed be%ore this can become standard o% care.
[Type text]
-imilar regimens o% tests and treatment are sed in the management o% pregnancies a%%ected b"
non0h4 alloimmni6ation$ sch as anti-0hc$ anti-= &=*'$ and anti-;. ?nce the mother is
diagnosed with an antibod" associated with hemol"tic disease$ an indirect 5oombs titer is
per%ormed$ along with paternal testing %or involved antigen and 6"gosit". ;aternal titers are
repeated &monthl" ntil 2+ weeksK gestation and then ever" 2 wk' ntil a threshold %or %etal
anemia is reached &*:+ %or =ell and *:/2 %or rest'.
Eetal antigen t"ping is per%ormed via amniocentesis or cell-%ree %etal 43A in maternal plasma i%
the %ather is %ond to be hetero6"gos &*..D %or =*$ 65D %or ;'. 7hen the %ets is known to be
antigen positive$ srveillance %or severe %etal anemia is per%ormed$ with weekl" ;5A 4oppler
screening as earl" as *6-*+ weeks and 2C! is carried ot i% it e)ceeds *.5 ;?; with a deliver"
b" /+ weeksK gestation.
9,+:
;aternal alloantibodies to paternal lekoc"tes have been shown to reslt in Ec blockade and to
redce the severit" o% %etal hemol"tic anemia. !his ma" be sed in the %tre.
Management o" the sensiti!ed neonate
;ild hemol"tic disease acconts %or 5.D o% newborns with positive direct antibod" test reslts.
;ost o% these newborns are not anemic &cord hemoglobin 9(b: G*, g/dI' and have minimal
hemol"sis &cord bilirbin J , mg/dI'. Apart %rom earl" phototherap"$ the" re<ire no
trans%sions. (owever$ these newborns are at risk o% developing severe late anemia b" /-6 weeks
o% li%e. !here%ore$ monitoring their (b levels a%ter hospital discharge is important.
;oderate hemol"tic disease acconts %or appro)imatel" 25D o% a%%ected neonates. ;oderate
hemol"tic disease o% newborn is characteri6ed b" moderate anemia and increased cord bilirbin
levels. !hese in%ants are not clinicall" 8andiced at birth bt rapidl" develop ncon8gated
h"perbilirbinemia in the %irst 2, hors o% li%e. Aeripheral smear shows nmeros ncleated
0B5s$ decreased platelets$ and$ occasionall"$ a large nmber o% immatre granloc"tes. !hese
newborns o%ten have hepatosplenomegal" and are at risk o% developing bilirbin encephalopath"
withot ade<ate treatment. @arl" e)change trans%sion with t"pe-? 0h-negative %resh 0B5s
with intensive phototherap" is sall" re<ired. Cse o% 2L2B in doses o% ..5-* g/kg in a single or
mltiple dose regimen have been able to e%%ectivel" redce need %or e)change trans%sion.
9,9:
A prospective randomi6ed controlled std" has shown earl" high-dose 2L2B * g/kg at *2 hors
o% age to redce dration o% phototherap" and hospital sta" and to prevent e)change trans%sion
in neonates with moderate-to-severe 0h isoimmni6ation.
95.:
!hese newborns are also at risk o%
developing late h"poregenerative anemia o% in%anc" at ,-6 weeks o% li%e. (owever$ one
randomi6ed doble-blind placebo-controlled trial %ailed to show the bene%it o% proph"lactic 2L2B
therap" ..75 g/kg within , hors o% age in severel" a%%ected neonates who were treated with
intraterine trans%sion %or 0h isoimmni6ation.
95*:
-evere hemol"tic disease acconts %or the remaining 25D o% the alloimmni6ed newborns who
are either stillborn or h"dropic at birth. !he %etal h"drops is predominantl" cased b" a capillar"
leak s"ndrome de to tisse h"po)ia$ h"poalbminemia secondar" to hepatic d"s%nction$ and
high-otpt cardiac %ailre %rom anemia. Abot hal% o% these %etses become h"dropic be%ore /,
weeksK gestation and need intensive monitoring and management o% alloimmni6ed gestation as
described earlier. ;ild h"drops involving ascites reverses with 2L!s in onl" ++D o% cases with
[Type text]
improved srvival bt severe h"drops casing scalp edema and severe ascites and pleral
e%%sions reverse in /9D o% cases and are associated with poor srvival.
Management o" A(2 incompatibility
;anagement o% h"perbilirbinemia is a ma8or concern in newborns with AB? incompatibilit".
!he criteria %or e)change trans%sion and phototherap" are similar to those sed in 0h
alloimmni6ation. 2L2B has also been ver" e%%ective when administered earl" in the corse. !in
&-n' porph"rin a potent inhibitor o% heme o)"genase$ the en6"me that catal"6es the rate-limiting
step in the prodction o% bilirbin %rom heme$ has been shown to redce the prodction o%
bilirbin and redce the need %or e)change trans%sion and the dration o% phototherap" in
neonates with AB? incompatibilit".
!in or 6inc protoporph"rin or mesoporph"rins have been stdied in newborns. !he" mst be
administered intramsclarl" in a dose based on bod" weight$ and their e%%ectiveness appears to
be dose related in all gestations.
952:
!heir possible to)ic e%%ects inclde skin photosensiti6ation$
iron de%icienc"$ and possible inhibition o% carbon mono)ide prodction. !heir se in 0h
hemol"tic disease o% newborn has not been reported. !heir rotine se cannot be recommended
"et becase o% lack o% long-term sa%et" data.
2mmnomodlators
Class Summary
!hese agents normali6e antibod" levels in patients with primar" de%ective antibod" s"nthesis.
!he" prevent and treat certain bacterial and viral in%ections and redce the immne-mediated
hemol"sis and phagoc"tosis.
Liew %ll drg in%ormation
.ntraenous immunoglobulin +%amimune/ %ammagard/ Sandoglobulin/ %ammar'P-

-everal stdies have reported sccess in minimi6ing the need %or e)change trans%sion in severe
(43 with 2L2B. @%%ective ad8nct to phototherap". ;echanism o% action appears to be related to
blockage o% Ec receptors in the neonatal reticloendothelial s"stem. -tdies have also
docmented decreased hemol"sis a%ter administration o% 2L2B sing carbo)"hemoglobin levels.
Administration in doses o% 5..-*... mg/kg in the %irst %ew hors o% li%e to a newborn with
severe hemol"sis shold be considered. (owever$ e%%icac" depends on timing o% administration$
dration o% treatment$ and severit" o% hemol"sis. -hold be prepared b" and dispensed %rom
pharmac" and shold not be mi)ed with normal saline. 4ispensed as either /D or 6D soltion.
5olon"-stimlating Eactor
Class Summary
!hese agents ma" be re<ired to correct anemia.
Liew %ll drg in%ormation
[Type text]
Epoetin al"a/ recombinant +Epogen/ Procrit-

Ari%ied gl"coprotein prodced %rom mammalian cells modi%ied with gene coding %or hman
er"thropoietin &@A?'. Amino acid se<ence is identical to that o% endogenos @A?. Biological
activit" mimics hman rinar" @A?$ which stimlates division and di%%erentiation o% committed
er"throid progenitor cells and indces release o% reticloc"tes %rom bone marrow into the blood
stream.
5ompetitive heme o)"genase inhibitor
Class Summary
Ahase 222 clinical trials have been completed in the Cnited -tates on stannsopor%in$ a competitive
heme o)"genase inhibitor. !he drg is crrentl" available via a compassionate se protocol.
Stannsopor"in +SnMP/ Stanate-

Also known as tin-mesoporph"rin. 2nvestigational in the Cnited -tates. Ahase 222 clinical trials
completed. -trctral analog o% heme that blocks heme o)"genase &(?-*'$ a rate-limiting
en6"me in bilirbin prodction$ thereb" preventing the conversion o% heme to bilirbin. (eme is
e)creted nchanged in bile and is not stored in tisse. 2t is inert and does not enter the brain or
interact with 43A. 2t does not a%%ect previosl" %ormed bilirbin con8gation or e)cretion in
liver. -everal randomi6ed$ controlled and$ when possible$ blinded stdies over the last decade
that involved G7.. neonates with all principle %orms o% neonatal 8andice have shown -n;A to
be e%%ective in preventing and blocking 8andice progression. Ahototherap" was eliminated in
97D o% treated in%ants.
Also inhibits nitric o)ide s"nthase and solble gan"l"l c"clase. 0epeated doses lead to
inhibition o% intestinal heme o)"genase involved in iron absorption and ma" lead to anemia. 2t
also stimlates (?-* transcription and protein levels. !he hal%-li%e as measred in health" adlt
volnteers is /.+ h.
Available at : http://emedicine.medscape.com/article/97+/52-overviewWshowall
Backgrond
3eonatal sepsis ma" be categori6ed as earl"-onset or late-onset. ?% newborns with earl"-onset
sepsis$ +5D present within 2, hors$ 5D present at 2,-,+ hors$ and a smaller percentage present
within ,+-72 hors. ?nset is most rapid in prematre neonates.
@arl"-onset sepsis is associated with ac<isition o% microorganisms %rom the mother.
!ransplacental in%ection or an ascending in%ection %rom the cervi) ma" be cased b" organisms
[Type text]
that coloni6e the motherUs genitorinar" &BC' tract1 the neonate ac<ires the microorganisms as
it passes throgh the coloni6ed birth canal at deliver". !he microorganisms most commonl"
associated with earl"-onset in%ection inclde the %ollowing
9*:
:
Brop B Streptococcus &BB-'
Escherichia coli
5oaglase-negative Staphylococcus
Haemophilus influenae
!isteria monocytogenes
!rends in the epidemiolog" o% earl"-onset sepsis show a decreasing incidence o% BB- disease.
!his can be attribted to the implementation o% a prenatal screening and treatment protocol %or
BB-.
2n a 2..9 std" involving ,696 women$ prenatal cltres showed a BB- coloni6ation rate o%
2,.5D$ with a positive cltre rate o% *+.+D at the time o% labor. As man" as *.D o% prenatall"
cltre-negative women were %ond to have positive cltres at the time o% labor. 7ith
intrapartm antibiotic proph"la)is rates o% 9/./D$ ../6 o% *... in%ants developed earl"-onset
BB- disease.
92$ /:
Iate-onset sepsis occrs at ,-9. da"s o% li%e and is ac<ired %rom the caregiving environment.
?rganisms that have been implicated in casing late-onset sepsis inclde the %ollowing:
5oaglase-negative Staphylococcus
Staphylococcus aureus
E coli
"lebsiella
Pseudomonas
Enterobacter
Candida
BB-
Serratia
#cinetobacter
Anaerobes
!rends in late-onset sepsis show an increase in coaglase-negative streptococcal sepsis1 most o%
these isolates are ssceptible to %irst-generation cephalosporins.
92:
!he in%antUs skin$ respirator"
tract$ con8nctivae$ gastrointestinal &B2' tract$ and mbilics ma" become coloni6ed %rom the
environment$ and sch coloni6ation to the possibilit" o% late-onset sepsis %rom invasive
microorganisms. Lectors %or sch coloni6ation ma" inclde vasclar or rinar" catheters$ other
indwelling lines$ or contact with caregivers who have bacterial coloni6ation.
Anemonia is more common in earl"-onset sepsis$ whereas meningitis and bacteremiaare more
common in late-onset sepsis. Arematre and ill in%ants are more ssceptible to sepsis and sbtle
nonspeci%ic initial presentations1 considerable vigilance is there%ore re<ired in these patients so
that sepsis can be e%%ectivel" identi%ied and treated.
7hen neonatal sepsis is sspected$ treatment shold be initiated immediatel" becase o% the
neonateUs relative immnosppression. Begin antibiotics as soon as diagnostic tests are
per%ormed &see !reatment'.
[Type text]
Eor patient edcation in%ormation$ see -epsis &Blood 2n%ection'.
Aathoph"siolog"
!he in%ectios agents associated with neonatal sepsis have changed since the mid-2.th centr".
4ring the *95.s$ S aureus and E coli were the most common bacterial pathogens among
neonates in the Cnited -tates. ?ver the ensing decades$ BB- replaced S aureus as the most
common gram-positive organism that cased earl"-onset sepsis.
4ring the *99.s$ BB- and E coli contined to be associated with neonatal in%ection1 however$
coaglase-negative Staphylococcus epidermidis is now more %re<entl" observed. Additional
organisms$ sch as ! monocytogenes$ Chlamydia pneumoniae$ H influenae$ Enterobacter
aerogenes$ and species o% %acteroides and Clostridium have also been identi%ied in neonatal
sepsis.
;eningoencephalitis and neonatal sepsis can also be cased b" in%ection with adenovirs$
enterovirs$ or co)sackievirs. Additionall"$ se)all" transmitted diseases
&eg$ gonorrhea$ s"philis$ herpes simple) virs 9(-L: in%ection$ c"tomegalovirs
95;L:in%ection$ hepatitis$ hman immnode%icienc" virs
9(2L: in%ection$ rbella$ to)oplasmosis$ trichomoniasis$ and candidiasis' have all been
implicated in neonatal in%ection.
Bacterial organisms with increased antibiotic resistance have also emerged and have %rther
complicated the management o% neonatal sepsis.
9,:
!he coloni6ation patterns in nrseries and
personnel are re%lected in the organisms crrentl" associated with nosocomial in%ection. 2n
neonatal intensive care nits &325Cs'$ in%ants with lower birth weight and in%ants who are less
matre have an increased ssceptibilit" to these organisms.
S epidermidis$ a coaglase-negative Staphylococcus$ is increasingl" seen as a case o%
nosocomial or late-onset sepsis$ especiall" in the prematre in%ant$ in whom it is considered the
leading case o% late-onset in%ections. 2ts prevalence is likel" related to several intrinsic
properties o% the organism that allow it to readil" adhere to the plastic medims %ond in
intravasclar catheters and intraventriclar shnts.
!he bacterial capsle pol"saccharide adheres well to the plastic pol"mers o% the catheters. Also$
proteins %ond in the organism &Atl@ and --A-*' enhance attachment to the sr%ace o% the
catheter. !he adherence creates a capsle between microbe and catheter$ preventing 5/
deposition and phagoc"tosis.
Bio%ilms are %ormed on indwelling catheters b" the aggregation o% organisms that have
mltiplied nder the protection provided b" the adherence to the catheter. -limes are prodced at
the site %rom the e)tracelllar material %ormed b" the organism$ which provides a barrier to host
de%ense as well as to antibiotic action$ making coaglase-negative staph"lococcal bloodstream
in%ection &B-2' more di%%iclt to treat. !he to)ins %ormed b" this organism have also been
associated with necroti6ing enterocolitis.
2n addition to being a case o% neonatal sepsis$ coaglase-negative Staphylococcus is bi<itos
as part o% the normal skin %lora. 5onse<entl"$ it is a %re<ent contaminant o% blood and
cerebrospinal %lid &5-E' cltres. 7hen a cltre grows this organism $ the clinical setting$
colon" conts$ and the presence o% pol"morphonclear netrophils &A;3s' on Bram staining o%
[Type text]
the sbmitted specimen o%ten help di%%erentiate tre in%ection and positive cltre %rom a %alse-
positive or contaminated specimen.
2n addition to the speci%ic microbial %actors mentioned above$ nmeros host %actors predispose
the newborn to sepsis. !hese %actors are especiall" prominent in the prematre in%ant and involve
all levels o% host de%ense$ inclding celllar immnit"$ hmoral immnit"$ and barrier %nction.
Cellular immunity
A;3s are vital %or e%%ective killing o% bacteria. (owever$ neonatal A;3s are de%icient in
chemota)is and killing capacit". 4ecreased adherence to the endothelial lining o% blood vessels
redces their abilit" to marginate and leave the intravasclar space to migrate into the tisses.
?nce in the tisses$ the" ma" %ail to degranlate in response to chemotactic %actors.
Erthermore$ neonatal A;3s are less de%ormable and ths are less able to move throgh the
e)tracelllar matri) o% tisses to reach the site o% in%lammation and in%ection. !he limited
capacit" o% neonatal A;3s %or phagoc"tosis and killing o% bacteria is %rther impaired when the
in%ant is clinicall" ill. Einall"$ netrophil reserves are easil" depleted becase o% the diminished
response o% the bone marrow$ especiall" in the prematre in%ant.
3eonatal monoc"te concentrations are at adlt levels1 however$ macrophage chemota)is is
impaired and contines to e)hibit decreased %nction into earl" childhood. !he absolte nmbers
o% macrophages are decreased in the lngs and are likel" decreased in the liver and spleen as
well. !he chemotactic and bactericidal activit" and the antigen presentation b" these cells are
also not %ll" competent at birth. 5"tokine prodction b" macrophages is decreased$ which ma"
be associated with a corresponding decrease in !-cell prodction.
Althogh ! cells are %ond in earl" gestation in %etal circlation and increase in nmber %rom
birth to abot age 6 months$ these cells represent an immatre poplation. !hese naive cells do
not proli%erate as readil" as adlt ! cells do when activated$ and the" do not e%%ectivel" prodce
the c"tokines that assist with B-cell stimlation and di%%erentiation and granloc"te/monoc"te
proli%eration.
Eormation o% antigen-speci%ic memor" %nction a%ter primar" in%ection is dela"ed$ and the
c"toto)ic %nction o% neonatal ! cells is 5.-*..D as e%%ective as that o% adlt ! cells. At birth$
neonates are de%icient in memor" ! cells. As the neonate is e)posed to antigenic stimli$ the
nmber o% these memor" ! cells increases.
3atral killer &3=' cells are %ond in small nmbers in the peripheral blood o% neonates. !hese
cells are also %nctionall" immatre in that the" prodce %ar lower levels o% inter%eron gamma
&2E3-\' pon primar" stimlation than adlt 3= cells do. !his combination o% %indings ma"
contribte to the severit" o% (-L in%ections in the neonatal period.
Humoral immunity
!he %ets has some pre%ormed immnogloblin$ which is primaril" ac<ired throgh nonspeci%ic
placental trans%er %rom the mother. ;ost o% this trans%er occrs in late gestation$ so that lower
levels are %ond with increasing prematrit". !he neonateUs abilit" to generate immnogloblin
in response to antigenic stimlation is intact1 however$ the magnitde o% the response is initiall"
decreased$ rapidl" rising with increasing postnatal age.
[Type text]
!he neonate is also capable o% s"nthesi6ing immnogloblin ; &2g;' in tero at *. weeksU
gestation1 however$ 2g; levels are generall" low at birth$ nless the in%ant was e)posed to an
in%ectios agent dring the pregnanc"$ which wold have stimlated increased 2g; prodction.
2mmnogloblin B &2gB' and immnogloblin @ &2g@' ma" be s"nthesi6ed in tero. ;ost o% the
2gB is ac<ired %rom the mother dring late gestation. !he neonate ma" receive immnogloblin
A &2gA' %rom breast%eeding bt does not secrete 2gA ntil 2-5 weeks a%ter birth. 0esponse to
bacterial pol"saccharide antigen is diminished and remains so dring the %irst 2 "ears o% li%e.
5omplement protein prodction can be detected as earl" as 6 weeksU gestation1 however$ the
concentration o% the varios components o% the complement s"stem varies widel" %rom one
neonate to another. Althogh some in%ants have had complement levels comparable to those in
adlts$ de%iciencies appear to be greater in the alternative pathwa" than in the classic pathwa".
!he terminal c"toto)ic components o% the complement cascade that lead to killing o% organisms$
especiall" gram-negative bacteria$ are de%icient. !his de%icienc" is more marked in preterm
in%ants. ;atre complement activit" is not reached ntil in%ants are aged 6-*. months. 3eonatal
sera have redced opsonic e%%icienc" against BB-$ E coli$ and Streptococcus
pneumoniae becase o% decreased levels o% %ibronectin$ a serm protein that assists with
netrophil adherence and has opsonic properties.
(arrier "unction
!he ph"sical and chemical barriers to in%ection in the hman bod" are present in the newborn bt
are %nctionall" de%icient. -kin and mcos membranes are broken down easil" in the prematre
in%ant. 3eonates who are ill$ prematre$ or both are at additional risk becase o% the invasive
procedres that breach their ph"sical barriers to in%ection.
Becase o% the interdependence o% the immne response$ these individal de%iciencies o% the
varios components o% immne activit" in the neonate conspire to create a ha6ardos sitation
%or the neonate e)posed to in%ectios threats.
Cardiopulmonary response to sepsis
2n overwhelming sepsis$ there ma" be an initial earl" phase characteri6ed b" plmonar"
h"pertension$ decreased cardiac otpt$ and h"po)emia. !hese cardioplmonar" distrbances
ma" be de to the activit" o% granloc"te-derived biochemical mediators$ sch as h"dro)"l
radicals and thrombo)ane B2 &an arachidonic acid metabolite'.
!hese biochemical agents have vasoconstrictive actions that reslt in plmonar" h"pertension
when the" are released in plmonar" tisse. A to)in derived %rom the pol"saccharide capsle o%
t"pe 222 Streptococcus has also been shown to case plmonar" h"pertension.
%astrointestinal inolement in sepsis
!he intestines can be coloni6ed b" organisms in tero or at deliver" throgh swallowing o%
in%ected amniotic %lid. !he immnologic de%enses o% the B2 tract are not matre$ especiall" in
the preterm in%ant. I"mphoc"tes proli%erate in the intestines in response to mitogen stimlation1
however$ this proli%eration is not %ll" e%%ective in responding to a microorganism$ becase
antibod" response and c"tokine %ormation are immatre ntil appro)imatel" ,6 weeks.
[Type text]
3ecroti6ing enterocolitis has been associated with the presence o% a nmber o% species o%
bacteria in the immatre intestine. ?vergrowth o% these organisms in the neonatal lmen is a
component o% the mlti%actorial pathoph"siolog" o% necroti6ing enterocolitis.
Meningitis
&entriculitis
Lentriclitis is the initiating event in meningitis$ with in%lammation o% the ventriclar sr%ace.
@)dative material sall" appears at the choroid ple)s and is e)ternal to the ple)s.
@pend"mitis then occrs$ with disrption o% the ventriclar lining and pro8ections o% glial t%ts
into the ventriclar lmen. Blial bridges ma" develop b" these t%ts and case obstrction$
particlarl" at the a<edct o% -"lvis.
!he lateral ventricles ma" become mltiloclated$ a process that is similar to %ormation o%
abscesses. ;ltiloclated ventricles can isolate organisms in an area$ making treatment more
di%%iclt.
;eningitis is likel" to arise at the choroid ple)s and e)tend via the ventricles throgh a<edcts
and into the sbarachnoid space to a%%ect the cerebral and cerebellar sr%aces. !he high gl"cogen
content in the neonatal choroid ple)s provides an e)cellent medim %or the bacteria. 7hen
meningitis develops %rom ventriclitis$ e%%ective treatment is complicated becase ade<ate
antibiotic levels in the cerebral ventricles are di%%iclt to achieve. 7hen ventriclar obstrction is
present$ it cases additional problems.
#rachnoiditis
Arachnoiditis is the ne)t phase o% the process and is the hallmark o% meningitis. !he arachnoid is
in%iltrated b" in%lammator" cells prodcing an e)date that is thick over the base o% the brain and
more ni%orm over the rest o% the brain. @arl" in the in%ection$ the e)date primaril" contains
A;3s$ bacteria$ and macrophages. 2t is prominent arond the blood vessels and e)tends into the
brain parench"ma.
2n the second and third weeks o% in%ection$ the proportion o% A;3s decreases1 the dominant cells
are histioc"tes$ macrophages$ and some l"mphoc"tes and plasma cells. @)date in%iltration o%
cranial roots /-+ occrs.
A%ter this period$ the e)date decreases. !hick strands o% collagen %orm$ and arachnoid %ibrosis
occrs$ which is responsible %or obstrction. ("drocephals reslts. @arl"-onset BB- meningitis
is characteri6ed b" mch less arachnoiditis than late-onset BB- meningitis is.
&asculitis
Lasclitis e)tends the in%lammation o% the arachnoid and ventricles to the blood vessels
srronding the brain. ?cclsion o% the arteries rarel" occrs1 however$ venos involvement is
more severe. Ahlebitis ma" be accompanied b" thrombosis and complete occlsion. ;ltiple
%ibrin thrombi are especiall" associated with hemorrhagic in%arction. !his vasclar involvement
is apparent within the %irst da"s o% meningitis and becomes more prominent dring the second
and third weeks.
[Type text]
Cerebral edema
5erebral edema ma" occr dring the acte state o% meningitis and ma" be severe enogh to
diminish the ventriclar lmen sbstantiall". !he case is nknown bt is likel" to be related to
vasclitis and the increased permeabilit" o% blood vessels. 2t ma" also be related to c"toto)ins o%
microbial origin. (erniation o% edematos spratentorial strctres does not generall" occr in
neonates$ becase o% the cranimUs distensibilit".
'nfarction
2n%arction is a prominent and serios %eatre o% neonatal meningitis$ occrring in /.D o% in%ants
who die. Iesions occr becase o% mltiple venos occlsions$ which are %re<entl"
hemorrhagic. !he loci o% in%arcts are most o%ten in the cerebral corte) and nderl"ing white
matter bt ma" also be sbepend"mal within the deep white matter. 3eronal loss occrs$
especiall" in the cerebral corte)$ and periventriclar lekomalacia ma" sbse<entl" appear in
areas o% neronal cell death.
@tiolog"
Early'onset neonatal sepsis
!he microorganisms most commonl" associated with earl"-onset neonatal sepsis inclde the
%ollowing
9*:
:
BB-
E coli
5oaglase-negative Staphylococcus
H influenae
! monocytogenes
0isk %actors implicated in neonatal sepsis re%lect the level stress and illness e)perienced b" the
%ets at deliver"$ as well as the ha6ardos terine environment srronding the %ets be%ore
deliver". !he most common risk %actors associated with earl"-onset neonatal sepsis are as
%ollows:
;aternal BB- coloni6ation &especiall" i% ntreated dring labor'
Arematre rptre o% membranes &A0?;'
Areterm rptre o% membranes
Arolonged rptre o% membranes
Arematrit"
;aternal rinar" tract in%ection
5horioamnionitis
?ther %actors that are associated with or predispose to earl"-onset neonatal sepsis inclde the
%ollowing
95$ 6:
:
Iow Apgar score &J 6 at * or 5 mintes'
;aternal %ever greater than /+]5
;aternal rinar" tract in%ection &C!2'
Aoor prenatal care
Aoor maternal ntrition
[Type text]
Iow socioeconomic stats
A%rican American mother
(istor" o% recrrent abortion
;aternal sbstance abse
Iow birth weight
4i%%iclt deliver"
Birth asph")ia
;econim staining
5ongenital anomalies
*ate'onset neonatal sepsis
?rganisms that have been implicated in casing late-onset neonatal sepsis inclde the %ollowing:
5oaglase-negative staph"lococci
S aureus
E coli
"lebsiella
Pseudomonas
Enterobacter
Candida
BB-
Serratia
#cinetobacter
Anaerobes
Iate-onset sepsis is associated with the %ollowing risk %actors
97:
:
Arematrit"
5entral venos catheteri6ation &dration G*. da"s'
3asal cannla or continos positive airwa" pressre &5AAA' se
(2 -receptor blocker or proton pmp inhibitor &AA2' se
B2 tract patholog"
Meningitis
!he principal pathogens in neonatal meningitis are BB- &/6D o% cases'$ E coli &/*D'$
and !isteria species &5-*.D'. ?ther organisms that ma" case meningitis inclde the %ollowing:
S pneumoniae
S aureus
S epidermidis
H influenae
Pseudomonas species
"lebsiella species
Serratia species
Enterobacter species
Proteus species
[Type text]
@pidemiolog"
!he incidence o% cltre-proven sepsis in the Cnited -tates is appro)imatel" 2 per *... live
births. ?% the 7-*/D o% neonates who are evalated %or neonatal sepsis$ onl" /-+D have cltre-
proven sepsis. !his disparit" arises %rom the catios approach to management o% neonatal
sepsis.
Becase earl" signs o% sepsis in the newborn are nonspeci%ic$ diagnostic stdies are o%ten ordered
and treatment initiated in neonates be%ore the presence o% sepsis has been proved. ;oreover$
becase the American Academ" o% Aediatrics &AAA'$
9+:
the American Academ" o% ?bstetrics and
B"necolog" &AA?B'$ and the 5enters %or 4isease 5ontrol and Arevention &545'
99:
all have
recommended sepsis screening or treatment %or varios risk %actors related to BB- in%ections$
man" as"mptomatic neonates now ndergo evalation.
Becase mortalit" %rom ntreated sepsis can be as high as 5.D$ most clinicians believe that the
ha6ard o% ntreated sepsis is too great to allow them to wait %or con%irmation in the %orm o%
positive cltre reslts. !here%ore$ most clinicians initiate treatment while awaiting cltre
reslts.
!he implementation o% a prenatal screening and treatment protocol %or BB- has reslted in a
decreasing incidence o% BB- sepsis. !his has changed the epidemiolog" o% earl"-onset sepsis
&see the image below'.
[Type text]
2ncidence o% earl"-onset and late-onset invasive grop B
-treptococcs &BB-' disease.
Age'/ sex'/ and race'related demographics
Black in%ants have an increased incidence o% BB- disease and late-onset sepsis. !his is observed
even a%ter the risk %actors o% low birth weight and decreased maternal age have been controlled
%or. !his ma" be in part de to higher carriage rates o% BB- among A%rican American women$
bt this does not e)plain all o% the variation.
96:
2n all races$ the incidence o% bacterial sepsis and
meningitis$ especiall" with gram-negative enteric bacilli$ is higher in males than in %emales.
Arematre in%ants have an increased incidence o% sepsis. !he incidence o% sepsis is signi%icantl"
higher in in%ants with a birth weight o% less than *... g &26 per *... live births' than in in%ants
with a birth weight o% *...-2... g &+-9 per *... live births'. !he risk o% death or meningitis
%rom sepsis is higher in in%ants with low birth weight than in %ll-term neonates.
Arognosis
7ith earl" diagnosis and treatment$ term in%ants are not likel" to e)perience long-term health
problems associated with neonatal sepsis1 however$ i% earl" signs or risk %actors are missed$
mortalit" increases. 0esidal nerologic damage occrs in *5-/.D o% neonates with septic
meningitis.
;ortalit" %rom neonatal sepsis ma" be as high as 5.D %or in%ants who are not treated. 2n%ection
is a ma8or case o% %atalit" dring the %irst month o% li%e$ contribting to */-*5D o% all neonatal
deaths. Iow birth weight and gram-negative in%ection are associated with adverse otcomes.
9*.:
3eonatal meningitis occrs in 2-, cases per *.$... live births and contribtes signi%icantl" to
mortalit" %rom neonatal sepsis1 it is responsible %or ,D o% all neonatal deaths.
2n preterm in%ants who have had sepsis$ impaired nerodevelopment is a concern.
9**:
Aroin%lammator" molecles ma" negativel" a%%ect brain development in this patient
poplation. 2n a large std" o% abot 6... prematre in%ants who weighed less than *... g at
birth$ preterm in%ants with sepsis who did not have meningitis had higher rates o% cognitive
de%icits$ cerebral pals"$ and other nerodevelopmental disabilities than in%ants who did not have
sepsis.
9*2$ */:
[Type text]
2n%ants with meningitis ma" ac<ire h"drocephals or periventriclar lekomalacia. !he" ma"
also have complications associated with the se o% aminogl"cosides$ sch as hearing loss or
nephroto)icit".
(istor"
An awareness o% the man" risk %actors associated with neonatal sepsis prepares the clinician %or
earl" identi%ication and e%%ective treatment$ thereb" redcing mortalit" and morbidit". Among
these risk %actors are the %ollowing:
;aternal grop B Streptococcus &BB-' stats
Arematre rptre o% membranes &A0?;'
Arematrit"
5horioamnionitis
Maternal %(S status
!he most common case o% neonatal bacterial sepsis is BB-. !here are 9 serot"pes$ each o%
which is related to the pol"saccharide capsle o% the organism. !"pes 2$ 22$ and 222 are commonl"
associated with neonatal BB- in%ection. !he t"pe 222 strain has been shown to be most highl"
associated with central nervos s"stem &53-' involvement in earl"-onset in%ection$ whereas
t"pes 2 and L have been associated with earl"-onset disease withot 53- involvement.
!he BB- organism coloni6es the maternal gastrointestinal &B2' tract and birth canal.
Appro)imatel" 25D o% women have as"mptomatic BB- coloni6ation dring pregnanc". BB- is
responsible %or appro)imatel" 5.$... maternal in%ections per "ear in women$ bt onl" ../6-2
neonates per *... live births are in%ected.
7omen with heav" BB- coloni6ation and chronicall" positive BB- cltre reslts have the
highest risk o% perinatal transmission. Also$ heav" coloni6ation at 2/-26 weeksU gestation is
associated with prematrit" and low birth weight. 5oloni6ation at deliver" is associated with
neonatal in%ection.
2ntrapartm chemoproph"la)is %or women with positive cltre reslts %or BB- has been shown
to decrease the transmission o% the organism to the neonate dring deliver". ;others ma" have a
negative prenatal cltre %or BB- bt a positive one at the time o% labor.
9/:
Premature rupture o" membranes
A0?; ma" occr in response to an ntreated rinar" tract in%ection &C!2' or birth canal
in%ection. ?ther risk %actors are previos preterm deliver"$ terine bleeding in pregnanc"$ and
[Type text]
heav" cigarette smoking dring pregnanc". 0ptre o% membranes withot other complications
%or more than 2, hors be%ore deliver" is associated with a *D increase in the incidence o%
neonatal sepsis1 however$ when chorioamnionitis accompanies the rptre o% membranes$ the
incidence o% neonatal in%ection is <adrpled.
A mlticenter std" demonstrated that clinical chorioamnionitis and maternal coloni6ation with
BB- are the most important predictors o% sbse<ent neonatal in%ection a%ter A0?;.
9*,:
-eaward
et al %ond that more than 6 vaginal digital e)aminations$ which ma" be carried ot as part o% the
evalation %or A0?;$ were associated with neonatal in%ection even when considered separatel"
%rom the presence o% chorioamnionitis.
9*,:
7hen membranes have rptred prematrel" be%ore /7 weeksU gestation$ a longer latent period
precedes vaginal deliver"$ increasing the likelihood that the in%ant will be in%ected. !he dration
o% membrane rptre be%ore deliver" and the likelihood o% neonatal in%ection are inversel"
related to gestational age. !hs$ the more prematre an in%ant is$ the longer the dela" between
rptre o% membranes and deliver" and the higher the likelihood o% neonatal sepsis.
Prematurity
2n addition to the relation between preterm A0?; and neonatal sepsis$ there are other
associations between prematrit" and neonatal sepsis that increase the risk %or prematre in%ants.
Areterm in%ants are more likel" to re<ire invasive procedres$ sch as mbilical catheteri6ation
and intbation. Arematrit" is associated with in%ection %rom c"tomegalovirs &5;L'$ herpes
simple) virs &(-L'$ hepatitis B virs &(BL'$(o)oplasma$*ycobacterium
tuberculosis$ Campylobacter fetus$ and !isteria species. 2ntraterine growth retardation and low
birth weight are also observed in 5;L in%ection and to)oplasmosis.
Arematre in%ants have less immnologic abilit" to resist and combat in%ection. 5onse<entl"$
the" are more ssceptible to in%ection cased b" common organisms sch as coaglase-
negative Staphylococcus+ an organism sall" not associated with severe sepsis.
Chorioamnionitis
!he relationship between chorioamnionitis and other risk variables is strong. -spect
chorioamnionitis in the presence o% %etal tach"cardia$ terine tenderness$ prlent amniotic %lid$
an elevated maternal white blood cell &7B5' cont$ and an ne)plained maternal temperatre
higher than *...,]E &/+]5'.
Ah"sical @)amination
!he clinical signs o% neonatal sepsis are nonspeci%ic and are associated with the characteristics o%
the casative organism and the bod"Us response to the invasion. !hese nonspeci%ic clinical signs
o% earl" sepsis are also associated with other neonatal diseases$ sch as respirator" distress
s"ndrome &04-'$ metabolic disorders$ intracranial hemorrhage$ and a tramatic deliver". 2n view
o% the nonspeci%icit" o% these signs$ it is prdent to provide treatment %or sspected neonatal
sepsis while e)clding other disease processes.
!o obtain the most in%ormation %rom the e)amination$ s"stematic ph"sical assessment o% the
in%ant is best per%ormed in a series that shold inclde observation$ ascltation$ and palpation$
[Type text]
in that order. 5hanges in %indings %rom one e)amination to the ne)t provide important
in%ormation abot the presence and evoltion o% sepsis.
9*5:
Congenital pneumonia and intrauterine in"ection
2n%lammator" lesions are observed post mortem in the lngs o% in%ants with congenital and
intraterine pnemonia. !he" ma" reslt not %rom the action o% the microorganisms themselves
bt$ rather$ %rom aspiration o% amniotic %lid containing maternal lekoc"tes and celllar debris.
!ach"pnea$ irreglar respirations$ moderate retraction$ apnea$ c"anosis$ and grnting ma" be
observed.
3eonates with intraterine pnemonia ma" also be criticall" ill at birth and re<ire high levels o%
ventilator" spport. !he chest radiograph ma" depict bilateral consolidation or pleral e%%sions.
Congenital pneumonia and intrapartum in"ection
3eonates who are in%ected dring the birth process ma" ac<ire pnemonia throgh aspiration o%
microorganisms dring deliver". "lebsiella species and S aureus are especiall" likel" to generate
severe lng damage$ prodcing microabscesses and emp"ema. @arl"-onset BB- pnemonia has
a particlarl" %lminant corse$ with signi%icant mortalit" in the %irst ,+ hors o% li%e.
2ntrapartm aspiration ma" lead to in%ection with plmonar" changes$ in%iltration$ and
destrction o% bronchoplmonar" tisse. !his damage is partl" de to the granloc"tesU release o%
prostaglandins and lekotrienes. Eibrinos e)dation into the alveoli leads to inhibition o%
plmonar" sr%actant %nction and respirator" %ailre$ with a presentation similar to that o% 04-.
Lasclar congestion$ hemorrhage$ and necrosis ma" occr. 2n%ectios pnemonia is also
characteri6ed b" pnematoceles within the plmonar" tisse.
5oghing$ grnting$ costal and sternal retractions$ nasal %laring$ tach"pnea or irreglar
respiration$ rales$ decreased breath sonds$ and c"anosis ma" be observed. 0adiographic
evalation ma" demonstrate segmental or lobar atelectasis or a di%%se reticlogranlar pattern$
mch like what is observed in 04-. Aleral e%%sions ma" be observed in advanced disease.
Postnatal in"ection
Aostnatall" ac<ired pnemonia ma" occr at an" age. Becase these in%ectios agents e)ist in
the environment$ the likel" case depends heavil" on the in%antUs recent environment. 2% the
in%ant has remained hospitali6ed in a neonatal intensive care nit &325C'$ especiall" with
endotracheal intbation and mechanical ventilation$ the organisms ma"
inclde Staphylococcus or Pseudomonas species.
Additionall"$ these hospital-ac<ired organisms %re<entl" demonstrate mltiple antibiotic
resistances. !here%ore$ the choice o% antibiotic agents in sch cases re<ires knowledge o% the
likel" casative organisms and the local antibiotic-resistance patterns.
Cardiac signs
2n overwhelming sepsis$ an initial earl" phase characteri6ed b" plmonar" h"pertension$
decreased cardiac otpt$ and h"po)emia ma" occr. !his phase is %ollowed b" %rther
progressive decreases in cardiac otpt with brad"cardia and s"stemic h"potension. !he in%ant
[Type text]
mani%ests overt shock with pallor$ poor capillar" per%sion$ and edema. !hese late signs o% shock
are indicative o% severe compromise and are strongl" associated with mortalit".
Metabolic signs
("pogl"cemia$ h"pergl"cemia$ metabolic acidosis$ and 8andice are all metabolic signs that
commonl" accompan" neonatal sepsis. !he in%ant has an increased glcose re<irement as a
reslt o% the septic state. !he in%ant ma" also be malnorished as a conse<ence o% diminished
energ" intake. ("pogl"cemia accompanied b" h"potension ma" be secondar" to an inade<ate
response %rom the adrenal gland and ma" be associated with a low cortisol level.
;etabolic acidosis is de to a conversion to anaerobic metabolism with the prodction o% lactic
acid. 7hen in%ants are h"pothermic or are not kept in a netral thermal environment$ e%%orts to
reglate bod" temperatre can case metabolic acidosis. >andice occrs in response to
decreased hepatic glcronidation cased b" both hepatic d"s%nction and increased er"throc"te
destrction.
1eurologic signs
;eningitis is the common mani%estation o% 53- in%ection. Acte and chronic histologic %eatres
are associated with speci%ic organisms.
;eningitis de to earl"-onset neonatal sepsis sall" occrs within 2,-,+ hors and is dominated
b" nonnerologic signs. 3erologic signs ma" inclde stpor and irritabilit". ?vert signs o%
meningitis occr in onl" /.D o% cases. @ven cltre-proven meningitis ma" not demonstrate
white blood cell &7B5' changes in the cerebrospinal %lid &5-E'.
;eningitis de to late-onset disease is more likel" to demonstrate nerologic signs &+.-9.D'1
however$ man" o% these ph"sical e)amination %indings are sbtle or inapparent. 3erologic signs
inclde the %ollowing:
2mpairment o% consciosness &ie$ stpor with or withot irritabilit"'
5oma
-ei6res
Blging anterior %ontanelle
@)tensor rigidit"
Eocal cerebral signs
5ranial nerve signs
3chal rigidit"
!emperatre instabilit" is observed with neonatal sepsis and meningitis$ either in response to
p"rogens secreted b" the bacterial organisms or %rom s"mpathetic nervos s"stem instabilit". !he
neonate is most likel" to be h"pothermic. !he in%ant ma" also have decreased tone$ letharg"$ and
poor %eeding. -igns o% nerologic h"peractivit" are more likel" when late-onset meningitis
occrs.
Approach 5onsiderations
Iaborator" stdies sed to evalate %or earl"-onset and late-onset sepsis inclde a complete
blood cont &5B5' and di%%erential$ blood and cerebrospinal %lid &5-E' cltres$ and
measrement o% levels o% 5-reactive protein &50A' and possibl" other in%ection markers. 2n some
[Type text]
cases$ serial 5B5 and 50A stdies ma" be appropriate. A Bram stain provides earl"
identi%ication o% the gram-negative or gram-positive stats o% the organism %or preliminar"
identi%ication.
Becase o% the low incidence o% meningitis in the newborn with negative blood cltre reslts$
clinicians ma" elect to cltre the 5-E o% onl" those in%ants with docmented or presmed
sepsis. (owever$ data %rom large stdies show a /+D rate o% cltre-positive meningitis in
neonates with negative blood cltre reslts and sspected sepsis. Accordingl"$ a lmbar
pnctre shold be part o% the evalation o% an in%ant with sspected sepsis.
@merging technolog" sing pol"merase chain reaction &A50'$ thogh not "et available clinicall"$
cold eventall" help achieve %aster identi%ication o% sepsis and the casative organism than can
be achieved with blood cltre alone.
9*6:
0apid pathogen detection with mltiple) A50 ma"
%acilitate more timel" selection o% targeted antibiotic therap" while limiting e)posre to broad-
spectrm antibiotics.
9*7:
2maging stdies emplo"ed in the workp o% neonatal sepsis ma" inclde chest radiograph" to
evalate plmonar" involvement$ as well as compted tomograph" &5!'$ magnetic resonance
imaging &;02'$ and ltrasonograph" o% the head in cases o% meningitis.
Iaborator" -tdies
Cultures
Aerobic and anaerobic cltres are appropriate %or most o% the bacterial pathogens associated
with neonatal sepsis. Anaerobic cltres are especiall" important in neonates who have
abscesses$ processes with bowel involvement$ massive hemol"sis$ or re%ractor" pnemonia.
Bacterial cltre reslts shold generall" reveal the organism o% in%ection within /6-,+ hors1
sbse<ent initial identi%ication o% the organism occrs within *2-2, hors o% the growth. -ingle-
site blood cltres are e%%ective %or isolating bacteria in neonates with sepsis.
9*+:
Crine cltres
are most appropriate %or the investigation o% late-onset sepsis.
Complete blood count and di""erential
A 5B5 and di%%erential ma" be ordered seriall" to determine changes associated with the
in%ection &eg$ thromboc"topenia or netropenia' or to monitor the development o% a le%t shi%t or
changes in the ratio o% immatre to total netrophils. -ch serial monitoring o% the 5B5 ma" be
se%l in aiding the di%%erentiation o% sepsis %rom nonspeci%ic abnormalities de to the stress o%
deliver".
Platelet count
!he platelet cont in the health" newborn is rarel" lower than *..$.../RI in the %irst *. da"s o%
li%e &normal$ P*5.$.../HI'. !hromboc"topenia &platelet conts J *..$.../RI' ma" be a
presenting sign o% neonatal sepsis and can last as long as / weeks1 *.-6.D o% in%ants with sepsis
have thromboc"topenia.
9*9:
Becase o% the appearance o% newl" %ormed platelets$ mean platelet volme &;AL' and platelet
distribtion width &A47' are signi%icantl" higher in neonatal sepsis a%ter 2-/ da"s o% li%e. !hese
measres ma" assist in determining the case o% thromboc"topenia. (owever$ becase o% the
[Type text]
m"riad o% cases o% thromboc"topenia and its late appearance in neonatal sepsis$ the presence o%
thromboc"topenia generall" does not aid the diagnosis o% neonatal sepsis.
,hite blood cell counts and ratios
Althogh white blood cell &7B5' conts and ratios are more sensitive %or determining sepsis
than platelet conts are$ the" remain ver" nonspeci%ic and have a low positive predictive vale.
3ormal 7B5 conts ma" be initiall" observed in as man" as 5.D o% cases o% cltre-proven
sepsis. 2n%ants who are not in%ected ma" also demonstrate abnormal 7B5 conts related to the
stress o% deliver" or to an" o% several other %actors.
A di%%erential ma" be o% se in diagnosing sepsis1 however$ these conts are largel" dependent on
the laborator" technician per%orming them. !he total netrophil cont &pol"morphonclear cells
9A;3s: and immatre %orms' is slightl" more sensitive %or determining sepsis than the total
lekoc"te cont &percent l"mphoc"te Y monoc"te/A;3s Y bands'.
Abnormal netrophil conts at the time o% s"mptom onset are observed in onl" two thirds o%
in%ants1 there%ore$ the netrophil cont does not provide ade<ate con%irmation o% sepsis.
3etropenia is also observed with maternal h"pertension$ severe perinatal asph")ia$ and
periventriclar or intraventriclar hemorrhage.
3etrophil ratios have been more se%l in diagnosing neonatal sepsis1 o% these$ the immatre-to-
total &2/!' ratio is the most sensitive &6.-9.D'. All immatre netrophil %orms are conted. !he
ma)imm acceptable 2/! ratio %or e)clding sepsis in the %irst 2, hors is ..*6. 2n most
newborns$ the ratio %alls to ..*2 within 6. hors o% birth. Becase elevated 2/! ratios ma" be
observed with other ph"siologic events$ their positive predictive vale is limited1 ths$ in the
diagnosis o% sepsis$ an elevated 2/! ratio shold be sed in combination with other signs.
C'reactie protein Procalcitonin and other mar#ers
levels o% 50A$ an acte-phase protein associated with tisse in8r"$ are elevated at some point in
5.-9.D o% in%ants with s"stemic bacterial in%ections.
92.:
50A levels rise secondar" to
macrophage$ !-cell$ and adipoc"te prodction o% interlekin &2I'Q6. !his is especiall" tre o%
in%ections with abscesses or celllitis o% deep tisse.
50A levels sall" begin to rise within ,-6 hors o% the onset o% in%ection$ become abnormal
within 2, hors o% in%ection$ peak within 2-/ da"s$ and remain elevated ntil the in%lammation is
resolved. !he 50A level is not recommended as a sole indicator o% neonatal sepsis bt ma" be
sed as part o% a sepsis workp or as a serial std" dring in%ection to assess the response to
antibiotics$ determine the dration o% therap"$ or identi%" a relapse o% in%ection.
2mmnogloblin ; &2g;' concentration in serm ma" be help%l in determining the presence o%
an intraterine in%ection$ especiall" i% the in%ection has been present %or some time. @levated 2g;
levels in mbilical cord serm sggest intraterine in%ection.
@vidence on the se o% in%ection markers sch as 54**b$ 546,$ 2I-6$ and 2I-+ %or evalation o%
sepsis in neonates shows that the" ma" be help%l as ad8nctive markers.
92*:
!heir vale ma" be
%rther enhanced b" per%orming serial measrements and sing combinations o% tests. At present$
however$ the consenss is that these tests shold not be sed alone to determine the need %or
[Type text]
antibiotic therap"$ thogh in some cases the" ma" prove se%l in determining when to stop
antibiotic therap".
Ievels o% other acte-phase reactants &eg$ procalcitonin and serm am"loid' are o%ten elevated
with the onset o% sepsis. Arocalcitonin$ a propeptide o% calcitonin prodced in monoc"tes and in
the liver$ ma" be more sensitive than 50A. 2t is more speci%ic to bacterial in%ection than viral
in%ection and has been shown to be se%l a%ter age 2, hors in neonates with sspected bacterial
sepsis. 2t can be elevated in in%ants with respirator" distress s"ndrome and in in%ants o% diabetic
mothers$ and it shold be sed in con8nction with the entire clinical sitation and not as a single
determinant o% treatment. @vidence o% se%lness o% procalcitonin in the neonate is monting$
and rapid trnarond times &9.-*2. min' are proving increasingl" se%l in a clinical setting.
Arocalcitonin ma" be sed in combination with other acte-phase reactants$ sch as 50A.
96$ 22$ 2/:
Coagulation studies
4isseminated intravasclar coaglation &425' can occr in in%ected in%ants. Aredicting which
in%ants will be a%%ected at the onset o% sepsis is di%%iclt.
92,:
2n%ants with 425 show abnormalities in the prothrombin time &A!'$ the partial thromboplastin
time &A!!'$ and %ibrinogen and 4-dimer levels$ and the" ma" need blood prodcts$ inclding
%resh %ro6en plasma &EEA' and cr"oprecipitate$ to replace coaglation %actors consmed in
association with 425. 2% in%ants show signs consistent with impaired coaglation &eg$ gastric
blood$ bleeding %rom intravenos 92L: or laborator" pnctre sites$ or other bleeding'$
coaglation shold be evalated b" checking these vales.
Imbar Anctre and 5-E Anal"sis
Imbar pnctre is warranted %or earl"- and late-onset sepsis$ thogh clinicians ma" be
nsccess%l in obtaining s%%icient or clear %lid %or all the stdies. 2n%ants ma" be positioned on
their side or in a sitting position with spport. !he insertion site shold be between I/ and I, to
ensre that it is below the lowest point o% the spinal cord in in%ants.
2% positive cltre reslts are obtained$ a %ollow-p lmbar pnctre is o%ten per%ormed within
2,-/6 hors a%ter initiation o% antibiotic therap" to docment 5-E sterilit". 2% organisms are still
present$ modi%ication o% the drg t"pe or dosage ma" be re<ired %or ade<ate treatment o% the
meningitis. An additional lmbar pnctre within 2,-/6 hors o% the change in therap" is
necessar" i% organisms are still present.
CSF analysis
5-E %indings in in%ective neonatal meningitis are as %ollows:
@levated 7B5 cont &predominantl" A;3s'
@levated protein level
4ecreased glcose concentration
Aositive cltre reslts
!he 5-E 7B5 cont is within the re%erence range in 29D o% grop B Streptococcus&BB-'
meningitis in%ections bt in onl" ,D o% gram-negative meningitis in%ections. 0e%erence-range
5-E protein and glcose concentrations are %ond in abot 5.D o% patients with BB- meningitis
[Type text]
bt in onl" *5-2.D o% patients with gram-negative meningitis. 5-E cltre is critical$ in that
neonatal meningitis o%ten occrs in patients withot bacteremia and with normal 5-E %indings.
925:
!he decrease in 5-E glcose concentration does not necessaril" re%lect serm h"pogl"cemia.
Blcose concentration abnormalities are more severe in late-onset disease and with gram-
negative in%ections.
Herpes simplex irus PCR testing
3o consenss has been reached regarding the inclsion o% herpes simple) virs &(-L' A50
testing o% 5-E as part o% a rotine sepsis workp in the neonate. 5rrentl"$ (-L A50 is reserved
%or in%ants with 53- abnormalities$ skin vesicles$ and 5-E abnormalities or %or in%ants who have
clinical s"mptoms bt have negative cltres and do not respond to antibiotics.
926:
(owever$
vesicles are not present in as man" as one third o% 53- (-L and disseminated (-L cases.
Erther research in this area is needed to provide clear practice recommendations.
0adiograph"$ 5!$ ;02$ and Cltrasonograph"
5hest radiograph" ma" reveal segmental or lobar in%iltrate bt more commonl" reveals a di%%se$
%ine$ reticlogranlar pattern$ mch like that seen in respirator" distress s"ndrome &04-'. Aleral
e%%sions ma" also be observed.
5! scanning or ;02 ma" be needed late in the corse o% comple) neonatal meningitis to
docment obstrctive h"drocephals$ the site where the obstrction is occrring$ and the
occrrence o% ma8or in%arctions or abscesses. -igns o% chronic disease &eg$ ventriclar dilation$
mltic"stic encephalomalacia$ and atroph"' ma" also be demonstrated on 5! scanning or ;02.
(ead ltrasonograph" in neonates with meningitis ma" reveal evidence o% ventriclitis$ abnormal
parench"mal echogenicities$ e)tracelllar %lid$ and chronic changes. -eriall"$ head
ltrasonograph" can reveal the progression o% complications.
Approach 5onsiderations
7hen neonatal sepsis is sspected$ treatment shold be initiated immediatel" becase o% the
neonateUs relative immnosppression. Begin antibiotics as soon as diagnostic tests are
per%ormed.
A neonate with sepsis ma" re<ire treatment aimed at the overwhelming s"stemic e%%ects o% the
disease. 5ardioplmonar" spport and intravenos &2L' ntrition ma" be re<ired dring the
acte phase o% the illness ntil the in%antUs condition stabili6es. ;onitoring o% blood pressre$
vital signs$ hematocrit$ platelets$ and coaglation stdies is vital. 3ot ncommonl"$ blood
prodct trans%sion$ inclding packed red blood cells &A0B5s'$ platelets$ and %resh %ro6en
plasma &EEA'$ is indicated.
An in%ant with temperatre instabilit" needs thermoreglator" spport with a radiant warmer or
incbator. ?nce the in%ant is stable %rom a cardioplmonar" standpoint$ parental contact is
important.
-rgical consltation %or central line placement ma" be necessar" in in%ants who re<ire
prolonged 2L antimicrobial therap" %or sepsis$ i% peripheral 2L access cannot be maintained. 2% an
[Type text]
abscess is present$ srgical drainage ma" be necessar"1 2L antibiotic therap" cannot ade<atel"
penetrate an abscess$ and antibiotic treatment alone is ine%%ective.
!he in%ant ma" re<ire trans%er to a level 222 perinatal center$ especiall" i% he or she re<ires
cardioplmonar" spport$ parenteral ntrition$ or prolonged 2L access. !he mltidisciplinar"
services available at larger centers ma" be necessar" i% the neonateUs condition is actel"
compromised.
Additional therapies have been investigated %or the treatment o% neonatal sepsis$ inclding
granloc"te trans%sion$ 2L immne globlin &2L2g' in%sion$ e)change trans%sion$ and the se
o% recombinant c"tokines. (owever$ no sbstantial clinical trials have shown that these
treatments are bene%icial.
Antibiotic !herap"
2n the Cnited -tates and 5anada$ the crrent approach to the treatment o% earl"-onset neonatal
sepsis incldes combined 2L aminogl"coside and e)panded-spectrm penicillin antibiotic
therap". !his provides coverage %or gram-positive organisms$ especiall" grop
B Streptococcus &BB-'$ and gram-negative bacteria$ sch as Escherichia coli. !he speci%ic
antibiotics to be sed are chosen on the basis o% maternal histor" and prevalent trends o%
organism coloni6ation and antibiotic ssceptibilit" in individal nrseries.
2% an in%ection appears to be nosocomial &late-onset sepsis'$ antibiotic coverage shold be
directed at organisms implicated in hospital-ac<ired in%ections$ inclding S aureus$ S
epidermidis$ and Pseudomonas species. ;ost strains o% S aureus prodce beta-lactamase$ which
makes them resistant to penicillin B$ ampicillin$ carbenicillin$ and ticarcillin. Lancom"cin has
been %avored %or this coverage1 however$ concern e)ists that overse o% this drg ma" lead to
vancom"cin-resistant organisms$ thereb" eliminating the best response to penicillin-resistant
organisms. Eor this reason$ some clinicians pre%er o)acillin therap" in this setting.
5ephalosporins are attractive in the treatment o% nosocomial in%ection becase o% their lack o%
dose-related to)icit" and their abilit" to reach ade<ate serm and cerebrospinal %lid &5-E'
concentrations1 however$ their se has led to resistance in gram-negative organisms. 5e%tria)one
displaces bilirbin %rom serm albmin and shold be sed with cation in in%ants with
signi%icant h"perbilirbinemia. 0esistance and sensitivities %or the organism isolated %rom
cltres are sed to select the most e%%ective drg.
^aidi et al compared the %ailre rates o% / clinic-based antibiotic regimens in .- to 59-da"-old
in%ants with possible serios bacterial in%ections in =arachi$ Aakistan. 2n a randomi6ed std"$ the
researchers %ond that otpatient therap" with in8ectable antibiotics is an e%%ective alternative
when hospitali6ation is not possible. Arocaine penicillin/gentamicin was sperior to oral
trimethoprim-sl%ametho)a6ole$ while ce%tria)one was more e)pensive and less e%%ective than
penicillin/gentamicin.
927:
Aminogl"cosides and vancom"cin both have the potential to prodce ototo)icit" and
nephroto)icit" and shold there%ore be sed with cation. !he serm drg level is assessed
arond the third dose or at ,+ hors a%ter the start o% treatment to determine whether levels are
within the therapetic range. !he drg dosage or interval ma" have to be ad8sted to optimi6e the
[Type text]
drg serm levels. 2n%ants who received aminogl"cosides shold ndergo adiolog" screening
be%ore discharge.
2% the in%antUs clinical condition has not improved$ a serm level ma" also be warranted to ensre
that a therapetic level has been reached. 2n addition$ renal %nction and hearing screening
shold be considered a%ter completion o% the therapetic corse to determine whether an" short-
or long-range to)ic e%%ects o% these drgs have occrred.
2% cltre reslts are negative bt the in%ant is at signi%icant risk %or or has clinical signs o% sepsis$
the clinician mst decide whether to provide contined treatment. 2n most cases$ 2-/ da"s o%
negative cltre reslts shold allow the clinician to be con%ident that sepsis is absent1 however$
a small nmber o% in%ants shown to have had sepsis b" postmortem e)amination had negative
cltre reslts dring their initial sepsis evalation.
;anagement is %rther complicated i% the mother received antibiotic therap" be%ore deliver"$
especiall" i% she received the therap" within several hors o% deliver". !his ma" reslt in
negative cltre reslts in an in%ant who actall" has bacteremia or sepsis. 7ith this in mind$ the
need %or contined therap" shold be based not on a single test$ bt on a review o% all diagnostic
data$ inclding the %ollowing:
5ltre reslts
;aternal and intrapartm risk %actors
5-E reslts
5omplete blood cell &5B5' cont and di%%erential
5-reactive protein &50A' trends
0adiographs
5linical progress
!reatment %or 7-*. da"s ma" be appropriate$ even i% cltre reslts remain negative at ,+-72
hors.
Additional 5onsiderations %or ;eningitis
2n%ants with bacterial meningitis o%ten re<ire di%%erent dosages o% antibiotics and longer corses
o% treatment. 2n addition$ these in%ants ma" re<ire an antimicrobial that has better penetration o%
the blood-brain barrier so that therapetic drg concentrations can be achieved in the 5-E.
!o determine whether the 5-E is sterile$ a %ollow-p lmbar pnctre is recommended within
2,-/6 hors a%ter initiation o% antibiotic therap". 2% organisms are still present$ modi%ication o%
the drg t"pe or dosage is re<ired to treat the meningitis ade<atel". 5ontine antibiotic
treatment %or 2 weeks a%ter sterili6ation o% the 5-E or %or a minimm o% 2 weeks with gram-
positive meningitis and / weeks with gram-negative meningitis.
;eningitis complicated b" sei6res or persistent positive cltres ma" re<ire e)tended 2L
antimicrobial therap". 5hloramphenicol or trimethoprim-sl%ametho)a6ole has been shown to be
e%%ective in the treatment o% highl" resistant bacterial meningitis. !rimethoprim-
sl%ametho)a6ole shold not be sed i% h"perbilirbinemia and kernicters are o% concern in the
newborn.
[Type text]
3entriculoperitoneal shunting "or hydrocephalus
2% h"drocephals is associated with neonatal meningitis and i% there is progressive accmlation
o% 5-E$ a ventricloperitoneal &LA' shnt ma" be necessar" to drain o%% the e)cess %lid. !he
immediate complications o% shnt placement are overdrainage$ e<ipment %ailre$ disconnection$
migration o% catheter$ and shnt in%ection. Abdominal obstrction$ omental c"sts$ and per%oration
o% the bladder$ gallbladder$ or bowel are ncommon.
!he LA shnt ma" case long-term nerologic complications$ inclding slit-ventricle s"ndrome$
sei6res$ nero-ophthalmologic problems$ and cranios"nostosis. 3evertheless$ the otcome %or
children with LA shnt placement is generall" good with care%l %ollow-p.
2nvestigational !herapies
Additional therapies that have been investigated %or the treatment o% neonatal sepsis inclde the
%ollowing:
Branloc"te trans%sion
2L2g in%sion
@)change trans%sion
0ecombinant c"tokine administration
%ranulocyte trans"usion
Branloc"te trans%sion has been shown to be sitable %or in%ants with signi%icant depletion o%
the storage netrophil pool1 however$ docmentation o% storage pool depletion re<ires bone
marrow aspiration$ and the granloc"te trans%sion mst be administered <ickl" i% it is to be
bene%icial. !he nmber o% potential adverse e%%ects &eg$ gra%t-verss-host reaction$ transmission
o% c"tomegalovirs 95;L: or hepatitis B$ and plmonar" lekoc"te se<estration' is
considerable. 5onse<entl"$ this therap" remains e)perimental.
.3.g in"usion
!he rationale %or 2L2g in%sion is that it cold provide t"pe-speci%ic antibodies$ thereb"
improving opsoni6ation and phagoc"tosis o% bacterial organisms and enhancing complement
activation and chemota)is o% neonatal netrophils. 2t has been stdied as a possible therap" %or
neonatal sepsis$ bt at present$ the data do not spport its rotine se %or this prpose. !he main
di%%iclties with 2L2g therap" are as %ollows:
!he e%%ect has been transient
5linicall" available 2L2g soltions do not contain t"pe-speci%ic antibod"
!he adverse e%%ects associated with the in%sion o% an" blood prodct can occr
2n addition$ dose-related problems with 2L2g in%sion limit its se%lness in neonatal poplations.
0esearch has demonstrated no improvement in otcomes %or neonates with sepsis who receive
2L2g therap".
92+:
Recombinant human cyto#ine administration
Administration o% recombinant hman c"tokines to stimlate granloc"te progenitor cells has
been stdied as an ad8nct to antibiotic therap". 2t has shown promise in animal models$
especiall" %or BB- sepsis$ bt pretreatment or immediate treatment is re<ired to demonstrate its
[Type text]
e%%icac". !he se o% granloc"te-macrophage colon"-stimlating %actor &B;-5-E' and
granloc"te colon"-stimlating %actor &B-5-E' has been stdied in clinical trials$ bt the se o%
these agents in clinical neonatolog" remains e)perimental.
4iet
Becase o% gastrointestinal &B2' s"mptoms$ %eeding intolerance$ or poor %eeding$ it ma" be
necessar" to give the neonate nothing b" moth &nil per os1 3A?' dring the %irst da"s o%
treatment. 5onsider parenteral ntrition to ensre that the patientUs intake o% calories$ protein$
minerals$ and electrol"tes is ade<ate dring this period.
Eor the in%ant whose condition is seriosl" compromised$ %eeding ma" be restarted via a
nasogastric tbe Eor most in%ants$ breast milk is the enteral diet recommended b" the American
Academ" o% Aediatrics &AAA'.
Arevention
!he 5ommittee on 2n%ectios 4iseases o% the AAA recommends that obstetric care inclde a
strateg" %or managing earl"-onset BB- disease. 7omen with BB- bacteriria shold be treated
dring pregnanc" when the condition is diagnosed and dring the intrapartm period. !he
committee also recommends that women who have previosl" given birth to an in%ant with
invasive BB- disease receive antibiotic proph"la)is dring labor and deliver".
!o minimi6e the risk o% earl"-onset BB- disease$ practitioners shold obtain screening vaginal
and rectal cltres at /5-/7 weeksU gestation in all pregnant women nless the patients have had
BB- bacteriria in the crrent pregnanc" or have previosl" had a child with invasive BB-
disease. 2mplementation o% a screening protocol has led to a signi%icant decrease in the incidence
o% neonatal BB- disease &see the %irst image below'. 0ecommendations have been %ormlated %or
antibiotic proph"la)is regimens &see the second image below'.
[Type text]
2ndications %or intrapartm grop B -treptococcs &BB-'
antibiotic proph"la)is. 0ecommended regimens %or intrapartm antimicrobial
proph"la)is %or perinatal grop B -treptococcs &BB-' disease prevention.
?ther methods o% preventing late-onset sepsis$ particlarl" in the preterm neonate$ are nder
investigation. Administration o% lacto%errin$ the ma8or whe" protein in mammalian milk$ is
thoght to have properties that contribte to innate immne host de%enses.
929:
5onsltations
An in%ectios disease consltation is se%l$ especiall" i% the in%ant is not responding to
treatment$ is in%ected with an nsal organism$ or has had a complicated clinical corse. 2%
neonatal meningitis is identi%ied$ consltation with a pediatric nerologist ma" be necessar" %or
assistance with otpatient %ollow-p o% nerologic se<elae. 2npatient consltation ma" be
necessar" i% meningitis is complicated b" sei6res.
5onsltation with a pediatric pharmacologist ma" be help%l %or obtaining advice on the most
appropriate antibiotic or dosage to se i% changes in the drg regimen prove necessar" becase o%
inade<ate or to)ic drg levels obtained with therapetic monitoring. A pediatric srgical
consltation ma" be necessar" i% sepsis is complicated b" abscess$ i% the di%%erential diagnosis
incldes necroti6ing enterocolitis &3@5'$ or i% central line placement is re<ired.
Iong-!erm ;onitoring
!he primar" care provider &A5A' shold evalate the in%ant with neonatal sepsis within * week
o% discharge %rom the hospital. !he in%ant can be evalated %or sperin%ection and bacterial
coloni6ation associated with antibiotic therap"$ especiall" i% the therap" was prolonged. !he A5A
shold evalate growth and determine whether the %eeding regimen and activit" have retrned to
normal.
!he >oint 5ommission on 2n%ant (earing o% the AAA recommends that in%ants who received
aminogl"cosides shold receive %ollow-p adiolog" testing$ in addition to adiolog" screening
[Type text]
be%ore hospital discharge. -creen these in%ants at / monthsVbt no later than 6 monthsVa%ter
discharge to determine whether damage has occrred.
2% neonatal sepsis was associated with meningitis$ prolonged h"po)ia$ e)tracorporeal membrane
o)"genation therap"$ or brain abscess %ormation$ the in%ant shold be observed %or several "ears
to assess nerodevelopment. 2% problems are %ond$ the child shold receive appropriate earl"
intervention services and therapies.