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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
92:
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
[Type text]
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 *..$...'
had abnormal nerological otcomes at the time o% discharge.
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[Type text]
Csing these data$ 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
[Type text]
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.
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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.
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[Type text]
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.
96:
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.
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.
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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.
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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.
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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 ;?;.
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2t has been shown to redce
the need %or invasive diagnostic procedres sch as amniocentesis and cordocentesis b" more
than 7.D.
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;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.
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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:
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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.