ARTICLE

Immune Status in Very Preterm Neonates

AUTHORS: Mallika Azizia, MD, MRCOG,a Jillian Lloyd, MD,
MRCOG,a Meredith Allen, FRACP, FRCPCH, PhD,b Nigel Klein,
MRCP, PhD, FRCPCH,b and Donald Peebles, MD, FRCOGa
aInstitute for Womens Health, and bInstitute of Child Health,
University College London, London, United Kingdom

KEY WORDS
preterm delivery, cytokines, immune response, sepsis,
inammation
ABBREVIATIONS
hCAhistological chorioamnionitis
ILinterleukin
IUGRintrauterine growth restriction
LPSlipopolysaccharide
MHCmajor histocompatibility complex
PPROMpreterm premature rupture of membranes
PTLpreterm labor
TNFatumor necrosis factor a
Drs Peebles and Klein conceived and designed the study; Drs
Azizia and Lloyd acquired consent and recruited women,
extracted the clinical data, collected the samples, and
performed assays; Drs Allen and Azizia did data analysis
including statistical analysis; Drs Azizia, Klein, and Peebles
interpreted the data; and Drs Azizia, Lloyd, Allen, Klein, and
Peebles drafted and approved the manuscript.
www.pediatrics.org/cgi/doi/10.1542/peds.2011-1579
doi:10.1542/peds.2011-1579
Accepted for publication Dec 7, 2011
Address correspondence to Donald Peebles, MD, FRCOG, Institute
for Womens Health, University College London, 2nd Floor Medical
School Building, 74 Huntley St, London WC1E 6AU, United Kingdom.
E-mail: d.peebles@ucl.ac.uk
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
FUNDING: This work was funded by project grant 03UCL01 from
SPARKS (Sport Aiding medical Research for Kids) charity. The
study was undertaken at University College London Hospitals/
University College London, which received a proportion of
funding from the Department of Healths National Institute for
Health Research Biomedical Research Centres funding scheme.
Dr Aziza is registered as a PhD student with the University
College London, United Kingdom.

WHATS KNOWN ON THIS SUBJECT: The very preterm neonate is

more susceptible to bacterial infection; this is thought to be due
to immaturity of the innate immune response.
WHAT THIS STUDY ADDS: Monocytes have an anti-inammatory
prole at birth and are hyporesponsive to inammatory stimuli in
fetuses born very prematurely. This reects the response to the
pro-inammatory events leading to preterm birth as well as
gestational immaturity.

abstract
OBJECTIVES: Preterm neonates are at increased risk of sepsis compared with those born at term. We investigated immune status at
birth and early neonatal life in very preterm neonates and its association with short-term outcomes.
METHODS: Prospective observational study conducted at a university
hospital recruiting 113 preterm neonates (2332 weeks) and 78 controls. Monocyte major histocompatibility complex (MHC) class II expression, serum, and ex vivo lipopolysaccharide stimulated levels of
six cytokines (tumor necrosis factor a, interleukin (IL)-1b, IL-6, IL-8, IL10, and IL-12p70) were measured in umbilical cord blood and over
the rst 7 days. The presence of neonatal sepsis and histologic
chorioamnionitis was recorded.
RESULTS: Prematurity (preterm labor and preterm premature rupture
of membranes cohorts), neonatal sepsis, and histologic chorioamnionitis were associated with signicant reduction in monocyte MHC class
II expression. Neonates who had evidence of subsequent protracted
sepsis had low levels of MHC class II expression at birth. Serial monocyte MHC class II expression revealed a fall by day 2, in all preterm
neonates, with the degree being inuenced by both prematurity
and sepsis, and incomplete recovery by day 7, suggesting immunoparalysis in preterm premature rupture of membranes and preterm labor
cohorts. Whole blood lipopolysaccharide stimulation assay showed signicantly lower tumor necrosis factor a, values in preterm neonates
who subsequently developed sepsis indicating a degree of immunoparalysis.
CONCLUSIONS: Our data support the concept that fetal exposure to
inammation before preterm delivery leads to subsequent endotoxin
hyporesponsiveness (immunoparalysis), which increases the risk of
subsequent sepsis and associated organ dysfunction. Pediatrics
2012;129:e967e974

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Preterm birth remains 1 of the main

causes of perinatal mortality and longterm morbidity despite advances in
neonatal intensive care.13 Sepsis has
a large contribution to perinatal mortality and morbidity in this setting.46
Susceptibility to bacterial infections is
thought to be due to immaturity of the
innate immune system and organs.710
Recently it has been shown that the
immune response to a microbial stimulus is biphasic with an early proinammatory phase and a later antiinammatory phase, thought to help
regulate the potentially deleterious
effects of the initial inammatory reaction.1113 The second phase, also
termed immunoparalysis, can be profound and is characterized by decreased
monocyte major histocompatibility
complex (MHC) class II expression,
suboptimal functional response of
monocytes to endotoxin (tumor necrosis factor a [TNFa]), and elevated
anti-inammatory cytokines, including
interleukin (IL)-10. We and several
other groups have previously described
the presence and effects of immunoparalysis in several clinical settings including sepsis,14,15 severe trauma,16
stroke,17 postcardiac surgery,18 burns,19
pancreatitis,20 and preterm labor.21
Also we and others have shown that
bacterial colonization of the choriodecidual space leads to chorioamnionitis
and that chorioamnionitis is associated with preterm labor (PTL), preterm

premature rupture of membranes

(PPROM), and development of subsequent neonatal sepsis.710,2224 On this
basis, we hypothesized that exposure to
the pro-inammatory environment associated with preterm birth would lead
to fetal and neonatal immune paralysis,
rendering the neonate more susceptible to bacterial infection. To investigate
this hypothesis, we measured monocyte
MHC class II expression and circulating
cytokine levels in very preterm infants
from birth to 7 days of age. The inuence
of gestation, antenatal inammation
(histologic chorioamnionitis), and mode
of delivery on monocyte function and
class II expression were assessed and
related to clinical and laboratory indices
of neonatal sepsis.

METHODS
Patient Selection
One hundred ninety-one infants were
recruited in this prospective observational study conducted at University
College London Hospitals (October 2003
to September 2007) approved by the
University College London/University
College London Hospitals Research
Ethics Committee (the study groups are
dened in Table 1). There were no major changes in the clinical indications
for preterm delivery over this time
period. Recruitment and the assays
were performed by a clinical research
fellow who was independent of the
clinicians caring for infants or mothers

and the pathologist performing routine

clinical tests. These individuals were in
turn blinded to the cytokine and cord
monocyte MHC class II expression data.
We excluded neonates with known
congenital anomalies (except feticide
cohort) or with a history of maternal
complications, namely, immunosuppressive disorders, gestational diabetes mellitus, or preexisting diabetes
mellitus and retroviral infection. Clinical signs and laboratory evidence
(white cell count, C-reactive protein,
and blood cultures) of infection were
routinely sought in preterm infants.
Neonates were classied as having
sepsis (presumed or proven) at 3 times
(early onset 03 days, onset within 07
days, and late onset 728 days of life)
by using recently dened consensus
criteria.25 In summary, sepsis is dened as evidence of a systemic inammatory response in the presence
of suspected or proven infection. Systemic inammatory response is the
presence of at least 2 of 4 altered
physiologic variables (temperature,
heart rate, respiratory rate, leukocyte
abnormalities) of which 1 must be either abnormal temperature or leukocyte count. Infection is either suspected
(clinical syndrome associated with
a high probability of infection, positive
ndings on examination, imaging, or
laboratory test including elevated
C-reactive protein) or proven (positive
bacteriological culture). Neonates were
classied as having sepsis at 3 times

TABLE 1 Demographic Details of the Cohorts of Neonates Included in This Study

Cohorts

Term Labor

Term LSCD

Feticide

IUGR

PTL

PPROM

n
Gestation, d
Birth wt, g
Gender Male, %
Singleton, %
Vaginal delivery, %
hCA, %
Neonatal sepsis (1st wk), n (%)

33
282 (279289)
3450 (30903800)
51.5
100
100

2 (6)

25
272 (269275)
3270 (31003580)
60
100
0

5 (20)

20
164.5 (161178)

90

13
201 (194212)
863 (6301030)
69
84.6
0
0
7 (53.8)

42
186 (172199)
952 (7391265)
37
57
82
44.8
16 (45.7)

48
191 (177208)
903 (7091360)
64.4
73.3
72
71.1
28 (62.2)

The cohorts were as follows (1) term neonates delivered by spontaneous vaginal delivery, (2) term neonates delivered by elective lower-segment caesarean delivery (LSCD); (3) fetuses
undergoing feticide before termination of pregnancy in the second or third trimesters for fetal abnormality, (4) neonates delivered prematurely (,32 weeks gestation) because of known
intrauterine growth restriction (n = 13), and (5) neonates born following preterm labor or PPROM at ,32 completed weeks gestation (up to 23 wk). The median and interquartile ranges for
both gestational age and birth wt are shown.

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(early onset 03 days, onset within 07

days, and late onset 728). Histologic
chorioamnionitis was determined from
examination of placentas.
Measurement of Monocyte MHC
Class II Expression

concentrations were assayed by using

the cytometric bead array kit as described earlier. Whole blood lipopolysaccharide (LPS) stimulated cytokine
response is a surrogate marker of
monocyte cytokine response.
Statistics

A previously optimized dual staining technique was used to determine monocyte MHC class II expression.18,21 Briey,
monocytes were ow sorted after
staining with R-phycoerythrin conjugated antibody to CD14, uorescein
isothiocyanate conjugatedconjugated
antibody to MHC class II and mouse
immunoglobulin G1 antibody raised against keyhole limpet hemocyanin for
MHC class II (Dako, Ely, United Kingdom).

Data analysis was performed by using

Microsoft Excel/Access and Statistical
Package for the Social Sciences version
14 (Chicago, IL) and Sigmaplot program
version 9 (SYSTAT, Washington, DC).
Unless specied, nonparametric MannWhitney U test was used to identify
statistical signicance. x 2 test was
used for testing the association of
variables in a 2 by 2 table format.

Cytokine Measurement

RESULTS

Whole blood was spun at 1200 g for 10

minutes, and plasma was stored at
70C in aliquots. Frozen aliquots were
thawed immediately before analysis.
TNFa, IL-1b, IL-6, IL-8, IL-10, and IL-12p70
were assayed by using a commercially
available BD Cytometric Bead Array
Human Inammation Kit (BD Bioscience, Oxford, United Kingdom) per
manufacturers recommendation (test
performance available from manufacturer). Data were analyzed by using
manufacturers supplied BD CBA software (BD Bioscience). The sensitivity of
the assay was 3 pg/mL for TNFa, IL-6, IL8, IL-10, and IL-12p70, and 100 pg/mL for
IL-1b.
Whole Blood Lipopolysaccharide
Stimulation Assay
Whole blood and controls were incubated with an equal volume of RPMI1640 with L-glutamate and 100 ng/mL of
Escherichia coli 0111.B4 lipopolysaccharide (Sigma, Poole, United Kingdom)
for 24 hours at 37C in 5% CO2. Supernatant was removed and frozen at 70
C in aliquots until later use to avoid
interference with assay results from
repeated freeze-thaw cycles. Cytokine

Patient Characteristics
Onehundred and ninety-oneinfantswere
recruited to the study; data on 10 were
not included because early death meant
that insufcient samples were taken (7
PTL and 3 PPROM neonates). The demographic characteristics and gestational ages oftheparticipantsareshown
in Table 1. Histologic chorioamnionitis
(hCA) was more common in the PPROM
cohort compared with the PTL (P , .05).
Expression of MHC Class II on Cord
Blood Monocytes
At term, there was no effect of mode of
delivery (elective caesarean delivery
and vaginal delivery) on monocyte MHC
class II on cord blood. It is of note that
even in these control groups, there was
a relatively wide range of expression
(from 99.9% to 26.8%; Fig 1).
It was difcult to assess the effect of
gestation on monocyte class II expression because the circumstances of
birth for most premature infants are
not normal and include factors, independent of gestation that might inuence class II expression. We therefore
studied a control cohort of fetuses

having blood taken during feticide for

fetal abnormality. Monocyte MHC class II
expression was found to be signicantly
lower in feticides compared with term
infants. The percentage of monocytes
expressing MHC class II was also signicantly lower in both PTL and PPROM
groups when compared with preterm
controls (feticides). There was no difference between PPROM and PTL groups
(Fig 1).
Cord Blood Monocyte Class II
Expression and hCA
Histologic chorioamnionitis, the presence of an inammatory inltrate in
fetal membranes, acts as a marker of
prenatal exposure to an inammatory/
infectious stimulus. Cord blood monocyte MHC class II expression was
studied in preterm neonates who were
born with or without evidence of hCA
(see Fig 2). Median monocyte MHC class
II expression was signicantly lower in
infants with hCA compared with those
without (P , .05). Interestingly, even the
preterm group without chorioamnionitis had lower MHC class II expression
than the feticide control group (P ,
.05). The cohort with the lowest percent
expression at birth was those preterm
infants that had evidence of hCA and
then went on to develop sepsis in the
rst 3 days of life (n = 13, data not
shown). In contrast, those infants with
no evidence of hCA and who did not
develop early-onset sepsis (n = 13) had
high expression, with levels comparable
to feticide controls (P , .05).
Cord Blood Monocyte MHC Class II
Expression and Evidence of
Neonatal Sepsis
Infants with evidence of sepsis during
the rst week of life already had lower
expression of MHC class II antigen in
their cord blood monocytes than infants
without sepsis (see Fig 3). Of the 58
infants delivered in the term control
groups, 7 were unexpectedly admitted

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Postnatal Changes in Monocyte

MHC Class II Expression

FIGURE 1
Cord blood monocyte MHC class II expression (%, median with interquartile range) in term infants, born
by elective lower segment caesarean delivery (LSCD) or vaginal delivery (Term), and preterm infants
(,32 weeks gestation) born after PPROM, preterm labor, or caesarean delivery for severe IUGR. An
additional cohort of samples from fetuses undergoing feticide (,32 weeks gestation) is also included.
The gures at the bottom of the panels show group size. Symbols indicate signicant differences
between the following groups: * compared with feticide group Mann Whitney P . .05; ** compared with
term, Mann Whitney P , .05; *** compared with feticide group, Mann Whitney P , .01.

to the neonatal unit and treated with

antibiotics for presumed sepsis; these
infants had lower MHC class II expression than nonseptic control infants
(P , .01). A similar pattern was seen in
the preterm groups (PTL and PPROM),
with septic infants showing signicantly lower MHC class II expression on
cord monocytes than those infants that
showed no evidence of sepsis during
the rst week of life (P , .01; see Fig 3).
The link between low monocyte MHC
class II expression in cord blood and
neonatal sepsis was strengthened by
additional data looking at the length of
antibiotic use as a surrogate marker of
protracted clinical sepsis. Overall,
preterm neonates requiring more than
10 days of antibiotics (n = 17) had
signicantly lower cord blood monocyte MHC class II expression compared
with preterm neonates requiring less
e970

than 10 days of antibiotic (n = 27) median 34.5% (27.956.0) vs 70.4% (61.8

81.8, P = .0001); the ndings were
similar when PTL and PPROM groups
were analyzed individually.
Chorioamnionitis Is Associated
With Sepsis in Preterm Neonates
Of the 90 neonates recruited into the PTL
and PPROM groups, 72 had histologic
assessment of their placenta as well as
clinical data in the rst week of life.
Neonatal septicemia was strongly associated with the presence of hCA. Fiftysix percent (25/45) of neonates born
with hCA developed sepsis within 72
hours compared with 19% (5/27) of
neonates born with no hCA (odds ratio:
5.5; 95% condence interval: 1.816.5).
Histologic chorioamnionitis was evident in 47.5% and 62.2% of PTL and
PPROM cases, respectively.

Monocyte MHC class II expression was

determined serially at birth (cord
blood) and on days 1 to 2 (2448 hours)
and day 7 after delivery (Fig 4). The
majority of neonates had $2 measurements in the rst week of life. Feticides served as gestational matched
controls for cord samples. Because
serial samples from feticides are not
possible, serial samples from growthretarded preterm neonates (IUGR)
were used for comparison. IUGR neonates showed comparable cord expression to controls (feticides), followed
by a modest fall in MHC class II expression at 24 to 48 hours; numbers
at day 7 (n = 6) were small, but there
appeared to be a trend toward subsequent recovery of expression to
baseline levels. Both preterm cohorts
revealed a postnatal drop in monocyte
MHC class II expression at 24 to 48
hours of birth that had not returned
fully to baseline levels by day 7. The
effect of sepsis, at any given time point,
was to lower the monocyte MHC class II
expression (data not shown).
Raised Cord Cytokines in Preterm
Neonates
Levels of cytokines were determined in
cord blood in all term and preterm
groups. In the preterm cohorts (PTL and
PPROM, n = 46), the cord IL-6 levels
were signicantly higher (median: 41
pg/mL; interquartile range: 9.5192.8)
compared with gestation matched (1.7
pg/mL [14.3] and term controls 6.8
pg/mL [123.4], P = .0001). Additional
analysis of the preterm cohorts
showed signicantly elevated cord IL-6
levels in those with hCA (77.4 pg/mL;
34.4525.7) compared with those
without hCA (9.8 pg/mL; 7.828.6; P =
.002). Likewise, preterm neonates who
went on to develop sepsis (proven or
suspected) within the rst week of life
had a tendency to have high cord IL-6 at

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birth [97.7 pg/mL; 14.4242) compared

with those who did not (18.3 pg/mL;
7.959.5; P = .08). Interestingly, preterm neonates with no evidence of hCA
still had signicantly elevated cord IL-6
(9.8 pg/mL; 7.828.6) when compared
with gestation-matched controls (1.7
pg/mL; 1.04.3; P = .001). Also, preterm
neonates with no evidence of sepsis in
the rst week of life still had signicantly elevated cord IL-6 when compared
with gestational matched controls (18.3
pg/mL; 7.959.5 vs 1.7 pg/mL; 14.3, n =
22 and 16, respectively, P , .01).
The cord levels of IL-8 and IL-10 closely
mirrored the pattern seen with IL-6. Low
range variations not attaining statistical signicance were seen in the other
cytokines tested (IL-12, TNFa, IL1b).
FIGURE 2
Cord blood monocyte MHC class II expression (%) in preterm neonates (PTL and PPROM groups
combined) with (CA) or without (NCA) evidence of histologic chorioamnionitis. Feticides act as a control
group. Symbols indicate signicant differences between the following groups: ** compared with feticide,
Mann Whitney P , .05; *** compared with NCA group, Mann Whitney P , .01.

FIGURE 3
Cord blood monocyte MHC class II expression (%) in term and preterm infants (born after IUGR, PPROM,
and PTL) with (SEP) or without evidence of sepsis (NS) in the rst week of life. Symbols indicate signicant
differences between the following groups: ** compared with term with no evidence of sepsis Mann
Whitney P , .01; *** compared with PTB with no sepsis, Mann Whitney P , .01.

Whole Blood Response to Endotoxin

Stimulation
Having demonstrated decreased levels
of monocyte MHC class II expression in
the cord blood of fetuses born after
PPROM and PTL, as well as elevated cord
IL-6, we sought to investigate whether
the circumstances leading to preterm
birth affected the functional competency of cord blood monocytes. This was
done by using an ex vivo whole blood LPS
stimulation assay. Feticides had low
levels of TNFa (Fig 5A) and IL-6 (Fig 5B)
compared with term cord blood after
LPS stimulation. Preterm neonates (PPROM
and PTL) also have reduced TNFa output compared with term, but IL-6 production was similar.
TNFa production was reduced in septic
preterm neonates when compared
with feticide (median: 41.3 pg/mL; 31.4
127.9 versus 265.9 pg/mL; 100.7389.3,
P = .045). In contrast, cord IL-6 production was not impaired in infants
that went on to develop sepsis in the
st week. This suboptimal selective
TNFa cytokine response to LPS stimulation suggests immunoparalysis in
preterm neonates (PPROM and PTL)
with sepsis.

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ence of pro-inammatory cytokines in

fetal blood, and the demonstration that
this correlates with the incidence of
major neonatal morbidity suggests
that factors other than immaturity may
be important in determining the outcome of very preterm infants.11 In this
study, we show that even at birth,
preterm infants (born before 32 weeks
gestation) have a lower expression of
MHC class II antigen on their monocytes than those from term infants;
they also have increased circulating
levels of IL-6 and impaired ex vivo
production of TNFa in response to
LPS. These ndings indicate a degree
of immune incompetence in preterm
fetuses.

DISCUSSION

A number of studies suggest that the

innate immune system of preterm
infants is immature.2629 Our nding
that MHC class II expression is lower in
blood taken from fetuses in the second
trimester before termination for fetal
abnormality (feticides) than in those
born at term would be consistent with
this conclusion. Although not a perfect
control group because these fetuses
had a structural abnormality, they
were not delivered preterm. This enabled us to explore the relative contributions of immaturity and preterm
labor on monocyte MHC class II expression. The process of preterm birth
appears to have an additional impact
on monocyte MHC class II expression
because both PTL and PPROM groups
had even lower expression than the
gestation matched feticide group (Fig 1).
A clue was provided by nding lower
MHC class II expression (Fig 2) in cord
blood from fetuses with evidence of an
inammatory response in the placenta/
membranes (hCA).

It has long been thought that complications observed in preterm neonates2,

4 occur because of immature organ
development. However, the identication of a fetal inammatory response
syndrome, characterized by the pres-

Our observation that MHC class II expression is lower in the cord blood of
fetuses born after PTL or PPROM than
gestation matched feticide controls or
iatrogenic preterm birth (IUGR) is consistent with monocytes having been

FIGURE 4
Changes in monocyte MHC class II expression (median %) comparing cord blood (day 0) with samples at
24 to 48 hours (day 2) and 7 days postdelivery. All preterm groups had lower expression on day 2
compared with at birth: IUGR 72.9 (53.587.5, n = 15) vs 34 (28.054.9; n = 7; P , .05), PTL 66.6 (40.680.9,
n = 22,) vs 28.5 (11.460.7, n = 19, P , .05), and PPROM 52.2 (37.966.5, n = 32) vs 34.7 (8.762.6, n = 20,
P , .05). There was no difference (P . .05) between groups on day 7 compared with the same group on
either days 0 or 2.

FIGURE 5
A, TNFa, and B, IL6 concentrations after ex vivo LPS stimulation of whole cord blood in term, feticide, PTL,
and PPROM groups. * Mann Whitney P , .05 compared with term.

Neonatal Survival and Cord Blood

Monocyte MHC Class II Expression
A complete data set was available for
41 preterm neonates (PTL and PPROM,
,32 weeks) of whom there were 36
survivors (.28 days) and 5 neonatal
deaths. In this small cohort, those
neonates who died had a nonsignicant trend toward lower monocyte MHC class II expression than
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survivors (48.1%; 35.780.9 vs 63.5%;

49.380.8).

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exposed to an inammatory stimulus. In

a study in sheep fetuses, Kramer et al
demonstrated that after intra-amniotic
injection of endotoxin, a known cause of
chorioamnionitis, the expression of
MHC class II antigen on fetal blood
monocytes was reduced after 1 day and
was even lower after 3 days.30,31 We
showed that MHC class II expression
was lower 24 to 48 hours after preterm
birth than in cord blood (Fig 4) and may
reect a developing monocyte hyporesponsiveness after exposure to
infection/inammation around the
time of preterm birth.
Two pieces of evidence suggest that
low monocyte MHC class II expression
is of functional signicance. First, we
have shown that neonates born with
low monocyte MHC class II expression
were more likely to be diagnosed with
sepsis and to require treatment with
antibiotics for .10 days. It is particularly striking that this was also
observed in the term group, with 7 of
10 infants born with MHC class II expression in the lowest quartile being

unexpectedly admitted for observation on the neonatal unit for suspected sepsis. Second, we showed
that when whole blood was stimulated with bacterial endotoxin ex
vivo, the production of TNFa was reduced, suggesting monocyte hyporesponsiveness. Other groups have
demonstrated a similar hyporesponsiveness to LPS after exposure to
sepsis3234 and suggested that in
combination with low monocyte MHC
class II expression, this could indicate a degree of immune paralysis.
The timing of MHC class II reduction and
impaired ex vivo cytokine production
would be consistent with an inammatory insult around the time of
delivery. It is tempting to relate these
observations to the presence of bacteria in the fetal membranes and amniotic uid found in women who deliver
preterm.24 However, we do not know
that noninfectious causes of premature labor (eg, placental abruption,
multiple gestation) may not lower
monocyte MHC class II expression.

Additional studies are required to fully

understand our observations.
Our ndings that monocyte MHC class
II expression is reduced in some
infants for at least the rst 48 hours of
life and that these infants are more at
risk for being diagnosed with sepsis
suggest that measurement of monocyte MHC class II expression in cord
blood could be used to identify
a group of infants that might be
particularly at risk for infection and
may be suitable for antibiotics and/or
immune modulation. A similar relationship between late-onset neonatal sepsis and monocyte HLA-DR
expression has recently been described
in term infants.15

CONCLUSIONS
These data support the concept of in
utero origins of neonatal sepsis at least in
the setting of preterm birth. Monocyte
MHC expression in cord blood may have
prognostic value as a robust marker of
fetal exposure to inammation.

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AZIZIA et al

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Immune Status in Very Preterm Neonates

Mallika Azizia, Jillian Lloyd, Meredith Allen, Nigel Klein and Donald Peebles
Pediatrics 2012;129;e967; originally published online March 26, 2012;
DOI: 10.1542/peds.2011-1579
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on August 22, 2015

Immune Status in Very Preterm Neonates

Mallika Azizia, Jillian Lloyd, Meredith Allen, Nigel Klein and Donald Peebles
Pediatrics 2012;129;e967; originally published online March 26, 2012;
DOI: 10.1542/peds.2011-1579

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/129/4/e967.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2012 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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