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Clin Chem Lab Med 2011;49(2):297–302
2011 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2011.048
Non-infectious conditions and gestational age influence
C-reactive protein values in newborns during the first
3 days of life
Nora Hofer*, Wilhelm Müller and Bernhard Resch
Research Unit for Neonatal Infectious Diseases and
Epidemiology, Division of Neonatology, Department of
Pediatrics and Adolescent Medicine, Medical University of
Graz, Graz, Austria
Abstract
Background: Our aim was to analyze C-reactive protein
(CRP) values in term and preterm infants and correlate
non-infection-associated increases with various neonatal
disorders.
Methods: Retrospective cohort study that included all new-
borns hospitalized at a tertiary care center between 2004 and
2007 with documented CRP values in the first 3 days of life.
Analysis of differences in CRP values between term and
preterm newborns and cases with CRP increases in sepsis
negative newborns.
Results: For diagnosis of blood culture proven sepsis (19
and 14 cases, respectively) in 353 preterm and 179 term
newborns, CRP at a cut-off of 8 mg/L had sensitivities of
53% and 86% and specificities of 91% and 88%, respective-
ly. The area under the receiver operating characteristics
curves were 0.799 and 0.890, respectively. Preterm newborns
had lower median values compared to term newborns in sep-
sis positive (9 vs. 18.5 mg/L, p-0.001) and negative new-
borns (0.5 vs. 2 mg/L, p-0.001). Increases in individuals
without infection were correlated significantly with meco-
nium aspiration syndrome and surfactant application in term
newborns (ps0.009 and 0.025, respectively) and with sur-
factant application and higher birth weight in preterm new-
borns (p-0.001 and 0.031, respectively).
Conclusions: CRP values were significantly lower in pre-
term compared to term newborns, and its application in the
diagnosis of sepsis in preterm newborns was not as reliable
as in term newborns. Meconium aspiration syndrome, sur-
factant application, and high birth weight were associated
significantly with increased CRP values.
Keywords: C-reactive protein; meconium aspiration syn-
drome; neonatal sepsis; surfactant; term and preterm
newborn.
*Corresponding author: Dr. Nora Hofer, Division of Neonatology,
Pediatric Department, Medical University of Graz,
Auenbruggerplatz 30, 8036 Graz, Austria
Phone: q43 316 385 81134, Fax: q43 316 385 2678,
E-mail: norahofer@gmx.net
Received April 18, 2010; accepted September 15, 2010;
previously published online December 3, 2010
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Introduction
Early onset sepsis (EOS) of the newborn is a serious diag-
nosis, with a reported incidence of 1–8 per 1000 live births
(1–3). The fear of missing and not treating a newborn with
suspected bacterial infection probably explains why the most
common discharge diagnosis in neonatal special care nurs-
eries is ‘‘rule out sepsis’’ (1). Additionally, antibiotics are
the most prescribed drugs in neonatal intensive care units
(4). Infants who receive antibiotics for more than 3 days are
at greater risk for abnormal bacterial colonization and for
increasing emergence of resistant organisms (5). Among
extremely low birth weight infants, prolonged antibiotic ther-
apy was recently shown to be associated with an increased
risk of necrotizing enterocolitis and/or death, with one infant
dying for every 21 infants treated unnecessarily for more
than 5 days (6).
Since its discovery by Tillet and Francis (7) in 1930, C-
reactive protein (CRP) is now one of the standard parameters
in the work-up of neonatal sepsis and has been described by
Da Silva as probably the best available single test for the
diagnosis of neonatal sepsis (2).
Although the diagnostic accuracy of CRP in the diagnosis
of sepsis in newborns has been evaluated, there are some
important details that have not been well addressed in the
literature. In this study, we aimed to analyze the influence
of gestational age on the diagnostic accuracy of CRP and to
examine neonatal disorders potentially influencing CRP val-
ues in EOS negative newborns during the first 3 days of life.
Materials and methods
Setting
This was a retrospective study based on chart and database review.
All newborns hospitalized between 2004 and 2007 at the neonatal
intensive care unit of the Pediatric Department of the Medical Uni-
versity of Graz, a tertiary care center, were analyzed. Data was
collected for the first 72 h of life by analyzing medical reports, case
histories and the electronic patient filing system (‘‘MEDOCS’’),
which includes perinatal data and detailed results of all clinical
examinations performed every 2–4 h during hospitalization. All
clinical, perinatal and laboratory data were cross checked to insure
the accuracy of the data.
Study population
Inclusion criteria were hospitalization within the first 72 h of life
with documented CRP values. Exclusion criteria were missing val-
ues of CRP in the first 72 h of life, incomplete data necessary for
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298 Hofer et al.: Elevated CRP values in term and preterm newborns
the definition of EOS or malformations or congenital anomalies
requiring surgical treatment and transfer to the department of pedi-
atric surgery. For analysis of the influence of gestational age on the
diagnostic accuracy of CRP, a group of true EOS positive newborns
and a control group were formed using all newborns with blood
culture positive sepsis and all other newborns, excluding those with
probable clinical sepsis or unclear infection status with negative
blood culture. Unit policies regarding algorithms for the work-up of
sepsis and antibiotic treatment did not change during the study
period.
Definition of sepsis
EOS was defined as a positive blood culture in cases of clinically
suspected sepsis during the first 3 days of life. Blood cultures were
performed on every patient with suspected infection. Blood for cul-
ture was obtained from a peripheral vein or, if available, from a
central venous catheter at the time of catheter insertion before start-
ing antibiotic treatment. Infants were considered to have proven
sepsis if a culture yielded pathogenic bacteria. Bacteria recovered
in cultures were considered to be pathogenic unless it consisted of
normal skin or upper respiratory flora. Cases of suspected sepsis
with negative cultures were excluded from the analyses; for exam-
ple, newborns with three or more clinical signs of sepsis with either
positive maternal risk factors or a negative laboratory sepsis screen.
Clinical signs of sepsis included: a) respiratory symptoms (apnea,
tachypnea, retractions, cyanosis, respiratory distress); b) cardiocir-
culatory symptoms (tachy- or bradycardia, arterial hypotonia);
c) neurological symptoms (lethargy, irritability, seizures); d) hypo-
or hyperthermia (core temperature -36.08C or )38.58C); e) poor
skin color or prolonged capillary refilling time )2 s (8, 9). Maternal
risk factors were preterm rupture of membranes ()18 h for term
newborns), intra-amniotic infection and fever during labor (10). For
a positive laboratory sepsis screen, at least two of four measured
parameters had to be out of the normal range: C-reactive protein
)8 mg/L, white blood cell count )34,000/mL or -9000/mL,
absolute neutrophil count )14,400/mL or -7000/mL (-2000/mL
in the first 24 h of life), immature to total neutrophil ratio )0.2
(11, 12). Thus, the reference group consisted of all EOS negative
newborns with a negative blood culture, fewer than three clinical
signs and/or negative maternal risk factors with a negative labora-
tory sepsis screen.
Determination of CRP
CRP was measured using the immunoturbidometric method with
the Tina-quant CRP kit (Roche Diagnostics GmbH, Mannheim, Ger-
many). The limit of detection was 1 mg/L. The cut-off threshold
for CRP was 8 mg/L (11). CRP measurements were performed as
part of the initial laboratory examination and were repeated, when
needed, in cases of suspicion of infection or for controlling the
response to antibiotic therapy. All measurements performed during
the first 72 h of life were included.
Statistical analysis
Statistical analysis was with SPSS version 17 (SPSS Inc., 2008,
Chicago, IL, USA) and Microsoft Excel 2007 (Microsoft Corpora-
tion, 2007, Redmond, USA). The incidence EOS and for cases of
CRP increases were calculated as well as sensitivity, specificity, pos-
itive and negative predictive values, and likelihood ratios with 95%
confidence intervals, and area under the receiver operating charac-
teristics (ROC) curve for predicting EOS in term ()37 weeks ges-
tational age) and preterm infants (F37 weeks’ gestational age). For
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this part of the analysis, where multiple CRP determinations were
performed in a single patient, the highest value was used. For cal-
culation of the median and 90th and 95th percentiles of CRP con-
centrations in groups of EOS positive and negative term and preterm
infants, we used the median of all CRP values measured in each
infant. Proportions were compared using the x2-test. The Mann-
Whitney test was used for comparing CRP values between term and
preterm newborns.
In the group of EOS negative newborns, the association of dif-
ferent neonatal diagnoses with increased CRP values was calculated
for term and preterm infants using the odds ratio with 95% confi-
dence intervals. Diagnoses included clinically silent meconium
staining of amniotic fluid, meconium aspiration syndrome (MAS,
symptoms of respiratory distress in newborns after delivery through
meconium stained amniotic fluid), severe (Apgar at 1 min: F3) and
moderate (Apgar at 1 min: 4–6) birth asphyxia, transient respiratory
distress syndrome/wet lung/aspiration of amniotic fluid, idiopathic
respiratory distress syndrome (IRDS) grade I–II and III–IV (symp-
toms of respiratory distress with compatible radiographic findings
on the chest X-ray), the application of surfactant (done either in
mechanically ventilated newborns or by transient intubation), and
syndrome of persistent fetal circulation (elevated pulmonary vas-
cular resistance and right-to-left shunting at the ductus arteriosus).
Multivariate linear regression analysis with stepwise variable selec-
tion was performed for term and preterm newborns including CRP
concentrations as an outcome variable and the diagnoses mentioned
above as predictor variables. In addition, gestational age at birth in
weeks and birth weight in grams were added as predictor variables.
CRP values were distributed with a tail to the right, but the loga-
rithm of value was approximately normally distributed. Therefore,
regression analysis was performed after log-transformation of CRP
values. Statistical significance was set at p-0.05.
Results
Of 863 newborns hospitalized during the study period, 152
had to be excluded because of missing CRP values. These
were primarily newborns with minor disorders who did not
have a complete sepsis work-up performed, and newborns
with congenital malformations with early transfer to pediatric
surgery. Twenty-one newborns were excluded because of
missing clinical or laboratory data. One hundred and fifty-
eight newborns had clinically suspected sepsis with negative
cultures and were not included in the final analysis. Thus,
the study population was comprised of 532 newborns with
a median gestational age of 34 (range 23–43) weeks and a
median birth weight of 2270 (500–5215) g. 179 newborns
(34%) were term and 353 (66%) were preterm. Perinatal data
are presented in Table 1.
Blood culture proven EOS was diagnosed in 33 newborns
(6%), with Group B streptococci being the most frequently
isolated pathogen (58%); 499 newborns were EOS negative
(94%). A total of 797 CRP samples were eligible for eval-
uation, with 59 being from EOS positive newborns.
CRP had a sensitivity, specificity, and positive and nega-
tive predictive values of 67% (95% confidence interval 48%–
82%), 88% (85%–91%), 27% (18%–38%) and 98% (96%–
99%), respectively, for then diagnosis of culture proven EOS.
Sensitivity, likelihood ratio, and area under the receiver oper-
ating characteristics curve in preterm vs. term newborns were
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Hofer et al.: Elevated CRP values in term and preterm newborns 299

Table 1 Perinatal data of study patients.a

Total study population 532 (100)

Birth weight, g 2270 (500–5215)
Gestational age, weeks 34 (23–43)
Gestational age -28 weeks 39 (7)
Gestational age 28–32 weeks 150 (28)
Gestational age 33–37 weeks 164 (31)
Gestational age )37 weeks 179 (34)
Gender (male:female) 290:242 (54:46)
Small for gestational age 54 (10)
Singletons:twins:triplets 420:100:12 (80:19:2)
Apgar 1 8 (0–10)
Apgar 5 9 (3–10)
Main reasons for admission (multiple nominations possible)
Prematurity 353 (66)
Symptoms of respiratory distress 467 (88)
Need for oxygen application, non-invasive or invasive mechanical ventilation 366 (69)
Asphyxia 113 (21)
Observation after maternal risk factors for sepsis 107 (20)
Main discharge diagnoses (multiple nominations possible)
Prematurity 353 (66)
IRDS 198 (37)
Delayed postpartum adaptation 194 (36)
Asphyxia 113 (21)
Wet lung 58 (11)
Meconium staining of the amniotic fluid/meconium aspiration syndrome 43 (8)
Blood culture proven sepsis 33 (6)
a
Data are presented as median (range) or number (%).

53% (29%–76%) vs. 86% (57%–98%), 4.6 (3.2–6.6) vs. 6.1
(3.8–9.7), and 0.799 (0.674–0.923) vs. 0.890 (0.831–0.950),
respectively. ROC analysis is shown in Figure 1. When cal-
culating the Youden Index (sensitivityqspecificity–1 for
each cut-off used in ROC-analysis), the highest value was
reached at a cut-off of 5.5 mg/L in preterm newborns (sen-
sitivity and specificity 74% and 86%, respectively) and
10.5 mg/L in term newborns (86% and 84%, respectively).
Preterm newborns had lower median CRP values in the
group of EOS positive (9 vs. 18.5 mg/L, p-0.001) and
negative infants (0.5 vs. 2 mg/L, p-0.001, see Table 2).
Exogenous factors possibly accounting for the observed dif-
ferences in the pre- and postnatal diagnoses and specific
management in preterm and term newborns are listed in
Table 3.
For the 499 EOS negative newborns, 60 (12%) had CRP
above 8 mg/L, with 29 of being preterm and 31 being term.
The majority had slightly increased concentrations up to
20 mg/L (76% of preterm and 48% of term newborns).
The x2-test showed that increased CRP concentrations
were associated significantly with meconium aspiration syn-
drome in term and with severe IRDS III–IV, and with the
application of surfactant in preterm newborns (p-0.001).
Detailed results for groups segregated according to gesta-
tional age; -28, 28–33, 34–37, )37 weeks are shown as
Supplemental material. Regression analysis showed CRP
values to be directly associated with application of surfactant
wregression coefficient 0.798 (95% confidence interval
0.533–1.064), p-0.001x and higher birth weight w0.0003
(0.00002–0.0004), ps0.031x, but not with IRDS in preterm
newborns and MAS w1.482 (0.377–2.568), ps0.009x and
surfactant application w1.070 (0.137–2.003), ps0.025x in
term newborns.
Discussion
Several trials report successful reductions in the duration of
antibiotic therapy based on CRP (13–15). In this study, we
showed different responses in CRP to infection in preterm
and term newborns, with CRP being associated with non-
infectious diagnoses, i.e., meconium aspiration syndrome and
application of surfactant, and higher birth weight.
Although CRP is well characterized for the diagnosis of
sepsis in the newborn, there are few studies evaluating its
correlation with gestational age (16–18). To the best of our
knowledge, this is the most comprehensive study on this
topic. We found that CRP was less reliable for early onset
of infection in preterm compared to term newborns, with a
lower area under the receiver operating characteristics curve
and lower median CRP values. Our data suggests a possible
benefit for diagnosis of EOS in preterm newborns by the use
of lower cut-off values. However, our retrospective single
center study needs to be repeated in a prospective trial.
In order to explain the observed differences in CRP
response to infection between preterm and term newborns,
we looked for differences in pre- and postnatal care, accom-
panying diseases, and blood collection (see Table 3). We
interpret the observed differences (i.e., more frequent mater-
nal risk factors, elevated maternal inflammatory markers, and

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300 Hofer et al.: Elevated CRP values in term and preterm newborns

response might be lower due to preterm newborns having a

Figure 1 Receiver operating characteristics curves for CRP in the
diagnosis of blood culture proven EOS in preterm and term newborns.
Sensitivity is plotted against (1-specificity) for each measured serum
CRP value during the first 3 days of life as cut-off value for preterm
newborns (ns353, 19 EOS positive) and term newborns (ns179,
14 EOS positive).
IRDS grade I–II in preterm newborns) as being age-specific
and without direct correlation to CRP. As far as endogenous
immune response depends on gestational age, the CRP
less mature immunological system.
To the best of our knowledge, this is the most compre-
hensive study on perinatal conditions confounding neonatal
serum CRP concentrations. We showed that CRP is a specific
marker of infection, although non-infectious conditions also
resulted in increases.
Our study shows a highly significant correlation of MAS
with high CRP concentrations. Meconium is known to irri-
tate the airways and lung parenchyma, resulting in a diffuse
pulmonary inflammation with release of proinflammatory
cytokines (19). Clear guidelines for the management of sick
neonates with established MAS are lacking, and although
prophylactic antibiotics are not justified, most of these
patients receive these during the first days of life (20).
In this study the application of surfactant was associated
with increased CRP values. CRP increases following the
administration of exogenous surfactant has been described
previously, particularly with use of natural porcine surfactant
(21–23) which is used in our neonatal intensive care unit.
We hypothesize that interaction with foreign proteins might
trigger a non-infectious inflammatory response. However,
further studies are needed to describe the pathophysiology.
There are certain limitations of this study that need to be
noted. This is a retrospective study performed at a single
center analysis that included patients enrolled over a large
period of time. Therefore, results can only be extrapolated,
with caution, to center-specific characteristics. Further, pro-
spective evaluations are needed before guidelines or recom-
mendations for clinical practice can be given. We used
positive blood cultures as diagnostic criterion for EOS, as
they are generally accepted as the gold standard. However,
they are known to lack sensitivity (24), and obtaining cul-
tures from neonates can be difficult as sample volumes are
small and a substantial number of cultures are contaminated
or negative (25). As a result, for our study the number of
culture positive newborns is limited and the true infection

Table 2 Median CRP values and 90th and 95th percentiles of CRP values (mg/L) in EOS positive and negative term and preterm newborns
during the first 72 h of life.

0–72 h 0–24 h 25–48 h 49–72 h

GA -37 weeks
EOS Median 0.5 0.0 1.0 0.0
Negative 90th P. 5.8 5.0 8.1 5.7
ns334 95th P. 9.0 8.0 11.0 12.8
EOS Median 9.0 6.0 6.0 9.0
Positive 90th P. 34.3 26.8 36.0 31.0
ns14 95th P. 40.4 41.3 48.4 50.0
GA )37 weeks
EOS Median 2.0 0.0 2.6 2.0
Negative 90th P. 14.9 7.3 23.6 18.0
ns165 95th P. 26.2 13.8 49.6 26.7
EOS Median 18.5 9.0 32.0 18.0
Positive 90th P. 54.6 50.5 106.4 128.0
ns19 95th P. 98.6 62.0 150.4 154.7
Undetectable values -1 mg/L were given the value 0 mg/L. GA, gestational age.

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 Table 3 Comparison of preterm and term EOS positive and negative newborns with respect to differences potentially accounting for the differences in CRP concentrations.

EOS negative newborns EOS positive newborns

% of preterm newborns (ns334)/ p-Value % of preterm newborns (ns19)/ p-Value
% of term newborns (ns165) % of term newborns (ns14)
Positive maternal risk factorsa 25/7 -0.001 53/7 -0.01
Elevated maternal inflammatory markers prior to deliveryb 14/2 -0.001 74/7 -0.001
Vaginal group B streptococci colonization 7/5 0.46 32/64 0.06
Antibiotic therapy of the mother prior to delivery 20/7 -0.001 53/29 0.17
Meconium staining of the amniotic fluid 3/13 -0.001 5/29 0.06
Moderate asphyxia (Apgar 1: 4–6) 17/12 0.17 32/14 0.25
Severe asphyxia (Apgar 1: 0–3) 6/4 0.42 11/0 0.21
IRDS I–II 35/8 -0.001 53/14 0.02

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IRDS III–IV 14/0 -0.001 26/29 0.89
Persistent fetal circulation syndrome 0/1 0.21 11/7 0.74
Meconium aspiration syndrome 0/4 -0.001 0/0 n.c.
-0.001

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Application of surfactant 25/6 63/43 0.25

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Need for oxygen application or mechanical ventilation 74/55 -0.001 95/79 0.16
Arterial hypotension 15/8 0.02 47/50 0.88
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Median preterm/term newborns Median preterm/term newborns

CRP: Timing of first blood sampling (day of life) 1/1 0.031 1/1.5 0.071
CRP: Number of samples per patient 1/1 0.951 2/2 0.815
a
Premature rupture of membranes, intra-amniotic infection, or fever during labor. bCRP )8 mg/L or white blood cell count )11.3=109/L.
Hofer et al.: Elevated CRP values in term and preterm newborns 301
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302 Hofer et al.: Elevated CRP values in term and preterm newborns
rate is probably underestimated. Using a larger cohort of
patients, results might have been more conclusive and sig-
nificant differences more evident. We chose to exclude all
cases of clinically suspected that were not confirmed by cul-
ture. In this way a reliable group of true sepsis positive new-
borns was formed. However, by excluding ‘‘gray zone’’
cases, the values for sensitivity and specificity are probably
unrealistically high and cannot be extrapolated to clinical
practice.
Procalcitonin and interleukins represent further potential
infection markers in the newborn. In our population, they
were available only in single cases. Therefore, it was not
possible to include them in the analysis. An exact character-
ization including potential confounders and accuracy in dif-
ferent gestational ages is an important factor for a proper
application. In view of their growing use and availability,
emphasis should be given to further studies in this field.
In conclusion, we found an association of surfactant appli-
cation and MAS in term newborns, and with surfactant appli-
cation and higher birth weight in preterm newborns with
increased CRP values but without evidence of bacterial
infection. Preterm newborns had lower CRP responses to
infection compared to term newborns. However, further
prospective analyses are needed to confirm our results.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that
there are no conflicts of interest regarding the publication of this
article.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
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