**6. CRP performance in diagnosis of neonatal sepsis and baseline CRP concentrations differ between term and preterm neonates**

The Role of C-Reactive Protein in the Diagnosis of Neonatal Sepsis 51

61.5 vs. 75 (preterm vs. term neonates)

53 vs. 86 (preterm vs. term neonates

Highest sensitivity in preterm infants at the cut-off 5.5 mg/l

0 vs. 18 15 vs. 52 (<35 weeks vs. ≥35 weeks)

0.2 vs. 2.0 9.0 vs. 26.2 (preterm vs. term neonates)

9.0 vs. 18.5 40.4 vs. 98.6 (preterm vs. term neonates)

By regression analysis mean CRP increased by 6% per week gestational age at delivery (p<.01) and per 2.4% per 100 g

proportion of a pronounced response >60 mg/l increased with gestational age from 8% in newborns from 24 to 27

weeks to 25% in newborns from 40 to 41 weeks.

Gestational age and birth weight significantly influence hsCRP concentration within 48 hours after birth. Infants with low gestational age and low birth weight had lower hsCRP

concentration (p=.013 and .024, respectively).

increase in birth weight (p<.01)

**Table 2.** Overview on current literature on the difference in CRP kinetics between term and preterm

**7. Performance of CRP in diagnosis of neonatal sepsis can further be** 

An important limitation of CRP is the low sensitivity during the early phases of sepsis. By then values are often still normal, though the consequences of the bacterial invasion are

**enhanced by combining it with early sensitive markers** 

3574 neonates In case of a clinically relevant CRP rise >10 mg/l, the

(74%) and at 10.5 mg/l in term infants (86%)

at 8 mg/l cut-off value)

to infection less distinct. Prematurity of the organ systems and maturational changes in the immune system might result in a more distinct CRP response to delivery in uninfected newborns and to bacterial invasion in infected newborns. The few studies so far addressing this issue suggest that the diagnostic accuracy of CRP in preterm infants may benefit from a

re-evaluation of the reference intervals in this age group. [25, 44, 48, 51]

Author Cohort

Kawamura et al. [25]

Hofer et al.

Doellner et al. [51]

Hofer et al.

Ishibashi et al. [46]

Chiesa et al.

Turner et al.

[44]

[50]

neonates.

[48]

[48]

Diagnostic accuracy Sensitivity (%)

CRP concentration median (mg/l) peak (mg/l)

348 neonates with suspicion of

532 uninfected and infected neonates

42 neonates with probable or proven sepsis

499 uninfected neonates

33 neonates with proven sepsis

110 uninfected symptomatic neonates

421 healthy neonates

infection

Even though advances in neonatal intensive care have led to increasing preterm birth rates and survival rates, the influences of prematurity on laboratory test results are poorly understood and have not been assessed systematically. This is also true for CRP, which is one of the most extensively studied infection markers in the neonatal period. Reports on the influence of gestational age on kinetics of CRP in infected and uninfected infants are limited:

Turner et al. [50] demonstrated an association of gestational age with the magnitude of clinically relevant CRP responses during the first seven days after birth. In case of a clinically relevant CRP rise >10 mg/l the proportion of a pronounced response >60 mg/l increased with gestational age from 8% in newborns from 24 to 27 weeks to 25% in newborns from 40 to 41 weeks.

Several other authors have contributed to the growing body of evidence further supporting the difference in CRP response to infection between term and preterm infants. In a cohort of 348 infants Kawamura et al. [25] reported a lower sensitivity of CRP in the diagnosis of neonatal sepsis in preterm compared to term newborns (61.5% vs. 75%).

Doellner et al. [51] described a significantly lower CRP increase induced by infection in preterm compared to term infants. In their cohort of 42 newborns with either culture proven or probable sepsis infants with a gestational age less than 35 weeks had lower CRP values and lower CRP peak values compared to infants with a gestational age greater than 35 weeks (CRP values 0 vs 18 mg/l, CRP peak values 15 vs 52 mg/l).

We have recently reported on a lower CRP response to infection in preterm compared to term newborns with a lower sensitivity (53% vs. 86%), lower median values (9 vs. 18.5 mg/l), and a lower area under the receiver operating characteristics curve (0.799 vs. 0.890). [48]

What might explain the observed differences of CRP values between term and preterm newborns? One fact might be the differences in pre- and postnatal care regarding more frequent prophylactic antibiotic treatment in preterm infants and their mothers during birth. Timing of blood sampling might be another critical point being possibly earlier in preterm newborns. CRP is thought to play an important role in innate immunity, as an early defence system against infections. As far as the endogenous immune response depends on gestational age CRP responses might be lower due to a less mature immunological system of the preterm newborn.

Table 2 gives an overview on current literature on the association of CRP kinetics with gestational age and/or birth weight.

For neonates, assessment of laboratory tests occurs within a complex context of prenatal growth and neonatal development. [52] Though the current literature reveals some minor disagreement on the effect of gestational age on CRP there is a body of growing evidence suggesting that the so far reported characteristics of CRP may not be as suitable for the use in preterm as in term newborns. Their baseline CRP values may be lower and their response to infection less distinct. Prematurity of the organ systems and maturational changes in the immune system might result in a more distinct CRP response to delivery in uninfected newborns and to bacterial invasion in infected newborns. The few studies so far addressing this issue suggest that the diagnostic accuracy of CRP in preterm infants may benefit from a re-evaluation of the reference intervals in this age group. [25, 44, 48, 51]

50 Neonatal Bacterial Infection

newborns from 40 to 41 weeks.

of the preterm newborn.

gestational age and/or birth weight.

**6. CRP performance in diagnosis of neonatal sepsis and baseline CRP** 

Even though advances in neonatal intensive care have led to increasing preterm birth rates and survival rates, the influences of prematurity on laboratory test results are poorly understood and have not been assessed systematically. This is also true for CRP, which is one of the most extensively studied infection markers in the neonatal period. Reports on the influence of gestational age on kinetics of CRP in infected and uninfected infants are limited: Turner et al. [50] demonstrated an association of gestational age with the magnitude of clinically relevant CRP responses during the first seven days after birth. In case of a clinically relevant CRP rise >10 mg/l the proportion of a pronounced response >60 mg/l increased with gestational age from 8% in newborns from 24 to 27 weeks to 25% in

Several other authors have contributed to the growing body of evidence further supporting the difference in CRP response to infection between term and preterm infants. In a cohort of 348 infants Kawamura et al. [25] reported a lower sensitivity of CRP in the diagnosis of

Doellner et al. [51] described a significantly lower CRP increase induced by infection in preterm compared to term infants. In their cohort of 42 newborns with either culture proven or probable sepsis infants with a gestational age less than 35 weeks had lower CRP values and lower CRP peak values compared to infants with a gestational age greater than 35

We have recently reported on a lower CRP response to infection in preterm compared to term newborns with a lower sensitivity (53% vs. 86%), lower median values (9 vs. 18.5 mg/l), and a lower area under the receiver operating characteristics curve (0.799 vs. 0.890). [48]

What might explain the observed differences of CRP values between term and preterm newborns? One fact might be the differences in pre- and postnatal care regarding more frequent prophylactic antibiotic treatment in preterm infants and their mothers during birth. Timing of blood sampling might be another critical point being possibly earlier in preterm newborns. CRP is thought to play an important role in innate immunity, as an early defence system against infections. As far as the endogenous immune response depends on gestational age CRP responses might be lower due to a less mature immunological system

Table 2 gives an overview on current literature on the association of CRP kinetics with

For neonates, assessment of laboratory tests occurs within a complex context of prenatal growth and neonatal development. [52] Though the current literature reveals some minor disagreement on the effect of gestational age on CRP there is a body of growing evidence suggesting that the so far reported characteristics of CRP may not be as suitable for the use in preterm as in term newborns. Their baseline CRP values may be lower and their response

**concentrations differ between term and preterm neonates** 

neonatal sepsis in preterm compared to term newborns (61.5% vs. 75%).

weeks (CRP values 0 vs 18 mg/l, CRP peak values 15 vs 52 mg/l).


**Table 2.** Overview on current literature on the difference in CRP kinetics between term and preterm neonates.
