C reactive protein and procalcitonin: Reference intervals for preterm and term newborns during the early neonatal period

https://doi.org/10.1016/j.cca.2011.02.020Get rights and content

Abstract

Background

There is still no study evaluating the influence of gestational age (GA) per se on C reactive protein (CRP) and procalcitonin (PCT) reference intervals. We therefore investigated how length of gestation, age (hours), and prenatal and perinatal variables might influence the levels of CRP and PCT. We also determined 95% age-specific reference intervals for CRP and PCT in healthy preterm and term babies during the early neonatal period.

Methods

One blood sample (one observation per neonate) was taken for CRP and PCT from each newborn between birth and the first 4 (for term), or 5 days (for preterm newborns) of life by using a high-sensitive CRP and PCT assays.

Results

Independently of gender and sampling time, GA had a significantly positive effect on CRP, and a significantly negative effect on PCT. Compared with healthy term babies, healthy preterm babies had a lower and shorter CRP response, and, conversely, an earlier, higher, and longer PCT response. CRP reference intervals were affected by a number of pro-inflammatory risk factors.

Conclusions

Age- and GA-specific reference ranges for both CRP and PCT should be taken into account to optimize their use in the diagnosis of early-onset neonatal sepsis.

Introduction

The utility of C reactive protein (CRP) for the diagnosis of early-onset neonatal infection has been the subject of controversy because of its unsatisfactory sensitivity. The CRP concentration increases physiologically in newborns within the first days after birth. This dynamic behavior may in part account for the low diagnostic accuracy of CRP measurements in neonatal infection, particularly when measured shortly after birth. Similarly, other markers of inflammation including procalcitonin (PCT) demonstrate a natural increase within a few days after birth, necessitating careful adjustments to the normal ranges. Thus, in estimating the sensitivities and specificities of these neonatal markers for the diagnosis of sepsis throughout the first days of life, it is important to consider their normal kinetics and their pattern(s) of response in the healthy neonate.

Data pertaining to reference intervals for CRP during the neonatal period are limited. In the majority of published reports, CRP upper limits have been obtained from symptomatic uninfected patients [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. There are few studies of upper limits for CRP in the healthy newborn [12], [13], [14], [15]. Furthermore, most of these were based on relatively small sample sizes with wide-ranging postnatal ages [12], [13], [14]. More important, although advances in neonatal intensive care have led to increasing preterm birth rates, to our knowledge, there is still no study evaluating the influence of gestational age (GA) per se in the development of CRP reference intervals during the neonatal period. Finally, though high-sensitivity assay for CRP has become available over the last decade in standard clinical laboratories, there is no study assessing the CRP postnatal changes in the healthy preterm and term neonates using this analytic method.

Data pertaining to reference intervals for PCT are also limited. In a previous cross-sectional study, we showed that in the healthy term neonates circulating concentrations of PCT increase gradually from birth to reach peak values at about 24 h of age and then decrease gradually by 48 h of life [16]. No similar normogram exists for the healthy preterm infants even though they may have different pharmacokinetics.

For these reasons, we sought to describe the reference ranges for both CRP and PCT in a large sample of healthy preterm and term newborns during the first days of life by using more sensitive CRP and PCT assays than those previously reported [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18].

Section snippets

Subjects

Our population consisted of healthy preterm and term infants who, from birth, were prospectively recruited over an 18-month period to the Neonatal Unit of Policlinico Umberto I° Hospital, Sapienza University of Rome. The study protocol was approved by the clinical research ethics committee of the Hospital. Eligible for enrollment were neonates who were delivered from singleton pregnancies with birth weights (BWs) appropriate for GA and with normal results on physical examination at birth that

Subject characteristics

Table 1 presents maternal and neonatal characteristics of the study population, of whom 221 were born at term (range 37.0–39.0 weeks) while 200 were preterm (range 30.0–36.0 weeks), with 27 out of the 200 preterm infants (13.5%) below 33 weeks of gestational age. Most babies (94.8%) were born to Caucasian mothers.

C reactive protein

Using multiple log-linear regression analysis, it was found that GA had a significant, positive effect on CRP independently of gender and sampling time. Babies' mean CRP increased by 6.0%

Discussion

The main purpose of this study was to determine age-related reference intervals for CRP and PCT in the preterm and term baby during the early neonatal period. Our data show that clinical use of CRP over the first days of life requires the use of cutoff values specific not only to postnatal age, but also to GA. In fact, we found that healthy preterm babies have a lower and shorter CRP response compared with that in healthy term babies, demonstrating the effects of development per se on CRP

Acknowledgments

We are indebted to Silvano Castrechini for his excellent technical assistance.

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