Study of C-reactive protein in healthy neonates

Introduction: C-reactive protein is widely used marker for early detection of neonatal sepsis.There is reported wide variation in normal CRP level of new born as well as its sensitivity and specificity regarding its use as an indicator for sepsis. It is known that cascade of events in sepsis leading to rise of CRP may take few hours to days to increase;therefore predictive value is higher after 24 to 48 hours of infection. Considering the above factors this work was taken to know the normal pattern of CRP during initial days of birth in healthy neonates & to have a cut off value. Materials and Methods: The present study was conducted in association with pediatric& biochemistry department in IMS & SUM Hospital, Bhubaneswar to observe normal CRP level during zero hour (cord blood) and 48 hours in apparently healthy new born babies. Babies having perinatal asphyxia and other severe complications and babies of mother with preexisting chronic diseases were excluded from the study. CRP was estimated by turbidometry method. Data were collected and analyzed with appropriate statistical application. Results: After excluding babies as per exclusion criteria, finally 48 new born data were included for study and analysis. Upper reference value for CRP at birth & at 48hrs was established. CRP value was small in cord blood healthy newborn babies. There is significant rise in CRP by 48hrs compared to that at birth. Maternal problems like PROM, perinatal fetal distress and gestational hypertension affected CRP positively. Conclusion: Maternal and fetal factors can affect the neonatal CRP value and should be kept in mind while considering CRP as an indicator of sepsis.


Introduction
As we all know that early neonatal sepsis is a known difficult problem for diagnosis. CRP is a known marker commonly used for early detection of neonatal sepsis in nursery. There is reported wide variation in normal CRP level of newborns as well as its sensitivity & specificity regarding its use as indicator of sepsis. The fear of missing a case of neonatal septicemia leads to overuse of antibiotics. In addition to infections, CRP hasbeen shown to be elevated in non-infectious conditions in neonates including meconiumaspiration, respiratory distress syndrome,fetal hypoxia and intraventricular hemorrhage [1].
Different cut-off values for raised CRP have been suggested by various studiesusing varying protocols [2].
Although several studies confirm that CRP levels are useful in the early diagnosis of sepsis, there are reports to the contrary [3][4][5][6]. It is known that cascade of events in sepsis leading to rise of CRP may take few hours to days to increase; therefore predictive value is higher after 24 to 48 hours of infection. Considering the above factors this work was taken to know the normal pattern of CRP during initial days of birth in healthy neonates & to have a cut off value.

Materials & Methods
The present study was conducted in association with pediatric department & biochemistry department in IMS & SUM Hospital, Bhubaneswar during January to May 2016.

Inclusion Criteria
Healthy term (>37weeks) & near term babies (34-37weeks) born in hospital without significant risk factors for sepsis or severe asphyxia. Laboratory method:Approximately 5ml of blood was collected from the umbilical cord after clamping & cutting of the cord. About 48hrs after birth, approximately 2ml of blood was collectedby venipuncture from the newborn. Samples were transported without any delay to the laboratory for CRP estimation. CRP was estimated by turbidometry method.

Exclusion Criteria
Data collection and analyses:CRP value was calculated at birth & 48hrs after birth. Newborn babies were observed for signs of sepsis for at least 48h. Clinical data were collected using a questionnaire. Data were analyzed using SPSS software. For all statistical analyses the p value was considered to be significant at p < 0.05 This table shows distributions of mothers whose babies blood CRP were studiedaccording to age, parity and mode of delivery. The samples were collected from babies of all age groups of mothers and there is normal distribution of samples and maximum mothers were in the age group of 25-35years. The parity wise distribution of mothers show normal distribution and most of the mothers were multiparous. This table also signifies babies were distributed normally in all categories of delivery.    This shows distribution of CRP value in accordance with the sex of the baby. Sex has no effect on CRP value as P value is insignificant.  This table shows linear regression analysis to see the influence of factors to see the influence of factors like low APGAR & PROM over CRP value at 48 hrs. In our study there was positive correlation of factors like 5 min APGAR<8 and PROM (>18hrs) with the neonatal CRP at 48hrs. CRP value could be up to 1.52 times when APGAR<8 and in PROM (>18hrs) up to 1.3 times. This can be shown in the linear regression analysis for confounding factors. That may not be suggestive of sepsis when considered as single criteria.

Discussion
It is generally acknowledged that neonatal sepsis remains an important diagnostic consideration in many infants [7]. CRP rises in response to inflammation or tissue necrosis [8]. Although it is a nonspecific marker, it has repeatedly shown to increase with bacterial sepsis &meningitis [8,9,[10][11][12]. So it is difficult to ignore use of antibiotic during early neonatal period. The present study was designed to evaluate the normal pattern of CRP during initial days of birth in healthy neonates & to have a cut off value.
In our study CRP value is small in healthy babies at birth with a median value of 3.2mg/L & 95 th percentile of 4.36mg/L. CRP value significantly increases in first 48hrs of life in healthy babies with a median value of 6.05mg/L & 95 th percentile of 13.10mg/L. This shows wide variation of CRP value. CRP value can rise up to 13.10mg/L even if sepsis is not there. Wasunna et al found no evidence that intraventricular haemorrhage was associated with elevation of CRP in neonates with no evidence of infection [13]. Schouten-Van Meeteren et al demonstrated no significant difference between the CRP levels of neonates with perinatal asphyxia, prolonged rupture of membranes, hyperbilirubinemia or respiratory distress syndrome, and those of a control group [14]. Xanthou et al also found no difference between the CRP levels in neonates with asphyxia compared to controls [15]. Gestational maturity & sex of baby did not influence the cord blood CRP or CRP at 48hrs.Chiesa et al showed that mean CRP concentration at birth was increased by a factor of 1.50 (95% CI, 1.32 to 2.03) if the 5-min Apgar score was <8 and by a factor of 1.32 (95% CI, 1.07 to 1.61) if the time from rupture of membranes was >18 hours [16]. This effect on CRP was no longer present by 48 hours of life.In our study CRP concentration at 48hrs was increased by 1.52 times if the 5 min APGAR score was <8 & by a factor of 1.3 times if the time from rupture of membrane was >18hrs. But this may not be suggestive of sepsis when considered as single criteria. CRP value can rise by 48 hrs compared to that birth even if sepsis not there. So CRP taken alone has a negative predictive value rather than positive predictive value.

Conclusion
CRP is most widely & extensively used marker of neonatal sepsis. Intrapartum risk factors for early onset sepsis can cause elevation of cord & neonatal CRP levels in the absence of infection. Maternal & fetal factors should be kept in mind while considering CRP as an indicator of sepsis.