Cord blood nucleated red blood cell level: is it a predictive marker for neonatal jaundice?

Introduction

Although indirect hyperbilirubinemia in the neonatal period is usually a benign condition that resolves spontaneously, the follow-up of jaundiced babies due to permanent brain damage caused by high bilirubin levels is of clinically great importance [1]. Neonatal hyperbilirubinemia results from a number of mechanisms including increased enterohepatic circulation, impaired conjugation of bilirubin, deficiency of hepatic uptake and increased production of bilirubin [2], [3]. Short postpartum hospital stays have become a common practice 4]. It is evident that hyperbilirubinemia is the most common cause for readmission in the early neonatal period [5], [6]. Severe hyperbilirubinemia and bilirubin encephalopathy can occur in healthy, term neonates who were discharged early 7]. Thus, it is very important to predict which infants carry high risk for significant hyperbilirubinemia.

Nucleated red blood cells (nRBCs) are precursors of erythrocytes and frequently found in the peripheral blood of neonates and the number of nRBCs varies widely at birth [8], [9]. It has been shown that the number of nRBCs is increased in perinatal problems such as fetal hypoxia 10]. Increased nRBC counts may occur in different conditions other than fetal hypoxia such as fetal erythropoiesis, blood loss and hemolysis, maternal diabetes, intrauterine infections, intrauterine growth restriction and preeclampsia 8].

Bilirubin is an important antioxidant at physiological limits, but acts as a stronger pro-oxidant at higher levels. It is generated by the degradation of heme, whose source is red blood cells. The investigation of relation between hyperbilirubinemia and the increase of nRBCs in perinatal problems may be therefore of great importance. The aim of this study is to evaluate whether the cord blood nRBC can predict the development of hyperbilirubinemia in healthy neonates.

Materials and methods

Results

Overall, 149 eligible newborn infants were enrolled into the study. The mean gestational age was 38.4±1.4 week, the mean birth weight 3190.8±433 g and 76 (51%) babies were male. Sixty-three newborns were delivered vaginally. History of neonatal hyperbilirubinemia in siblings was present in 23 infants.

There was no statistically significant difference for the clinical parameters such as birth weight, gestational age, gender, delivery type and history of neonatal hyperbilirubinemia in siblings (Table 1). The cutoff value with sensitivity and specificity of the first measurement of serum bilirubin in cord blood is 3.00 mg/dL, 86.8% and 62.1%, respectively.

The comparison of cord blood complete blood count parameters, nRBC and absolute nRBC counts, and total serum bilirubin levels are presented in Table 2. Complete blood counts were not statistically different between the groups. Significant statistical differences between the groups were found for nRBC and absolute nRBC counts (p=0.01 and 0.02, respectively). The nRBC count and absolute nRBC counts and total serum bilirubin levels were higher in the group 3 infants.

The AUC calculations from ROC analysis were 0.66 for nRBC count and 0.62 for absolute nRBC count (Figure 1). The sensitivity of the absolute nRBC score was higher than the nRBC count. However, specificity was higher in nRBC count. The negative predictive value was similar whereas the nRBC count has the higher positive predictive value than the absolute nRBC count (Table 3).

Figure 1:

ROC of the sensitivity and specifity of nRBC and absolute nRBC.

Discussion

Neonatal jaundice is a common and generally benign condition, occurring in 60%–70% of healthy term infants [11]. However, permanent neurological damage occurs due to bilirubin encephalopathy in severe hyperbilirubinemia. The most important method to prevent bilirubin encephalopathy is to predict the babies who will develop severe neonatal hyperbilirubinemia. Implementation needs to be a system-based approach that allows for individualized care to accommodate the clinician’s concerns, informed participation of the family and monitoring of the progression of hyperbilirubinemia of at-risk newborns [12]. To prevent bilirubin encephalopathy, it is recommended to determine the clinical risk factors for severe hyperbilirubinemia and measure bilirubin levels before discharge [13].

As far as we know, our study is the first study to evaluate nRBC levels in newborn infants with jaundice. In this study, nRBC and absolute nRBC counts in cord blood were significantly higher in newborns with jaundice. However, they seem insufficient to detect the babies who need phototherapy. Our findings suggest that the increase of nRBCs may be a valuable marker to predict the development of neonatal hyperbilirubinemia.

Bilirubin is considered as a toxic compound when it accumulates in high amounts in an organism [14]. In vivo, reactive oxygen free radicals are produced during environmental metabolism as well as due to environmental pollutants. The adverse effects of these oxidants on the cell are eliminated by various antioxidants. The disequilibrium between oxidant and antioxidant systems is involved in the pathogenesis of many systemic diseases [15]. Bilirubin is an important antioxidant at physiological limits, but acts as a stronger pro-oxidant at higher levels. Especially in the neonatal period, bilirubin acts as an important cytoprotectant as the antioxidant defense systems of infants do not provide adequate protection against circulating free radicals [16]. Research shows that increased oxidative stress may result in triggering hyperbilirubinemia in neonates, and high serum bilirubin level may protect the cells from oxidative damage [17], [18]. In addition, heme oxygenase may play an important role in the process of oxidative stress. The promoter region of heme oxygenase-1 contains an antioxidant response element. Therefore, the induction of heme oxygenase occurs as a general response to oxidant stress [19], [20], [21]. These mechanisms may influence bilirubin production as a protection against oxidative stress by affecting the erythroid series in newborn infants with oxidative stress.

In conclusion, we emphasize that increased nRBC counts in cord blood may be indicative of increased levels of bilirubin in the newborn. This may be due to the toxic effect of bilirubin or increased bilirubin production to reduce oxidative stress. The nRBC count in cord blood may be an effective method for predicting hyperbilirubinemia. Evaluation of nRBC in cord blood is a non-invasive, easy and inexpensive method. Therefore, it can be used as a new marker to guide the physicians for following the infants to reduce the anxieties of the families and to prevent performing unnecessary tests.