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ORIGINAL ARTICLE
Year : 2013  |  Volume : 26  |  Issue : 2  |  Page : 127-131

Predictive ability of first-day serum bilirubin and haptoglobin for subsequent significant hyperbilirubinemia in healthy-term and near-term newborn


Pediatric Department, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt

Date of Submission19-Mar-2013
Date of Acceptance06-Jun-2013
Date of Web Publication31-Jan-2014

Correspondence Address:
Noha M Ashour
MBBCh, Pediatric Department, Faculty of Medicine, Menoufiya University, El-Masna3 Street, Shebin el Kom, Menoufiya
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.126143

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  Abstract 

Objective
Predicting significant neonatal hyperbilirubinemia using cord blood haptoglobin and bilirubin on the first day of life.
Background
Neonatal jaundice is the result of an imbalance between the production and elimination of bilirubin. Bilirubin conjugation in newborns is significantly impaired in the first few days; even a small increase in the rate of production can contribute toward the development of hyperbilirubinemia. Hemolysis plays a significant role in bilirubin increase in newborns. When hemolysis takes place, a decrease in the haptoglobin blood level-binding hemoglobin in the environment occurs.
Patients and methods
A total of 61 healthy newborns of at least 35 weeks' gestation were followed in the first 5 days of life for the development of significant hyperbilirubinemia. All newborns were subjected to cord blood haptoglobin and bilirubin measurement soon after delivery. Total serum bilirubin (TSB) was measured on the fifth day of life. Only 46 newborns were brought in on the fifth day for follow-up.
Results
A total of 25/46 newborns (54.3%) developed significant hyperbilirubinemia (TSB on the fifth day≥17 mg/dl) and were considered as positive cases. A significant negative correlation was found between cord blood haptoglobin levels and the TSB values on the fifth day. A significant positive correlation was found between cord blood bilirubin levels and the TSB levels on the fifth day. A cut-off level of haptoglobin in cord blood of 7.5 mg/dl was determined to have the highest sensitivity (100%), specificity (81%), and positive predictive value (89%) in the prediction of occurrence of significant hyperbilirubinemia, whereas a cut-off level of cord blood TSB 2.73 mg/dl had the highest sensitivity (100%), specificity (90%), and positive predictive value (93%) in the prediction of significant neonatal hyperbilirubinemia.
Conclusion
The haptoglobin value and TSB value taken from the blood of the umbilical cord can be used as a guiding indicator to demonstrate the future occurrence of significant hyperbilirubinemia in newborns.

Keywords: Bilirubin, cord blood, haptoglobin, hemolysis, hyperbilirubinemia, jaundice, near term


How to cite this article:
El-Gendy FM, Hassane FM, Khattab AA, El-Lahony DM, Ashour NM. Predictive ability of first-day serum bilirubin and haptoglobin for subsequent significant hyperbilirubinemia in healthy-term and near-term newborn. Menoufia Med J 2013;26:127-31

How to cite this URL:
El-Gendy FM, Hassane FM, Khattab AA, El-Lahony DM, Ashour NM. Predictive ability of first-day serum bilirubin and haptoglobin for subsequent significant hyperbilirubinemia in healthy-term and near-term newborn. Menoufia Med J [serial online] 2013 [cited 2020 Feb 17];26:127-31. Available from: http://www.mmj.eg.net/text.asp?2013/26/2/127/126143


  Introduction Top


Jaundice refers to the yellowish coloration of the skin and sclera caused by accumulation of bilirubin in the skin and mucous membranes [1] . Neonatal jaundice is a common disorder, with more than half of all newborns being affected in the first 3-5 postnatal days. Because of the increasing number of early discharged newborns, there is a corresponding danger of failing to diagnose severe hyperbilirubinemia in time (and start the treatment) as reports about kernicterus in full-term healthy newborns indicate [2] . Neonatal jaundice is the result of an imbalance between the production and elimination of bilirubin. Bilirubin conjugation in newborns is significantly impaired in the first few days; even a small increase in the rate of production can contribute toward the development of hyperbilirubinemia [3] .

Approximately 60% of term and 80% of preterm babies develop jaundice in the first week of life and about 10% of breastfed babies are still jaundiced at 1 month of age. In most babies with jaundice, there is no underlying disease and this early jaundice (termed physiological jaundice) is generally harmless. Jaundice may also have other causes, including blood group incompatibility (most commonly rhesus or ABO incompatibility); other causes of hemolysis are sepsis, bruising, and metabolic disorders. Deficiency of a particular enzyme, glucose-6-phosphate-dehydrogenase, can cause severe neonatal jaundice [1] . Common risk factors for hyperbilirubinemia include fetal maternal blood group incompatibility, prematurity, and a previously affected sibling; cephalohematoma, bruisings, and trauma from instrumented delivery may increase the risk for serum bilirubin elevation. Delayed meconium passage also increases the risk. Infants with risk factors should be monitored closely during the first days to weeks of life [4] . Few term newborns with hyperbilirubinemia have a serious underlying pathology. Jaundice is considered pathologic if it presents in the first 24 h after birth, the total serum bilirubin increases by more than 5 mg/dl/day, or the infant has signs and symptoms suggestive of serious illness [4] .

In young babies, unconjugated bilirubin can penetrate the membrane that lies between the brain and the blood. Unconjugated bilirubin is potentially toxic to neural tissue (brain and spinal cord). Entry of unconjugated bilirubin into the brain can cause both short-term and long-term neurological dysfunction (bilirubin encephalopathy). The term kernicterus refers to the clinical features of bilirubin encephalopathy. The risk of kernicterus is increased in term babies with very high bilirubin levels. Kernicterus is also known to occur at lower levels of bilirubin in term babies who have risk factors and in preterm babies [1].

Increased heme catabolism is an important mechanism responsible for hyperbilirubinemia in the first days after birth [5] . Hemoglobin (Hb) released from erythrocytes into the circulation by intravascular hemolysis binds immediately with haptoglobin (Hp), a serum glycoprotein, and forms a stable Hb-Hp complex. The presence of specific receptors on liver parenchymal cells that recognize and endocytose the Hp-Hb complex has led to a widely held belief that the major function of Hb binding by Hp is to target plasma Hb for rapid clearance and degradation in the liver [6] .

Therefore, this study aimed to determine whether Hp and cord blood bilirubin are early indicators of neonatal jaundice by checking Hp and bilirubin obtained from the umbilical cord (UC) after delivery.


  Patients and methods Top


A total of apparently healthy 61 newborns were initially enrolled in the study. Only 46 newborns were brought for follow-up on the fifth day. During the study period, all newborns of gestational age between 35 and 40 completed weeks were consecutively enrolled. Exclusion criteria were small for gestational age and large for gestational age, any congenital malformation, respiratory distress, sepsis, newborns with a family history of glucose-6-phosphate-dehydrogenase, and newborns with suspected hemolytic disease of newborns (ABO and Rh incompatibility).

Cord blood sample was obtained from the newborn soon after delivery and serum (S) was separated and kept in the fridge at 8°C for a period of 4 days. The Hp level was measured using the simple nephelometric method. Cord blood serum bilirubin was determined using the Jendrassik and Grof method with a Synchron CX9 apparatus (Beckman coulter). Cord blood Hb and reticulocytic count were performed and not repeated on the fifth day. Blood group including Rhesus factor, serum direct, and indirect bilirubin levels were determined routinely in all newborns on the day of birth to exclude hemolytic diseases of the newborns. The total bilirubin level in serum was monitored during the first 5 days of life and measured on the fifth day.

Statistical analysis of the collected data was carried out; normally distributed quantitative data were analyzed using a t-test, whereas non-normally distributed quantitative data were analyzed using the Mann-Whitney U-test. Normally distributed qualitative data were analyzed using χ2 -test, and whenever one of the expected cells was less than 5, Fisher's exact test was used. Pearson correlation was used for normally distributed quantitative variables, whereas Spearman correlation was used for non-normally distributed quantitative variables or when one of the variables was qualitative. A P value of less than 0.05 was considered statistically significant. The ROC curve was used to determine the cut-off points, sensitivity, and specificity for quantitative variables of interest (cord blood bilirubin and Hp cut-off points that can predict hyperbilirubinemia on the fifth day).


  Results Top


Mothers ranged in aged between 22 and 45 years, mean 30.54 years. The gestational ages of the newborns were 35-40 weeks, mean 37.69 weeks. Nineteen mothers had normal vaginal delivery (41.3%) and 27 mothers had cesarean section delivery (58.7%). Birth weights of the babies were 2.3-3.7 kg. All newborns were breastfed after delivery. Of the total deliveries, there were 21 males (45.7%) and 25 females (54.3%). There were 19 (41.3%) near-term newborns and 27 (58.6%) full-term newborns [Table 1].
Table 1: Demographic and clinical data of the cases studied

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Cord blood Hb ranged between 12 and 17 g/dl, mean 14.28 1.28 gm/dl. The mean corrected reticulocytic count in cord blood (D0) was 2.34 ± 0.83%. The mean cord blood Hp was 8.63 ± 3.73 mg/dl. The mean cord blood serum bilirubin was 3.11 ± 1.67 mg/dl [Table 2].
Table 2: Distribution of the mean values of laboratory findings among the cases studied

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Twenty five newborns of the 46 newborns in whom the serum bilirubin was actually measured on the fifth day had a serum bilirubin level of at least 17 mg/dl and were considered positive cases.

Sixty percent (15 newborns) of the positive cases were males whereas 40% (10 newborns) of the positive cases were females. Twelve newborns (48%) of the positive cases were delivered by normal vaginal delivery whereas 13 newborns (52%) were delivered by CS [Table 3].
Table 3: Comparison between negative and positive cases of demographic and clinical data

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The mean values of cord blood Hb were significantly lower in the positive cases than in the negative cases (13.90 ± 1.23 vs. 14.73 ± 1.22 g/dl) whereas the mean values for cord blood corrected reticulocytic count were significantly higher in the positive cases than in the negative cases (3.02 ± 0.46 vs. 1.53 ± 0.23%). The mean values for cord blood Hp were significantly lower in the positive cases than in the negative cases (5.26 ± 1.9 vs. 12.15 ± 1.72 mg/dl) whereas the mean values for cord blood bilirubin were significantly higher in the positive cases than in the negative cases (1.53 ± 0.94 vs. 4.44 ± 0.69 mg/dl) [Table 4].
Table 4: Comparison between negative and positive cases of the mean values of laboratory findings

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A cut-off level of Hp in cord blood of 7.5 mg/dl as obtained by the ROC curve was determined to have the highest sensitivity (100%), specificity (81%), and positive predictive value (PPV) (86%) in the prediction of occurrence of significant hyperbilirubinemia on the fifth day, whereas a cut-off level of cord blood bilirubin 2.73 mg/dl could predict subsequent significant hyperbilirubinemia by having sensitivity (100%), specificity (90%), and PPV (93%) [Figure 1].
Figure 1:

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  Discussion Top


The growing practice of early hospital discharge of newborns has resulted in a re-emergence of bilirubin-related neurological sequelae. Severe hyperbilirubinemia can occur without an apparent reason in healthy infants, and some may develop kernicterus. Therefore, it is important to establish safe markers for the development of significant hyperbilirubinemia [7] .

The prevention of fatal outcomes is based on the early detection of infants at risk of developing significant hyperbilirubinemia, and especially of detecting those in further need of therapeutic interventions [8] .

In our study, we used UC blood, which is free for use in almost all cases. Furthermore, it keeps the baby free from pain and, most importantly, the data are available immediately after birth. It was aimed, in this study, to prospectively determine the critical UC blood Hp and bilirubin (total serum bilirubin) levels to predict significant hyperbilirubinemia in healthy-term and near-term newborns on the basis of serum bilirubin measurements performed within 5 days of life.

In terms of the clinical data, males represented 60% of the positive cases in the study and females represented 40%; the difference was statistically significant. This was in agreement with studies carried out by Maisels and Kring [9] and Satrya et al. [10] , in which there were more males than females among positive cases. This was in contrast to a study carried out by Taksande et al. [11] , who found no statistical significance in the sex of the newborns. Our study showed no statistically significant difference between the positive and the negative cases in the mode of delivery. This is in agreement with studies carried out by Taksande et al. [11] , Rostami and Mehrabi [12] , and Satrya et al. [10] . This was in contrast to a study carried out by Awashi and Hasibur [13] who showed that peak serum bilirubin was significantly higher in neonates delivered by vaginal delivery.

In terms of the laboratory data, the study showed that the mean values of cord blood Hb were significantly lower in the positive cases than in the negative cases (13.90 ± 1.23 vs. 14.73 ± 1.22 g/dl), with a significant negative correlation between the fifth-day bilirubin and cord blood Hb, whereas the mean values of corrected reticulocytic count were significantly higher in the positive cases than in the negative cases (3.02 ± 0.46 vs. 1.53 ± 0.23%), with a significant positive correlation between the fifth-day bilirubin and reticulocytic count [Table 5]. This was in agreement with a study carried out by Sarici et al. [14] , who showed the same statistical positive correlation between significant hyperbilirubinemia and the reticulocytic count, but was not in agreement with the study carried out by Cakmak et al. [3] .
Table 5: Correlation between the fifth-day bilirubin and laboratory findings among the studied group

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Our study also showed that the mean values for cord blood Hp were significantly lower in the positive cases than in the negative cases (5.26 ± 1.9 vs. 12.15 ± 1.72 mg/dl), with a significant negative correlation between the fifth-day bilirubin and cord blood Hp; this was in agreement with Cakmak et al. [3] , whose study also showed the same negative correlation. The mean values for cord blood bilirubin were significantly higher in the positive cases than in the negative cases (1.53 ± 0.94 vs. 4.44 ± 0.69 mg/dl), with a significant positive correlation between the fifth-day bilirubin and the cord blood bilirubin; this was in agreement with the study carried out by Zakia et al. [15] , Satrya et al. [10] , Baharath [16] , and Ipek et al. [17] , who found a significant positive correlation between the occurrence of hyperbilirubinemia and the cord blood bilirubin levels.

A cut-off point level of Hp in cord blood of 7.5 mg/dl in our study was determined to have the highest sensitivity (100%), specificity (81%), and PPV (86%). Thus, prediction of neonatal hyperbilirubinemia can be performed in newborns with cord blood Hp levels less than 7.5 mg/dl [Figure 2].
Figure 2:

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A cut-off point level of bilirubin in cord blood of 2.73 mg/dl was determined to have the highest sensitivity (100%), specificity (90%), and PPV of 93%. Bernaldo and Segre [18] , in a similar study, reported a cut-off point for cord blood bilirubin of 2 mg/dl. Knüpfer et al. [8] , in another study, used a cut-off point of 1.76 mg/dl for cord blood bilirubin for the prediction of hyperbilirubinemia. Taksande et al. [11] , in a similar study, showed that a cord bilirubin level of more than 2 mg/dl had the highest sensitivity in the prediction of neonatal hyperbilirubinemia. A critical value of 2.5 mg/dl was used by Zakia et al. [15] as a cut-off point for cord blood bilirubin in the prediction of hyperbilirubinemia. Satrya et al. [10] found that the total bilirubin level in cord blood of 2.54 mg/dl had the highest sensitivity in the prediction of hyperbilirubinemia, whereas a study carried out by Baharath [16] found that critical cord bilirubin level higher than 2.15 mg/dl had the highest sensitivity in the prediction of hyperbilirubinemia. A similar study carried out by Ipek et al. [17] identified newborns at a high risk of developing hyperbilirubinemia using a cord blood bilirubin cut-off level of 2.60 mg/dl; they found a PPV of 41.18%, a negative predictive value of 97.9%, and a sensitivity of 50%. This was in contrast to a study carried out by Rostami and Mehrabi [12] , who concluded that assessment of cord bilirubin level could not help identify newborns with neonatal hyperbilirubinemia.


  Conclusion Top


Our data clearly show that assessments of umbilical blood Hp and bilirubin are useful tests to predict hyperbilirubinemia in healthy-term and near-term newborns. Thus, we recommend using UC blood for measurement of serum bilirubin and Hp as it is a painless and easy method. The results of this study should be confirmed in additional studies that include larger numbers of newborns with significant hyperbilirubinemia and hemolytic disease of the newborns.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.Rennie J, Aride C, Benjamin Y, Cottrell S, Ford K, Ives K, et al. Neonatal jaundice. NICE guideline DRAFT 2009; 3.  Back to cited text no. 1
    
2.Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics 1995; 96 :730-733.  Back to cited text no. 2
    
3.Cakmak A, Calik M, Atas A, Hirfanoglu I, Erel O.. Can haptoglobin be an indicator for the early diagnosis of neonatal jaundice? J Clin Lab Anal 2008; 22 :409-414.  Back to cited text no. 3
    
4.Stoll BJ. Jaundice and hyperbilirubinemia in the newborn. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 18th ed. Philadelphia: Saunders; 2008. p. 758.  Back to cited text no. 4
    
5.Maisels MJ, Kring E. The contribution of hemolysis to early jaundice in normal newborns. Pediatrics 2006; 118 :276-279.  Back to cited text no. 5
    
6.Okuda M, Tokunaga R, Taketani S. Expression of haptoglobin receptors in human hepatoma cells. Biochim Biophys Acta 1992; 1136 :143-149.  Back to cited text no. 6
    
7.Bhutani VK, Johnson LH. Managing the assessment of neonatal jaundice: importance of timing. Indian J Pediatr 2000; 67 :733-737.  Back to cited text no. 7
    
8.Knüpfer M, Pulzer F, Gebauer C, Robel-Tillig E, Vogtmann C. Predictive value of umbilical cord blood bilirubin for postnatal hyperbilirubinaemia. Acta Paediatr 2005; 94 :581-587.  Back to cited text no. 8
    
9.Maisels MJ, Kring EA. Length of stay, jaundice and hospital readmission. Pediatrics 1998; 101 :995-998.  Back to cited text no. 9
    
10.Satrya R, Effendi SH, Gurnida DA. Correlation between cord blood bilirubin level and incidence of hyperbilirubinemia in term newborns. Paediatr Indones 2009; 49 :349-354.  Back to cited text no. 10
    
11.Taksande A, Vilhekar K, Jain M, Zade P, Atkari S, Verkey S. Prediction of the development of neonatal hyperbilirubinemia by increased umbilical cord bilirubin. Curr Pediatr Res 2005; 9 (1&2) :5-9.  Back to cited text no. 11
    
12.Rostami N, Mehrabi Y. Identifying the newborns at risk for developing significant hyperbilirubinemia by measuring cord bilirubin levels. J Arab Neonatal forum 2005; 2 :81-85.  Back to cited text no. 12
    
13.Awashi S, Hasibur R. Early detection of neonatal hyperbilirubinemia. Indian J Pediatr 1998; 65 :131-139.  Back to cited text no. 13
    
14.Sarici SU, Yurdakök M, Serdar MA, Gönül SR. An early (sixth-hour) serum bilirubin measurement is useful in predicting the development of significant hyperbilirubinemia and severe ABO hemolytic disease in a selective high-risk population of newborns with ABO incompatibility. Pediatrics 2002; 109 :e53.  Back to cited text no. 14
    
15.Zakia N, Shahidukkah AM, Mannan A, Kumar S, Mitra U, Selmuzzaman SM. The value of umbilical cord blood bilirubin management in predicting the development of significant hyperbilirubinemia in healthy newborn. Bangladesh J Child Health 2009; 33 :50-59.  Back to cited text no. 15
    
16.Bharath AP. Cord blood bilirubin can be used as an early predictor of Neonatal hyperbilirubinemia. Karnataka: MD thesis in Rajiv Gandhi University of Health Sciences; 2011.  Back to cited text no. 16
    
17.Ipek IO, Bozaykut A, Çaðril S, Sezer R. Does cord blood bilirubin level help the physician in the decision of early postnatal discharge? J Matern Fetal Neonatal Med 2012; 25 :1375-1378.  Back to cited text no. 17
    
18.Bernaldo AJN, Segre CAM. Bilirubin dosage in cord blood: could it predict neonatal hyperbilirubinemia? Sao Paulo Med J 2004; 122 :99-103.  Back to cited text no. 18
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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