Cord Blood Alkaline Phosphatase as an Indicator of Neonatal Jaundice

AUTHORS

Mousa Ahmadpour-Kacho 1 , Yadollah Zahed Pasha 1 , Mohsen Haghshenas 1 , Zahra Akbarian Rad 1 , Alireza Firouzjahi 1 , Ali Bijani 1 , Abdollah Dehvari 2 , * , Mehrangiz Baleghi 1

1 Babol University of Medical Sciences, Babol, IR Iran

2 Children And Adolescent Health Research Center, Zahedan University of Medical Sciences, Zahedan, IR Iran

How to Cite: Ahmadpour-Kacho M, Zahed Pasha Y, Haghshenas M, Akbarian Rad Z, Firouzjahi A, et al. Cord Blood Alkaline Phosphatase as an Indicator of Neonatal Jaundice, Iran J Pediatr. 2015 ; 25(5):e718. doi: 10.5812/ijp.718.

ARTICLE INFORMATION

Iranian Journal of Pediatrics: 25 (5); e718
Published Online: October 6, 2015
Article Type: Research Article
Received: February 16, 2015
Accepted: July 29, 2015
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Abstract

Background: Management of hyperbilirubinemia remains a challenge for neonatal medicine because of the risk of neurological complications related to the toxicity of severe hyperbilirubinemia.

Objectives: The purpose of this study was to examine the validity of cord blood alkaline phosphatase level for predicting neonatal hyperbilirubinemia.

Patients and Methods: Between October and December 2013 a total of 102 healthy term infants born to healthy mothers were studied. Cord blood samples were collected for measurement of alkaline Phosphatase levels immediately after birth. Neonates were followed-up for the emergence of jaundice. Newborns with clinical jaundice were recalled and serum bilirubin levels measured. Appropriate treatment based on serum bilirubin level was performed. Alkaline phosphatase levels between the non-jaundiced and jaundiced treated neonates were compared.

Results: The incidence of severe jaundice that required treatment among followed-up neonates was 9.8%. The mean alkaline phosphatase level was 309.09 ± 82.51 IU/L in the non-jaundiced group and 367.80 ± 73.82 IU/L in the severely jaundiced group (P = 0.040). The cutoff value of 314 IU/L was associated with sensitivity 80% and specificity 63% for predicting neonatal hyperbilirubinemia requiring treatment.

Conclusions: The cord blood alkaline phosphatase level can be used as a predictor of severe neonatal jaundice.

Keywords

Fetal Blood Hyperbilirubinemia Jaundice Alkaline Phosphatese Newborn

Copyright © 2015, Growth & Development Research Center.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Due to early discharge of infants from the hospital, readmission has been increased (1). Therefore, early diagnosis of jaundice and timely actions are necessary. Several methods have been used to determine risk of neonatal hyperbilirubinemia. The measurement of bilirubin level (2) and alpha fetoprotein (3) in cord blood have been used for this purpose. For the first time Aysin Nalbantoglu et al. used alkaline phosphatase (ALP) level 6 hours after birth as a marker for determining hemolysis and hyperbilirubinemia (4). Alkaline phosphatase is a hydrolase enzyme and responsible for removing phosphate from many types of molecules (5). Alkaline phosphatase is found in almost all body cells, including red blood cells (4-6).

2. Objectives

Therefore, we hypothesized that it can be used as a marker for early diagnosis of hyperbilirubinemia. This study was conducted to evaluate the ALP level as a marker for early diagnosis of neonatal jaundice.

3. Patients and Methods

In this prospective study, between October and December 2013, infants who were born at the Babol-Clinic Hospital in Babol, Northern Iran, were selected. A total of 105 healthy term infants with gestational age between 37 and 42 weeks, weighing more than 2500 g born to healthy mothers were studied. Five milliliter cord blood was taken after birth and sent for determination of ALP level. Serum alkaline phosphatase was measured with auto analyzer (Sinnowa-DS301, China, 2013). Infants who were born to mothers with diseases such as eclampsia, diabetes, bone, kidney and liver diseases, and infants who were found suffering from other diseases except jaundice were excluded from the study. Three cases were lost to the study, so 102 cases were monitored for the emergence of clinical jaundice based on clinical observation by parents or physicians up to 10 days after birth. Infants with clinical jaundice were recalled and serum bilirubin level was measured and treated based on American Academy of Pediatrics (AAP) protocols. These were assigned as the treatment group and neonates without clinical jaundice were assigned as the non-jaundiced group. In treatment group, to determine the cause of hyperbilirubinemia, work-up including complete blood count, reticulocyte count, estimation of blood group in mother and neonate, peripheral blood smear, evaluation of G6PD level and Coombs test, was done. Demographic information of all infants including gestational age, birth weight and Apgar score was recorded. The results were analyzed by SPSS 22 software.

4. Results

A total of 105 cases were followed-up. Three cases were lost to the study. The remaining 102 cases consisted of 50 (49%) males and 52 (51%) females. Ninety eight (96%) infants were born by cesarean section and 4 (4%) by vaginal delivery. Apgar scores were normal (9 - 10) at birth in all cases. The mean gestational age was 38.7 weeks and the mean birth weight 3649.59 grams (Table 1). The incidence of clinical jaundice during follow-up was 47%. In 39.2% bilirubin reached a peak of ≤ 10 mg/dL. The rate of need for treatment was 9.8% (10 cases), of which 5 cases were ABO incompatible, one case Rh incompatible, 2 cases G6PD deficient and in 2 cases the cause of jaundice remained unknown. Hct levels and reticulocyte count were in normal range and Coombs test was negative in these cases. None of the neonates needed exchange transfusion.

There was no difference between groups with regard to gestational age, birth weight and Apgar scores, but the comparison of cord blood alkaline phosphatase levels revealed a significant difference between the two groups (P value = 0.041) (Table 2).

Table 1. Baseline Demographic Data of Neonates
NMinimumMaximumValues a
Gestational age, wk10237.2840.2838.7059 ± 0.60277
Weight, g1012600.005000.003640.5941 ± 422.88964
Alkaline phosphatase, IU/L102138.00545.00325.2451 ± 85.03248

a Values are presented as mean ± SD.

Table 2. Comparison of GA, W, and ALP in Non-Jaundiced and Jaundiced
GroupNValues aP Value
Gestational age, wk0.265
Non-jaundiced5438.7689 ± 0.66151
Clinically-jaundiced4838.6350 ± 0.52690
Weight, g0.591
Non-jaundiced533662.2642 ± 419.81059
Clinically-jaundiced483616.6667 ± 429.41491
Alkaline phosphatase, IU/L0.041
Non-jaundiced54309.0926 ± 82.51295
Clinically-jaundiced48343.4167 ± 84.99057

a Values are presented as mean ± SD.

Comparison of cord blood alkaline phosphatase levels between non-jaundiced group and jaundiced newborns in whom bilirubin level had reached ≤ 10 mg/dL, revealed a significant difference (P value = 0.016) (Table 3).

Table 3. Comparison of GA, W, and ALP in Non-Jaundiced and Jaundiced Group With Total Serum Bilirubin Level ≥ 10 mg/dL
GroupNValues aP Value
Gestational age, wk0.139
Non-jaundiced5438.7689 ± 0.66151
TSB ≥ 10, mg/dL4038.5770 ± 0.55053
Weight, g0.415
Non-jaundiced533662.2642 ± 419.81059
TSB ≥ 10 mg/dL403592.5000 ± 388.54594
Alkaline phosphatase, IU/L0.016
Non-jaundiced54309.0926 ± 82.51295
TSB ≥ 10 mg/dL40352.6000 ± 88.64241

a Values are presented as mean ± SD.

Comparison of the non-jaundiced group with neonates who required treatment according to AAP protocol (the treatment group) showed a significant difference in cord blood alkaline phosphatase levels (P value = 0.040) (Table 4).

Table 4. Comparison of GA, W, and ALP in Non-Jaundiced and Treatment Group
GroupNValues aP Value
Gestational age, wk0.473
Non-jaundiced5438.7689 ± 0.66151
Treatment1038.6080 ± 0.55707
Weight, g0.745
Non-jaundiced533662.2642 ± 419.81059
Treatment103710.0000 ± 443.34586
Alkaline phosphatase, IU/L0.040
Non-jaundiced54309.0926 ± 82.51295
Treatment10367.8000 ± 73.82231

a Values are presented as mean ± SD.

A comparison of the ROC curves of the alkaline phosphatase levels between the non-jaundiced and treatment groups (Figure 1) revealed that a cord blood alkaline phosphatase level > 314 IU/L was the most suitable cutoff value for predicting severe jaundice (that needs treatment). This cut-off value was associated with 80% sensitivity and 63% specificity.

Figure 1. Receiver Operating Characteristic (ROC) Curve of Cord Blood Alkaline Phosphatase
Receiver Operating Characteristic (ROC) Curve of Cord Blood Alkaline Phosphatase

(ALP) at the treatment group, area under the curve is 0.730.

Of 60 neonates whose cord blood alkaline phosphatase measured less than 314 IU/L, only two neonates needed treatment. Thus, the negative predictive value of cord blood alkaline phosphatase for occurrence of hyperbilirubinemia was 96.6%.

5. Discussion

To our knowledge this is the first clinical study that examines cord blood alkaline phosphatase level as an indicator to predict severe neonatal jaundice. The results of our study indicate that measurement of cord blood alkaline phosphatase may be a predicting marker for neonatal jaundice that can exceed 10 mg/dL and necessitates treatment in the first week of life. Cord blood alkaline phosphatase level with sensitivity and specificity of 80% and 63% respectively in cutoff level > 314 IU/L predicts a need for treatment.

Nalbantoglu et al. used blood alkaline phosphatase levels 6 hours after birth. They found that ALP levels were significantly higher in patients with hyperbilirubinemia requiring treatment, either with phototherapy or exchange transfusion (P value 0.0001) (4). In our study, there was a significant difference in the levels of cord blood alkaline phosphatase between the non-jaundiced and clinically jaundiced newborns, and it was significantly higher in patients with hyperbilirubinemia requiring treatment. Moreover, the ALP levels were significantly higher in newborns whose serum bilirubin level reached a level ≥ 10 mg/dL. These findings confirm the results of Nalbantoglu et al. (4). One of advantages in our study was the site of sample collection, which was taken from cord blood. Cord blood sample predicts hyperbilirubinemia earlier than a sample taken after birth does. In addition, the neonate may not be lost to follow-up because of early discharge.

Chou et al. measured cord blood hydrogen peroxide level for prediction of neonatal hyperbilirubinemia. The cord blood hydrogen peroxide signal level of 2500 counts/10 seconds was an appropriate cutoff for predicting severe hyperbilirubinemia with sensitivity and negative predictive value of 76.2% and 93.3%, respectively (7). Our study showed that the alkaline phosphatase level of 314 IU/L was associated with sensitivity and negative predictive value of 80% and 96.6%, respectively.

The rate of need for treatment of jaundice in our study was 9.8% (10 cases). Of these, 5 cases were ABO incompatible, one Rh incompatible, 2 G6PD deficient and 2 cases were of unknown etiology. According to these findings, it seems that the alkaline phosphatase level has a higher validity in disclosing hemolytic processes.

Various tests have been studied to predict hyperbilirubinemia. Knupfer et al. (8) used the cord blood bilirubin level to predict the need for phototherapy. By a cord bilirubin cut-off level of 30 μmol/L this revealed a sensitivity of 70.3% and a negative predictive value of 65.6%. Our study had a sensitivity and negative predictive value of 80% and 96.6%, respectively. The measurement of end tidal carbon monoxide (9) at the cutoff level of 1.8 μ/L (ppm) showed a negative predictive value 97%; our study showed a negative predictive value of 96.6%, which is comparable to this expensive and low accessible test. The first day serum bilirubin (10) and sixth hour serum bilirubin (11) have been used for prediction of hyperbilirubinemia. These tests require venous blood sampling (in many countries as in ours), and so are not suitable for screening all neonates.

In our study the mean level of alkaline phosphatase in the studied newborns was 325.24 ± 85.03 IU/L, which is more than that in the existing reports. Fenton et al. found the mean level of cord blood alkaline phosphatase 159 ± 49 IU/L (12). Compared with our results, there is a big difference. Another local study by Abbasian et al. in Shahrood, Iran showed that mean cord blood alkaline phosphatase level was 314.34 ± 122.42 IU/L, which is compatible with our findings (13). The average level of cord blood alkaline phosphatase in Iranian newborns seems to be higher than in other populations.

Jaundiced newborns had higher cord blood alkaline phosphatase levels than non-jaundiced newborns. Cord blood alkaline phosphatase level is a useful indicator in predicting subsequent jaundice in healthy term newborns.

Acknowledgements

References

  • 1.

    Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal hyperbilirubinemia in Canada. CMAJ. 2006; 175(6) : 587 -90 [DOI][PubMed]

  • 2.

    Zeitoun AA, Elhagrasy HF, Abdelsatar DM. Predictive value of umbilical cord blood bilirubin in neonatal hyperbilirubinemia. Gaz Egypt Paediatr Assoc. 2013; 61(1) : 23 -30 [DOI]

  • 3.

    Tan KL, Loganath A, Roy AC, Goh HH, Karim SM, Ratnam SS. Cord plasma alpha-fetoprotein values and neonatal jaundice. Pediatrics. 1984; 74(6) : 1065 -8 [PubMed]

  • 4.

    Nalbantoglu A, Ovali F, Nalbantoglu B. Alkaline phosphatase as an early marker of hemolysis in newborns. Pediatr Int. 2011; 53(6) : 936 -8 [DOI][PubMed]

  • 5.

    Tinnion RJ, Embleton ND. How to use... alkaline phosphatase in neonatology. Arch Dis Child Educ Pract Ed. 2012; 97(4) : 157 -63 [DOI][PubMed]

  • 6.

    Monanu MO, Uwakwe AA, Onwubiko D. In vitro effects of sodium benzoate on the activities of aspartate and alanine amino transferases, and alkaline phosphatase from human erythrocytes of different genotypes. Biokemistri. 2005; 17(1) : 33 -8 [DOI]

  • 7.

    Chou HC, Chien CT, Tsao PN, Hsieh WS, Chen CY, Chang MH. Prediction of severe neonatal hyperbilirubinemia using cord blood hydrogen peroxide: a prospective study. PLoS One. 2014; 9(1)[DOI][PubMed]

  • 8.

    Knupfer M, Pulzer F, Gebauer C, Robel-Tillig E, Vogtmann C. Predictive value of umbilical cord blood bilirubin for postnatal hyperbilirubinaemia. Acta Paediatr. 2005; 94(5) : 581 -7 [DOI][PubMed]

  • 9.

    Okuyama H, Yonetani M, Uetani Y, Nakamura H. End-tidal carbon monoxide is predictive for neonatal non-hemolytic hyperbilirubinemia. Pediatr Int. 2001; 43(4) : 329 -33 [PubMed]

  • 10.

    Alpay F, Sarici SU, Tosuncuk HD, Serdar MA, Inanc N, Gokcay E. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns. Pediatrics. 2000; 106(2)[PubMed]

  • 11.

    Sarici SU, Yurdakok M, Serdar MA, Oran O, Erdem G, Tekinalp G, et al. 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(4)[PubMed]

  • 12.

    Fenton TR, Lyon AW, Rose MS. Cord blood calcium, phosphate, magnesium, and alkaline phosphatase gestational age-specific reference intervals for preterm infants. BMC Pediatr. 2011; 11(1) : 76 [DOI]

  • 13.

    Abbasian M, Chaman R, Delvarian Zadeh M, Amiri M, Raei M, Norouzi P, et al. Investigating the prevalence of calcium deficiency and some of its influencing factors in pregnant women and their neonates [in Persian]. Knowledge Health . 2012; 7(1) : 39 -43

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