Paediatrica Indonesiana

VOLUME 49 NUMBER 6 November 2OO9

Original Article
Paediatr Indones, Vol. 49, No. 6, November 2009 349
Correlation between cord blood bilirubin level and
incidence of hyperbilirubinemia in term newborns
Rudy Satrya, Sjarif Hidayat Effendi, Dida Akhmad Gurnida
From the Department of Child Health, Medical School, Padjadjaran
Universitv, Hasan Sadikin Hospital, Bandun,, lndonesia.
Reprint requests to: Rudy Satrya, MD, Department of Child Health,
Medical School, Padjadjaran Univeristy, Hasan Sadikin Hospital, Jl.
Pasteur no. 3o, Bandun, 11O61, lndonesia. 1el/ lax. 62-22-2O35957.
l-mail: rd_stry@yahoo.co.id.
aundice is a clinical condition that is often
present and constitutes one of the major issues
during neonatal period due to transient bilirubin
conjugation deficiency, including hepatic uptake
and intracellular transport deficiency, and increased
enterohepatic circulation.
1,2
Although jaundice affects
nearlv all newborns, 5' to 6' of healthv term newborns
develops si,nificant hvperbilirubinemia (> 12.9 m,/dl).
3
1his condition can cause cellular dama,e, especiallv
brain neuron damage resulting in neurological problems
after several years or even death.
4
American Academy
of Pediatrics (AAP) reports that kernicterus has at least
1O' mortalitv and 7O' lon,-term morbiditv if total
serum bilirubin (1SB) level is hi,her than 2O m,/dl.
5
Dischar,in, healthv term newborns from
the hospital after delivery at increasingly earlier
postnatal ages has recently become a common
practice due to medical, social, and economic
reasons. Association between an earlv dischar,ed
newborn and the risk of readmission to the hospital
has previouslv been reported, and it was most
commonly caused by hyperbilirubinemia.
6
A study by
Seidman et al
6
ln United States showed that O.36'
Abstract
Background Dischar,in, healthv term newborns from the
hospital after delivery at increasingly earlier postnatal ages has
recently become a common practice due to medical, social, and
economic reasons, however it contributes to readmission because
of jaundice.
Objective 1o investi,ate the correlation between level of cord
blood bilirubin and development of hyperbilirubinemia among
healthv term newborns.
Methods Prospective observational studv was performed on
oo healthv term newborns. Cord blood was collected for the
total bilirubin, conjugated bilirubin, unconjugated bilirubin
level measurement and blood group test. Measurements of total
bilirubin, conju,ated bilirubin, and unconju,ated bilirubin were
repeated on the 5
th
dav with serum samplin,, or as soon as the
newborn appeared to be jaundice.
Results Subjects were cate,orized into hvperbilirubinemia and
non-hvperbilirubinemia newborns. 1here was a correlation
between cord blood and the 5
th
day bilirubin level. By ROC
analvsis, cord blood bilirubin level of ~2.51 md/dl was determined
to have hi,h sensitivitv (9O.5'), specificitv of o5', and accuracv
of o6.1'.
Conclusions 1here is a correlation between cord blood bilirubin
level and hvperbilirubinemia in healthv term newborns. Cord
blood bilirubin level at or ,reater than 2.51 m,/dl can predict
the development of hyperbilirubinemia. [Paediatr Indones.
2009;49:349-54].
Keywords: cord blood, hyperbilirubinemia, early
detection, newborn, jaundice
J
Rudy Satrya et al: Cord blood bilirubin level and hyperbilirubinemia
350 Paediatr Indones, Vol. 49, No. 6, November 2009
of healthv term newborns developed severe neonatal
hvperbilirubinemia in the first postnatal week and
had to be readmitted to the hospital.
6
1he problem
is the recognition of jaundice becomes more difficult.
Severe jaundice, and even kernicterus, can occur in
some full-term healthv newborns with no apparent
hemolvsis, jaundice in the first 21 hours, or anv causes
other than breastfeeding hyperbilirubinemia.
Early detection and recognition of risk factors
before dischar,in, newborns from the hospital are
the primary prevention of severe hyperbilirubinemia
development. Some studies use the first 21 hours of
newborns total serum bilirubin (1SB) as a predictor
of hvperbilirubinemia development, while others
try to find another methods such as transcutaneous
bilirubinometry and cord blood bilirubin measurement.
Venipuncture, which is performed to ,et the blood
sample for 1SB examination, is an invasive procedure
and has a risk of injury or infection, is not a practical
procedure to be done as a routinely. Examination of
newborns' cord blood bilirubin level is a non-invasive
procedure and can increase early detection coverage to
prevent severe hyperbilirubinemia.
7,o
We investi,ated
the correlation between level of cord blood bilirubin at
birth and the development of hyperbilirubinemia in the
first week of life amon, healthv term newborns.
Methods
1his was a prospective cohort studv, carried out at
Perinatology Division, Department of Child Health,
Hasan Sadikin Hospital, Bandung, during the period
Januarv to lebruarv 2OO9. We enrolled healthv full-term
newborns (37-12 weeks of ,estation as determined bv
New Ballard Score), both ,enders, delivered bv va,inal
deliverv or cesarean section with birth wei,ht ~ 25OO ,
and Ap,ar score ~ 7 at 5 minutes. Newborns with AB
incompatibilitv were excluded.
All subjects were cared with the roomin,-
in method to ensure the practice of exclusive
breastfeedin,. lnformed consent was obtained from
all parents. 1he studv was approved bv the 1he
Health Research Ethics Committee, Medical School,
Padjadjaran University, Bandung.
Historv takin, was performed to the mother,
includin, mother's a,e, ethnic, medical historv,
pre,nancv historv, dru,, siblin,'s historv of jaundice,
and parents' blood ,roup. Cord blood samples were
collected from all newborns that complied with
the inclusion criteria protocol at the delivery. An
amount of 2 ml cord blood was required and sent to
clinical laboratory of Hasan Sadikin Hospital for the
measurement of total bilirubin, conjugated bilirubin,
Figure 1. Nomogram of risk determination in well newborns at 36 or more weeks gestational
age with birth weight of 2000 g or more or 35 or more weeks gestational age and birth
weight of 2500 g or more based on the hour-specic serum bilirubin values
Rudy Satrya et al: Cord blood bilirubin level and hyperbilirubinemia
Paediatr Indones, Vol. 49, No. 6, November 2009 351
unconju,ated bilirubin level (referred as 1B
O
, CB
O
,
UB
O,
thereafter) and blood ,roup test. 1he newborns
were then followed up accordin, to the routine
neonatal unit admission procedure. Measurement of
total bilirubin, conjugated bilirubin, unconjugated
bilirubin level were repeated on dav 5 (1B
5
, CB
5
,
UB
5
) with serum samplin,, or as soon as the newborn
appeared to be jaundice. Newborns whose parents
were dischar,ed earlv, were su,,ested to visit the
perinatology clinic in the outpatient department on
dav 5, or as soon as the newborns appeared to be
jaundiced. 1otal bilirubin (1B) level was measured
usin, Vitros 25O Chemistrv Svstem Spectrophotometer
(rtho-Clinical Dia,nostics, Johnson c Johnson
Companv) at room temperature. Subjects with 1B
level of ~ 12.9 m,/dl on the 5
th
dav or when the
newborns appeared to be jaundice were defined as
having hyperbilirubinemia and they had to undergo
phototherapy.
Non-phvsiolo,ic hvperbilirubinemia was defined
as level of 1SB above the 95
th
percentile based on the
normogram (Figure 1).
9,1O
Blood group incompatibility
was defined as a newborn with non- blood ,roup
who was delivered bv blood ,roup mother, or
rhesus-positive newborns who were delivered from
rhesus-ne,ative mother.
11
1he correlation between cord blood bilirubin
level and 1SB on dav 5 or when the newborns appeared
to be jaundice was determined bv the linear re,ression
analvsis. 1he correlation stren,th of these variables
was determined usin, Pearson correlation coefficient.
1he cut-off point of total cord blood bilirubin level was
determined using the receiver operating characteristic
(RC) curve analvsis, then sensitivitv, specificitv, and
accuracv were obtained. Cord blood bilirubin level and
confoundin, risk factors were analvzed with lo,istic
re,ression, and P values with si,nificance of less than
O.O5 were considered statisticallv si,nificant.
Results
A total of oo newborns was enrolled, 5O (57') were
male and 3o (13') female. Mean ,estational a,e
was 3o.9 weeks, and mean birth wei,ht was 3O57
,rams. Sixtv-six newborns (75') were delivered
va,inallv, the rest were delivered bv cesarean section.
1wentv-one newborns (21') developed si,nificant
Table 1. Characteristics of subjects
Characteristics Hyperbilirubinemia
P Yes (n=21) No (n=67)
Gender - n
Male
Female
Delivery mode - n
Vaginal
Cesarean
Subjects blood group - n
A
B
O
AB
Mothers blood group - n
A
B
O
AB
Feeding pattern - n
Breast milk
Partially breast milk
Formula milk
Gestational age - weeks
Mean (SD)
Range
Birth weight - g
Mean (SD)
Range
Maternal age - yr
Mean (SD)
Median
Range
Parity - n
Mean (SD)
Interval
16
5
16
5
8
4
7
2
11
5
5
0
8
13
0
38.7 (1.42)
37-42
2981(326)
2500-3600
27.76(7.6)
27.0
17-40
0.86 (1.24)
0-4
34
33
50
17
23
16
23
5
29
15
18
5
39
24
4
39 (1.30)
37-42
3080(428.3)
2500-4170
27.43(5.74)
27.0
17-39
1.01(1.39)
0-9
0.040
0.885
0.956
0.587
0.08
0.287

0.402

0.833

0.439

T test analysis

Mann-Whitney test analysis

Figure 2. ROC curve analysis
Rudy Satrya et al: Cord blood bilirubin level and hyperbilirubinemia
352 Paediatr Indones, Vol. 49, No. 6, November 2009
hvperbilirubinemia (total serum bilirubin ~ 12.9 m,/
dl on dav 5). 1here was a si,nificant difference in
sex between newborns who developed and did not
develop si,nificant hvperbilirubinemia (P~O.O1).
Characteristics of subjects are presented in Table 1.
Statistical analvsis with Mann-Whitnev test
showed that conju,ated and unconju,ated bilirubin
level in cord blood was si,nificantlv different
(P<O.OO1) between both ,roups (Table 2). Re,ression
analvsis was used to determine correlation between
total bilirubin in cord blood and on dav 5 with
equation: v~ 6.o251.16Ox (r~O.71O, P<O.OO1).
By ROC analysis (Figure 2), it was determined
that total bilirubin level in cord blood of ~ 2.51 m,/
dl had a hi,h sensitivitv (9O.5'), hi,h specificitv
(o5'), and accuracv of o6.1' (Table 3). Reliabilitv
was determined with Kappa lndex (K) of O.66o
(substantial a,reement).
lo,istic re,ression analvsis was used to determine
risk factors involved in the development of significant
hvperbilirubinemia, and sex that in bivariables showed
significant association (Table 4).
Discussion
1here is a concern about increasin, incidence
of kernicterus in healthy term neonates, and
hyperbilirubinemia is one of the most common causes
for readmission of the newborns. 1he need for earlv
detection of hyperbilirubinemia in early discharged
newborns from the hospital is therefore important.
Knowled,e of infants at risk of developin, jaundice
allows simple bilirubin reducin, methods to be
implemented before bilirubin levels reach critical
levels.
13
1his studv showed a si,nificant correlation
between total bilirubin level in cord blood and
incidence of si,nificant hvperbilirubinemia (P<O.OO1)
and critical level of 2.51 m,/dl could predict the
development of significant hyperbilirubinemia in the
first week of life with sensitivitv of 9O.5', specificitv
of o5', and accuracv of o6.1'.
Bernaldo and Segre
11
found that the critical
bilirubin level of ~ 2.O m,/dl indicated 53' probabilitv
of the need for further treatment by phototherapy,
and when the level was 3.O m,/dl, the probabilitv of
needin, treatment was o6'. lf it was 3.5 m,/dl, the
Table 2. Bilirubin level in subjects cord blood
Bilirubin in
cord blood
Hyperbilirubinemia
Z
M-W
P value
Yes (n=21) No (n=67)
Total bilirubin (mg/dL)
Mean (SD)
Median
Interval
Conjugated bilirubin (mg/dL)
Mean (SD)
Median
Interval
Unconjugated bilirubin (mg/dL)
Mean (SD)
Median
Interval
3.77(1.07)
3.50
2.34-6.60
0.23(0.31)
0.0
0.0-0.86
3.53(1.20)
3.40
1.71-6.60
2.14(0.58)
2.03
0.90-4.22
0.18(0.28)
0.0
0.0-0.87
1.94(0.60)
1.90
0.80-3.93
6.084
0.659
5.564
<0.001
0.51
<0.001
SD=Standard deviation; Z
M-W
= Mann-Whitney test
Tabel 3. Sensitivity, specicity, and accuracy of total bilirubin
critical level in cord blood on development of significant
hyperbilirubinemia
Total Bilirubin Critical Level
in Cord Blood (mg/dL)
Hyperbilirubinemia
Total
Yes (n=21) No (n=67)
2.54
<2.54
19
2
10
57
29
59
Total 21 67 88
Tabel 4. Logistic regression analysis
Variable B
Coefcient
SE(B) P
value
OR
(95%CI)
Cord total bilirubin
(2.54 mg/dL)
Gender
( to )
Constanta
4.473
-2.026
-0.824
0.925
0.826
-
<0.001
0.014
-
87.60
(14.3 to 536.68)
0.132
(0.026 to 0.665)
Model Accuracy: 90.9%
SE: standard error
Rudy Satrya et al: Cord blood bilirubin level and hyperbilirubinemia
Paediatr Indones, Vol. 49, No. 6, November 2009 353
probabilitv went up to 93' (P<O.OO1). Sun et al
15
found that cord blood bilirubin level could predict
the development of significant hyperbilirubinemia in
healthv term newborns. 1his studv show the bilirubin
in cord blood critical level of ~ 35 umol/l (2 m,/dl)
had positive predictive value of 15.6o' and sensitivitv
of 6o.27 (P<O.OO1).
Rataj et al
16
carried out a studv in oOO healthv
term newborns and the results showed a similaritv
with the current studv as reported that critical
bilirubin level in cord blood of >2.5 m,/dl had a
probabilitv of o9' for the development of si,nificant
hvperbilirubinemia in newborns.
Knudsen,
17
in 19o9, carried out a studv to
demonstrate that jaundiced newborns presented
higher umbilical cord blood bilirubin levels than
newborns without clinical jaundice. ln addition,
the number of jaundiced newborns under,oin,
phototherapv was si,nificantlv hi,her when these
levels were hi,her than 2.3 m,/1OO dl, in comparison
with number of jaundiced newborns with no need for
treatment whose bilirubin levels were lower than or
equal to 2.3 m,/1OO dl. 1his proved the possibilitv of
definin, a newborn risk ,roup for developin, neonatal
hyperbilirubinemia at birth.
1here are conflictin, reports of the predictabilitv
of cord blood bilirubin of later hyperbilirubinemia.
A studv in lran, concluded that cord bilirubin levels
could not identifv newborn infants who were at risk for
developing significant hyperbilirubinemia.
1o
A total of
631 healthv term and exclusivelv breast-fed newborns
were enrolled in this studv. Seventv-six newborns
(11.o') had si,nificant hvperbilirubinemia (~11 m,/
dl) with mean level of bilirubin in cord blood of 37.1
(SD 17) umol/l (2.2 (SD 1.O) m,/dl) and mean level
of bilirubin in cord blood was 31 (SD 16) umol/l (2.O
(SD O.9) m,/dl) in newborns who did not develop
significant hyperbilirubinemia. Based on the data there
was no si,nificant difference between two ,roups.
Critical level of bilirubin in cord blood found
was 1 m,/dl with sensitivitv of 7.9', specificitv
of 97.7', positive predictive value of 31.6', and
ne,ative predictive valeu of oo.o'. Based on the
data, it was found that bilirubin level in cord blood
could not predict the development of significant
hvperbilirubinemia in newborns.
We found that male newborns had hi,her risk of
developin, si,nificant hvperbilirubinemia (P~O.O1).
AAP had reported male gender as one of the minor risk
factor,
12
this was in a,reement with previous studies.
1o,19
lourteen subjects were dropped out from our follow-up
and this condition could influence statistical analysis
in this studv. limited period of follow up, also not dailv
total and unbound bilirubin measurements were also
considered as the weakness of our studv.
We conclude that bilirubin level in cord blood
has a correlation with the incidence of si,nificant
hvperbilirubinemia in term newborns. Bilirubin level
of ~2.51 m,/dl could predict the development of
si,nificant hvperbilirubinemia in term newborns.
References
1. Maisels MJ. Jaundice. ln: MacDonald MO, Seshia MMK,
Mullett MD, editor. Averv's neonatolo,v. 6
th
edition.
Philadelphia: lippincott Williams c Wilkins, 2OO5, p.
76o-o16.
2. Rubaltelli l, Dani C. Neonatal jaundice. ln: Kurjak A,
Chervenak lA, editor. 1extbook of perinatal medicine. 2nd
edition. New York: lnforma Healthcare, 2OO6, p. 5o-6o.
3. Bhutani VK, Oourlev OR, Adler S, Kreamer B, Dalin C,
Johnson LH. Noninvasive measurement of total serum
bilirubin in a multiracial predischar,e newborn population
to assess the risk of severe hyperbilirubinemia. Pediatrics.
2OOO,1O6:e17.
1. Arimbawa lM, Soetjinin,sih, Kari lK. Adverse effects of
hyperbilirubinemia on the development of healthy term
infants. Paediatr lndones. 2OO6,17:51-6.
5. lp S, Chun, M, Kuli, J, 'Brien R, Se,e R, Olicken S, et al.
An evidence-based review of important issues concernin,
neonatal hvperbilirubinemia. Pediatrics. 2OO1,111:e13O-53.
6. Seidman DS, Stevenson DK, lr,az z, Oale R. Hospital
readmission due to neonatal hyperbilirubinemia. Pediatrics.
1995,96:727-9.
7. Bernaldo AJN, Se,re CAM. Bilirubin dosa,e in cord blood:
could it predict neonatal hvperbilirubinemia' Sao Paulo Med
J. 2OO1,122:99-1O3.
o. Martin l. Cord blood samplin,-cord blood tests |homepa,e
on the internet]. c2OOo |cited 2OOo Mav 29]. Available from:
www.medicineonline.com/topics/C/2/cord-blood-samplin,/
cord-blood-tests/info/html.
9. Madan A, MacMahon JR, Stevenson DK. Neonatal
hvperbilirubinemia. ln: 1aeusch HW, Ballard RA, Oleason
CA, editor. Averv's diseases of the newborn. o
th
ed.
Philadelphia: WB Saunders Co, 2OO5, p. 1226-53.
Rudy Satrya et al: Cord blood bilirubin level and hyperbilirubinemia
354 Paediatr Indones, Vol. 49, No. 6, November 2009
1O. Madan A, Won, RJ, Stevenson DK. Clinical features and
management of unconjugated hyperbilirubinemia in term and
near term infants |homepa,e on the internet]. c2OOo |cited
2OOo Mav 29]. Available from: https://store.utdol.com/app/
index.asp. uptodate.
11. Nicolaides KH, Sebire NJ. Mana,ement of the red cell
isoimmunized pre,nancies. ln: Kurjak A, Chervenak lA,
editor. 1extbook of perinatal medicine. 2nd edition. New
York: lnforma Healthcare, 2OO6, p. 1151-61.
12. American Academv of Pediatrics Subcommittee on
Hyperbilirubinemia: Management of hyperbilirubinemia in
the newborn infant 35 or more weeks of ,estation. Pediatrics.
2OO1,111:297-316.
13. Rostami N, Mehrabi Y. ldentifvin, the newborns at risk for
developing significant hyperbilirubinemia by measuring cord
bilirubin levels. J Arab Neonatal lorum. 2OO5,2:o1-5.
11. Sun O, Wan, Yl, lian, Jl, Du lz. Predictive value of
umbilical cord blood bilirubin level for subsequent neonatal
jaundice. zhon,hua lr Ke za zhi. 2OO7,15:o1o-52.
15. Rataj J, Kornacka M, Korman l. Usefulness of measurin,
bilirubin level in cord blood for predicting hyperbilirubinemia
in newborns. Oinekol Pol. 1991,65:276-oO.
16. Knudsen A. Prediction of the development of neonatal
jaundice by increased umbilical cord blood bilirubin. Acta
Paediatr. 19o9,7o:217-21.
17. Rostami N, Mehrabi Y. ldentifvin, the newborns at risk for
developing significant hyperbilirubinemia by measuring cord
bilirubin levels. J Arab Neonatal lorum. 2OO5,2:o1-5.
1o. Newman 1B, Xion, B, Oonzales VM, lscobar OJ. Prediction
and prevention of extreme neonatal hyperbilirubinemia in
a mature health maintenance organization. Arch Pediatr
Adolesc Med. 2OOO,151:111O-7.
19. Maisels MJ, Krin, lA. len,th of stav, jaundice and hospital
readmission. Pediatrics 199o,1O1:995-o.