Original Article

Does Prophylactic Phototherapy Prevent Hyperbilirubinemia in

Neonates with ABO Incompatibility and Positive Coombs Test?
Hakam Yaseen, MD, CES, DUN
(France), FRCPCH (UK)
Mona Khalaf, MRCP
Najat Rashid, PhD
Maha Darwich, MD, CES

OBJECTIVE:

The objective of the study was to determine whether initiation of early

phototherapy in positive direct Coombs test (DCT) with ABO-incompatible
newborns would prevent severe jaundice.
STUDY DESIGN:
A prospective controlled study was performed at Al Qassimi Hospital.
Infants born at term and weighing >2000 g with ABO incompatibility and
a positive DCT were included in the study. Within their first 4 hours of life
and after parental consent, infants were enrolled into one of two groups:
prophylactic phototherapy group, which received phototherapy during the
first 24 hours of life (group I), or no prophylactic phototherapy, which
represents the control group (group II). Selection of infants to either
group was by 2-week alternative strategy.
Blood group, complete blood count (CBC), reticulocyte count, blood
smears, total serum bilirubin (TSB) and DCT were performed on cord
blood of all neonates born to mothers with O-positive blood group. CBC,
reticulocytes and TSB level were obtained in all enrolled infants at 12, 24,
48, 72, and 96 hours of life.
RESULTS:
During the study period, 242 newborns with positive DCT were enrolled. A
total of 102 infants were allocated to the prophylactic phototherapy arm
and 140 as controls.
Prophylactic phototherapy was associated with a significant decrease in
the TSB at 24 hours ( p 0.002) and at 48 hours ( p 0.003) but not
later on. The total number of patients who had hyperbilirubinemia at any
time during the first 96 hours was significantly less in the prophylactic

Pediatric/Neonatal Department (H.Y., M.K.), Al Qassimi Hospital, Sharjah, United Arab Emirates;
Laboratory Department (N.R.), Al Qassimi Hospital, United Arab Emirates; and Pediatrics
Department (M.D.), Al Falah Hospital, Sharjah, United Arab Emirates.
Address correspondence and reprint requests to Hakam Yaseen, MD, CES, DUN (France),
FRCPCH (UK), PO Box 25624, Sharjah, United Arab Emirates.

group (17 vs 45 F p 0.006). Prolonged hospital stay because of

phototherapy was more frequent in the control group (p 0.03).
CONCLUSION:
Prophylactic phototherapy was associated with a significant reduction of
TSB in the first 48 hours of life but not later on. Clinical benefits of this
strategy could not be proven.
Journal of Perinatology (2005) 25, 590594. doi:10.1038/sj.jp.7211356;
published online 21 July 2005

INTRODUCTION
Hyperbilirubinemia is a frequent cause of readmission to neonatal
units.1 In a retrospective analysis of readmitted neonates who
had significant jaundice with total serum bilirubin (TSB) of
Z340 mmol/l, ABO incompatibility was found as the main cause
of readmission.2 ABO incompatibility occurs in 20 to 25% of
pregnancies and hemolytic disease develops in around 10% of such
offspring.3
A presumptive diagnosis of hemolysis is based on the presence of
ABO incompatibility, unconjugated hyperbilirubinemia, a positive
direct Coombs test (DCT), spherocytes in the blood smear,
increased reticulocytes, with extensive polychromasia and increased
numbers of nucleated red blood cells.3 Positive DCT, high
reticulocyte count and positive family history of neonatal jaundice
are strong predictors of hyperbilirubinemia in ABO-incompatible
newborns.4 It is also known that the risk of neonatal jaundice is
four times higher in infants with positive DCT compared to those
with negative DCT.5 However, severe jaundice and even kernicterus
can occur in some of these neonates with no apparent early
findings of hemolysis.6 Thus, early diagnosis and perhaps
preventive treatment may be useful. Guidelines for phototherapy
management in ABO incompatibility with positive DCT were
previously published by Osborn et al.7In our unit, phototherapy is
utilized when TSB is Z95% according to the time-based bilirubin
nomogram.8
Recently, Stanley et al.9 reported that there was no evidence to
suggest that phototherapy for neonatal hyperbilirubinemia had any
long-term adverse neurodevelopmental effects. Efficacy of
prophylactic phototherapy in babies with positive DCT and ABO
incompatibility has been evaluated previously in two studies with
inconclusive results.10,11 Phototherapy was initiated relatively late
with mean age at study entry of more than 50 hours. The authors
Journal of Perinatology 2005; 25:590594
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Prophylactic Phototherapy in ABO Incompatibility

of one study10 felt that poor response to phototherapy was related

to a significant delay in starting the light therapy. We conducted
this prospective, quasirandomized study to determine whether
earlier initiation of prophylactic phototherapy prevents
hyperbilirubinemia in ABO-incompatible newborns with positive
Coombs test.

METHODS
Participant Criteria
This study was performed between March 2001 and February 2003.
The study was approved by the hospital research and ethical
committee. According to our units policy, cord blood should be
obtained from all newborns with group O mothers. The TSB, blood
group, DCT, complete blood count (CBC) with smear and
reticulocyte count were carried out on each sample.
Infants were eligible for enrolment into the study if they
had completed 37 weeks of gestation and had a birth weight
>2000 g, and if their blood group was either A, B or AB with
positive DCT.
Exclusion criteria were (1) neonates having any illness that
would require admission to the neonatal intensive care unit as
respiratory distress requiring oxygen, (2) sepsis or severe congenital
malformations, (3) infants with other causes of jaundice including
breastfeeding jaundice, dehydration, cephalohematoma and
(4) hemolytic diseases other than ABO incompatibility such as
Rh incompatibility, minor blood group incompatibility or
glucose-6-phosphate dehydrogenase (G6PD) deficiency. Informed
consent was obtained from all parents before enrolling infants
in the study.
Study Design
This was a prospective controlled study including all
ABO-incompatible term newborns with positive DCT diagnosed
within 4 hours of life. Infants were quasirandomized into two
groups: the phototherapy prophylactic group (group I), which
received phototherapy started within the first 4 hours of life until
completed 24 hours of life, and the control group (group II), which
did not receive prophylactic phototherapy. Selection of patients to
either group was by 2-week alternative strategy; for example,
Infants who were born in the first 2 weeks of this study were
enrolled into group I, infants born in the second 2 weeks were
enrolled into group II, next 2 weeks were assigned for group 1 and
so on through out the study period.
The babies were placed in the incubator seminaked except for
eye shield, 40 cm from the source of light, which was six
fluorescent light tubes (four blues and two whites) (AMEDA Engell
(EN 60 601-1), Hunenberg). Light tubes were tested for irradiance
every 200 hours. Spectral irradiance is measured at multiple sites
by a radiometer with desired values of 8 to 10 microwaves/cm2/nm.
Adequate fluid intake was ensured by completing breast feeds with
Journal of Perinatology 2005; 25:590594

Yaseen et al.

artificial feeds if necessary. CBC, reticulocyte count, and serum

direct and indirect bilirubin levels were performed in all enrolled
infants at 12, 24, 48, 72 and 96 hours of life. TSB was monitored
every 4 hours for infants whose serum bilirubin was increasing in
spite of phototherapy and in all neonates requiring intensive
phototherapy.
Minor group identification and measurement of the G6PD were
performed in the following conditions: high reticulocytes >6%,
poor response to phototherapy when TSB Z20 mg/dl, or in infants
who had family history of G6PD deficiency.
Serum bilirubin level was measured using a Diminsion
bilirubinmeter (DADE Behring Diminsion RXL-France). Coombs
test was performed using the standard Direct Autoglobulin
Test (DAT).
Hyperbilirubinemia was defined as TSB Z95th percentile
according to the percentile-based hourly bilirubin nomogram.10
Rescue phototherapy for infants in both groups was indicated in
case of hyperbilirubinemia. Rescue phototherapy was discontinued
whenever the TSB decreased 1 mg/dl below the 95th percentile. TSB
levels were monitored after 12 and 24 hours of phototherapy
discontinuation. Intensive phototherapy (Mediprema, GDE 1596,
France) was indicated when TSB continued to increase in spite of
initiation of standard phototherapy or if the serum bilirubin level is
>20 mg/dl and just before preparing for exchange blood
transfusion procedures. Our intensive phototherapy equipment
usually provided >30 microwaves/cm2/nm. Exchange transfusions
were performed in both groups when TSB exceeded 20 mg/dl
(342 mmol/l) and did not decrease below that level within 4 hours
of intensive phototherapy.
In all cases, the following was recorded: gender, birth weight,
daily weight gain, gestational age, mode of delivery route, feeding
pattern, Apgar scores, chronic maternal diseases (e.g. hypertension,
diabetes mellitus, etc.) during pregnancy and whether there were
any siblings with neonatal jaundice. According to our hospital
policy, ABO-incompatible neonates who have positive DCT are
discharged home at 48 hours if their TSB <95th percentile. For
these babies, TSB was monitored at 72 and 96 hours of life in the
pediatric ambulatory clinic. Prolonged hospital stay was defined as
failure to discharge an infant by 48 hours of age because of
hyperbilirubinemia requiring phototherapy.
Evaluation Criteria
Efficacy of prophylactic therapy was monitored by comparing the
two groups on their major outcome variables such as daily TSB,
number of hyperbilirubinemic neonates, number of infants who
received intensive phototherapy or exchange transfusion, number
of infants who had prolonged hospital stay or readmission after
hospital discharge for jaundice.
Statistical data were analyzed with the independent t-test for
continuous data and by w2 analysis for categorical data.
Significance of these tests was determined as p<0.05.
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Yaseen et al.

Prophylactic Phototherapy in ABO Incompatibility

Table 1 Perinatal Characteristics of the Two Groups

Birth weight (g)

Gestational age (weeks)
Cesarean delivery (%)
Breastfeeding (%)
Sibling with jaundice (%)
Cord hemoglobin (g/dl)
Cord reticulocytes (%)
Cord TSB (mg/dl)

Table 2 Comparison of Outcome Between the Two Groups

Prophylactic
group
(n 102)

Control
group
(n 140)

p-Values

3302401
391.1
17 (17)
78 (76)
31 (30)
14.31.5
7.55
2.21.05

3282503
390.7
24 (17)
103 (74)
44 (31)
13.92
73
2.30.88

0.74
0.12
0.9
0.54
0.86
0.09
0.42
0.34

Birth weight, gestational age, hemoglobin and total serum bilirubin (TSB) are
calculated as meanSD.

RESULTS
During the 2-year study period, a total of 9611 live-born term
neonates were delivered at our institution. Of these, 1222 neonates
(13%) had ABO incompatibility (mothers blood group was O and
their neonates were A, B or AB. From this population, 980 were
excluded for the following reasons: 851 were negative Coombs test,
63 were G6PD deficient, 53 had hemolytic disease due to Rh or
minor group incompatibles and 13 patients due to incomplete data.
Our study population included 242 positive Coombs ABOincompatible neonates. They were divided into two groups: 102
neonates were enrolled as the prophylactic phototherapy group
(57% were maternal type O and infant type A, and 43% were
maternal type O and infant type B) and 140 neonates were enrolled
as the control group (81% type O and A, and 19% type O and B).
No type O mother with an AB infant was found.
Perinatal characteristics of both groups are reported in Table 1,
with no significant differences.
Evaluation of Prophylactic Phototherapy
Prophylactic phototherapy during the first day of life was associated
with a significant decrease in the TSB at 24 hours (p 0.002) and
at 48 hours (p 0.003) but not at 72 and 96 hours (Table 2). In
order to evaluate the clinical significance of these results, we
determined the number of neonates in each group who developed
hyperbilirubinemia with TSB Z95th percentile at 24, 48 and
96 hours of life. At 24 hours of life, hyperbilirubinemia was detected
in 15 patients (15%) in the prophylactic group compared with 45
controls (32%) (p 0.006).
All of the controls who required phototherapy did so in the first
24 hours with a mean age of 177 hours of life (ranging between
8 and 24 hours of life). With initiation of rescue phototherapy, the
difference in number of hyperbilirubinemic patients was not
significant at 48 hours (nine patients in the prophylactic group vs
18 controls) and at 96 hours, with seven patients in both groups.
592

12h-TSB (mg/dl)
24h-TSB (mg/dl)
48h-TSB (mg/dl)
72h-TSB (mg/dl)
96h-TSB (mg/dl)
Hyperbilirubinemic infants (%)
Prolonged hospitalization* (%)
Readmission (%)

Prophylactic
group
(n 102)

Control
group
(n 140)

p-Values

5.92.7
6.42.7
8.22.8
11.43.7
10.54.9
17 (17)
9 (9)
6 (6)

6.62
7.73
9.43.1
12.42.6
114.7
45 (32)
26 (19)
13 (9)

0.2
0.002
0.003
0.25
0.51
0.006
0.03
0.33

h hours of life; TSB (total serum bilirubin) was calculated as meanSD.

*Hospital stays for more than 48 hours.

The total number of infants who developed hyperbilirubinemia

at any time during the first 96 hours was significantly lower in the
prophylactic group with only 17 patients (17%) compared to 45
controls (32%) (p 0.006) (Table 2). The number needed to be
treated (NNT) for prevention of hyperbilirubinemia was 7. Three
patients from the prophylactic group required intensive
phototherapy compared to nine patients in the control group
(p 0.21). Blood exchange transfusion was performed in three
patients of the control group and none in the prophylactic group.
Prolonged hospital stay for more than 48 hours because of the
need for rescue phototherapy was significantly lower in the
prophylactic group with nine patients compared to 26 controls
(p 0.03). Out of the 26 controls, 17 stayed between 49 and
72 hours, seven stayed >72 hours and <120 hours and the
remaining two infants stayed >120 hours. Out of the nine Infants
in the prophylactic group, six stayed between 49 and 72 hours and
three stayed between 73 and 120 hours.
In an attempt for an early prediction of a group with positive
Coombs ABO-incompatible neonates who might develop
significant jaundice, which would require rescue phototherapy and
prolonged hospital stay, we analyzed the data of the 26 patients
from the control group who had prolonged hospital stay
Z48 hours for rescue phototherapy. Table 3 summarizes the
accuracy of different tests for early prediction of
hyperbilirubinemia.

DISCUSSION
Prophylactic phototherapy when applied during the first 24 hours
of life in positive Coombs ABO-incompatible neonates was
associated with a significant decrease in TSB at 24 and 48 hours of
life but not at 72 and 96 hours.
Significant clinical jaundice was defined by Bhutani et al.8 as
hyperbilirubinemia with TSB Z95th percentile corrected for
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Prophylactic Phototherapy in ABO Incompatibility

Yaseen et al.

Table 3 Measuring the Accuracy of Different Tests for Early Prediction of Hyperbilirubinemia at Z48 hours in the Control Group

Cord retics >6

Cord TSB Z4 mg/dl
24h-TSB Z8 mg/dl

Sensitivity (%)

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

LR

p-Value

95
24
96

61
95
78

39
55
53

98
84
99

2.4
4.8
4.4

<0.0001
0.002
<0.0001

LR likelihood ratio, h hours of life, TSB total serum bilirubin, Retics reticulocytes.

postnatal age. Based on their data, the probability of subsequent

severe hyperbilirubinemia was increased from two- to three-fold if
the predischarge TSB was Z95th percentile. A new hour-specific
serum bilirubin nomogram for infants with hemolysis has been
recommended by the American Academy of Pediatrics (AAP).12 It is
largely similar to the nomogram that was used in the Method
section of this present study.
In our study, the number of patients in whom TSB was Z95th
percentile was significantly lower in the prophylactic group at
24 hours of life but not later on. A recent evidence-based review
showed that phototherapy had an absolute risk-reduction rate of 10
to 17% for prevention of hyperbilirubinemia in healthy jaundiced
infants.9 Our study demonstrated a similar reduction of 15%. The
absence of difference in number of hyperbilirubinemic patients
between 48 and 96 hours was explained by the initiation of early
rescue phototherapy within the first 24 hours in the controls.
Although prophylactic phototherapy was associated with lower
bilirubin levels during the first 48 hours of life, we believe that
such strategy would not lead to a significant clinical benefit for the
following reasons: first, it was noted that 68% of the controls did
not need phototherapy, so a significant number of infants in the
prophylactic group received phototherapy needlessly. Second, the
difference in TSB between the two groups was not clinically
significant beyond 48 hours of life. Third, the majority of controls
(65%) who had prolonged hospital stay were discharged by
72 hours of life. Fourth, the readmission rate for
hyperbilirubinemia was not significantly different between the two
groups.
We found that cord TSB Z4 mg/dl (Z68 mmol/l) was highly
specific of subsequent hyperbilirubinemia. Risemberg et al.13 found
that all ABO-incompatible newborns in whom the cord bilirubin
was greater than 4 mg/dl developed severe hyperbilirubinemia with
TSB >16 mg/dl at 12 to 36 hours. Other investigators showed
similar results.14,15 Prophylactic phototherapy was previously
recommended for newborns with cord TSB Z4 mg/dl.11 However,
as it is shown in Table 3, cord TSB Z4 mg/dl has a very low
sensitivity, with a high level of false-negative cases. We found that
the best predictor of hyperbilirubinemia at Z48 hours of life was
the 24-hour TSB when it was Z8 mg/dl.
These results support the necessity for routine predischarge
measurement of TSB at 24 hours in ABO affected infants.
Predischarge measurement of the bilirubin level and/or assessment
Journal of Perinatology 2005; 25:590594

of clinical risk factors were strongly recommended by the AAP.12

Alpay et al.16 demonstrated that a critical bilirubin level of 6 mg/dl
in the first 24 hours of life predicted nearly all of term newborns
who developed subsequently significant hyperbilirubinemia.
Limitations to our study may be the selection of patients
who were only quasirandomly distributed. Secondly, we retrospectively calculated the ideal sample size to detect the effect
of phototherapy to decrease the TSB from 32 to 17% with 5%
level of significance and 80% power. The ideal sample size for
this study is around 270, which is slightly higher than our sample
size (242).
In conclusion, prophylactic phototherapy in positive
Coombs test ABO-incompatible newborns was associated with
a significant decrease in TSB within the first 48 hours of life;
however, it did not result in a sustained clinical benefit. Hence, our
results do not support the use of prophylactic phototherapy in
babies with ABO incompatibility and a positive DCT. Frequent
monitoring of TSB and early rescue phototherapy was an
acceptable management strategy for these patients. TSB Z8 mg/dl
at 24 hours of life was the best predictor of hyperbilirubinemia
at Z48 hours of life.
Acknowledgements
We extend our thanks and gratitude to Pr. Khalid Haque Reader in Neonatal
Pediatrics, University of London and Consultant Neonatologist at Queen Mary
children hospital in UK, and to Professors Arne Ohlsson and Balf from the
University of Toronto for their helpful comments. We also thank Ms. Noha Yaseen
for typing this manuscript.

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