Early Human Development 140 (2020) 104909

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Early Human Development

journal homepage: www.elsevier.com/locate/earlhumdev

The spectrum of bilirubin neurotoxicity in term and near-term babies with T

hyperbilirubinemia: Does outcome improve with time?
⁎
Sarah S. ElTatawya, , Esraa A. Elmazzahya, Amira M. El Shennawyb, Hanan A. Madanib,
Hazem Abou Youssefb, Iman F. Iskandera
a
Cairo University Children's Hospital, Cairo University, Egypt
b
Kasr Al Ainy Hospital, Cairo University, Egypt

A R T I C LE I N FO A B S T R A C T

Keywords: Background: While neonatal jaundice is generally a common benign condition; severe hyperbilirubinemia has a
BIND score devastating potential for brain injury.
Neurodevelopment Aim: To detect the impact of severe neonatal hyperbilirubinemia on motor and mental development and its
Bayley scales of infant development (BSID) progress over time in the first year of life using the Bayley scales of infant development (BSID) II.
Psychomotor
Study design and patients: 177 term/near-term infants admitted for neonatal hyperbilirubinemia to the NICU of
Developmental index (PDI)
Cairo University Children's Hospital were enrolled. Clinical examination, BIND score and laboratory tests were
Mental developmental index (MDI)
Auditory impairment performed at admission. Neurodevelopmental assessment using BSIDΙΙ was performed at 3 months for 147/177
Auditory brain stem response (ABR) neonates, and at 6 months and 12 months for 139/177 neonates. Auditory brainstem evoked potential was re-
Bilirubin induced neurologic dysfunction corded at 3 months of age and repeated if abnormal.
Hyperbilirubinemia Outcome measures: Psychomotor (PDI) and mental developmental indices (MDI) using BSIDII. Auditory im-
Kernicterus pairment using Auditory Brainstem Response (ABR).
Results: TSB levels ranged from 10 to 63 mg/dL (179.6–1077 μmol/L) with a mean of 25.52 ± 6.5 mg/dL
(436 ± 112.9 μmol/L) and BIND scores ranged from 0 to 7. By one year of age, 19/139 patients were affected; 8
had classic kernicterus, 3 had isolated auditory impairment, 1 had severe motor and mild mental delay and 7 had
mild motor delay. TSB level and BIND score had positive correlation with auditory impairment and lower scores
for PDI (which improved with time) and MDI (which remained stationary). Duration of exposure to hyperbi-
lirubinemia negatively affected neurodevelopmental scores.
Conclusion: The impact of severe hyperbilirubinemia is mainly on motor and auditory impairment. Mild mental
delay was detected by BSIDII in few patients. Neurodevelopmental outcome improves over time.

1. Introduction
Despite increased awareness regarding severe neonatal hyperbilir-
ubinemia (SNH) and its sequelae, kernicterus still occurs. A recent study
from Sweden reported 13 kernicterus cases/million births, accounting
this to professional non-adherence to best practice guidelines in the
management of SNH [1]. In developing countries, guidelines for
screening and management of SNH in many hospitals may not exist or
are not implemented, thus increasing the risk of kernicterus. In Nigeria,
severe neonatal hyperbilirubinemia persists as a major contributor to
neonatal mortality and developmental disability [2]. A recent study
from one tertiary center in Cairo, Egypt reported that 12% of 674 babies
admitted with severe neonatal hyperbilirubinemia suffered from acute
bilirubin encephalopathy among whom 9 died [3].
Kernicterus as defined by choreoathetoid cerebral palsy, impaired
upward gaze, and hearing loss has always been the synonym for bilir-
ubin induced neurological damage. Recent literature however, has
highlighted suspicious subtle forms of neurological dysfunction such as
cognitive impairment, diminished executive function, and behavioral
disorders that may pass unnoticed until childhood [4]. Whether those
subtle changes are caused by severe or milder degrees of hyperbilir-
ubinemia (previously considered safe levels) needs to be confirmed. The

Abbreviations: ABE, acute bilirubin encephalopathy; ABR, auditory brain stem response; BIND, bilirubin induced neurological dysfunction; BSID, Bayley scales of
infant development; DQ, developmental quotient; MDI, mental developmental index; NICU, neonatal intensive care unit; PDI, psychomotor developmental index;
SNH, severe neonatal hyperbilirubinemia; TSB, total serum bilirubin
⁎
Corresponding author at: AboulRish, Cairo University Childrens Hospital, 1 Aly Ibrahim Basha St, Sayeda Zeinab, 11617, Egypt.
E-mail address: statawy@cu.edu.eg (S.S. ElTatawy).

https://doi.org/10.1016/j.earlhumdev.2019.104909
Received 23 May 2019; Received in revised form 10 October 2019; Accepted 15 October 2019
0378-3782/ © 2019 Elsevier B.V. All rights reserved.
S.S. ElTatawy, et al. Early Human Development 140 (2020) 104909

aim of this study was to systematically evaluate the spectrum of motor
and possible mental impairment secondary to severe hyperbilir-
ubinemia and to monitor the evolution of the condition over the first
year of life.
2. Methods
This prospective cohort study was conducted at Cairo University
Children's Hospital Neonatal intensive care unit (NICU), a tertiary re-
ferral center. The study was approved by the ethical committee of Cairo
University Pediatric Department. An informed consent was obtained
from the parents of all enrolled newborns.
2.1. Patients
Patients were enrolled from October 2014 to February 2015, and
follow up was performed over the subsequent 12 months. During the
study period, 244 newborns were admitted to the NICU of Cairo
University Children's Hospital with unconjugated hyperbilirubinemia
requiring intervention (whether phototherapy or exchange transfusion)
of whom 177 term or near-term infants (≥35 weeks gestational age)
were enrolled in the study. According to our exclusion criteria, 18 ba-
bies with admission age > 14 days, 5 with evidence of perinatal hy-
poxia, 21 premature babies < 35 weeks gestation, 14 with proven
clinical disease other than jaundice and 9 unable to attend follow up
due to remote residence were excluded from the study.
2.2. Neonatal evaluation
All babies were outborn. Following admission and enrollment, full
antenatal, natal and postnatal history were taken together with a
thorough clinical examination. Gestational age was estimated using the
Ballard score [5] and admission weight was documented since gesta-
tional age and birth weight were not available for most cases. Neuro-
logical assessment included the Bilirubin induced neurological dys-
function (BIND) score and was performed by a single investigator for all
babies. BIND score is used to detect and grade the presence of acute
bilirubin encephalopathy by assessing mental status, muscle tone and
cry pattern. Scores of (1–3), (4–6), (7–9) indicate mild, moderate and
severe acute bilirubin encephalopathy (ABE) respectively [6].
age [8].
Auditory brainstem response (ABR) was recorded for all babies at
the first follow up appointment at 3 months of age. Babies with normal
ABR required no further auditory follow up, however if ABR was ab-
normal it was repeated at the 6 months follow up appointment. The test
was conducted in a sound proof room using circum-aural headphones
and disposable electrodes. Using “Brain stem evoked response audio-
meter: Amplaid MK12, Amplifon S.P.A., Milano, Italy”, auditory click
and tone stimuli were given, beginning at 90 dB intensity and decreased
down to 20 dB. The lowest decibel threshold of response was recorded
for each ear. Latency of waves I, III, V and inter-peak latencies of the
waves were measured. Two traces were obtained for every run.
Auditory impairment was diagnosed when reduced amplitudes and
increased latencies of ABR waves III and V were found [9]. Otoacoustic
emissions were not tested for therefore, auditory dyssynchrony could
not be defined.
Definitions
A. Acute bilirubin encephalopathy: If the BIND score ≥1 [6]
B. Classic Kernicterus: Motor and auditory predominant neurological
sequelae of bilirubin neurotoxicity [10]
C. Normal developmental index: PDI and MDI scores ≥85. Mild delay:
70–84. Severe delay ≤69 [8]
D. Auditory impairment: Abnormalities in ABR waves III and V [9]
E. Unfavorable outcomes (for the purpose of this study): MDI < 85,
PDI < 85, or abnormal ABR
F. Persistently unfavorable outcomes: Outcomes that did not improve
by 12 months of age
G. Hemolysis: Hb ≤13 g/dL (8 mmol/L) and reticulocytes ≥6% [11]
2.5. Statistical data
Data were analyzed using SPSS© Statistics version 24 (IBM© Corp.,
Armonk, NY, USA). Numerical data were expressed as arithmetic
mean ± SD and median (25th–75th percentiles). Inter-groups com-
parisons were done using t-test or Mann-Whitney test. Qualitative data
were presented as number (percent) and compared using Chi-square
(X2) test or Fisher's Exact test as appropriate. Correlations between
variables were detected using Spearman's correlation test. P values <
0.05 were considered statistically significant.

2.3. Laboratory investigations and treatment 3. Results

Total serum bilirubin (TSB) was measured at admission using the
AU 480-Chemistry auto-analyzer (Beckman Coulter Diagnostics-USA)
in addition to complete blood count and reticulocyte count which were
performed for all enrolled newborns. Both mothers and babies were
tested for ABO and Rh blood group. Coomb's test was performed
whenever available. All analyses were performed at the central la-
boratory of Cairo University Children's Hospital. A decision for photo-
therapy or phototherapy and exchange transfusion was made according
to the protocol of our unit which follows the American Academy of
Pediatrics guidelines for management of neonatal hyperbilirubinemia
[7].
Out of 177 enrolled babies, 147 (46% female, 54% male) attended
follow up at 3 months, and 139 (79%) completed the 1 year follow up (1
patient died and 7 dropped out). Their demographic data are shown in
Table 1. BIND scores at admission ranged from 0 to 7 with a median of
0 (0–2), TSB ranged from 10 to 63 mg/dL (179.6–1077 μmol/L) with a
mean of 25.5 ± 6.5 mg/dL (436 ± 112.9 μmol/L) and duration of
exposure to hyperbilirubinemia before admission ranged from 1 to
Table 1
Demographic, clinical and laboratory data of the studied neonates.
Data Range Median (25th–75th percentile)

2.4. Follow-up data Gestational age (weeks). 35–40 37.7 ± 0.99a

Weight (grams). 1820–4500 2885 ± 480a
Systematic neurodevelopmental assessment was performed for all Age of onset of jaundice (days). 1–13 2(1–3)
Age of admission (days). 1–14 5(3–7)
enrolled infants at three, six- and twelve-months chronological age by a Duration of exposure (days) 1–10 2(1–4)
blinded examiner using the Bayley scales of infant development ΙΙ. This BIND score 0–7 0 (0–2)
included a mental developmental index (MDI) and a psychomotor de- TSB (mg/dl). 10–63 25.52 ± 6.5a
velopmental index (PDI). BSID consists of a series of developmental (μmol/L) 179.6–1077 436 ± 112.9a
HGB (g/dl) 4.4–22 13.6 ± 2.8a
play tasks that are administered to the baby. It derives a developmental
(mmol/L). 2.7–13.7 8.4 ± 1.7a
quotient (DQ). Raw scores of successfully completed items are con- Reticulocyte count%. 0.01–52 3.2(0.9–9)
verted to scores that are used to determine the child's performance
a
compared with norms taken from typically developing children of their Data summarized as mean ± SD.

2
S.S. ElTatawy, et al. Early Human Development 140 (2020) 104909

Table 2
Type of jaundice among the studied neonates.
Type Number of casesa Subtypes

b
Confirmed hemolysis 44/147(30%). RH incompatibility: 6/44
ABO incompatibility: 30/44
RH and ABO incompatibility: 3/44
Others: 5/44
Incompatibility without frank evidence of hemolysis. 42/147 (29%). RH incompatibility without evidence of frank hemolysis: 2/42
ABO incompatibility without evidence of frank hemolysis: 38/42
RH and ABO incompatibility without evidence of hemolysis: 2/42
Non-hemolytic 61/147 (41%). Identified cause Suspected sepsis: 2/61
Cephalhematoma: 1/61
Polycythemia: 1/61
Unknown causes Unknown causes: 57/61

a
Percentages are rounded to the closest round figure.
b
Hemolysis: Hb ≤ 13 g/dL (8 mmol/L) + retics ≥ 6% [11].

10 days with a median of 2 (1–4) days (Table 1). Confirmed hemolysis

[11] was the cause of severe hyperbilirubinemia in 30% of the studied
cases although blood group incompatibilities were noted in 55% of our
cases (81/147) (Table 2).
While 147 patients attended the first follow up at 3 months, only
139 patients attended the 6 and 12 months follow up. Persistent neu-
rological dysfunction at 12 months of age was seen in 19/139 patients
(13.6%). The spectrum of bilirubin induced neurological dysfunction
noted among our patients included 8/19 with classic kernicterus (6 had
associated mild mental delay), 3/19 with isolated auditory impairment,
1/19 with severe motor and mild mental delay and 7/19 with mild
motor delay (Table 3).
A cutoff TSB of ≥27.5 mg/dL (470.3 μmol/L) was found to detect
classic kernicterus and/or auditory impairment at one year of age
(100% sensitive and 76% specific) (Fig. 1). Below this cut off level, 2
patients with mild motor delay (not considered to have classic ker-
nicterus) had TSB of 23 and 24 mg/dL (393 and 410 μmol/L). Both were
admitted at day 1 of life with severe hemolysis, positive Coomb's test
and reticulocyte counts of 15% and 20% respectively.
Among infants admitted with TSB levels > 40 mg/dL (684 μmol/L),
2/2 (100%) had persistently unfavorable outcome. Whereas among
infants presenting with TSB levels of 36–40 mg/dL (616–684 μmol/L),
31–35 mg/dL (530–599 μmol/L) and 26–30 mg/dL (445–513 μmol/L),
persistently unfavorable outcome was noted in 1/3 (33%), 8/16 (50%)
and 6/41 (15%) respectively. Mild isolated motor delay was noted in 2/
Fig. 1. ROC curve for TSB levels.
77 (3%) with bilirubin level ≤25 mg% (428 mmol/L).
The ROC curve shows that a TSB value of ≥27.5 mg/dL (470.3 μmol/L) was
Persistent poor neurodevelopmental outcome as well as hearing 100% sensitive and 76% specific to detect classic kernicterus at one year of age.
impairment at 12 months were positively correlated to high TSB, high
BIND scores, and longer duration of exposure to severe hyperbilir-
ubinemia. There was no significant correlation with hemolysis, age at outcomes. Analysis of this subset of patients showed that improvement
admission or gestational age (near term vs full term) (Table 4). in PDI was significant between 3–6 and 6–12 months of age (Fig. 2)
At 3 months follow up 60/147 (41%) patients had unfavorable (P = 0.000) and was inversely related to BIND score (P = 0.002) and
outcomes (PDI scores < 85, MDI scores < 85, or abnormal ABR). TSB (P = 0.003). Patients with lower bilirubin levels and lower BIND
Most of those improved over time. By 1 year of age only 19/139 pa- scores were more likely to improve in PDI. Regarding MDI, mild mental
tients (13.6%) attending follow up, showed persistently unfavorable affection (MDI scores < 85) was noted in 5% of patients and persisted
all through (Table 5). As for auditory impairment, improvement was
noted over the first year of life (Table 5) and correlated to lower TSB
Table 3 levels (P = 0.011).
Outcome of all patients at 12 months of age (n = 139).a
Outcome Number of cases 4. Discussion
Normal 120/139 (86.3%).
Classic kernicterus With mild mental affection: 6/139 The aim of this study was to systematically evaluate the spectrum of
(4.3%). bilirubin induced neurological dysfunction among jaundiced babies
Without mental affection: 2/139 (1.4%) ≥35 weeks' gestation admitted to Cairo University Children's Hospital
Isolated auditory impairment 3/139 (2%) and to monitor their progress over the first year of life. This is the first
Severe motor and mild mental delay 1/139 (0.7%).
Mild motor delay 7/139 (5%).
part of a larger follow up study of these patients at 5–6 years of age.
In our study, most babies were admitted with a mean bilirubin level
a
Out of 147 patients, 8 did not attend the 6 and 12 months follow up (7 of 25.5 mg/dL (436 μmol/L) and presented to our hospital around the
patients dropped out and 1 died). age of 5 days, despite jaundice being observed several days before

3
S.S. ElTatawy, et al. Early Human Development 140 (2020) 104909

Table 4
Correlation between MDI and PDI scores at 3, 6 and 12 months and risk factors (Gestational age, duration of exposure to hyperbilirubinemia, admission age, TSB,
BIND score, and hemolysis).
MDI PDI MDI PDI MDI PDI

(3 months) (6 months) (12 months)

GA r 0.099 0.151 0.069 0.050 0.032 −0.006

Duration of exposure r −0.064 −0.146 −0.226⁎ −0.231⁎ −0.174⁎ −0.222⁎
Age at admission r −0.067 −0.099 −0.163 −0.177⁎ −0.116 −0.256⁎
TSB r −0.428⁎ −0.495⁎ −0.323⁎ −0.193⁎ −0.303⁎ −0.174⁎
BIND score r −0.484⁎ −0.547⁎ −0.504⁎ −0.535⁎ −0.534⁎ −0.464⁎
Hemolysis P 0.50 0.46 0.80 0.47 0.79 0.7

⁎
Significant P value (< 0.05).

[15–18]. Older literature on kernicterus repeatedly emphasized extra-

pyramidal and hearing impairment but found minimal adverse mental
affection [16]. However, Shapiro et al. suggested possible subtle mental
effects of bilirubin encephalopathy [19] and some retrospective studies
associated hyperbilirubinemia with attention deficit hyperactivity dis-
orders (ADHD), autism, as well as lower rates of school completion
[20,21].
Bilirubin neurotoxicity is known to affect the motor system through
selective deposition of bilirubin in the globus pallidus [19] yet the
principle that hyperbilirubinemia can affect cognition is plausible, but
not definite. Koziol et al. stated that since basal ganglia have a role in
governing cognitive and behavioral systems through the control of in-
hibitory impulses to the cerebral cortex; their dysfunction could in-
crease impulses to the cerebral cortex causing stimulation overload,
distractibility and inattention [22].
It was noted in our study that mild mental delay (MDI < 85) oc-
curred in 6/8 babies with classic kernicterus and 1 baby with severe
motor impairment. Those babies all have severe physical disabilities
Fig. 2. Time-linear chart of MDI and PDI scores in patients with unfavorable and may be trapped in bodies that do not obey their orders, i.e. their
outcomes (n = 60). cognitive function may be intact but uncommunicable due to their
physical limitations thus leading to unjust scores on standardized tests.
Table 5 In addition, auditory deprivation secondary to hearing loss may also
Percentage of developmental delay at 3, 6 and 12 months. negatively affect cognition and language [23].
Outcome 3 months 6 months 12 months
The cutoff value for TSB at which classic kernicterus was noted at
(n = 147) (n = 139) (n = 139) one year of age was ≥27.5 mg/dL (470.3 μmol/L). Previous studies
reported a cut off value > 30 mg/dl (513 μmol/L) for the occurrence of
Mild delay Motor 35% 12% 8% ABE in infants without risk factors [24,25]. This does not contradict
Mental 5% 3% 5%
Significant delay Motor 5% 4% 4%
with our study since the patients with neurologic sequalae at TSB levels
Mental 0 0 0 ≤30 mg/dL (513 μmol/L) had risk factors, namely hemolysis due to
Auditory impairment 10% 8% 8% ABO incompatibility or lower gestational ages (< 37 weeks).
In this study, 65% of babies with bilirubin levels above the cutoff
value (TSB ≥ 27.5 mg/dL (470.3 μmol/L)) had normal outcome at
admission in many of those cases. Late presentation of babies with se- follow up. The variability of response of different babies to the same
vere hyperbilirubinemia increases the risk of ABE [12], therefore ker- TSB level may be due to variation in the permeability of the blood brain
nicterus will never be prevented without parental education and strict barrier to free bilirubin, or genetic predisposition to bilirubin injury
implementation of screening for the risk of severe hyperbilirubinemia [14].
before discharge from maternity hospitals. It has previously been proven that higher TSB levels correlate with
A specific cause for jaundice could not be identified in almost 40% poor neurodevelopmental outcome and hearing impairment [15]. Si-
of the study cases. In the absence of documented birth weight, breast milarly, in this study, TSB levels showed a significant negative corre-
feeding jaundice could not be established but none of the babies lation with both PDI and MDI at 3, 6 and 12 months. Higher BIND
showed signs of dehydration on admission. Some of the babies with scores indicating actual bilirubin encephalopathy also correlated sig-
significant blood group incompatibilities did not fulfill the criteria for nificantly with poor neurodevelopmental outcome, which compares
hemolysis used in this study [11]. In the absence of newer technologies well with the findings by El Houchi et al. [26].
for confirming hemolysis such as end tidal CO, hemolysis as a cause for Our results also confirmed that duration of exposure to severe hy-
SNH might have been missed in some cases. “Idiopathic neonatal perbilirubinemia prior to admission showed negative correlation to PDI
jaundice”, where regular testing could not identify a cause, has been and MDI scores. Time dependent bilirubin neurotoxicity has been ex-
described by other investigators as well [6,13]. Genetic predisposition, plained by Palmela et al. who confirmed the biphasic interaction of
with polymorphism across genes involved in bilirubin production and bilirubin with blood brain barrier endothelial cells; in which prolonged
metabolism as well as interactions with environmental contributors exposure (> 24 h) led to loss of tight junction between these cells with
may produce severe jaundice [14]. subsequent increased permeability [27]. Also, Silva et al. stated that at
The link between adverse neurological outcome and exposure to the cellular level, microroglia are originally neuroprotective when
extreme and hazardous hyperbilirubinemia is a well proven fact

4
S.S. ElTatawy, et al.
exposed to unconjugated bilirubin, but if exposed for long periods, lose
their functional defensive dynamic properties and ultimately die [28].
Using the Bayley score, we monitored PDI and MDI progress over
time to identify whether bilirubin induced neurologic injury was sta-
tionary or evolved over time. Significant improvement of PDI scores
were seen between 3 and 12 months of age among our patients which
optimistically shows that even babies who appear severely affected
early in life have a chance to show some improvement over time
especially in those with lower BIND scores and lower TSB levels.
Regarding MDI scores which monitor mental development, our
findings are similar to the literature [19] since despite very high TSB
levels, none of the patients showed significant mental delay. Whether
some of our babies with MDI scores < 85 on the standardized testing
will later on develop cognitive or attention deficit disorders affecting
their school performance, remains to be seen in the five year follow up.
Early and correct identification of these patients using specific tests
tailored to their physical abilities is essential in order to provide them
with any support they need.
Regarding auditory impairment, a positive significant correlation
was found between TSB and abnormal ABR results in this study which
has likewise been previously demonstrated by several authors [29–31].
Only babies with both auditory impairment and developmental delay
had high admission BIND scores, while those with isolated hearing loss,
had BIND scores ≤3. We reconfirm that both the BIND score and the
modified BIND score, which incorporates an added category for eye
movements [32] do not identify auditory impairment and therefore
ABR testing in the presence of severe jaundice should never be over-
looked even in a neurologically normal baby. Follow up of abnormal
ABRs also showed improvement over time which was significantly
correlated to lower TSB levels. The slow and lengthy period of CNS
maturation following the damaging effect of hyperbilirubinemia may
have led to auditory improvement [33].
This study is not without limitations. The inability to perform rou-
tine MRI scans, the unreliable availability of Coombs testing, the in-
accessibility of performing admission ABRs and otoacoustic emissions
are limiting factors. However, despite such limitations, this study pro-
vides insight into the effect of high bilirubin levels on the developing
brain and the evolution of the condition over time.
In conclusion, this study suggests that bilirubin induced neurolo-
gical damage may not be isolated to only motor and auditory impair-
ment but might lead to mild cognitive dysfunction in some cases.
Standardized testing may not be fair to such patients. There is evidence
that motor delay and auditory impairment improve over time.
Declaration of competing interest
All authors have approved the final article and have no conflict of
interest to declare.
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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