2009 Sciuto et al, publisher and licensee Dove Medical Press Ltd.

This is an Open Access article

which permits unrestricted noncommercial use, provided the original work is properly cited.
Therapeutics and Clinical Risk Management 2009:5 247250 247
S HORT R E P ORT
Incidence and causes of neonatal
hyperbilirubinemia in a center of Catania
Marco Sciuto
1
Gaetano Bertino
2
Mariangela Zocco
3
Ignazio Vecchio
4
Rocco Raffaele
4
Rosario R Trifiletti
5
Piero Pavone
3, 6
1
Neonatal Care Section, Valsalva
Hospital, Catania, Italy;
2
Department
of Internal Medicine, Hospital S Marta
University of Catania, Italy;
3
Pediatric Unit, Department
of Pediatric Hospital Civile,
Ragusa, Italy;
4
Department
of Neurology, University of Catania,
Italy;
5
Department of Neurology,
Morristown Memorial Hospital,
New Jersey, USA;
6
Pediatric Unit,
Department of Pediatric and Pediatric
Neurology, University of Catania, Italy
Correspondence: Piero Pavone
Divisione di Clinica Pediatrica, Clinica
Pediatrica, Universit di Catania, Via Santa
Soa 78 95125 Catania, Italy
Tel +39 095 378 2478/378 2394
Fax +39 095 222 532
Email ppavone@mbox.unict.it
Aim and scope: We conducted this study to estimate the incidence of hyperbilirubinemia
in a small neonatal care unit in Catania, Italy, and to determine the underlying causes, which
would be of value in identifying and implementing strategies to prevent morbidity from this
condition.
Background: Management of hyperbilirubinemia remains a challenge for neonatal medicine
because of the risk for serious neurological complications related to the toxicity of bilirubin.
Methods: From January 2006 to January 2007, we screened 525 newborns born at the Neonatal
Care Unit of Valsalva Hospital in Catania, Italy. Infants aged 35 days and with unconjugated
hyperbilirubinemia were included for assessment if they had a peak serum total bilirubin level
exceeding 6 mg/dl (102 mol/L). Sex, birth weight, gestational age, breast feeding, type of
birth, presence of facial bruising (including cephalohematoma) and ABO group were noted.
Patients with Toxoplasma or Cytomegalovirus infection, hepatic insufciency, or suspected
drug-induced hyperbilirubinemia were excluded from more detailed analysis.
Results: Our year-long nursery sample examined otherwise healthy-appearing term infants for
the prevalence of hyperbilirubinemia (dened as bilirubin levels exceeding 6 mg/dL [11mol/L]).
We found hyperbilirubinemia in 19% (100/525). Among the patients with hyperbilirubinemia,
almost all (99%) had peak levels of bilirubin 20 mg/dL, levels which are generally considered
to be potentially neurotoxic.
Conclusions: In our clinic experience, hyperbilirubinemia was generally a serious medical
issue and one whose etiology can usually be well dened.
Keywords: hyperbilirubinemia, newborns, incidence, breastfeeding
Introduction
Severe hyperbilirubinemia continues to be the most common cause of neonatal read-
mission for hospitals in North America.
15
This pattern continues despite attempts to
identify newborns at risk of clinically important hyperbilirubinemia before they are
discharged from hospital.
69
Long-term results of severe hyperbilirubinemia, including
bilirubin encephalopathy and kernicterus, were thought to be rare since the advent of
exchange transfusion, maternal Rh immunoglobulin prophylaxis, and phototherapy.
1012

However, cases of kernicterus have been reported recently in healthy near-term and
term infants without evidence of hemolytic disease or other risk factors.
13,14
We begin our study of this problem with a survey of a single clinic experience over
a year with respective to severity and probable causes of hyperbilirubinemia.
Background
Management of hyperbilirubinemia remains a challenge for neonatal medicine
because of the risk for serious neurological complications related to the toxicity of
bilirubin. The neonatal hyperbilirubinemia practice guidelines published in 2004 by
the American Academy of Pediatrics (AAP) expresses the pediatric communitys
concern regarding bilirubin-induced neurological pathology. Risk factors recognized
Therapeutics and Clinical Risk Management 2009:5
248
Sciuto et al
to be associated with severe hyperbilirubinemia in newborns
have included jaundice in the rst 24 hours of life, jaundice
noted before discharge from hospital, a sibling who had
jaundice treated with phototherapy, near-term gestational age
of 3536 weeks, and the presence of infant with bruising or
cephalohematoma.
Materials and methods
From January 2006 to January 2007, we screened 525 newborns
born at the Neonatal Care Unit of Valsalva Hospital in Catania,
Italy. Infants aged 35 days and with unconjugated hyper-
bilirubinemia were included for assessment if they had a peak
serum total bilirubin level exceeding 6 mg/dl (102 mol/L).
Sex, birth weight, gestational age, breast feeding, type of birth,
presence of facial bruising (including cephalohematoma),
and ABO group were noted. Patients with Toxoplasma or
Cytomegalovirus infection, hepatic insufciency, or suspected
drug-induced hyperbilirubinemia were excluded from more
detailed analysis.
We focused on healthy term infants without risk factors.
Infants who had known Rh iso-immunization were excluded
since antenatal and postnatal strategies already exist to
prevent the occurrence of severe neonatal hyperbilirubinemia
from this cause. Infants who were born at less than 36 weeks
gestational age were also excluded as well as newborn
with severe facial bruising or cephalohematoma from more
detailed analysis.
Data were summarized using descriptive statistics.
Continuous variables were analyzed using the independent
Students t-test and Fishers exact test. A chi square test was used
to test associations between all other categorical variables.
Results
We found 100 children with unconjugated hyperbilirubinemia.
Causes identied by laboratory investigations include Rh
and ABO incompatibility, as well as glucose-6-phosphate
dehydrogenase (G6PD) deciency. We found potentially
neurotoxic levels of hyperbilirubinema in only one case,
with value of peak bilirubin of 20 mg/dL (342 mmol/L),
treated with phototherapy. The other 99 cases had milder
hyperbilirubinemia and did not receive any treatment.
In our series, we found breastfeeding in 65 cases, cesarean
section in 61, and mild facial bruising in 16. Medicaments
during the pregnancy were used in 39 cases and post-pregnancy
in 35 (Table 1). A single case showed evidence of liver
disease (Gilbert disease). Cytomegalovirus and toxoplasmosis
infection were found in 2% and 6% of the cases, respectively
(Table 1). Maternal microcytosis was found in two cases.
We also evaluated the ABO group in the mothers and
in the newborns (Table 2). No signicant differences were
found in the examined group. No other risk factors were
found in those patients.
We tried to analyze the characteristics of neonatal
jaundice. We took in consideration over 525 children,
100 infants with a value of bilirubin level of more than
6 mg/dl (102 mol/L) (Table 3).
Discussion
Hyperbilirubinemia is felt to be a benign condition for
infants born at term or near-term gestation. In around 5%
of healthy term infants, however, serum bilirubin values
exceed 17 mg/dL (291 mmol/L), a value which the AAP
deems signicant.
4
Levels exceeding 20 mg/dL (342 mmol/L)
occur in 1.2% of healthy newborn infants.
11
The vast majority
of infants with serum bilirubin values of 20 mg/dL remain
well; mostly need minimal care other the occasional use of
phototherapy and careful monitoring of serum levels. Before
1990, kernicterus in the previously healthy-term infant was
extraordinarily rare and for most pediatricians, it was a
Table 1 Pregnancy factors
Yes No Total
Breastfeeding 65 35 100
Cesarian section 61 39 100
Spontaneous delivery 39 61 100
Bruising face 16 84 100
Drugs in pregnancy 39 61 100
Drugs after pregnancy 35 65 100
Liver disease 1 99 100
Cytomegalovirus in pregnancy 2 98 100
Microcytemic mother 2 98 100
Toxoplasmosis in pregnancy 6 94 100
Table 2 Blood groups
Blood group Maternal group Children group
0 5 6
0+ 52 48
A 2 2
A+ 17 29
B 6 1
B+ 16 13
AB+ 2 1
AB 0 0
Total 100 100
Therapeutics and Clinical Risk Management 2009:5
249
Incidence and causes of hyperbilirubinemia in childhood
disease they were unlikely to see in their practice lifetimes.
Since 1990, there has been an increase in the number of
reported cases of kernicterus in the United States.
7
Thirty-one
cases have been reported in term infants who were well at
the time of hospital discharge, and several additional cases
have occurred in near-term infants. Although it is unknown
whether there is an actual increase in the incidence of
kernicterus in the United States or simply better detection,
reported cases are thought to be attributable to a variety of
events including: shortened hospital stays with inconsistent
follow-up beyond discharge; an increase in the frequency
of breastfeeding; and a lack of concern about high bilirubin
levels among pediatric care providers.
Although the relationship between hyperbilirubinemia and
brain injury in healthy term infants has been recently ques-
tioned,
17
in a reevaluation of the data from the Collaborative
Perinatal Project, Newman and Klebanoff
10
could not dem-
onstrate a relationship between bilirubin levels 26 mg/dL
(342 uM/L) and an abnormal neurologic examination.
Breastfeeding is still debated as probably an important
variable in these patients. In the present series, almost 65%
of hyperbilirubemic patients were breastfed, as it has been for
the other cases of kernicterus reported in the literature.
3,7,17
In
our series, no signicance statistical difference in bilirubin
levels were found according to whether or not the infant
was breastfed.
In a case-controlled study Maisels
8
found that hyper-
bilirubinemia was the major reason for hospital readmission
during the rst two weeks of life. Moreover, the majority of
the jaundiced infants in their study were breastfed and had
a greater mean weight loss since birth than nonjaundiced
controls, suggesting that even mild degrees of dehydration
in conjunction with breastfeeding impacts on the severity of
hyperbilirubinemia.
Our series comes from a small center in Catania, Italy.
Catania is one of the sunniest spots on Earth, with approxi-
mately 225 sunny days per year (which does not include
partly cloudy days). It is possible that this plays some role
in the relatively low incidence of hyperbilirubinemia in
our studies as compared to previous studies. Furthermore
future studies should investigate the presence of individual
susceptibility, environmental factors, especially environmental
climate (daylight), and genetic factors to explain the different
incidences of the disease, and the frequency of such ndings
in infants with moderate degrees of hyperbilirubinemia and
possible modes of prevention and new therapeutic strategies.
Disclosure
The authors report no conicts of interest in this work. We are
grateful to Prof. Lorenzo Pavone for helpful suggestions and
critical review of the manuscript. We wish to thank Prof A
Bridgewood and International Science Editing, Compuscript
Ltd., Shannon Industrial Estate West Shannon, Co., Clare,
Republic of Ireland, for editing the manuscript.
References
1. Liu LL, Clemens CJ, Shay DK, Davis RL, Novack AH. The safety of
newborn early discharge: the Washington State experience. JAMA.
1997;278:293298.
2. Maisels MJ, Newman TB. Jaundice in full-term and near-term babies who
leave the hospital within 36 hours. Clin Perinatol. 1998;25:295302.
3. Johnson L, Bhutani VK. Guidelines for management of the jaundiced
term and near-term Infant. Clin Perinatol. 1998;25:555574.
4. American Academy of Pediatrics, Provisional Committee for Quality
Improvement and Subcommittee on Hyperbilirubinemia. Practice
parameter: management of hyperbilirubinemia in the healthy term
newborn. Pediatrics. 1994;94:558565.
5. Dennery PA, Rhine WD, Stevenson DK. Neonatal jaundice what now?
Clin Pediatr. 1995;34:103107.
6. Newman TB, Maisels MJ. Evaluation and treatment of jaundice in
the term newborn: a kinder and gentler approach. Pediatrics. 1992;
89: 809818.
7. Brown AK, Johnson L. Loss of concern about jaundice and the
reemergence of kernicterus in full-term infants in the era of managed
care. In: Faranoff AA, Klaus MH, editors. The Year Book of Neonatal and
Perinatal Medicine. St Louis, MO: Mosby-Year Book; 1996. p. 1728.
8. Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmis-
sion. Pediatrics. 1998;101:995998.
9. Volpe JJ. Neurology of the Newborn. Philadelphia, PA: WB Saunders;
1995:490514.
10. Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long-
term outcome: another look at the Collaborative Perinatal Project.
Pediatrics. 1993;92:651657.
11. Maisels MJ, Gifford K, Antle CE, et al. Normal serum bilirubin
levels in the newborn and the effect of breast feeding. Pediatrics.
1986;78:837843.
12. Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breastfed
term newborns. Pediatrics. 1995;96:730733.
13. Worley G, Erwin CW, Goldstein RF, et al. Delayed development of
sensorineural hearing loss after neonatal hyperbilirubinemia: a case
report with brain magnetic resonance imaging. Dev Med Child Neurol.
1996;38:271278.
Table 3 Characteristics
Characteristics
No (%) of infants*
n = 100
Gestational age: wk, mean (SD) 38.5 (1.4)
Sex: male 42 and female 68
Birth weight, g, mean (SD) 3250 (+/ 489)
Age at presentation of jaundice, h, mean (SD) 78.5
Breast-feeding 65
Peak total bilirubin level, mol/L,
mean (SD)
186 (76)
Therapeutics and Clinical Risk Management 2009:5
250
Sciuto et al
14. Palmer C, Smith MB. Assessing the risk of kernicterus using nuclear
magnetic resonance. Clin Perinatol. 1990;17:307329.
15. Nakamura H, Satoshi T, Shimabuku R. Auditory and brainstem
responses in newborn infants with hyperbilirubinemia. Pediatrics.
1985;73:703708.
16. Gourley GR. Bilirubin metabolism and kernicterus. Adv Pediatr.
1997;44:173229.
17. Newman TB, Maisels MJ. Does hyperbilirubinemia damage the brain
of full-term infants? Clin Perinatol. 1990;17:331358.