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Systematic Review: Risk Factors and Causes of Neonatal Hyperbilirubinemia:

A Systematic Review Study A B S T R A C T

Article in Journal of Pediatrics Review · October 2020

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 October 2020, Volume 8, Issue 4, Number 20

Systematic Review:
Risk Factors and Causes of Neonatal Hyperbilirubinemia: A
Systematic Review Study
Hassan Boskabadi1 , Forough Rakhshanizadeh1, Ali Moradi2, Maryam Zakerihamidi3*

1. Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
2. Orthopedic Research Centre, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
3. Department of Midwifery, School of Medical Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran.

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Citation Boskabadi H, Rakhshanizadeh F, Moradi A, Zakerihamidi M. Risk Factors and Causes of Neonatal Hyperbilirubinemia: A
Systematic Review Study. Journal of Pediatrics Review. 2020; 8(4):211-222. http://dx.doi.org/10.32598/jpr.8.4.293.3
: http://dx.doi.org/10.32598/jpr.8.4.293.3

ABSTRACT
Context: Jaundice is a common problem and the most common risk factor for hospitalization
during the neonatal period.
Article info: Objective: The prevention of neonatal hyperbilirubinemia would not be possible without
Received: 03 Nov 2019 identifying its predisposing risk factors. The present systematic review study aims to determine
First Revision: 23 Nov 2019 the risk factors of neonatal jaundice.
Accepted: 23 Jan 2020
Published: 01 October 2020 Data Sources: Databases including Science Direct, Cochrane Library, Web of Science (ISI),
PubMed, and Google Scholar were searched to identify all eligible papers concerning the risk
factors of neonatal hyperbilirubinemia.
Study Selection: This systematic review was performed to review the causes and risk factors
of neonatal hyperbilirubinemia. Finally, 18 articles were defined as eligible for further review.
Data Extraction: The keywords included neonates, jaundice, hyperbilirubinemia, and risk
factors. The inclusion criteria were studies determining jaundice risk factors, while papers with
only published abstracts were excluded.
Results: A total of 18 eligible articles (3 retrospective, 4 prospective, 10 cross-sectional, and 1
historical cohort) out of 421 retrieved articles were included in this review. The etiologic causes
for neonatal jaundice were ABO incompatibility (24.6%), infection (including UTI and sepsis)
(13.7%), G6PD deficiency (9.4%), Rh incompatibility (7%), and cephalohematoma (2.9%), while,
known predisposing factors for neonatal jaundice included unknown (33.2%), low birth weight
(30.9%), hyperbilirubinemia in siblings (22.7%), prematurity (20.1%), and infant of diabetic
mother (6.7%).
Key Words: Conclusion: According to our review with considering the studies, the etiologic causes for
Risk factor, neonatal jaundice are ABO incompatibility, infection (including UTI and sepsis), G6PD deficiency,
Neonatal, Jaundice, Rh incompatibility, and cephalohematoma. While, known predisposing factors for neonatal
Hyperbilirubinemia, jaundice include low birth weight, hyperbilirubinemia in siblings, prematurity, and infant of
Etiology diabetic mother.

* Corresponding Author:
Maryam Zakerihamidi, PhD.
Address: Department of Midwifery, School of Medical Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran.
Tel: +98 (911) 3934386
E-mail: [email protected]

211
October 2020, Volume 8, Issue 4, Number 20

1. Context tory of jaundice in the previous sibling, cephalohemato-

ma, trisomy 21 (6, 8, 9), ABO or Rh incompatibility (10),
aundice is a common problem and the most G6PD deficiency, and multiple births (11) are considered

J
common risk factor for hospitalization dur- as the genetic and environmental factors. Moreover, in-
ing the neonatal period (1). In most cases, fections, endocrine disorders, polycythemia, and hyper-
neonatal jaundice is physiologic and requires natremic dehydration can increase the risk of neonatal
no treatment; however, in about 10% of the hyperbilirubinemia (12).
cases, the bilirubin level passes the 95th per-
centile and needs further monitoring and In an epidemiologic study of the 321 neonates, 20 cases
treatment (2). Neonatal jaundice can lead to serious (6.2%) had RH incompatibility, 124 cases (36.6%) ABO
lifelong complications and disabilities such as kernic- incompatibility, 99 cases (30.8%) G6PD deficiency, and 5
terus, delayed speech, and motor disorders (3, 4). Early (1.6%) ABO and Rh incompatibilities, 27 cases (8.4%) ABO
detection of infants predisposed to jaundice can help in incompatibility and G6PD deficiency, 5 cases (1.6%) RH
preventing and treating serious jaundice complications incompatibility and G6PD deficiencies, and 4 cases (1.2%)
(5). The risk of pathologic jaundice is 1% in the absence RH and ABO incompatibilities and G6PD deficiency (13).
of risk factors and up to 59% in their presence (6).
Regarding the high prevalence of jaundice in Asian
With increasing hospital costs, the obstetricians and countries, including Iran (14), the identification of pre-
the mothers’ desire for discharge during the first 24 disposing factors helps in rapid diagnosis and treat-
hours after birth (early discharge) increases. As a re- ment, improved outcomes, and reduced complications.
sult, most jaundice cases are asymptomatic during the
hospital stay. Considerable weight loss, prematurity (7),
race, polycythemia, neonatal sepsis, male gender, his-

Figure 1. The flow diagram of the search strategy for eligible articles

212 Boskabadi H et al. Neonatal Hyperbilirubinemia. J Pediatr Rev. 2020; 8(4):211-222.

 October 2020, Volume 8, Issue 4, Number 20

2. Objective no/unspecified questions with the answers scored as 1,

-1, and 0, respectively, and a maximum score of 14 (15).
The current systematic review was designed to deter-
mine the risk factors of neonatal jaundice and update 6. Results
the previous reviews about the study topic.
A total of 18 eligible articles with a total sample size of
3. Study Selection 31961 neonates, including four prospective, three ret-
rospective, 10 cross-sectional, and one historical cohort
This study is a systematic review that the causes and article(s) were retrieved from 2010 to 2017. These ar-
risk factors of neonatal hyperbilirubinemia were exam- ticles were heterogeneous in terms of inclusion criteria
ined. Articles on the risk factors of jaundice in newborns for neonates, sample size, study place, and results (Table
were reviewed and those dealing with neonatal risk fac- 1). They were distributed in Iran (10 studies, 55.56%),
tors for neonatal jaundice (18 papers) were selected. Pakistan (1 study, 5.56%), India (2 studies, 11.11%),
The systematic review registration number was 970391. Bangladesh (1 study, 5.56%), Turkey (1 study, 5.56%),
Greece (1 study, 5.56%), Malaysia (1 study, 5.56%), and
4. Data Sources Nepal (1 study, 5.56%).

Science Direct, Cochrane Library, PubMed, Web of Sci- The overall most common etiologic causes of infantile
ence (ISI), and Google Scholar databases were system- hyperbilirubinemia consisted of ABO incompatibility, in-
atically searched using the following keywords: “risk fections and/or sepsis (Figure 2). The overall most com-
factors”, “causes”, “jaundice”, “hyperbilirubinemia”, and mon risk factors of infantile hyperbilirubinemia consist-
“neonates”. ed of unknown and low birth weight (Figure 3).

5. Data Extraction 7. Discussion

A total of 421 articles were included in the study and Despite the high prevalence and serious lifelong com-
imported to EndNote software. Out of which, 200 dupli- plications of neonatal hyperbilirubinemia, its predispos-
cates were deleted. Then, the titles and abstracts of the ing risk factors have not been well identified yet. In this
remaining articles were reviewed and 75 articles were systematic review, 18 eligible articles out of a total of
removed due to irrelevancy. In the next step, 157 pa- 421 retrieved articles were included to review the risk
pers were omitted due to incomplete data, clarity of the factors of neonatal jaundice. While ABO incompatibility,
study procedure, and lack of full text. Finally, 18 articles infection (including UTI and sepsis), G6PD deficiency, Rh
were defined as eligible for further review (Figure 1). incompatibility, and cephalohematoma were defined as
reasons for jaundice, the predisposing factors included
Articles with the following criteria were included in the low birth weight, hyperbilirubinemia in siblings, prema-
study: neonates as the study population, articles in Persian turity, and infant of diabetic mother.
and English language, confirmed neonatal jaundice, inves-
tigating jaundice risk factors, and sufficient study results. 7.1. Etiologic causes of neonatal hyperbilirubinemia

The following articles were excluded from the study: ABO incompatibility is the most frequent and reported
Articles with adult populations; studies dealing with the cause of neonatal hyperbilirubinemia in various stud-
treatment of neonatal jaundice; and articles with only ies. However, a diverse range of prevalence has been
available abstract. reported in different studies. This diversity, even in
Iranian studies, is most likely due to the differences in
The following data were extracted from the full-text designs and definitions of the studies. Also, neonates
articles and entered in Excel spreadsheets: author’s born with A or B groups from mothers with O as the
names, publication year, study design and place, sample most common blood group will be at high risk of ABO
size, risk factors, results of research, and conclusion. incompatibility. Moreover, screening of maternal blood
groups is not carried on in many hospital settings and
The methodological qualities of the studies were de- even though it is done, the infant’s blood group is not
termined using the quality control tool for diagnostic checked routinely. Low sensitivity of parents, health
accuracy scores (QUADAS). This tool consists of 14 yes/ care providers, and specialists to potential blood group
incompatibilities can also be a source of the problem.

Boskabadi H et al. Neonatal Hyperbilirubinemia. J Pediatr Rev. 2020; 8(4):211-222. 213

October 2020, Volume 8, Issue 4, Number 20

Table 1. Summary of studies on the causes and risk factors of neonatal jaundice (7, 12, 15-29)
Immunization of minor

ABO Incompatibility
Cephalohematoma

Rh Incompatibility
G6PD deficiency

Total studied cases

Polycythemia
Author (year)

Author (year)
Ecchymosis

Study method
blood group
Prematurity

Infection
Author

Location
(year)

Boskaba-
Boskabadi

17
Boskabadi

6
7
di (2011)

Pros.
Iran

237
558
2

(2011) (2011)
Mahmodi

12.95

16.46
0.69

2.25
Mahmodi
(2016)

Cross-
9.5

Iran

sec.
Mahmodi (2016)

579
(2016)
Boskaba-

12.6
14.8
3.3
Boskabadi

18
Boskabadi

Cross-
di (2015)

1069
Iran

sec.
(2015) (2015)
Boskaba-
Boskabadi
19
12

40 Boskabadi
6

Cross-
di (2016)

2658
Iran

sec.
(2016) (2016)
Wong
5.4

Malay-
Wong (2013) (2013)

Pros
Wong (2013)

318
sia
Bulbul

Turkey
(2014)

1198
Bulbul (2014)

Ret-
Bulbul (2014)

137

ros.
Najib
25.5

5.9
12

Cross-
Najib (2013) (2013)

Pros
Iran Najib (2013)

170

sec
Scrafford
Scrafford
Risk factor (%)

cohort
Etiology (%)

18985
Nepal

(2013)

Hist.
(2013) Scrafford (2013)

Zabeen
26.6

Cross-sec.
1.7

Zabeen Zabeen
Bangla-

(2010)
73.3

desh

60

(2010) (2010)
Korejo
52

Cross-

(2010)
Paki-

Korejo (2010)
stan

sec.

Korejo (2010)
100
39

Aiswarya
10.83
18.61

Aiswarya Aiswarya
Greece

(2016)
19.4

Pros.
231

(2016) (2016)
Devy
√

Case-

(2016)
cont.
India

Devy (2016) Devy (2016)

140
√

Mahmodi
12.95

Cross-sec.
3.45

Mahmodi (2016)
9.15

Iran

Mahmodi (2016)
579

(2016)
Shetty
11.6

42.5
4.6

9.4

Shetty (2014) Shetty

India
32.9

Ret-
753

ros.

(2014) (2014)
Bosk-
Boskabadi abadi Boskabadi
Pros.
Iran

336

(2011) (2011) (2011)

Bosk-
Boskabadi Boskabadi
Cross-

abadi
1072
Iran

sec.

(2014) (2014) (2014)

Bosk-
Boskabadi Boskabadi
Cross-
2207
3.33

Iran

sec.

abadi
3.3
9.2

(2017) (2017)
(2017)
Garosi
Cross-

Garosi (2016)
Iran

sec.

Garosi (2016)
455

(2016)

214 Boskabadi H et al. Neonatal Hyperbilirubinemia. J Pediatr Rev. 2020; 8(4):211-222.

October 2020, Volume 8, Issue 4, Number 20

215
Korejo (2010)
Bulbul (2014)

Garosi (2016)
Wong (2013)

Najib (2013)

Devy (2016)
Boskabadi

Boskabadi

Boskabadi

Boskabadi

Boskabadi

Boskabadi
Mahmodi

Mahmodi
Aiswarya
Scrafford

Zabeen

Shetty
(2011)

(2016)

(2015)

(2016)

(2013)

(2010)

(2016)

(2016)

(2014)

(2011)

(2014)

(2017)
Author (year)
Risk factor (%)
Unknown 30 53.1
Endocrinopathy 8
Hypernatremic Dehydra-
7
tion
Congenital heart disease 4

Boskabadi H et al. Neonatal Hyperbilirubinemia. J Pediatr Rev. 2020; 8(4):211-222.

Concealed bleeding 3
Crigler-Najjar syndrome 2
G6PD gene mutation
in male neonates with 7.8
Jaundice
G6PD gene mutation in
male neonates without 1.8
Jaundice
Pathologic weight loss √
Supplementary nutrition √
History of severe hyper-
bilirubinemia in previous 27.9 22.3
siblings
Early discharge √
Male gender √ 49.7
Female gender √
Birth weight ≥ 3000 g √
Nutritional problems √
Receiving cholesterol √
Ecchymosis during
√
childbirth
Traumatic labor √
Diabetes mellitus 35 √ 1.5
Low birth weight 55 √ 27.7
Hypothermia 44
October 2020, Volume 8, Issue 4, Number 20

Preterm premature rup-

Traditional supplements
History of phototherapy
or exchange transfusion

ture of the membranes

Gestational age 35 to 36

Length of hospital stay

Visible jaundice at the

Daily weight loss (%)

Total weight loss (%)

Intrauterine growth
Admission weight

Abortion history
Age of jaundice

Author (year)
Breastfeeding
first 24 hours

First delivery
Referral age
Hematocrit

restriction

Hemolysis
in siblings

Bilirubin
Author
weeks

(year)

Boskabadi Boskabadi
13

(2011) (2011)

Mahmodi Mahmodi
12

(2016) (2016)

Boskabadi Boskabadi
11

(2015) (2015)

Boskabadi Boskabadi
(2016) (2016)

Wong Wong (2013)

(2013)

Bulbul Bulbul (2014)

11

(2014)
Najib Najib (2013)
13

(2013)

Scrafford Scrafford

Risk factor (%)

12

(2013) (2013)

Zabeen Zabeen
12

(2010) (2010)

Korejo Korejo (2010)

30
13

(2010)

Aiswarya Aiswarya
13

(2016) (2016)

Devy (2016) Devy (2016)

12

√
√

Mahmodi Mahmodi
13

(2016) (2016)

Shetty Shetty
65.1
13

(2014) (2014)

Boskabadi Boskabadi
12

(2011) (2011)

Boskabadi Boskabadi
16.3

√
√
√
√
√
√
√
√

(2014) (2014)

Boskabadi Boskabadi
14.8

27.5
9.9
13

(2017) (2017)

Garosi Garosi (2016)

12

(2016)

216 Boskabadi H et al. Neonatal Hyperbilirubinemia. J Pediatr Rev. 2020; 8(4):211-222.

 October 2020, Volume 8, Issue 4, Number 20

Figure 2. The most common etiologic causes of infantile hyperbilirubinemia

Infection as an etiologic cause for jaundice was report- Rh incompatibility was reported in 7% of neonatal hy-
ed in 13.7% of infants in the reviewed articles. Evalua- perbilirubinemia cases. Different studies have reported
tion of urinary tract infection is recommended for neo- various prevalence rates from 2.25% to 14.8%. This
nates with jaundice without signs of sepsis after the first diversity can be attributed to the fact that pregnancy
week of life. Sepsis workup is necessary for neonates care, Rhogam injections during pregnancy and after
with symptoms of sepsis beside jaundice, especially dur- childbirth, and Rh screening are differently practiced in
ing the first week of birth (30). The pathogenesis of jaun- various studies.
dice during infections is not well understood; however, it
may be a risk factor due to hemolysis through microbial Cephalohematoma was seen in almost 3% of jaundice
toxins or UDPGT (uridine diphosphoglucuronyltransfer- cases. Even prophylactic treatment of jaundice may help
ase) delayed development as a result of infection (5, 31). these cases and reduce complications. Jaundice occurs
due to red blood cell lysis in these extravascular spaces
G6PD deficiency was one of the major causes of jaun- (8). It seems necessary to monitor every neonate with
dice in this review study (overall rate of 9.4%). Despite cephalhematoma for hyperbilirubinemia.
the well-identified role of G6PD deficiency in neonatal
hyperbilirubinemia, its pathophysiology is unclear yet 7.2. Predisposing factors for jaundice
(2, 16). Jaundice in these infants is most likely due to the
decreased hepatic conjugation rather than the increased No risk factor has been reported for almost one-third
production of bilirubin secondary to hemolysis (2). More- of the neonatal jaundice cases in the studied articles.
over, G6PD deficiency is most likely to be detected in hy- Recent studies and our previous works have proposed a
perbilirubinemic infants rather than through screening.

Figure 3. The most common risk factors of infantile hyperbilirubinemia

Boskabadi H et al. Neonatal Hyperbilirubinemia. J Pediatr Rev. 2020; 8(4):211-222. 217

October 2020, Volume 8, Issue 4, Number 20

Figure 4. Gender distribution of neonatal hyperbilirubinemia reported by different studies.

list of predisposing factors for neonatal hyperbilirubine- Male gender has been reported as a risk factor (risk
mia without mentioning the prevalence (Table 1). ratio: 1.76) for neonatal hyperbilirubinemia (15, 21).
According to previous studies, the majority of infants
Low Birth Weight (LBW) accounts for 30.9% of the with neonatal hyperbilirubinemia were male (Figure 4)
overall cases reported from Pakistan (55%) and India (20, 24, 39-42). A significant difference was also seen in
(27.7%). LBW and premature infants have shown a high- bilirubin levels between male (29.41 mg/dL) and female
er prevalence of jaundice with more adverse outcomes (25.77 mg/dL) hyperbilirubinemic infants in our previ-
(32); however, many studies have been performed on ous study (34). However, the exact mechanism through
term or near-term neonates, resulting in a false lower which male gender acts as a predisposing factor for neo-
prevalence (8, 24, 26, 33-35). natal jaundice is yet to be determined (41).

Nutritional problems and weight loss were seen in Infants of diabetic mothers are more likely to be at
almost one-third of neonates in our study. Pathologic risk of neonatal hyperbilirubinemia due to immaturity,
weight loss is indicative of insufficient nutrition and an probable polycythemia, and a higher concentration of
indirect increase in the enterohepatic bilirubin cycle and glucuronidase in breast milk that intensifies the entero-
a risk factor for severe hyperbilirubinemia (15). Accord- hepatic cycle (43, 44).
ing to a previous report, over 20% of severe hyperbiliru-
binemic infants referring to home has more than 10% One of the strong points of the present study is provid-
weight loss (36). Neonates with weight loss over 5% ing neonatal jaundice risk factors and determining the
have been proposed to rely mostly on breastfeeding; average incidence of each risk factor in one study. Lack
whereas, supplementary nutrition has been suggested of high quality and applicable reports was the most im-
for infants with over 10% weight loss to prevent severe portant limitation of the present study.
hyperbilirubinemia (37). Comparing the bilirubin levels
between the twin infants has shown a direct relation- 8. Conclusions
ship between the severe hyperbilirubinemia and weight
loss, indicating weight loss as a risk factor for high bili- According to our review and considering the region of
rubin levels in twin neonates with identical genetic and the studies, the etiologic causes for neonatal jaundice are
environmental factors (38). ABO incompatibility, infection (including UTI and sepsis),
G6PD deficiency, Rh incompatibility, and cephalohema-
Despite the higher prevalence of jaundice in neonates toma, while, known predisposing factors for neonatal
with the history of hyperbilirubinemia in their siblings, the jaundice include low birth weight, hyperbilirubinemia in
exact pathways are not clear yet; however, genetic, geo- siblings, prematurity, and infant of diabetic mother.
graphical, and socioeconomic mechanisms can be involved.

218 Boskabadi H et al. Neonatal Hyperbilirubinemia. J Pediatr Rev. 2020; 8(4):211-222.

 October 2020, Volume 8, Issue 4, Number 20

Ethical Considerations 7. Boskabadi H, Zakerihamidi M, Bagheri F. [Frequency of ma-

jor and minor risk factors associated with jaundice in hos-
Compliance with ethical guidelines pitalized newborns (Persian)]. Tehran University Medical
Journal. 2017; 75(2):141-51. http://tumj.tums.ac.ir/article-
1-8042-en.html
All ethical principles are considered in this article.
8. Saber A, Ferdowsi S, Askari F, Farsi L. [Epidemiology of patho-
Funding logical jaundice and its association with demographic fac-
tors in infants born in the 22 Bahman Hospital in Gonabad,
This research did not receive any grant from funding 2011 (Persian)]. Razi Journal of Medical Sciences. 2013;
agencies in the public, commercial, or non-profit sectors. 20(114):42-8. http://rjms.iums.ac.ir/article-1-2812-en.html

9. Porter ML, Dennis BL. Hyperbilirubinemia in the term newborn.

Authors' contributions American Family Physician. 2002; 65(4):599-606. [PMID]

Conceptualization, Supervision: Hassan Boskabadi; Meth- 10. Zarrinkoub F and Beigi A. [Epidemiology of hyperbiliru-
odology: Hassan Boskabadi, Forough Rakhshanizadeh, Ali binemia in the first 24 hours after birth (Persian)]. Tehran
University Medical Journal. 2007; 65(6):54-9. http://tumj.
Moradi, Maryam Zakerihamidi; Investigation, Writing – re-
tums.ac.ir/article-1-774-en.html
view & editing, Writing – original draft: All authors.
11. Kurjak A, Chervenak FA. Textbook of perinatal medicine. London:
Conflicts of interest Informa Healthcare; 2006. [DOI:10.3109/9781439814697]

12. Boskabadi H, Zakerihamidi M, Bagheri F, Boskabadi A. [Evalua-

The authors declared no conflict of interest.
tion of the causes of neonatal jaundice, based on the infant’s
age at disease onset and age at hospital admission (Persian)].
Tehran University Medical Journal. 2016; 73(10):724-31.
http://tumj.tums.ac.ir/article-1-7086-en.html

13. Saadat SH, Naderi S, Zare S, Khalili S, Darban B, Goodarzi

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