Acta Pdiatrica ISSN 0803-5253

REGULAR ARTICLE

Haemolytic and nonhaemolytic neonatal jaundice have different risk

factor profiles
Brian K. Lee1,2, Isabelle Le Ray2, Ji Yu Sun2, Agneta Wikman3,4, Marie Reilly2, Stefan Johansson (Stefan.Johansson@ki.se)5,6
1.Department of Epidemiology and Biostatistics, Drexel University School of Public Health, Philadelphia, PA, USA
2.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
3.Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
4.Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
5.Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
6.Department of Clinical Science and Education, Sachs Children and Youth Hospital, Karolinska Institutet, Stockholm, Sweden

Keywords ABSTRACT
ABO blood group, Alloimmunisation, Haemolytic Aim: This study examined maternal and pregnancy risk factors for haemolytic and
hyperbilirubinemia, Nonhaemolytic
hyperbilirubinemia, Rhesus negative nonhaemolytic neonatal jaundice in a large population-based cohort study.
Methods: We conducted a cohort study of 1 019 220 singleton live births from the
Correspondence
Stefan Johansson, Clinical Epidemiology Unit, Swedish medical birth register from 1987 to 2002, using information on neonatal jaundice
Department of Medicine, Karolinska Institutet, and maternal and pregnancy characteristics. Diagnoses of gestational hypertensive
118 83 Stockholm, Sweden.
disorders were obtained by linkage to the national inpatient register. Multivariate logistic
Tel: +46-8-6164623 |
Fax: +46-8-6164194 | regression analysis provided odds ratios for the risk factors of both forms of jaundice.
Email: Stefan.Johansson@ki.se Results: A total of 6057 (0.6%) births were affected by haemolytic jaundice and 36 869
Received (3.6%) by nonhaemolytic jaundice. The strongest risk factors for haemolytic jaundice were
17 December 2015; revised 19 April 2016; maternal alloimmunisation, blood group O and neonatal jaundice in older siblings. For
accepted 10 May 2016.
nonhaemolytic jaundice, the strongest risk factors were preterm birth, neonatal jaundice in
DOI:10.1111/apa.13470 older siblings, maternal origin from East or South-East Asia and maternal obesity. We
estimated that 13% of haemolytic jaundice was attributable to alloimmunisation and 39%
of nonhaemolytic jaundice was attributable to preterm birth.
Conclusion: Haemolytic and nonhaemolytic neonatal jaundice had different risk factor
profiles. Interventions to reduce maternal alloimmunisation, preterm birth and maternal
obesity may lower the prevalence of neonatal jaundice and the risk of consequent
neurological complications.

INTRODUCTION The aetiology of neonatal jaundice can be classified as

Neonatal jaundice arises from unconjugated hyperbiliru-
binemia caused by the mismatch between the turnover of
red blood cells (RBCs) and the immature conjugating
capacity of the newborn infants liver. While yellow
discoloration is seen in 60% of term and 80% of preterm
infants (1) and is usually transient and harmless, severe
jaundice can lead to hyperbilirubinemia-induced neurolog-
ical damage. The unconjugated form of bilirubin is lipid-
soluble and can be deposited in the central nervous system.
Despite effective treatment with phototherapy, bilirubin
encephalopathy or kernicterus is not just a major cause of
death and disability in low-income and middle-income
countries (2), as it also occurs in high-income countries (3).
Abbreviations
BMI, Body mass index; CI, Confidence interval; ICD, Interna-
tional Classification of Diseases; OR, Odds ratio; RBC, Red blood
cells.
nonhaemolytic or haemolytic. Nonhaemolytic, which is
unrelated to alloimmunisation, is more common and
involves abnormal liver function and, or, a higher rate of
foetal RBC turnover than that is seen in adults. Typical
examples are jaundice in preterm infants or term born infants
bruised by vacuum extraction. In contrast, haemolytic
Key notes
 We investigated the impact of risk factors for non-
haemolytic and haemolytic jaundice in 1 019 220
births using national register data.
 While risk factors for haemolytic jaundice were primarily
red blood cell alloimmunisation and blood group O,
nonhaemolytic jaundice was mostly related to preterm
birth, neonatal jaundice in older siblings and maternal
obesity.
 Interventions that reduce maternal alloimmunisation,
preterm birth and maternal obesity may lower the
prevalence of neonatal jaundice.

2016 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd 1
Risk factors for neonatal jaundice
jaundice results from immunological breakdown of RBCs by
maternal antibodies targeting blood group antigens.
Although there are numerous studies of diagnostic mark-
ers such as bilirubin during the first days of life, researchers
have paid less attention to examining maternal and neonatal
risk factors for neonatal jaundice. While the absolute risk of
bilirubin encephalopathy or manifest neurodevelopmental
damage is low, even in severe cases (4), neonatal jaundice
may increase the risk of neurodevelopmental conditions
such as autism (5), attention deficit hyperactivity disorder (6)
and developmental delays (7). The purpose of this study was
to investigate the impact of modifiable and unmodifiable risk
factors for nonhaemolytic and haemolytic jaundice in order
to help inform preventative strategies.
METHODS
Study sample
The population-based cohort included all singleton live
births in Sweden from 1987 to 2002, recorded in the
Medical Birth Register, which contains more than 98% of
all births in Sweden. In total, there were 1 124 193 births
with maternal blood typing and RBC antibody screening
information (8). We selected the 1 086 030 singleton births
and after we removed the births with missing antibody data
(63 461) and stillbirths (3349), the cohort consisted of
1 019 220 singleton live births for 668 167 women. Ethical
approval was obtained from the Stockholm Regional Ethics
committee.
Definition of outcomes
The occurrence of neonatal jaundice was assessed from
versions nine and 10 of the International Classification of
Disease codes (ICD-9 and ICD-10) recorded in the Medical
Birth Register. According to national guidelines (9), physi-
cians are instructed to only enter a code for jaundice if the
infant requires treatment, based on clinical and laboratory
results including gestational age and a direct antiglobulin
test. The national guidelines also include charts where
bilirubin levels can be plotted, to assist decisions about
treatment. Different threshold levels apply for treatment,
depending on the infants gestational age, postnatal age and
known risk factors. For example, the highest acceptable
bilirubin level at three days of age is 350 lmol/L for healthy
term infants and 300 lmol/L for term infants with a positive
direct antiglobulin test. We categorised neonatal jaundice as
follows: ICD-9 (773A-C) and ICD-10 (P550, P551, P558,
P559, P588, P589) for haemolytic jaundice and ICD-9
(774B-D, 774G) and ICD-10 (P590, P593, P599) for
nonhaemolytic jaundice. In total, 4.2% (42 926) of singleton
live births had one or more ICD codes for neonatal jaundice,
consistent with prior reports that up to 5% of Scandinavian
newborn infants require treatment for jaundice (9).
Other variables
The maternal and pregnancy risk factors that were examined
were body mass index (BMI), age, birth year, country of
origin, smoking status, parity, the infants sex, preterm birth
2 2016 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd
Lee et al.
and a family history of neonatal jaundice. BMI was assessed
at the first antenatal visit at a median gestational age of
10 weeks and categorised according to convention (kg/m2):
underweight (BMI < 18.5), normal (18.5 BMI < 25), over-
weight (25 BMI < 30) and obese (BMI 30). Because
data on maternal height and weight were not available in the
Medical Birth Register until 1992, approximately one-third of
the study sample had missing data on BMI. Gestational
hypertensive disorders during pregnancy, including pre-
eclampsia and severe pre-eclampsia, were assessed from
ICD codes in the national inpatient register (ICD-9: 642;
ICD-10: O13, O14, O15) (10). Preterm birth was defined
according to the ICD-9 codes 644 and 765 and the ICD-10
codes O601, P072 and P073, as our database did not include
gestational age at birth. The maternal country of origin was
categorised as Sweden, another Nordic country, East or
South-East Asia and other. A history of neonatal jaundice
requiring treatment in an older sibling of the infant was
defined according to the ICD codes above.
Information on maternal ABO and Rhesus blood groups,
RBC antibody alloimmunisation and any history of trans-
fusions before and during pregnancy was extracted from the
Scandinavian Donations and Transfusions database (8,11).
Maternal RBC antibody alloimmunisation during the cur-
rent pregnancy with any one of more than 60 RBC
antibodies was classified as either a yes or no (8). Because
many of the antibodies were rarely detected, we conducted
further analysis of specific erythrocyte antibodies for the
most frequently observed RBC antigen systems; Rhesus,
Lewis, MNS and Kell.
Statistical methods
We performed multivariate logistic regression to calculate
odds ratios (OR) and 95% confidence intervals (95% CI)
separately for haemolytic and nonhaemolytic jaundice,
adjusted for the covariates above. To account for clustering
in sibling relationships, robust standard errors for clustered
data were used. Nonlinear effects of maternal age and BMI
were explored using generalised additive models. We also
calculated attributable fractions for each risk factor, which
were the theoretical percentage reductions in the number of
cases if all pregnancies affected by the risk factor were
changed to the reference condition, assuming that all other
covariates stayed the same. For example, a Swedish study of
infant mortality found an attributable fraction of 6.9% for
maternal smoking during pregnancy, which means that if
smoking during pregnancy were completely eliminated,
infant mortality would be expected to decrease by 6.9% (12).
We calculated adjusted attributable fractions by mod-
elling the expected decrease in jaundice cases with the
removal of specific risk factors in multiple logistic regres-
sion models adjusted for all covariates. Data extraction and
preparation was conducted in SAS version 9.2 (Sas Insti-
tute, Cary, NC, USA), and data analysis was performed in
R 3.0.2 (R Foundation for Statistical Computing, Vienna,
Austria).
Several sensitivity analyses were conducted. Because
preterm births have longer hospital stays and are monitored
Lee et al. Risk factors for neonatal jaundice

more closely, the infants are more likely to be diagnosed
with jaundice. Therefore, we repeated analyses excluding
preterm births. We also evaluated models in separate strata
including Rhesus negative women, women with type O
blood and women who were not alloimmunised.
RESULTS
Of 1 019 220 singleton live births, there were 6057 (0.6%)
newborn infants with haemolytic jaundice and 36 869
(3.6%) with nonhaemolytic jaundice. While 41.2% of
infants with nonhaemolytic jaundice were born preterm,
only 7.7% of infants with haemolytic jaundice were preterm
(Table 1). The distribution of maternal blood risk factors
differed between haemolytic jaundice and nonhaemolytic
jaundice: 84.2% versus 39.5%, respectively, were blood
group O and 30.4% versus 15.5% were Rhesus negative. In
addition, cases of haemolytic jaundice were more likely to
have been alloimmunised with an RBC antibody (16.6%
versus 1.4%) or received a blood transfusion prior to
pregnancy (4.6% versus 2.6%) or during pregnancy (1.3%
versus 0.5%).
In adjusted models, haemolytic jaundice and non-
haemolytic jaundice displayed large differences in risk
factor profiles (Table 2). The highest odds ratio (OR) for
haemolytic jaundice was maternal alloimmunisation with
any RBC antibody, followed by maternal blood group O
versus A, neonatal jaundice in older siblings, transfusion
during the index pregnancy and preterm birth. In contrast,
the highest OR for nonhaemolytic jaundice was preterm
birth, followed by neonatal jaundice in an older sibling,
maternal origin from East or South-East Asia, being a

Table 1 Characteristics of 1 019 220 singleton live births, Sweden, 19872002

No jaundice Haemolytic jaundice Nonhaemolytic jaundice
N = 976 294 N = 6057 N = 36 869

Male sex of child 498 912 (51.1) 2990 (49.4) 21 437 (58.1)
Maternal age, mean (SD) years 29.4 (5.1) 30.0 (5.2) 29.4 (5.4)
Maternal country of origin
Sweden 826 400 (84.7) 4677 (77.2) 31 074 (84.3)
Other Nordic 34 696 (3.6) 183 (3.0) 1233 (3.3)
E/SE Asia 7139 (0.7) 77 (1.3) 568 (1.5)
Other 108 059 (11.1) 1120 (18.5) 3994 (10.8)
Maternal BMI at first antenatal visit*
Underweight (BMI < 18.5) 17 882 (1.8) 95 (1.6) 737 (2.0)
Normal (18.5 BMI < 25) 422 971 (43.3) 2415 (39.9) 14 478 (39.3)
Overweight (25 BMI < 30) 147 092 (15.1) 946 (15.6) 5757 (15.6)
Obese (BMI 30) 55 364 (5.7) 353 (5.8) 2791 (7.6)
Missing 332 985 (34.1) 2248 (37.1) 13 106 (35.6)
Maternal smoking at first antenatal visit
None 757 019 (77.5) 4844 (80.0) 28 375 (77.0)
19 cigarettes/day 103 378 (10.6) 508 (8.4) 3750 (10.2)
10+ cigarettes/day 56 931 (5.8) 277 (4.6) 2027 (5.5)
Missing 58 966 (6.0) 428 (7.1) 2717 (7.4)
Parity
1 403 328 (41.3) 2201 (36.3) 21 522 (58.4)
2+ 572 966 (58.7) 3856 (63.7) 15 347 (41.6)
Gestational hypertensive disorders
No 926 543 (94.9) 5736 (94.7) 32 104 (87.1)
Yes 40 127 (4.1) 271 (4.5) 4425 (12.0)
Missing 9624 (1.0) 50 (0.8) 340 (0.9)
Preterm birth 21 373 (2.2) 468 (7.7) 15 172 (41.2)
Maternal ABO blood group
A 445 057 (45.6) 695 (11.5) 16 071 (43.6)
O 364 271 (37.3) 5100 (84.2) 14 559 (39.5)
B 114 802 (11.8) 172 (2.8) 4307 (11.7)
AB 52 164 (5.3) 90 (1.5) 1932 (5.2)
Maternal Rh group: Rh- 151 778 (15.6) 1844 (30.4) 5698 (15.5)
Any maternal RBC antibodies 11 938 (1.2) 1003 (16.6) 515 (1.4)
Transfusion prepregnancy 21 599 (2.2) 281 (4.6) 947 (2.6)
Transfusion during pregnancy 1313 (0.1) 76 (1.3) 193 (0.5)
History of neonatal jaundice in prior siblings 16 956 (1.7) 615 (10.2) 1774 (4.8)

Categorical variables are summarised as N (%); continuous variables are summarised as mean (standard deviation).
*Data on height and weight were not available until 1992.

2016 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd 3
Risk factors for neonatal jaundice Lee et al.

and the Kell system (Table 3). While there was an elevated
Table 2 Odds ratios and 95% CI of pregnancy characteristics and neonatal jaundice
risk with MNS antibodies (OR = 1.31), it did not attain
(N = 1 019 220)
statistical significance at p < 0.05. The presence of antibod-
Nonhaemolytic
ies in the Lewis system was not associated with haemolytic
Haemolytic jaundice jaundice
jaundice.
OR (95% CI) OR (95% CI)
When an older maternal age of 35 years plus was
Male sex of child 0.92 (0.88, 0.97) 1.34 (1.31, 1.37) compared with 2529 years, it was associated with a
Maternal age similarly increased risk of both haemolytic and non-
<20 0.95 (0.78, 1.16) 0.85 (0.79, 0.92) haemolytic jaundice (ORs of 1.20 and 1.28, respectively).
2024 0.98 (0.91, 1.07) 0.94 (0.91, 0.97) While maternal overweight and obesity at the first antenatal
2529 Ref Ref
visit were associated with an increased risk of non-
3034 1.14 (1.07, 1.22) 1.05 (1.02, 1.08)
haemolytic jaundice (ORs of 1.19 and 1.49, respectively),
35+ 1.20 (1.11, 1.30) 1.28 (1.23, 1.33)
Maternal country of origin
neither of these were associated with the risk of haemolytic
Sweden Ref Ref jaundice. Figure 1 illustrates that advancing maternal age
Other Nordic 0.99 (0.84, 1.16) 0.99 (0.92, 1.05) was associated with a higher risk of nonhaemolytic jaundice
E/SE Asia 2.21 (1.71, 2.85) 2.26 (2.03, 2.51) in a monotonic fashion, although an increase in risk was
Other 1.86 (1.73, 2.01) 1.04 (1.00, 1.08) seen at around 35 years of age. In contrast, while higher
Maternal BMI at first antenatal visit maternal BMI was associated with an increased risk of
Underweight (BMI < 18.5) 0.91 (0.73, 1.14) 1.03 (0.95, 1.13) nonhaemolytic jaundice, there was suggestive evidence that
Normal (18.5 BMI < 25) Ref Ref a low BMI of less than 20 also increased the risk, although
Overweight (25 BMI < 30) 1.08 (1.00, 1.17) 1.19 (1.15, 1.23)
this was not statistically significant.
Obese (BMI 30) 1.04 (0.92, 1.18) 1.49 (1.42, 1.56)
In sensitivity analyses that excluded preterm births, the
Missing 1.03 (0.96, 1.12) 1.11 (1.07, 1.15)
ORs for haemolytic jaundice did not show any meaningful
Maternal smoking at first antenatal visit
None Ref Ref differences. However, there were several slight changes for
19 cigarettes/day 0.78 (0.71, 0.86) 0.88 (0.85, 0.92) nonhaemolytic jaundice (Table S1). Maternal underweight
10+ cigarettes/day 0.73 (0.64, 0.83) 0.82 (0.78, 0.87) was associated with an increased risk of nonhaemolytic
Missing 1.05 (0.94, 1.17) 0.97 (0.92, 1.02) jaundice, and transfusions before and during pregnancy
Parity were both associated with increased risk. Sensitivity anal-
1 1.10 (1.03, 1.16) 2.11 (2.06, 2.17) yses in Rhesus negative women, women with type O blood
2+ Ref Ref and women who were not alloimmunised indicated no
Gestational hypertensive disorders differences (data not shown).
No Ref Ref
The attributable fractions we estimated for haemolytic
Yes 0.95 (0.83, 1.09) 1.29 (1.23, 1.35)
and nonhaemolytic jaundice further highlighted the differ-
Missing 0.82 (0.62, 1.09) 1.10 (0.98, 1.24)
Preterm 3.18 (2.87, 3.53) 28.8 (28.0, 29.6)
ences in risk factors for the two outcomes (Table 4). The
Any maternal RBC antibody 16.5 (15.2, 17.9) 1.19 (1.08, 1.32) top three risk factors that accounted for the largest
alloimmunisation attributable fractions of haemolytic jaundice were all
Maternal ABO blood group maternal blood factors: blood group O (75.4%), Rhesus
Non-O Ref Ref negative (14.8%) and alloimmunisation (13.3%). In con-
O 9.96 (9.31, 10.7) 1.15 (1.12, 1.17) trast, the top three risk factors for nonhaemolytic jaundice
Maternal Rh group: Rh- 2.07 (1.95, 2.20) 1.00 (0.97, 1.03) were all pregnancy factors: preterm birth (39.0%), first born
Transfusion prepregnancy 1.29 (1.11, 1.49) 1.05 (0.97, 1.13) child (28.1%) and maternal overweight or obesity (6.2%).
Transfusion during pregnancy 3.56 (2.72, 4.66) 0.98 (0.80, 1.20)
History of neonatal jaundice 5.32 (4.81, 5.88) 3.25 (3.04, 3.47)
in prior siblings
DISCUSSION
Estimates are adjusted for all covariates listed in addition to birth year (not In a population-based cohort study of more than one
shown). million births, we identified maternal and pregnancy char-
acteristics that were associated with increased risks of
haemolytic and nonhaemolytic jaundice. Even though the
firstborn child and maternal obesity. Maternal smoking was two conditions share some common risk factors, such as
associated with decreased risks of both haemolytic and advancing maternal age and a history of neonatal jaundice
nonhaemolytic jaundice. in an older sibling, they appear to have distinct risk factor
Maternal alloimmunisation with any RBC antibody was profiles. The largest odds ratios and attributable fractions
associated with increased risks of both haemolytic and for haemolytic jaundice were maternal blood factors,
nonhaemolytic jaundice, although with a much stronger including type O and Rhesus negative blood, and RBC
effect on haemolytic jaundice (ORs of 16.5 and 1.19, antibody alloimmunisation. In contrast, pregnancy factors
respectively). In terms of the risk of haemolytic jaundice were the dominant risk factors for nonhaemolytic jaundice,
associated with specific antigen systems, anti-D carried the including preterm birth, being the first born child and
most risk, followed by other antibodies in the Rhesus system maternal overweight or obesity.

4 2016 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd
Lee et al.
Table 3 Associations of neonatal haemolytic jaundice and maternal red blood cell
alloimmunisation with antibodies against specific antigens and antigen systems
Anti-D
Nonanti-D antibodies in Rh system
Antibodies in Lewis system
Antibodies in MNS system
Antibodies in Kell system
Odds ratios are estimated from logistic regression models with cluster robust
standard errors to account for multiple pregnancies per mother. Estimates
are adjusted for all covariates in Table 2.
Norman et al. (13) published a similarly large study that
included term infants born in Sweden from 1999 to 2012.
Although our cohort included births from 1987 to 2002, our
findings were similar regarding the rates of jaundice and the
associations with maternal age, parity and BMI. However,
there were some noteworthy differences. We had detailed
maternal blood group data, which meant that we could
estimate risks related to blood group, red blood cell
alloimmunisation and transfusion history. Furthermore,
our data included information on other siblings and
maternal smoking, meaning that we could also adjust for
those factors. Our database did not include the Medical
Birth Register variable for gestational age. Although we
could utilise ICD codes for preterm birth to estimate the
jaundice risk among preterm infants, we could not discrim-
inate between the risks for different degrees of immaturity.
Given these limitations, we were unable to create mean-
ingful prediction models, as our data lacked important
factors such as mode of delivery, gestational length and
birthweight.
A major strength of the present study was the large,
nationwide study sample. Data were prospectively collected
and were evaluated by objective assessment of medical
records and laboratory tests so that, with the exception of
0.040
Probability of nonhemolytic jaundice
0.035
0.030
0.025
0.020
0.015
20
Figure 1 Relationship between maternal age and body mass index with the probability of nonhaemolytic jaundice. Probability estimates were obtained from
generalised additive models, adjusted for all of the covariates listed in Table 2. The 95% CIs are indicated by dashed lines. Plots are shown for the 0.5 percentile through
to the 99.5 percentile for both maternal age and BMI.
2016 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd
Risk factors for neonatal jaundice
self-reported smoking, our data were not subject to recall
bias. A major limitation was the lack of bilirubin levels, which
would have allowed us to examine the relationship between
Haemolytic jaundice
the risk factors and jaundice in greater detail. While most
OR (95% CI)
newborn infants develop visible jaundice, only 4.2% of the
24.7 (20.6, 29.6) births in our sample had a recorded diagnosis of jaundice. We
9.14 (7.30, 11.5) recognise that using ICD codes for the outcome definition
0.95 (0.56, 1.61) may be subject to misclassification. Nevertheless, one of the
1.31 (0.68, 2.53) authors (SJ) reported that one Swedish neonatology unit
4.13 (2.65, 6.43) only recorded ICD codes for jaundice if the cases required
phototherapy or exchange transfusion, as instructed in the
national guidelines (9). Furthermore, the rates of jaundice
reported for our 19872002 cohort were very similar to those
recorded by Swedish cohort mentioned above, which cov-
ered 19992012 (13). Our rates of haemolytic jaundice were
0.59% and 0.49%, and the rates of nonhaemolytic jaundice in
term infants were 2.2% and 1.9%, respectively. Despite the
possibility that not all cases were given diagnostic ICD codes,
it seems unlikely that such misclassification would have led
to differential errors. Some infants may also have been
entered in the wrong jaundice group. For example, as the
clinical diagnosis of haemolytic jaundice relies on a positive
direct antiglobulin test, cases of jaundice that were haemo-
lytic in origin may have been categorised as nonhaemolytic,
underestimating the prevalence of haemolytic jaundice (14).
There is some support for this, with the counterintuitive
finding that maternal RBC antibody alloimmunisation was
also associated with nonhaemolytic jaundice. However, in
sensitivity analyses that removed all alloimmunised women,
all the other odds ratio estimates for nonhaemolytic jaundice
were unchanged. Thus, a misclassification of this type was
not likely to have changed our conclusions.
Unfortunately, the data from the Medical Birth Register
only included a restricted subset of variables. For example,
it lacked information on mode of delivery, instrumental
delivery, gestational length and birthweight. Another limi-
tation is that we did not have access to indicators of
socioeconomic status that might have confounded the
associations we studied. However, the provision of
0.040
Probability of nonhemolytic jaundice
0.035
0.030
0.025
0.020
0.015
25 30 35 40 20 25 30 35 40
Maternal age Maternal BMI
5
Risk factors for neonatal jaundice Lee et al.

Table 4 Attributable fractions (95% CI) of risk factors for neonatal jaundice
Haemolytic jaundice Nonhaemolytic jaundice

Maternal blood group O 75.4% (72.9%, 77.7%) Preterm birth 39.0% (37.9%, 40.0%)
Maternal Rh group Rh- 14.8% (11.2%, 18.0%) Firstborn child 28.1% (26.8%, 29.5%)
Maternal RBC antibody alloimmunisation 13.3% (10.0%, 16.4%) Maternal BMI overweight or obese 6.2% (4.8%, 7.6%)
History of neonatal jaundice in prior siblings 8.6% (4.9%, 11.7%) Maternal blood group O 4.4% (2.9%, 5.7%)
Maternal origin outside Sweden 8.0% (4.2%, 11.3%) Maternal age 30 years 3.9% (2.4%, 5.5%)
Maternal age 30 years 6.3% (1.7%, 10.9%) History of neonatal jaundice in prior siblings 3.1% (2.1%, 4.3%)
Firstborn child 4.7% (0.5%, 8.7%) Gestational hypertensive disorders 1.5% (0.4%, 2.8%)
Preterm birth 3.2% ( 0.6%, 6.4%) Maternal origin outside Sweden 1.3% (0.1%, 2.5%)
Maternal transfusion during pregnancy 0.08% ( 3.2%, 3.5%) Maternal RBC antibody alloimmunisation 0.2% ( 0.9%, 1.4%)
Maternal BMI overweight or obese Not estimated Maternal Rh group Rh- Not estimated
Maternal history of transfusion prepregnancy Not estimated Maternal transfusion during pregnancy Not estimated
Gestational hypertensive disorders Not estimated Maternal history of transfusion prepregnancy Not estimated

Attributable fractions may be interpreted as the theoretical per cent reduction in cases if all pregnancies affected by a particular risk factor are changed to the
reference condition, assuming all other covariates stay the same. For example, if all mothers who were 30 years of age gave birth at 29 years of age or younger
instead, the number of cases of haemolytic jaundice is estimated to decrease by 7%. Estimates are based on logistic regression models of a subset of data that is
not missing data on any of the covariates (N = 625 909), and are adjusted for all covariates shown as well as maternal smoking (not shown, due to smoking
having a protective effect) and birth year (not shown, due to being a nuisance variable). Maternal ABO blood group was dichotomised to O versus non-O.
Maternal age was categorised as <30, 3034 and 35 years. Maternal BMI was dichotomised as overweight/obese versus normal/underweight. Attributable
fractions are not estimated when risk factors are not associated with a statistically significant increased risk of the outcome or when the attributable fraction is
below zero.

universal health care in Sweden reduced the likelihood of
differential identification of cases by socioeconomic status.
Furthermore, the risk of nonhaemolytic jaundice was
increased among children of immigrant mothers, who were
more likely to be of lower socioeconomic status than
nonimmigrants (15), but this increase was only important
when the mother came from East or South-East Asia,
suggesting that any confounding by socioeconomic status
was minor. Surveillance bias, for example closer monitoring
of births with complications for jaundice, was another
possible limitation and could have inflated the estimated
risk of jaundice associated with preterm birth. However,
sensitivity analyses that excluded preterm births suggested
that risk estimates were not influenced by this possible bias.
Finally, our data did not include specific information on
other risk factors for neonatal jaundice, such as infant
feeding and genetic risk factors for conditions such as
Gilbert syndrome and glucose-6-phosphate dehydrogenase
deficiency.
The findings presented here are generally consistent with
the known literature, although there are several noteworthy
observations. First, the importance of pregnancy risk factors
such as older maternal age and higher maternal BMI for
nonhaemolytic jaundice provide a plausible link between
multiple disparate causes of nonhaemolytic jaundice. To
our knowledge, the association with maternal obesity has
only been previously reported in another publication based
on a Swedish cohort (13). Mothers with higher BMI are
more likely to have infants with complications such as birth
trauma, bacterial sepsis and preterm birth, conditions that
are linked with jaundice (16,17). Second, maternal smoking
was associated with a decreased risk of both forms of
jaundice (18). It has been hypothesised that cigarette smoke
induces the microsomal enzyme glucuronyl transferase,
thereby increasing the metabolism of bilirubin (19). Finally,
although we did not observe a statistically significant
association between overall MNS antibodies and haemoly-
tic jaundice in this Swedish sample, there have been reports
of haemolytic disease in newborn infants associated with
MNS alloimmunisation (20,21).
The estimated attributable fractions present an interesting
perspective with regard to the public health impact of the
various risk factors examined. In general, both haemolytic
and nonhaemolytic jaundice were largely due to unmodi-
fiable risk factors, such as blood type and parity, and the
disease burden from modifiable risk factors was relatively
small. However, in an absolute sense, a substantial decrease
could be achieved by changing some modifiable risk factors.
We acknowledge the difficulty of eliminating maternal
overweight or obesity, but this would theoretically reduce
the incidence of nonhaemolytic jaundice by 6%. It should
be emphasised that only 32% of the women in our sample
were overweight or obese. In contrast, nearly half of the
women of childbearing age in the United States are
overweight or obese (22), suggesting that reducing maternal
BMI may have a larger impact elsewhere than estimated in
this Swedish sample. Furthermore, 39% of nonhaemolytic
jaundices were attributable to preterm birth, underlining
that any progress in the global priority of lowering preterm
birth rates would have a large impact on neonatal jaundice
incidence and its associated disease burden.
CONCLUSION
Our findings indicated that maternal risk factors, such as
blood type, older maternal age, high BMI and parity,
were associated with increased risks of neonatal jaundice.
This information, together with early serum bilirubin

6 2016 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd
Lee et al.
measurements and gestational age, may be useful for
identifying neonatal infants at greatest risk of jaundice.
FUNDING SOURCE
This work was supported by grants from the Swedish
Research Council (contract numbers 60521601 and
C0320601). The sponsors had no role in the study design,
data collection, data analysis, preparation of the manuscript
or decision to publish.
CONFLICT OF INTERESTS
The authors have no conflict of interests to declare.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Table S1 Odds ratios and 95% CI of pregnancy character-
istics and neonatal jaundice excluding preterm births (total
N = 982 207).
7